 |
|
Newsletter of HoloGenomics
|
|
|
|
Newsletter of HoloGenomics
|
Genomics, Epigenomics integrated into Informatics:
HoloGenomics
HoloGenomics for a Song (read Lyrics of Regulatin' Genes)
view YouTube-s
Regulatin' Genes YouTube
NOW BEYOND 100,000 VIEWS
Skip to HoloGenomics Table of Contents
For HoloGenomics News articles before 2010 see Archive here.
Archives before Hologenomics (before mid-2008) are listed in Archives, bottom here.
 |
Eric Lander (Science Adviser to the President and Director of Broad Institute) et al. delivered the message
on Science Magazine cover (Oct. 9, 2009) to the effect:
"Mr. President; The Genome is Fractal !"
On this joyful occasion, when first with the Personal Genomes conference at Cold Spring Harbor (Sept. 14-17, 2009) and now on Science Cover Article (Oct. 9, 2009) the establishment embraced fractal recursive algorithm, the International HoloGenomics Society may wish to make some technical comments, as well as a projection.
First, it may seem to be trivial to rectify the statement in "About cover" of Science Magazine by AAAS. The statement "the Hilbert curve is a one-dimensional fractal trajectory" needs mathematical clarification. While the paper itself does not make this statement, the new Editorship of the AAAS Magazine might be even more advanced if the previous Editorship did not reject (without review) a Manuscript by 20+ Founders of (formerly) International PostGenetics Society in December, 2006.
Second, it may not be sufficiently clear for the reader that the reasonable requirement for the DNA polymerase to crawl along a "knot-free" (or "low knot") structure does not need fractals. A "knot-free" structure could be spooled by an ordinary "knitting globule" (such that the DNA polymerase does not bump into a "knot" when duplicating the strand; just like someone knitting can go through the entire thread without encountering an annoying knot):
Just to be "knot-free" you don't need fractals
Note, however, that the above "strand" can be accessed only at its beginning - it is impossible to e.g. to pluck a segment from deep inside the "globulus".
This is where certain fractals provide a major advantage - that could be the "Eureka" moment for many readers. For instance, the mentioned Hilbert-curve is not only "knot free" - but provides an easy access to "linearly remote" segments of the strand. This fractal property is sketched below:
 |
If the Hilbert curve starts from the lower right corner (see turquoise circle) and ends at the lower left corner, for instance the red path shows the very easy access of what would be the mid-point if the Hilbert-curve was measured by the Euclidean distance along the zig-zagged path. Likewise, even the path (shown in blue) from the beginning of the Hilbert-curve is about equallly easy to access - in fact it is easier than to reach from the origin a point that is about 2/3 down the path. The path shown in purple illustrates that the Hilbert-curve provides an easy access between two points within the "spooled thread"; from a point that is about 1/5 of the overall length to about 3/5 is also in a "close neighborhood". This may be the "Eureka-moment" for some readers, to realize that the strand of "the Double Helix" requires quite a finess to fold into the densest possible globuli (the chromosomes) in a clever way that various segments can be easily accessed, moreover - as we'll see - in a way that distances between various segments are minimized. To better illustrate this marvellous fractal structure, look at the 3D rendering of the Hilbert-curve below (source). If your browser can show the animated .gif (left, below), you can observe the "slits of the kimono" feature of the complex 3D structure. As it rotates, in some position you can "see through", for easy access of otherwise remote points. In case your browser will not show the rotating "ultra-dense, but ultra see-through" 3D structure, a still picture on the right will demonstrate how easily one can cut through the entire structure to reach even segments at the "most distant" positions. Once you'll observe such fractal structure, you'll never again think of a chromosome as a "brillo mess", would you? It will dawn on you that the genome is orders of magnitudes more finessed than we ever thought so.
 |
 |
Most readers should probably stop here, with the basic lesson learned that Fractal DNA, while it may appear fanciful, is most importantly an ultimately practical structure - and non-Euclidean geometries require much attention if the instruction of ENCODE is to be headed ("the scientific community will need to rethink some long-held views" - Francis Collins, June 14, 2007).
Those who are ready to engage in the "why" and "how" might wish to contact the Authors - and even this researcher has his answers for future advancements; pellionisz_at_junkdna.com.
Those embarking at a somewhat complex review of some historical aspects of the power of fractals may wish to consult the ouvre of Mandelbrot (also, to celebrate his 85th birthday this November 20th). For the more sophisticated readers, even the fairly simple Hilbert-curve (a representative of the Peano-class) becomes even more stunningly brilliant than just some "see through density". Those who are familiar with the classic "Traveling Salesman Problem" know that "the shortest path along which every given n locations can be visited once, and only once" (a very practical task for Salesmen and Presidents) requires fairly sophisticated algorithms (and tremendous amount of computation if n>10 (or much more). Some readers will be amazed, therefore, that for n=9 the underlying Hilbert-curve helps to provide an empirical solution:
 |
On the source page of this diagram (Takahashi), one can click any number of "destinations" on the Hilbert-curve (here, if your browser is Java-enabled) - and see the resulting path as a solution to the Traveling Salesman Problem emerge.
Unification of Recursive Algorithms of Fractal DNA and Neural Networks that the Genome governs to physiologically (or pathologically) grow
Briefly, the significance of the above realization, that the (recursive) Fractal Hilbert Curve is intimately connected to the (recursive) solution of Traveling Salesman Problem, a core-concept of Artificial Neural Networks can be summarized as below.
Accomplished physicist John Hopfield (already a member of the National Academy of Science) aroused great excitement in 1982 with his (recursive) design of artificial neural networks and learning algorithms which were able to find reasonable solutions to combinatorial problems such as the Traveling Salesman Problem. (Book review Clark Jeffries, 1991, see also 2. J. Anderson, R. Rosenfeld, and A. Pellionisz (eds.), Neurocomputing 2: Directions for research, MIT Press, Cambridge, MA, 1990):
"Perceptrons were modeled chiefly with neural connections in a "forward" direction A -> B -* C -- D. The analysis of networks with strong backward coupling proved intractable. All our interesting results arise as consequences of the strong back-coupling" (Hopfield, 1982).
The Principle of Recursive Genome Function surpassed obsolete axioms that blocked, for half a Century, entry of recursive algorithms to interpretation of the structure- and function of (Holo)Genome.
This breakthrough, by uniting the two largely separate fields of Neural Networks and Genome Informatics, is particularly important for those who focused on Biological (actually occurring) Neural Networks (rather than abstract algorithms that may not, or because of their core-axioms, simply could not represent neural networks under the governance of DNA information).
Tensor Network Theory of the Central Nervous System (see Encyclopedia of Neuroscience, Figs. 1. and 2., 1987) took the structural geometry of existing cerebellar neural networks (with principal components of so-called Purkinje brain cells), and explained the well-known function of the cerebellum (space-time coordination of sensori-motor activities) in terms of the extrinsic Euclidean (Minkowski) space-(time) embedded into a curved multidimensional functional geometry, where the cerebellar neural networks act as the metric tensor of the intrinsic space; thus capable of transforming non-executable sensory-vectors (that are, in the slang of tensor-geometry "covariant expressions") into precisely executable motor-vectors (that are "contravariant"). The author resigned to the general observation that appreciation of geometrization of biology (following the required understanding) may call for a period of 20-25 years in experimental neuroscience. Thus, meanwhile focused on utilization of an artificial electronic cerebellum to automatically regain the balance of severely misconfigured fighters, such as F15 for NASA. Since such compute-intensive operation literally "on the fly- with supersonic speeds" the approach used parallel computers "Transputers" for the project based on at that time classified defense info [see a near-disaster, initiating the project, on YouTube]).
Unification in functional geometry of Genome Informatics and Neural Networks, in significance goes way beyond the elegance of unified algorithms and thus better computation-performance. There is no denial that (biological) Neural Networks develop under the governance of Genome Information. Thus, the embedding of fractal curves in metrical (albeit often curved) spaces is not just an opening of an avalanche of algorithms of novel genome informatics, but ultimately unifies Fractal DNA (structure and function) with Fractal development of organelles, organs and organisms (FractoGene, 2002, 2008, 2009).
With the "affordable full DNA sequences" already here, deploying tools of advanced mathematics for interpretation (see also here) to the very same parallel computing means already developed for earlier defense applications) is even more vital than earlier. This time, not only those in the frontline, but all "in the homelands" (our health and prevention of diseases) are affected.
Computing architecture for The Genome Based Economy will hinge on algorithmic understanding and building the most effective implementation.
For archived HoloGenomics News articles before 2010 click here.
Articles before Hologenomics (before mid-2008) are listed in Archives, bottom here.
"Personal" study shows gene maps can spot disease
Reuters,
Maggie Fox, Health and Science Editor
WASHINGTON
Wed Mar 10, 2010 6:40pm EST
Drs. Gibbs and Lupski (from left)
(Reuters) - Two studies published on Wednesday show it is possible to sequence the entire gene maps of families with inherited diseases and pinpoint the offending bit of DNA.
The studies, which would not have been possible a year or two ago, are the first real delivery of the promised transformation of medical science from the Human Genome Project's mapping of the human genetic code.
One was also made possible by some of the $5 billion that U.S. President Barack Obama directed to the National Institutes of Health in September from the $787 billion economic stimulus package.
And in that study, the genetic researcher was himself one of the patients.
Dr. James Lupski of the Baylor College of Medicine in Houston has a recessive genetic disease called Charcot-Marie-Tooth syndrome. It affects the nerves stretching from the spinal cord to the arms, legs and feet.
Lupski has been experimenting on himself and his own family for years.
"We tried every other method for 25 years to find out which mutation was important," he said in a telephone interview.
"With this methodology we were able to do it. This is the first time whole genome sequencing has applied to actually find the cause of a disease."
Lupski had been taking blood samples from his grandparents, parents and siblings for years. He got close but the research was considered too risky for funding by the National Institutes of Health.
"He was only able to complete this study because of the stimulus money that we got," said Dr. Story Landis, director of the National Institute of Neurological Disorders and Stroke.
Her institute designated Lupski's project for about half a million dollars of the money that Obama directed to the NIH.
RECESSIVE GENES
Lupski's team used a gene sequencer from Carlsbad, California-based Life Technologies to read the entire DNA code in the samples from Lupski and three of his siblings who have the syndrome, his parents and four other siblings who do not.
"It is a recessive disease and neither of my parents have the disease. Each of us who has it got one mutant allele (gene) from my mom and one mutant allele from my dad," he said.
Researchers know about 40 different genes that can cause Charcot-Marie-Tooth. But in each family, only one of these genes is involved.
The sequencing revealed a gene called SH3TC2, the researchers reported in the New England Journal of Medicine. Other groups are already working on a drug that may affect that gene, Lupski said.
The researchers also found that family members who inherited just one faulty copy of the gene had a predisposition to carpal tunnel syndrome, in which a nerve in the wrist can get pinched.
As prices are coming down on the cost of sequencing a human genome, more such research will be possible.
"We estimate that the entire effort would currently cost less than $50,000," the researchers wrote.
In a second study, Jared Roach of the Institute for Systems Biology in Seattle and colleagues sequenced the entire genomes of a family of four affected by two recessive genetic diseases -- Miller syndrome, which can cause facial disfigurement, and primary ciliary dyskinesia, a lung disorder that raises the risk of respiratory infections because the hairlike extension on cells called cilia fail to move properly.
"Our results demonstrate the unique value of complete genome sequencing in families," they wrote in the journal Science.
They used a sequencer made by another one of the companies exploiting genomic sequencing, Complete Genomics based in Mountain View, California.
[Welcome to the era of Personal Genomics diagnosing the root-causes of hereditary diseases. While full human DNA sequencing has been done for ~100 people, including Dr. Richard Gibbs sequencing the full DNA of Dr. Jim Watson, using 454 Roche sequencing equipment some two years ago, Dr. Watson does not suffer from syndromes (other than he was advised based on his full DNA that he is partially lactose-intolerant - and switching to soy products instead of dairy his mild syndrome disappeared). For full sequencing of Dr. Lupski and relatives the "shotgun sequencer" SOLiD was used, that is still relatively expensive (in the order of $50k apiece) - but it is worthy of mentioning that the other publication reports on a study of a family of four, using Complete Genomics sequencing technology, with nominal cost of $5k apiece - i.e. for the family in the range of $20k. With the cost of full human DNA sequencing dropping faster than Moore's law dictates the drop of costs of electronics, two (intimately connected) industries are emerging. One is affordable sequencing (like cars rolling off from assembly-lines), and the other is "genome analysis and interpretation" of the said sequences (like a network of gas-stations, without which car manufacturing would be unsustainable). One can further belabor the metaphor that "family comparisons" are already possible (as demonstrated by the two separate publications; maybe compared to "gas filling stations" that are the easiest part, not requiring the actual knowledge how the complex machinery works) - while for stations with repair shops an understanding of the structure and function of the machinery is essential. In some "genome regulation diseases" (most notably, cancers), the pathology involves hundreds if not thousands of genomic "structural variants" as well as "epigenomic pathway derailments" (like methylation-pattern aberrations in recursive genome function), calling for as serious genome informatics as fractal analysis and neural net pattern-recognition of not only full genomes compared, but also monitoring the temporal sequence of such derailments. This is the harder part, not only "genome analysis" but also "genome interpretation", absolutely certainly resulting in Centers emerging for this critical role. As demonstrated (and "stimulus monies" on their way out...) it is just as highly unlikely that such Centers will emerge financed by the government (turning down the very best minds as "too risky" for mediocre minds) - as with the migration of the Internet from government to private industry the quantum-leap will happen as some families will pay the "$20k-range" costs that in turn will sustain industrial genome informatics. (A similar disruption caused the mostly government-sponsored "gene-technology" becoming Genentech a generation ago). - Pellionisz, Founder of HolGenTech, Inc.]
A Vision for Personalized Medicine
Genomics pioneer Leroy Hood says a coming revolution in medicine will bring enormous new opportunities.
By Emily Singer
March 9, 2010
MIT Technology Review
Leroy Hood has been at the center of a number of paradigm shifts in biology. He helped to invent the first automated DNA sequencing machine in the 1980s, along with several other technologies that have changed the face of molecular biology. And in 2000, he founded the Institute for Systems Biology, a multidisciplinary institute in Seattle dedicated to examining the interactions between biological information at many different levels, and to moving forward a new perspective for studying biology. The next revolution he plans to help shape is in medicine, using new technologies and new knowledge in biology and informatics to make its practice more predictive, preventative and personal.
Hood says that with each of the major transitions he's been a part of, he has faced skepticism. The human genome project, for example, had many naysayers. But he says the best way to overcome doubts is with results. To that end, Hood has founded a startup called Integrated Diagnostics, which is developing cheap diagnostics that could be used to detect diseases at earlier, more treatable stages. He has also developed a partnership between the Institute for Systems Biology and Ohio State Medical School, where he hopes to show how combining existing medical and genomics technologies can affect the practice of health care today.
Hood contends that digitizing medical records--the health-care industry's major push at the moment--is just one small part of the informatics overhaul the field needs to undergo. And pharmacogenomics--the practice of using an individual's genetic makeup to choose drugs --provides only a limited example of the potential power of personalized medicine.
TR: How do you see the future of personalized medicine?
LH: I think personalized medicine is too narrow a view of what's coming. I think we'll see a shift from reactive medicine to proactive medicine. I define it as "P4" medicine--powerfully predictive, personalized, preventative--meaning we'll shift the focus to wellness--and participatory. That means persuading the various constituencies that this medicine is real and it's here. Physicians will have to learn a medicine they didn't learn in medical school.
TR: What new technologies will drive the revolution in medicine?
LH: Individual genomes will become a standard of medical records in 10 years or so, and we will have the power to make inferences [about an individual's health] when combined with phenotypic information. Then we can begin to plan strategies for individual health care in ways we have never done before.
Nanotechnology approaches to protein measurement--such as measuring 2,500 proteins from a drop of blood--will also be important. We want to develop tests to asses 50 organ-specific proteins from 50 organs as way of interrogating health rather than disease.
The third technology that is going to be transformational is the ability to get detailed analysis from a single cell. We can analyze transcriptomes and RNAomes, proteomes and metabolomes [the collection of transcribed genes or messenger RNA, total RNA, proteins and metabolites, respectively, in the cell]. That information will reveal quanti cellular states that will say lots about normal mechanisms and disease mechanisms. For example, we are doing an experiment now where we take 1,000 cells from glioblastomas [a type of brain tumor] and select transcripts from each of those cells. We're discovering interesting new things about what constitutes a tumor.
The final driver is going to be what I generally call computational and mathematical tools, the ability to deal with data dimensionality that is utterly staggering. If we have patients in 10 years with billions of data points, being able to compare that with individual genotype-phenotype correlations will give us deep and fundamental new insights into predictive medicine. But the challenge is, where will we get the cycles to make those computations and where will we get storage for all this data?
TR: So IT has a major role to play in personalized medicine?
LH: Medicine is going to become an information science. The whole health-care system requires a level of IT that goes beyond mere digitization of medical records, which is what most people are talking about now. In 10 years or so, we may have billions of data points on each individual, and the real challenge will be to develop information technology that can reduce that to real hypotheses about that individual.
TR: Will there be consequences beyond medicine?
LH: I think the P4 medicine revolution has two enormous societal consequences. It will absolutely transform the business plans of every sector of health care. Which will adapt and which will become dinosaurs? That's an interesting question, but it will mean enormous opportunities for companies.
I also think it will lead to digitization of medicine, the ability to get relevant data on a patient from a single molecule, a single cell. I think this digitization in the long run will have exactly the same consequences it has had for the digitization of information technology. In time, the costs of health care will drop to the point where we can export it to the developing world. That concept, which was utterly inconceivable a few years ago, is an exciting one.
TR: What will be the challenges in implementing this vision of medicine?
LH: I think the biggest challenges will be societal acceptance of the revolution. We are putting together something we call the P4 Medical Institute. The idea is to bring in industrial partners as part of this consortium to help us transfer P4 medicine to the patient population at Ohio State University, which is both the payer and provider for its employees. We plan to announce further details of this project in two or three months.
Comments
Desktop Personalized Health Care
Today we have desktop engineering as a given and are skirting desktop manufacturing. It is very encouraging to note that very soon we will have desk top health care. Then desk top surgery could not be far off.We will soon realize the holy grail of affordable health care of the universe. It is great to be alive and part of a great world with positive advances in science.
dancrissco
03/09/2010
Re: Desktop Personalized Health Care
P4 is not just for desktops (e.g. Personal Genome Computer) - but, especially in Asia but also in the US it is on mobile, see Personal Genome Assistant YouTube
We better call P4 in longhand "Personalized Health Care" (rather than "Personalized Medicine"), since according to Dr. Hood, the challenge is to embrace Information Technology. "Medicine" is a monopoly that is mush slower to embrace Information Technology than e.g. the yuppie generation of techie students, eager to practice Predictive, Personalized, Participatory Prevention as the core of future health care.
pellionisz_at_junkdna.com
Genome Service Available for Predicting Illnesses [in Korea!]
The Korea Times
Nation
03-03-2010
By Bae Ji-sook
Staff reporter
A private institute has launched a service providing a person their full genetic information within six weeks of a request for a fee of 1 million won [USD 875].
The first commercial genome analysis service in Asia is expected to help many people "predict" and "avoid" diseases that have a genetic component, Theragen, the operator of the Theragen Bio Institute, said
Each human has a complicated genetic map called a genome that is unique to every person.
The company's service, "Hellogenom," decodes 1 million genome pairs per person. If a person sends a saliva sample in a kit, they will be notified on their susceptibility to 50 to 100 widely known diseases.
"It tells whether a person has the genetic predisposition to develop diseases such as diabetes and some cancers among others," the company spokesman, Sung Se-hun, said.
While the information isn't 100 percent reliable in defining whether a person will get a certain disease or not, it will allow them to pay extra attention to their health, he added.
The institute's procedure will be supervised by Prof. Kim Sung-jin of Gachon University of Medicine and Science, who decoded 3 billion pairs of genomes in 2008.
The company said reaching out for a wider use of the genetic information will come in the future.
In Western countries, where large corporations are stepping in as investors, the information is used in finding people's heritage.
Sung also said the technique could be used in verifying the identity of children reported missing or ethnic Koreans living overseas.
However, he said the institute will focus more on providing health data. "We will lead the market, which is expected to mark 200 trillion won in 2015 worldwide. We are already seeing some positive signs for expansion into China, India and other Asian countries."
From Genomics_org
Dec. 30th 2009.
Theragen Inc. in Korea launched full genome and SNP based personal genome project, GenomeCare Project.
The company is the first in Asia to commercialize the full genome and SNP based personal genome information service.
HelloGene: SNP chip based personal gene information service
HelloGenome: Full genome based sequencing and information service
The Genome Care Project was launched by Theragen BiO Institute led (Director, Jong Bhak).
The price for the full personal genome service (Gold) is $200,000 USD. A standard version (Silver) is $150,000 USD.
The price for a full personal SNP genome typing service (Premium) is $2000 USD. A standard version is $1000 USD.
This service is the first commercial personal genome service in Asia.
The Theragen BiO Institute (BiO institute) has analyzed the first personal Korean genome in Dec. 2008. The BiO institute researchers also participated in PASNP project that used 73 Asian ethnic groups using Affy 50K gene chips. The results of the first Korean genome (Dr. Kim Seong-Jin's) was published in May 2009 in Genome Research.
The result of the PASNP consortium was published in Science magazine in Dec. 2009.
The GenomeCare project is to map all the Asian ethnic groups for personalized medicine.
[This twin-article, first as an early announcement in 2009 of intentions, and now the actual start of the low-end (SNP-based) DTC service, is certain to shake-up DTC worldwide. First, DTC originated from DeCodeMe (Iceland), based on the pioneering R&D by Kari Stephansson. - but since Iceland went bankrupt, the company has just gotten reorganized. The leading US DTC companies (23andMe and Navigenics) had to break through rather stiff opposition of regulatory agencies (last summer the State of California issued a ban on genomic testing - only to be lifted in 6 weeks when KPCB "special partners" Colin Powell and Al Gore questioned if "prevention" was cheaper for the state budget than taking care of an avalanche of Alzheimer's and Parkinson's patients). The Great State of New York has only weeks ago lifted their ban - and only for Navigenics. In addition, the "privacy issue", paramount as is in the USA, handicaps not only Navigenics and 23andMe - but precludes even some formidable and most suitable "Big IT" from joining the fray. Lastly, the US population is probably the most "ethnically mixed" power, and DTC already bumped into the difficulty of interpreting even raw SNP results for customers with "mixed ethnicity".
Asia will be completely different - and thus expected to take the lead in DTC sooner than the US is prepared for it. Korea, one of the ethnically most homogeneous country is already the trail-blazer, but the also highly homogeneous (and also gizmo-oriented) Japan are likely to expand the presently open-loop business model of DTC with "barcode-shopping" via the pervasively used "smart phones" that can help with personalized barcode-shopping. Singapore, while it has citizens of almost all countries of the world, is still about 72% Chinese - and thus can be the model how the simple "Caucasian or Asian?" boxes of US DTC can be made a whole lot more sophisticated. While in Korea or Japan most do not need a "genealogy genomic test" to start with (to see which SNP-interrogation custom-array needs to be used), non-Chinese in Singapore, and most of the US customers will first undergo a preliminary "genealogy genomic test" - and then the most fitting ethnic profile will be used both for testing for "structural variants" characteristic to the given ethnic group as well as the "barcode-shopping" recommendations will factor in the ethnicity. Fortunately for Asian countries where the interest of the society overrules the interest of individuals, neither the regulatory nor the privacy issues will erect the huge barriers we see in the USA - with the added advantage that in most of the civilized world health-care is a government service as opposed to a for-profit private industry. Prevention will be an incentive for governments to steer society towards avoidance of those diseases that are most burdensome for the society (e.g. Alzheimer's in the aging Japan). - Pellionisz_at_junkdna.com
It will not be a DNA Data-Deluge. Get ready for a Tsunami while the data-level is at a low-ebb
[The eerie coincidence of the Marco Island meeting on DNA sequencing with the 8.8 earthquake in Chile - creating a tsunami visually predictable by water-levels dropping in Hawaii before a wall of water hit them (reaching even Japan) reminds us to replace the "DNA Data-Deluge" with a more befitting metaphor. It will not be an ordinary deluge when the DNA data will hit us. It will amount to a Tsunami.
Please find below a mosaic of coverage, which might astound the reader that it is not just Complete Genomics and Pacific Biosciences that are in the lead of faster-better-cheaper sequencing coming in a sequence of earth-shaking tremors, but the number is at least five. Add (the non-presenting Oxford Nanopore), the $50k desktop-printer size sequencer of Ion Torrents (by Rothberger, former Founder of 454, see below) with semiconductor-read H ions as peeling off from DNA recombination; and the Life Sciences giant coming out with their molecular sequencing, tagged by quantum dots tethered to polymerases that sequence DNA fixed on a slide - potentiallly yielding "reads" with unlimited lenghts!
People tend to waste extremely precious time window when mesmerized by a receding water-level of Oceans - instead of rushing to the high ground.
From the example of PacBio, burning through close to $300 M as nearing release of 10 instruments in June, it is fair to estimate that several $Bn will have been invested into DNA sequencing in a couple of years. If investment of that magnitude will not be monetized - will crush the industry (only the US government can throw $Bn-s as "stimulus" - private industry will not). Sequencer instrumentation is now bought by "stimulus monies" to a large extent. Once stimulus monies are gone and the market will realize that full human DNA sequences are not "affordable" but actually worthless (if Genome Analysis and Interpretation Centers are not built in time), the backlash might be devastating. - Pellionisz_at_JunkDNA.com ]
Genome Web
March 01, 2010
On the last day of AGBT, attendees crowded the room for the session everyone had been waiting for: New Genomic Frontiers, highlighting sequencing advances from Pacific Biosciences, Complete Genomics, Life Technologies, Ion Torrent, and Helicos. At Genetic Interference, Luke Jostins gives a quick run-down of each and he notes that "we are starting to see a divergence in sequencing technologies … This means that the scientists themselves can more closely tailor their choice of tech to fit their situation."
Joe Beechem's talk about the third-gen platform from Life Tech probably generated the most buzz after the session; the combination of the VisiGen concept with quantum dots had attendees genuinely interested. "The most shocking thing about the technology is that in theory it can be used to generate reads of unlimited length," says Daniel MacArthur at Genetic Future.
[View astouding technology of Ion Torrents]
Jonathan Rothberg, who gave the Ion Torrent presentation, wins the Daily Scan award for most theatrical — his talk was punctuated by narrated commercials on the technology as well as staff members carrying the instrument through the room for all to see. Pinning him down on details was difficult: Rothberg refused to answer a question about the instrument's sample prep requirements, but did note that libraries prepped for other next-gen systems could be used on the platform. Our sister publication In Sequence adds that the instrument will cost $50,000, among other details. Keith Robison also blogs about Ion Torrent here.
At its own workshop, Pacific Biosciences presented its new sequencing instrument, Pacbio RS. Stephen Turner said that the system could produce reads as long as 20,000 bases, though Daniel MacArthur adds that only a few reads will be that length. MassGenomics' Dan Koboldt blogs that he asked Turner whether PacBio's ability to detect "dark bases" had improved and he was told that there aren't any "dark bases," but there are missed bases. "Turner was almost comically evasive (as Daniel MacArthur put it) in stating how often they occur," Koboldt says.
New players in sequencing debut at AGBT
Posted on: February 28, 2010 11:00 AM, by Daniel MacArthur
The main theme of this year's Advances in Genome Biology and Technology meeting should come as no surprise to regular readers: sequencing. Generating as many bases of DNA sequence as quickly, cheaply and accurately as possible is the goal of the moment, and the number of companies jostling to achieve that goal is growing rapidly.
The meeting saw impressive performances from established players in the field, especially Illumina: their new HiSeq 2000 instrument seems to have dug in as the platform of choice for generating vast amounts of high-quality short-read data. Life Technologies seem to be slowly abandoning the research genomics market (already dominated by Illumina) with their SOLiD platform, focusing instead on capturing the clinical sequencing market; they showed some impressive accuracy improvements for their technology.
As I mentioned in my previous post, PacBio largely underwhelmed the audience with their theatrical unveiling of a massive box with quite limited applications, although we'll have to wait and see how much its specifications improve over the next couple of years. Meanwhile, Complete Genomics gave an understated but seriously impressive series of presentations on their human genome sequencing service; I'll have more on them in a day or two.
Anyway, in this post I want to focus on the two brand new platforms announced in the emerging technologies session on the last day of the conference: the newcomer Ion Torrent, and Life Technologies' futuristic quantum dot technology.
Ion Torrent: quick, cheap, low-volume next-gen sequencing
Probably the only real surprise at this year's Advances in Genome Biology and Technology meeting has been the emergence of yet another player in the next-generation sequencing market: Ion Torrent. The company seems to have been operating in stealth mode for some time, and hit the meeting with a functioning instrument (which was happily displayed to a steady stream of conference attendees during the meeting).
The fundamental idea behind Ion Torrent is pretty cool: it relies on the fact that as nucleotides are added to a growing DNA strand there is a release of hydrogen ions. The platform immobilises DNA strands in tiny wells within a semiconductor chip, and then washes As, Cs, Gs and Ts one by one over the wells. As each base is incorporated it releases hydrogen ions that can be detected as they pass through a pore at the base of each well.
The downside is that the technology is susceptible to the same kind of homopolymer stretch problem that plagued the 454 second-gen technology: if there are seven Gs in a row in your DNA strand, all will be incorporated at once - and distinguishing the signal corresponding to 6 Gs vs that produced by 7 Gs will be very challenging. Rothberg showed data suggesting that it was possible to accurately read across homopolymers up to 6 bases long, but it's unclear how well it will do for longer stretches.
The instrument itself is extremely compact compared to most other next-gen machines (especially compared to the utterly mammoth Pacific Biosciences instrument), and both the machine and runs will be cheap: $50,000 to get the box, and just $500 per run for reagents and sample prep. Initially, reads will be 100 bp long. The yield (150 Mb per run) is not yet competitive with other second-gen instruments.
While this is not yet a technology that will enable the production of cheap human genomes, it may well turn out to be a useful machine for quick-and-dirty assays - for example, checking out the quality of DNA preparations before investing in expensive sequencing on a more high-throughput technology.
Ion Torrent got an extremely positive buzz throughout the meeting, although this was dampened somewhat by a fairly unimpressive presentation by Rothberg. I got the impression that given the low cost of the machine and its potential applications there will be plenty of potential customers lining up
Life Technologies' new platform: quantum dot single-molecule sequencing
Life Technologies' Joseph Beechem debuted a brand new single-molecule sequencing platform developed by the company that provides the second-gen SOLiD platform
The physics underlying the system is above my pay-grade, but basically involves tethering quantum dot nanocrystals to DNA polymerase molecules. These dots have the effect of amplifying the signal resulting from the addition of a fluorescent nucleotide to a growing DNA strand, allowing signals to be read from a single DNA molecule.
The most shocking thing about the technology is that in theory it can be used to generate reads of unlimited length. Beechem showed that the run could be interrupted mid-way through to wash off existing polymerase molecules and replace them with new ones, thus replacing any molecules that have been inactivated by chemical damage. After the replacement the strand continues to grow; that means that in theory the wash-and-replace process could be repeated over and over to continue reading each DNA strand until you run out of molecule. Beechem suggested that by instrument release each cycle would probably generate 1,000-1,500 bases, which is an impressive achievement in itself.
If that's true, and if it can be done at scale, it is extraordinarily cool: reads of unlimited length would profoundly transform genomics. However, we're yet to hear the hard numbers on error rates and throughput that are required to fully evaluate the promise of the system.
Instruments will apparently be available to early collaborators by the end of the year (far sooner than I would have expected given the science-fiction feel to the technology), so it sounds as though we'll be getting these numbers in the not-too-distant future.
----
First Analysis Securities Corporation
on Marco Island
Life Science Tools
Analyst: Dan Leonard
Last week we attended the Advances in Genome Biology and Technology (AGBT) annual meeting, the premier event for sequencing, in Marco Island.
Post the meeting, we are slightly more positive on Illumina, slightly more negative on Life Technologies, and more negative on Roche 454 and Helicos. The only things we can say with any certainty, though, is that the market is becoming increasingly competitive -- Pacific Biosciences, Complete Genomics, and Ion Torrent Systems all had a more prominent presence at the meeting this year -- and the technology is evolving at a rapid pace.
While the new sequencing technologies are all exciting, we continue to believe government/academic budgets are a rate limiting factor on the adoption of this technology. Meeting attendance from folks in the pharma/biotech industry was sparse, and broad application in diagnostics, while theoretically interesting, appears years away.
We continue to believe that Illumina can drive strong revenue growth in 2010 due to its major new product launch, the HiSeq 2000. Several customers we spoke with plan to purchase HiSeq's in 2010. With a list price of ~$690,000 (compared to <$500,000 for its predecessor, the GAII), this instrument headlines a series of new products that could drive growth in 2010. While Illumina claims the HiSeq is capable of generating 200 gigabases (Gb) of data per run, the company showed data from recent internal runs that generated north of 300 Gb, suggesting the 200 Gb claim is conservative.
What remains to be seen is whether the reduced sequencing costs enabled by this higher throughput drive additional sequencing volume.
We have reduced our revenue estimates for Life Technologies in 2010 to reflect some additional conservatism for its Genetic Systems business, driven by the absence of a big ticket product launch. While all SOLiD users we spoke with plan to upgrade to the SOLiD 4 as well as purchase the company's EZ Bead system, these are relatively inexpensive purchases. The SOLiD 4hq is a more expensive upgrade (>$100,000), but this upgrade won't be available until fall 2010, around the same time the company expects early adoption of its recently introduced SOLiD PI (list of $230,000).
Life Tech displayed a poster which suggests it can increase the theoretical throughput of its SOLiD instrument to 501 Gb per run by shrinking its bead diameters to 500 nanometers (nm) (down from 750 nm for the SOLiD 4hq).
During its workshop, the company further suggested it could ultimately increase the throughput of the system to 852 Gb per run by both reducing the size of the beads to 500 nm and increasing the size of the flow cells by 1.7x.
These throughput improvements compare to an expected throughput of 100 Gb per run for the SOLiD 4 (planned spring 2010 availability) and 300 Gb per run for the SOLiD 4hq (planned fall 2010 availability).
Life Tech also introduced the science behind its single-molecule effort, something it views as complementary to its other sequencing offerings. This technology employs quantum dots tethered to polymerases that sequence DNA fixed on a slide. Thus, the sequencer is essentially a reagent, which offers some advantages, including the ability to circumvent problems associated with polymerase degradation. A degraded polymerase can be washed from the slide and replaced with a fresh polymerase, which picks up the sequence where the old polymerase left off. The company believes this feature offers not only long read lengths (1,000 1,500 bps per cycle) but also "tunable" accuracy. Another potential advantage of this system is the intensity of the quantum dots, which emit a fluorescent signal that is 200x that emitted by other flourophores. The depiction of the instrument itself looked pretty slick and fits on a benchtop.
Several scientists we spoke with were excited about the potential of this technology. However, we believe the effort is far from commercialization. The company plans to offer the instrument on an early access basis beginning in Q4 2010, but we are unsure what this means, and Life Tech has yet to sequence anything besides synthetic oligos internally. The company did not disclose its commercial launch plans, but we expect this instrument is two to three years behind the efforts of Pacific Biosciences, Complete Genomics, and Ion Torrent.
Roche discussed plans to launch a kit to increase the read lengths of its 454 FLX instrument to ~700 base pairs (bps) (up from perhaps 400 to 500 today) sometime during 2010. This would make the FLX's read lengths comparable to those achieved on Life Technologies' Sanger instruments. However, we don't think this improvement necessarily poses a major threat to Sanger usage. At this point, we believe Sanger instruments are primarily used for validation work, specifically in the research market, and customers' cumulative experience with the platforms provides some stickiness for validation applications. Roche also promoted its Junior instrument, a smaller and cheaper version of the FLX, expected to be available in the summer of 2010. We received heavy skepticism on the market potential for this instrument from several conference participants, though perhaps the AGBT crowd, with its heavy contingent of folk from large, well-funded centers, might not be the target audience.
Our poster walk this year suggests the 454 FLX is becoming less relevant amongst the AGBT contingent. Of the 56 posters we observed which presented data and/or methods using a next generation sequencing platform (excluding those sponsored by the vendors themselves), only 14% used the 454 FLX, down from 28% a year ago. Observations of Life Tech's SOLiD increased to 25% of total, up from 14% last year, while Helicos got on the scoreboard with 5%, up from 0% last year. Observations of Illumina's Genome Analyzer remained consistent with a year ago at 55%, which, among other considerations, further strengthens our belief that the company has maintained its market leadership.
We believe the outlook for Helicos is bleak and the feedback we received from conference participants was mostly (though not entirely) negative. Instrument issues aside, several conference participants we spoke with were aware of the company's tight cash position and expressed doubts about its financial viability.
New kids on the block
Pacific Biosciences unveiled its PacBio RS instrument, which it plans to ship to 10 early adopters in mid-2010. Because customers haven't used the instrument yet, we could only get feedback on expectations and not performance. The early adopters we spoke with are eager to use the instrument and excited about its potential. Feedback we received from a broader group was more mixed though. While some were very excited about the instrument's potential, others were pointedly skeptical following three years of presentations and no instrument placements.
Our early guess is that the advantages offered by PacBio's long reads and fast time to result will find a meaningful place in the market. The potential for ultra long-reads (company has achieved 20,000 bp reads internally) and fast run time (15 minutes) are sharp differentiators from current technology. We're still unclear, though, on cost per experiment and error rates.
Early adoption of PacBio's system should not come at the expense of existing players, though, as we expect PacBio will be supply constrained until 2012 and target initial applications that are additive to the existing market, specifically applications in infectious disease, cancer, and ag/bio. The company believes its instrument ultimately has the headroom to be cost competitive with existing nextgen technologies in 2-3 years.
The only presentation we saw at the AGBT event given by someone from pharma occurred at Complete Genomics' workshop. A customer from Genentech presented data on a lung cancer tumor and normal pair that were sequenced by Complete. Complete Genomics, which offers its next generation sequencing technology as a service, continues to plan capacity to sequence 500 genomes per month this year, with a goal to sequence 1 million genomes over the next 5 years.
Ion Torrent Systems created a lot of buzz at the AGBT event. The company introduced its sequencing instrument, the Personal Genome Sequencer, which it plans to sell for less than $50,000 with consumables that cost less than $500 per run. These price points represent dramatic improvements compared to currently available technology. The instrument, a small, benchtop device, is also much more compact than existing technology. It weighs only 45 lbs, compared to ~500 lbs for Illumina's HiSeq and ~1,800 lbs for Helicos' Heliscope. The instrument performs sequencing on a semiconductor chip, and does not use any lasers, optics, cameras, or other technology that adds to the cost of existing instruments. Read lengths at launch (planned for 1H 2010) will be 100 bp to 200 bp, while the company believes read lengths will eventually extend to 400 bp to 500 bp. However, the company did not provide any information on sample prep methods, a big unanswered question in the workflow.
Last Day of Eavesdropping on Marco Island
Saturday, February 27, 2010
Blog by Keith Robison
Today was the last day of the Marco Island conference, so I won't be hammering Twitter again for quite a while. The afternoon session focused on emerging technologies.
Complete Genomics appears to have dispelled the skepticism they had been met with last year. It certainly helped that two customers presented data (Anthony Fejes' notes on CG workshop). Apparently they hinted at some additional technological improvements coming down the pike to get even more data out.
Life Technologies presented on their single molecule system, which they hope to get to early access customers by the end of the year. It's a single molecule system with many similarities to Pacific Biosciences. One interesting twist is that they can add new polymerase when the old ones die, so in theory they can keep sequencing to extremely long lengths. This could be a huge plus for the system in de novo and metagenomic settings.
One other neat PacBio tidbit, thanks to Dan Koboldt, is that the polymerase reaction rates are so uniform that fragments can be sized (and therefore structural variants detected) by the time required to go from end-to-end.
Ion Torrent presented and apparently was received well, though the amount of detail available remotely is still frustratingly thin. A lot of key questions I have don't seem to have been answered, which I'm guessing is due to limited information in their presentation (though one can't rule out blogging fatigue hitting my sources). It also isn't helping that Twitter seems to be experiencing difficulty, perhaps because of the traffic due to the natural catastrophe in Chile & curiosity about tsunamis in the Pacific.
Ion Torrent's general scheme is to trap DNA (single molecules or clusters?) in wells in a micromachined plate (much like 454, though apparently no beads) and detect the release of a proton each time a nucleotide is incorporated. Detection is via a proprietary semiconductor detector built into the bottom of each well.
It isn't clear, for example, whether each of the micromachined wells in the system is watching a single DNA molecule or some sort of cluster of molecules. If the latter, what is the amplification scheme? The run times described seem incompatible with amplification.
How much sample goes in? What preparation is needed upstream? What sort of tagging is needed? Can, for example, the Ion Torrent machine be used to resequence (or QC) libraries from the other systems? Does the sample need to be linear, or can you sequence plasmids directly (I doubt it, due to supercoiling, but it's worth asking).
Ion Torrent is making several bold assertions. One is "The Chip is the Machine", which decodes to the fact that the chips (now seen on the website) determine the key performance attributes of the system; the box (reputedly $50K) is simply interface, data collection and reagent fluidics. Another bold claim is that the chips can be fabricated in any CMOS fab in the world. Of course, that presumably leaves out the specialized microfluidic setup on top. Still, that is an impressive supplier base.
Somewhere I saw a throughput of 160Mb per 1 hr experiment for $500 in consumables. The Ion Torrent website's video hints that part of their business model will be selling different chips of different densities for different applications. One nice feature of the consumables is that they should be just standard polymerases and unlabeled nucleotides. Of course, there could easily be some magic buffer components, but one part of the cost of many of the other systems is the need for either labeled nucleotides (everybody but 454) or complicated enzyme cocktails (454). Furthermore, it is the presence of unlabeled nucleotides in the reagents that are a major contributor to loss-of-phase in clonal systems and probably to "dark bases" in single molecule systems. Simple reagents should translate to low costs, and perhaps to high reliability and long reads.
How long? That's another key attribute I haven't seen. Again, knowing whether this is a single molecule system (in which case what would kill reads?) or clonal (with the dephasing problem) would be informative. How many reads per run? For some applications, getting lots of reads is more important than long reads -- and of course for others length is really important.
Error rates or modes? I haven't seen anything beyond an apparent bulletpoint that Ion Torrent sequenced E.coli (in a single run?) to 13X coverage, 99+% of genome in assembly and 99.9+% accuracy. Supposedly homopolymeric runs can be read out, but how accurately? Is there a length beyond which things get confusing?
One more neat aspect of the Ion Torrent system: no images. Sure, the traces from each pH run (the world's smallest pH meters, according to the website) should be much more compact, but not nothing -- though it is implied that the signal is sharp enough that there is no need to store them. Hence, unlike all the other systems there's no need for beefy on-board computers and no headache of storing enormous numbers of high resolution images.
A final thought: $500 per 1 hour run is attractive, but if you really kept one instrument going quite a tab would run up. Suppose one got in 10 runs in a day (does it have any autoloading capability?) -- that's $5K/day. Even keeping that up in the approximately 200 business days in a year is $1M in chips -- something Ion Torrent and their backers are licking lips over but will have to be faced by those who get the machines. Of course, you don't have to run the system constantly (and that's hardly constantly!) -- but if I had one, I'd certainly want to!
4 comments:
Kevin Davies said...
The lack of detail on the sample prep was perhaps the only detraction from a wonderfully exciting and typically flamboyant presentation from Rothberg. There was speculation afterwards that perhaps it involves emulsion-PCR, which wouldn't be ideal. In any event, Rothberg said it was reason to come here him give his next talk, whenever/wherever that may be. We're hoping it's at the CHI XGen Congress in 3 weeks in San Diego... www.xgencongress.com
Sunday, February 28, 2010 12:28:00 PM
Jack Leonard said...
I attended this very exciting talk. Based on discussions with reliable sources at AGBT, I believe it relies on sequencing amplified clones on beads. Presumably you need to change the H+ concentration enough to have a good S:N ratio, and single molecules in a 1.3 micron well just wouldn't accomplish that. The output per run was unclear. I heard 100 M reads per run, but this output might still be on the drawing board. Combined with 100 base reads/run that would output 10Gb, or 50 Gb/run, if you can push this to 500 base read length as is possible for the 454 platform. So this platform appears to have a lot of runway left. Yes, the front end seems unresolved, but the future seems very bright (actually dark, since it is light-free) for Ion Torrent.
Sunday, February 28, 2010 2:18:00 PM
Jack Leonard said...
Ion Torrent raw output probably will be influenced by a number of factors including chip size, well size, well density, and active bead occupancy.
Some reasonable assumptions:
Chip size (postage stamp size) ~ 2 cm^2
Well size ~ 1.3 um diam.
Well density/spacing = 1.95 um on center distance.
Active bead occupancy (Wells with beads which give clonal reads) = 50%
So you could fit about ~105 M wells onto a 2 cm^2 chip. If the average read length was 100 bases and half of the wells gave usable reads, then one could expect ~5.2 Gb/run. If the average read length was instead 500 bases, then the output would be close to 26 Gb/run.
It might be a tricky business getting a 1 um bead into a 1.3 um well, but if Complete Genomics can get a 200 nM DNA nanoball to stick to a 250 nM spot on their arrays (also made photolithographically?), then I suppose that it must be possible. From a technical perspective, it seems they should work together, even though their business models seem completely at odds (i.e., CG is trying to industrialize genome sequencing, while Ion Torrent is trying to decentralize it). If Ion Torrent could work at Complete Genomic's densities of 750 nm on center distance spacing as described by Rade Drmanac, then by my calculations Ion Torrent would have approximately 711 M potential reads per run which would output 36Gb @100 base read length or 178 Gb @500 base readlength (at 50% active occupancy). Just a thought--- Ion Torrent might want to consider a nanoball-like RCA approach which would support a higher density while still producing enough protons for detection.
Sunday, February 28, 2010 4:35:00 PM
neekoh said...
Maybe this patent application describes some of your questions:
http://www.freepatentsonline.com/y2010/0035252.html
Monday, March 01, 2010 1:36:00 PM
Doctors ‘lack training in genetics to cope with medical revolution’
TimesOnline (UK)
February 24, 2010
Mark Henderson, Science Editor, San Diego
Doctors must be taught more about genetics to prepare them for a revolution in personalised medicine, says one of America’s senior scientists, who is a pioneer of the Human Genome Project.
Francis Collins, director of the US National Institutes of Health, who led the international team that first sequenced the human genetic code, said that far too many doctors in Britain and America lacked the training they will need to use DNA-based medicine.
The falling costs of reading DNA, and growing understanding of the links between genetic variation and common disorders, were poised to have a huge impact on the way GPs and hospital doctors treated patients, he said.
Individuals’ genetic profiles would soon be used to prescribe drugs that were most likely to be safe and effective. Few doctors, however, understood enough about the way genetics contributed to drug responses and common diseases to exploit such advances, he told the American Association for the Advancement of Science conference in San Diego.
Many doctors were also resistant to reforming medical school syllabuses to include more genetics. Some claimed genetics was unimportant to their clinical practice, despite its contribution to disorders such as heart disease, diabetes and Alzheimer’s. “Changing medical education is one of the most challenging aspects of what needs to happen,” Dr Collins said. “We are working against great resistance, I am afraid. There are many practising docs out there who will tell you that genetics is irrelevant. They might have just seen two patients with diabetes, one with heart disease, another with Alzheimer’s, but genetics, they would say, is irrelevant to their practice. I was on the faculty of the University of Michigan for ten years, trying to get a little more genetics into the curriculum. You can’t believe the blood that got spilt over just one hour — it was easier to sequence the human genome than to change one hour of medical curriculum.”
The costs of reading DNA have fallen so sharply that many scientists predict it will be possible to sequence any individual’s entire genetic code for less than £1,000 within a year or two. Research has also revealed hundreds of genetic variations that affect an individual’s risk of disease or response to medicines. Companies such as 23andMe and Pathway Genomics are selling genome scans directly to consumers for between £300 and £600.
A House of Lords report said last year that medical education should be revised to take account of these developments, and The Times revealed that the National Genetics Education and Development Centre has begun a review of the medical curriculum.
Dr Collins predicted that patient demand would accelerate change.
“They will come in waving sheets of paper, saying, ‘I have just had my DNA analysed by 23andMe and it says I am at risk for diabetes, and will you interpret that?’. Docs don’t like to be embarrassed, so I suspect that will drive some degree of urgency.
“The good news is that genetics is pretty straightforward. You need to know a bit of the principles, and a little statistical risk prediction information, and you can do this.”
[There is no question that Dr. Collins (an M.D./Ph.D. is right with his premise that practicing medical doctors "lack training in genetics to cope with medical revolution". This is an undeniable fact - how could they have training when during their school years the "genome revolution" hasn't even happened yet? Worse, if anybody thinks that practicing doctors have the time to keep up with the "state of art" of the genome revolution is just flat mistaken. They don't have the time. At Cold Spring Harbor (Sept, 2009) a participant (M.D./Ph.D.) publicly said that "the most we can hope for is that we institutionalize 1 hour/year in 'continuing medical education' for practicing doctors in genomics". (That is about 10% of the time I spend DAILY on keeping abreast of the genome revolution ...). It will take a similar transition for medical doctors NOT to be embarrassed about their lag behind "state of art" as it already happened to experts of other trades. Take, for instance an average car mechanic. It used to be that customers expected (and the car mechanic delivered) a thorough familiarity of the car mechanic with all the parts and the mechanics how they work. State-of-the art cars contain maybe 100 "computers" (embedded chips) to control just about everything digitally - that used to be controlled mechanically before the "digital age". Is the car mechanic embarrassed that he/she has hardly any idea how "embedded chips" work - let alone never even attempts to "fix" them. Another computer (for "diagnosis") simply pinpoints which embedded chips have to be replaced, and the mechanic (or skillful teenager...) buys them on eBay unplugs the bad chips and replaces with new ones. Within minutes, for a couple of dollars - requiring zero understanding how embedded chips actually work.
Most medical doctors today outright refuse to see e.g. "23andMe" or other DTC "SNP raw data file" - for the good reason that the mind-boggling list of SNP "licence plate numbers" and A,C,T,G SNP-findings are flat uninterpretable by them. They will NOT see them in the future, either! Numbers are for computers - and the consumer does not even have to know his/her "medical terms" for "hereditary syndromes and statistical proclivities". The system will be automated; see YouTube of HolGenTech - requiring resources of 36 months and $10 M (threshold). Pellionisz_at_JunkDNA.com]
Genetic testing may yield personalized health treatments
By Rita Rubin, USA TODAY
Heart disease patient Terence Gooding and breast cancer survivor Kathy Negro live 2,000 miles apart, but they stand shoulder-to-shoulder in the burgeoning field of personalized medicine.
They are among a small but growing number of American patients who have sought genetic testing to help guide their treatment. The genes in question, passed from parent to child, carry the blueprints for liver enzymes involved in processing many medications.
GENES: Some labels note how they affect drug effectiveness
Scientists expect that in the not-too-distant future patients will be tested routinely for a variety of genes that affect their response to drugs. The results should help doctors decide what and how much to prescribe, a major step forward in personalizing treatments for a range of ailments.
In the next three to five years, the cost of sequencing a person's genome will drop below $1,000 — less than the price of a colonoscopy, says National Institutes of Health director Francis Collins, who led the Human Genome Project to completion in 2003. Says Collins: "I think that will finally make pharmacogenomics" — the study of how variations in the human genome affect a person's responses to medications — "really practical."
ALZHEIMER'S: Gene raises risk, but testing for it doesn't raise anxiety
USE: Is it worth testing your genes?
Gooding and Negro illustrate both the promise and the problems of using pharmacogenomics in treating patients.
Gooding, 75, whose medical history could fill a cardiology textbook, took a saliva test last fall to see whether he had inherited fully working copies of a gene involved in converting Plavix — the blockbuster drug given to reduce heart patients' risk of lethal blood clots — to its active form.
Negro, 41, who already had had nearly every type of breast cancer treatment since her diagnosis at age 39, took a blood test to see whether she had inherited working copies of a gene involved in converting tamoxifen — prescribed to reduce the risk of a recurrence — to its active form.
Some health care organizations already offer pharmacogenomic testing to select patients, such as Gooding, and some test manufacturers are marketing directly to consumers, such as Negro, through the Web. As the cost of sequencing the genome drops, doctors can expect to see more patients who already know their genetic status when it comes to metabolizing certain drugs.
But before they pay for pharmacogenomic testing, some insurers want more evidence that it leads to better patient care, says Robert Epstein, chief medical officer of Medco Health Solutions, a pharmacy benefit manager that in January acquired DNA Direct, which sells such tests.
In late January, a Centers for Medicare and Medicaid Services advisory panel concluded that there was insufficient evidence to determine whether testing for the gene involved in processing tamoxifen leads to better outcomes for breast cancer patients.
Who would fund such research isn't clear, Epstein says. Meanwhile, he says, "we believe that you have to look at the weight of the evidence that's out there, the seriousness of the (health) problem and whether there is an alternative therapy."
Some scientists, echoing insurers, also question whether the tests are ready for prime time.
"We're having genetic tests commercially available and reasonably affordable before the evidence has fully matured," Duke University breast cancer specialist Jeff Peppercorn says.
One problem, Peppercorn and others say, is the lack of research into what to do with test results. And genetic variations aren't the only factors that affect drug metabolism, which also can be inhibited by obesity, older age and interactions with other medications and dietary supplements.
"Genes don't act by themselves," notes University of Maryland endocrinologist Alan Shuldiner.
Another issue is doctors' inexperience with genetic testing. "I don't think they are anywhere near prepared for it," Collins says. "They are so buffeted about by other demands on their time."
Treatments need body's help
As it comes out of a pill bottle, neither Plavix nor tamoxifen is an active drug, ready to battle blood clots or breast cancer. Each needs something to flip its switch into the "on" position: a molecule in the liver called an enzyme.
Specific enzymes convert Plavix and tamoxifen into their active forms. When medications are active to begin with, these enzymes can turn them off, preventing the accumulation of too much in the body.
Genes carry the blueprints for these enzymes, and genetic variations can cause a shortage. The two enzymes involved with Plavix and tamoxifen also play a role in processing about a quarter of all drugs, says Issam Zineh of the Food and Drug Administration's clinical pharmacology office. Many drugs have such a wide safety and effectiveness window, he says, it probably doesn't matter if you're a poor metabolizer.
But with Plavix, studies consistently have shown that poor metabolizers might as well be taking a sugar pill than the standard dose, because their risk of heart attacks and strokes is much higher than that of other Plavix users.
More than 2 million Americans taking Plavix — 5% of the 48 million in total — are poor metabolizers, because they didn't inherit any fully functioning copies of CYP2C19, the gene involved in converting the drug into its active form. Most don't know it, because they haven't been tested.
"How can we leave these people in the lurch any longer?" asks cardiologist Eric Topol, chief academic officer of Scripps Health, a health care delivery network in San Diego.
In September, Scripps Health began offering CYP2C19 testing to Gooding and others who get coronary stents at Scripps Green Hospital.
Each year, about 1 million Americans get such stents, and afterward they're usually prescribed Plavix, now the second-best-selling drug in the world, behind only the statin Lipitor.
Gooding, a San Diego resident who had been on Plavix for more than two years, learned that neither of his parents had passed on working copies of the gene, so he's a poor metabolizer. His doctor doubled his Plavix dose, an approach that hasn't yet been studied.
Blood tests show Gooding seems to be responding well. He has a brother and a son on Plavix who plan to be tested to determine whether they also are poor metabolizers.
But how best to treat such patients isn't clear, says David Flockhart, clinical pharmacology chief at the Indiana University School of Medicine.
"Do you double the dose of Plavix?" he asks. "Do you take Effient (a competing drug)? Or do you give them aspirin (which also trims blood clot risk) and pray?"
Still, despite the uncertainty about what to do with the results, Flockhart says, "if I was a patient who'd been stented after a heart attack, I'd want to know."
The question of how well a patient metabolizes Plavix will carry more weight if, as expected, it goes off patent next year, paving the way for cheap generic versions. Then, many patients now on Effient, an expensive brand-name drug, probably will be switched to generic Plavix.
Studies sponsored by Effient's co-marketers, Daiichi Sankyo and Eli Lilly, indicated that among Plavix users, poor metabolizers didn't do as well as normal, or "extensive," metabolizers. Genetic status didn't appear to affect Effient metabolism, but in the studies, 2.4% of Effient users experienced the side effect of serious internal bleeding, compared with 1.8% of Plavix users.
'Opening a can of worms'
Negro, a Detroit resident, had been on tamoxifen for a year. The former pharmaceutical sales rep hoped testing would provide peace of mind and show that she, like most, had two working CYP2D6 genes. Her cancer doctor warned that "you could be opening a can of worms, because we're not sure what to do" with the results, but went along with her desire to be tested last fall.
Research about whether having no working CYP2D6 genes raises tamoxifen users' breast cancer recurrence risk has been mixed, although some scientists blame the lack of clarity on flawed studies, not on the absence of a real connection.
If she had no fully working copies of the gene, Negro figures she'd have her ovaries removed, an aggressive move to put her into menopause and make her eligible for an aromatase inhibitor — tamoxifen alternatives that can be taken only by postmenopausal women. Premenopausal, she had no choice but tamoxifen.
But the test showed she has one working copy and one non-working copy of the gene, putting her in the gray area of "intermediate," or so-so, metabolizers.
"Now I'm kind of standing still," she says, explaining she'll probably stay on tamoxifen for now because she's not ready to have her ovaries removed.
One concern about pharmacogenomic testing of breast cancer patients is that the results might spur some to quit taking tamoxifen, says Vered Stearns, a Johns Hopkins breast cancer specialist. Even for premenopausal poor metabolizers, she says, "tamoxifen is the drug of choice."
In postmenopausal women, studies have found aromatase inhibitors to be slightly more effective than tamoxifen in reducing recurrence risk, although some scientists say that may be a result of including poor tamoxifen metabolizers in the studies.
By pooling results from various studies, Mayo Clinic breast cancer researcher Matthew Goetz hoped to settle the debate about whether CYP2D6 status affects tamoxifen users' recurrence risk.
Goetz's own study had seemed to answer that question. In December 2008, he reported at the annual San Antonio Breast Cancer Symposium that tamoxifen users who didn't have any fully working copies of the gene were nearly four times as likely to have an early recurrence as those with two copies.
In a press release at the time, Goetz said his results "strongly suggest" that postmenopausal patients considering tamoxifen be tested first to see whether they're poor metabolizers.
But at the same meeting a year later, Goetz reported that when he lumped his findings with those of other studies, he didn't find a link between CYP2D6 status and tamoxifen users' recurrence risk. "It's a little bit disappointing," he says, noting that many studies lacked important information such as dose size.
For now, Goetz says, he tells postmenopausal patients who are considering tamoxifen that some studies have shown CYP2D6 status to be important, while others haven't.
Most, he says, choose to be tested.
[There are some total misunderstings afoot in the "Genome Revolution". One absurdity is that Genome Regulation is "turning genes on and off" (when you regulate the acceleration of your car, do you "turn on and off" you gas pedal? NO. You apply continuously variable pressure...). The other total misunderstanding is if genomic testing is, or is not, "ready for prime time". Nonsense. The question (and emphatic YES answer) is if genomic testing is ready for the "5'o Clock News in the Morning". You never start anything with the "prime time" - as that is the most expensive slot that only the most mature shows can pay for. The question analyzed above is pretty brutal - and is brutally simple. When will Insurance Companies realize that it becomes CHEAPER (for them!) to require prior genomic testing to establish that certain drugs actually work - rather than paying insurance coverage for (sometimes extremely expensive) drugs that occasionally are not only completely useles, but their side-effects cost insurance companies even further expenditure. This is a 5' clock "wake up call" for Insurance Companies, not "prime time entertainment. - Pellionisz_at_JunkDNA.com]
Splash Down: Pacific Biosciences Unveils Third-Generation Sequencing Machine
Bio-IT World
By Kevin Davies
February 26, 2010 | MARCO ISLAND, FL—Pacific Biosciences will introduce what it describes as the first “third-generation” [molecular] DNA sequencing instrument at the Advances in Genome Biology and Technology (AGBT) meeting later today. “It’s really the world’s most powerful real time, single-molecule microscope,” said PacBio CEO and chairman Hugh Martin.
During a preview of the highly anticipated instrument for the press, Martin hailed the machine as “a quantum leap” for the field. “We sold the ten beta units just like that—fully paid for!” PacBio intends to ship those first ten instruments to customers, all in North America, by this June.
The first thing one notices about the $695,000 machine is that, for an instrument sequencing single molecules of DNA, it’s awfully big. The floor-standing machine weighs about 1900 pounds and is 6 1/2 feet wide and 29 inches deep. The instrument is accompanied by a separate blade center for the real-time data processing, which sits apart from the main instrument.
“If you look at what’s inside there, it’s packed,” says Martin by way of justification. Much of the instrument’s girth is taken up by the robotic sample mixing and staging system. The base is packed with four high-speed cameras, optics, and a carbon-fiber stage good to +/- 5 nm in six dimensions. Martin says the PacBio machine’s spec sheet states it can be installed on any floor, but admits: “You need a pretty heavy duty floor.”
Talking about 3rd [Molecular] Generation
Martin argues that 2nd-generation technology is flattening out, despite the healthy competition between Life Technologies and Illumina. “454 Life Sciences is not moving very much relative to longer read applications. Helicos, I think, has become sort of irrelevant. Complete [Genomics]—it’ll be interesting to see what happens to their cost model, because I think a lot of people in the world are going to be enabled to be service providers using [Life and Illumina] boxes to compete with Complete.”
As for other companies preparing to launch new detection systems, such as Ion Torrent Systems and Avantome (Illumina), Martin argued they are still 2nd-generation technologies that involve pausing the DNA polymerase and doing some sort of an inspection. “You can speed that up a bit, you can make it inexpensive in the hardware and consumables, but you’re still on that performance curve of 2nd gen. What the world really needs is to move to a whole new curve… Customers definitely want longer read lengths and have huge issues with 8-10 day run times.”
So what exactly is his definition of “third-generation sequencing”?
Surprisingly, perhaps, Martin did not cite some profound conceptual differentiator such as the real-time hallmark of the platform. For Martin, his platform is “everything that 2nd gen is—throughput, cost per base, etc.—with the addition of very long read lengths, extremely low reagent or consumable cost and very fast run times. Those three.”
Of course, PacBio can expect some company soon: Martin acknowledged that systems under development at Oxford Nanopore, Life Technologies (StarLite), and perhaps Halcyon check the same three boxes as PacBio. In his view, however, Complete Genomics, does not, as it employs short reads and longer run times. “It’s essentially a SOLiD system on steroids,” says Martin.
For the past six months, PacBio has used a dozen prototype systems for internal development and external customers, working with researchers at Stanford, The Genome Center (Washington University) and elsewhere. Martin promises a range of applications that go beyond DNA sequencing, including the study of transcription (RNA) and translation (ribosomes). And there is scalability with the promise of increased polymerase performance, yield, and multiplex time.
Welcome to the Machine
The PacBio machine is a marriage of advances in semiconductor processing, enzymology, surface chemistry, synthetic chemistry, hardware, parallel processing, optical and camera design, bioinformatics and software, not to mention product design that produces an undeniably handsome machine—an impressive achievement in just two years, even allowing for the $250 million raised and more than 300 employees.
According to PacBio’s Geoff Otto, the DNA sample prep takes place off the instrument in only 5-6 hours, requiring just 500 nanograms of starting material. The starting DNA is sheared into double-stranded linear structures sizes ranging from 200 bp to 10 kb, then attached to the SMRT adapters, which produce a topologically closed circle enabling consensus sequencing of the same template if desired. For longer read lengths of several kilobases (kb), it is likely the sample would be read linearly. The DNA template is complexed with the polymerase, a stable assembly that does not require immediate processing, before loading onto the machine. (The method by which the DNA polymerase is fixed to the bottom of each well was not disclosed.)
The front of the machine contains two drawers for sample loading, which open with a satisfying whirring noise. One is for DNA and reagents, the other for up to 96 SMRT (single molecule real time) cells. Each SMRT cell houses 80,000 zero-mode waveguides (ZMWs), about one third of which are used in a given experiment. The SMRT cells are lined into strips of eight (dubbed ‘8-packs’); 12 of these strips can be loaded at a time, in a 96-well format. Each SMRT cell is individually sealed, so an instrument run could involve just a single SMRT cell, returning to the other cells in the 8-pack strip later.
The run time for an individual SMRT cell is about 15 minutes, depending on the desired read length. In the current version, the polymerases runs at about 1-3 nucleotides/second. “As soon as you start collecting data, you start processing. You can make iterations or changes in real time. If there’s a change in the protocol, you can make that happen in real time,” says Otto. From sample to an instrument run to retrieving data takes less than a day.
In addition to linear and consensus sequencing, PacBio offers a strobe method, which would be used for longer read lengths from 3-10 kb, producing multiple shorter reads interspersed with ‘dark’ segments to preserve the enzyme. “If you have 10-kb fragment, you can target a 3-kb span, but then change the instrument specs without having to change the prep,” says Otto. In other words, a combination of all three modes can be programmed to run on different SMRT cells in the same run.
The strobe mode overcomes photophysical damage to the polymerase inflicted by excited fluorophores that occasionally “go into a bad state,” as Martin puts it. PacBio hopes to minimize such damage going forward by: limiting oxygen exposure, introducing protective additives, and mapping and re-engineering the surface residues on the polymerase that are most prone to damage. Martin’s goal is to create “a sunburn-proof enzyme” that in 2-3 years, will be able to produce read lengths of 40,000 bases and more than 100,000 bases under strobe conditions.
Using a remote workstation running Windows, a user can design a run, monitor the instrument, and view completed results. The maximum run time for the machine initially is 12 hours, although that will increase.
Project manager Dana Underwood demonstrated a typical sample run. On the touch screen, from a list of plates created on a remote interface, he instructs the instrument what to run. In one drawer, he loaded two reagent plates, the mixing plate, and a sample plate. In the other drawer, he loaded the final 8-pack of SMRT cells. The instrument checks for any missing or misaligned plates, and if everything is in order, the “Start” button becomes active.
After the first SMRT cell is extracted from the 8-pack and moved to the prep station, one of two pipettors deposits reagents in the SMRT cell and sequencing begins. The run time remaining ticks down on the front display, along with a hypnotic portion of the multi-colored ZMWs flashing in real time. When the run is complete, a gripper removes the old SMRT cell, and the next one is swapped in.
Dwarfed by the instrument itself is the blade center, which handles the robotics and real-time data processing. Edwin Hauw, senior product manager, said PacBio’s software package “covers everything in the sequencing workflow from run design to instrument loading, run monitoring, primary and secondary analysis.”
The blade center, unusually slim (26 inches wide) and mounted from the top down to minimize the footprint, handles the instrument robotics as well as real-time data collection and signal processing. The system uses a hardware accelerator, but PacBio has not yet decided whether to settle on a GPU (graphics processing unit) or FPGA (field programmable gate array). There are four blades, each blade has dual Intel Nehalem quad-core processors and 12 Terabytes, with a total of 192 Gigs RAM. One blade handles the robot, the other three data analysis, movie-to-trace, and trace-to-pulse-to-base call. There is sufficient storage for 24 hours worth of base calls and quality values.
Real Time Sequencing
Martin did not preview trace data or discuss error rates in the machine preview. However, at full release later this year, he said the average read length will be 1000-1250 bases, fractionally longer than 454 or Sanger sequencing, with 5% reads between 3-5 kb. For a targeted sequencing experiment, “you’ll get 5% of 30% [the Poisson limit] of 80,000 [ZMWs]—so you get 1,000 reads in the 3-5 kb range for $99.” Despite the lower throughput compared to the high-end second-generation machines, Martin pointed to an advantage in flexibility, for example allowing diagnostic samples to be run without having to wait until sufficient samples make it worthwhile for a run on a 2nd-gen box.
“We’re the first mover. There’s no one else out there in 3rd gen.” Martin noted that it has taken PacBio two years to progress from presenting a 50-base sequence run (at AGBT 2008) to unveiling an instrument. “Oxford [Nanopore] is a long way from showing you a 50-base trace,” he said. “Life [Technologies] may make some noises, but I don’t think they have one yet. So we have got at least 2-3 years of free running room, which is very exciting.”
PacBio is targeting customer shipments in the second half of 2010. For the most part, the customers “want to add end value to Illumina reads,” Martin said, “or they’re unplugging 454 or [Sanger sequencers], i.e. longer-read lengths. I think it’ll be additive to the market.”
Martin says he could have sold 30 instruments to early access clients, and admits there are some unhappy people not include in that first tranche, notably the Wellcome Trust Sanger Institute in the UK, and the Beijing Genomics Institute in China. “It’s difficult for us in a beta environment,” he says. “We want a lot of feedback from our customers. So we’re not doing ‘rest of world.’ There are some major centers not getting machines. They will. We’d planned on going rest-of-world in 2011. We’ve changed that: we’re going rest-of-world in 2010.”
Even with future upgrades, Martin says the current machine will not be the one that delivers the ‘15-minute genome,’ as PacBio founder Stephen Turner claimed two years ago. Although the number of ZMWs on a SMRT cell will be doubled to 160,000 ZMW over time, PacBio will need 1 million to get the genome. “It’s probably [capable of delivering] a 2- or 3-hour genome.” The V2 instrument will reach the 15-minute target, but that isn’t scheduled for release now until 2014.
Martin hinted strongly that he is positioning PacBio for a public offering, possibly in 2010. “We wanted to build a really big company, a publicly independent company. Everybody here probably came from one of the companies that might [hypothetically] acquire us, but we all left for a reason and none of us want to go back!”
[There you have it. Third generation (molecular) affordable full human DNA sequencing is here, unstoppable. Equivalent to landing a man on the Moon. Now comes the harder part (like getting the man safely back to Earth); Emergence of "Genome Analysis and Interpretation Center" based on algorithmic (software-enabling) theory of recursive genome function, that puts the affordable full human DNA sequences into a business model sustaining the entire private "Genome Industry" - Pellionisz_at_JunkDNA.com]
The Future Has Already Happened - How it might unfold by Complete Genomics and Pacific Biosciences?
Based on Single Nucleotide Polymorphisms alone, Francis Collins’ book on Personalized Medicine early this year stated in Chapter I. page 1. that “The Future Has Already Happened”. While Dr. Collins (Head of NIH, an M.D./Ph.D.) as recently as two years was hesitant about Direct-to-Customers genome testing, his book fully endorses the course – flabbergasting even some “professional” futurologists, who confused the projected business model of “Shopping for your Life YouTube” by HolGenTech, Inc. with its full implementation. Those who are business-savvy easily note that the proposal and its implementation are about $10 M apart!
Now enter “affordable full human DNA sequencing” by Complete Genomics and Pacific Biosciences – both having secured “first adopters” from Pfizer to Monsanto, with most major contenders for a much needed “Genome Analysis and Interpretation Center” that is presently not completely filled by either by Cold Spring Harbor on the East Coast, Baylor at Houston in the Midwest, or Stanford on the West Coast.
First let’s review (in a "tongue in cheek") the “old fashioned medicine” – to be contrasted by the unfolding and disruptive industrial trend.
You go for your annual check-up. Luckily, the only time that you see a doctor per year. About 15 minutes worth. Nobody can afford to have his/her primary physician to accompany the customer to every grocery-shopping. “You are on your own” – with some vague guidance “to eat right and exercise”. Of course, your labwork is ready before you get to see the doc, with your routine blood test showing that your PSA is holding well below 1 and steady over the years (no sign of prostate cancer). A quick check of your knew-jerk shows that you are alive – and thus will probably pay. However, your “bad cholesterol” is elevated, in spite of some “statins” prescribed first some years ago – that made you a “repeat customer” to the pharmacy, paying through the nose if you don’t have coverage for the “brand name” newest and greatest of “statins” (some can set you back $360 per month, easily…). Of course, you can go “generic” – but your genome may render you to be the type who suffers from side-effects of muscle pains… only to be found out by you (“not tested on rabbits”). For a “good repeat customer” there is always some new drug to experiment with – unless and until your liver-panel shows red flags that you’ve had enough of brutal interventions of its ill-understood finer working. The past is not entirely satisfactory – though it is a lucrative business model of “repeat customers”.
Enter “present (im)perfect”. Meanwhile, some doctors are of the view that your “bad” blood cholesterol may not even be relevant for CAD (cardiac coronary artery disease) – findings in animal experiments were reported just yesterday or so that expression of some “separate genes” is under tremendous influence of your “Junk DNA” scattered hundreds of thousands of nucleotides away, having severe effects on your CAD ... (Enter “FractoGene”).
Now, peek into the “future” – lurking just around the corner. Your “annual physical” will surely include an “extended blood test” – in addition to your existing “blood-” and “liver-panels” (etc) also displaying your “genome-panel” – based on affordable full DNA sequencing, that is already approaching the price of quite routine preventive-exploratory examination of e.g. colonoscopy.
Affordable full human DNA sequencing is not a goal – but a means for an array of emerging industries, including Participatory Personalized Preventive Medicine. Thus, a key question is the “business model” how the new resource will fit into an emerging “ecosystem”.
DTC, even in its early stage have focused on hereditary symptoms that are “actionable” (see first and now re-organized DeCodeMe, after its bankruptcy, 23andMe that lost one of the two Founders, and Navigenics that lost both Founders, thus far two CEO-s and now having received major funding from Consumer Product Company Procter & Gamble). Clearly, there are “non-actionable” utilizations, like ancestry-research and playful applications in social media – but according to the early stage, alas, they are insufficient to sustain the industry.
What is the most “actionable” hereditary condition? Consumer shopping! Most (if not all) of conditions checked by Navigenics, for example, are syndromes with a non-trivial “dietary considerations”, and a good number of them are clearly “genome regulatory diseases”. Perhaps the most important such condition focused on by Navigenics is Alzheimer’s (likewise, the focus of 23andMe, Parkinson’s disease) appear to be conditions both with “dietary considerations” as well as “genome regulatory diseases” – so are stomach cancer, Crohn’s disease, etc., etc. For both major neural degenerative diseases the algorithmic (software enabling) approach to genome function as fractal iterative recursion (FractoGene) actual software was developed (by FractoSoft, now acquired for its IP by HolGenTech, Inc.) – see FractoGem Miner (FractoSet). The budding FractoSoft was too far ahead from at least three viewpoints, since a) The Principle of Recursive Genome Function had to be anchored in the science establishment first (Cold Spring Harbor) – b) the “fractal defect mining” called for HPC as fractal analysis of full DNA is extremely CPU-intensive, and c) full human DNA sequences were simply not available for statistically significant correlations at any price – while now both the price-tag and the data-pool is rapidly becoming friendly to this lucrative approach.
With affordable full human DNA sequences in larger pools, DTC will advance from microarray-interrogation to algorithmic full DNA-mining for the entire arsenal of “structural variants”, including fractal defects. As for the underlying business model, closing it on the consumers, empowering them by a handy barcode-reader smart phone for genome-based shopping, the ecosystem is set for a perhaps initially slow ramp-up, but certainly for a hyper-escalation in the near future, as Consumer Product Giants (for instance Procter & Gamble) have already joined the fray. Likewise, “Big IT” like Intel (first IntelVC for sequencing with PacBio) and now $3.5 Bn by Intel Alliance for emerging businesses including biotechnology, the ecosystem is most certainly proceeding into a new phase.
Your “genome panel” in your annual check-up will make you a repeat customer to DNA sequencing, since success of your genome-based recommendation program for your daily shopping will have to be monitored by keeping an eye (not just on a single number of your PSA), but on the entire methylation-pattern of your genome. Your aging process suddenly accelerating by flare-ups, your derailments (of any) of genome regulation would have to be carefully monitored year after year; in a Personal, Participatory Prevention program; compelling specific tests (such as colonoscopy) sometimes many years before they would be due for the “one size fits all” consumer. (Who is not to be confused with “patient”).
Everything is suddenly “falling into their place”? As some see it, definitely yes. Others are hesitant even to look, since they afraid of what they might see.
Just like with all paradigm-shifts in the history of R&D throughout so many Centuries. And while the weary hesite, those who dare - accomplish.
[Pellionisz_at_JunkDNA.com]
Pacific Biosciences Names First Ten Early Access Sequencer Customers
By Bio-IT World Staff
February 23, 2010
Pacific Biosciences has announced its first ten early access customers for its next-generation DNA sequencing system – a real-time detection method at the single-molecule level.
The first ten early-access customers for PacBio’s SMRT (single molecule real time) system, all from North America, are:
• Baylor College of Medicine
• Broad Institute of MIT and Harvard
• Cold Spring Harbor Laboratory
• U.S. Department of Energy Joint Genome Institute
• The Genome Center at Washington University
• Monsanto Company
• National Cancer Institute/SAIC-Frederick
• National Center for Genome Resources
• Ontario Institute for Cancer Research
• Stanford University
The first shipments to these organizations will commence in the next few months, with early-access programs for customers in Europe and Asia due to follow later this year.
"We are very excited about this opportunity," Dick McCombie, professor at Cold Spring Harbor Laboratory, told Bio-IT World. "We were an early adopter of the Solexa technology and we have really seen it change the way we do a lot of biology in my lab as well as in other labs at CSHL. I think that the PacBio technology will likely be disruptive in that same way. It will help us with our work on cognitive disorders by allowing us even better resolution and ultimately increased speed in looking at the genomic changes associated with these disorders. We are already getting exciting results there and this will let us really ramp up those efforts."
McCombie added that the PacBio instrument should open up novel approaches to address some of those disease questions. "One reason that we are happy to be involved in the early phase is that it gets us a head start in the area of creative, new applications," he said.
Other early adopters also expressed pleasure in joining the first cadre of users. “We see this as a potentially valuable tool that can be applied to a wide range of studies because of its versatility,” said Michael Snyder, professor and chair of genetics and director, Stanford Center for Genomics and Personalized Medicine. “We are excited to have the opportunity to be one of the first institutions to access this technology with the potential to revolutionize personalized medicine,” said John McPherson, director of cancer genomics, Ontario Institute for Cancer Research. McPherson said he would explore the longer read lengths of the PacBio system for targeted human sequencing and viral sequencing.
PacBio chairman and CEO Hugh Martin said he was delighted with the breadth of organizations in the early access program, and that the program had sold out. “The wide array of applications that will be explored by our initial customers will benefit from the key advantages of the SMRT system: long reads, fast cycle times, flexibility, and single-molecule resolution. This is what defines third-generation DNA sequencing.”
PacBio will use the early access program to ensure it is prepared for commercial launch of its sequencing system in the second half of 2010. PacBio will formally unveil the SMRT system at the end of this week during a workshop at the Advances in Genome Biology and Technology conference in Marco Island, Florida, as well as presenting examples of applications including DNA sequencing, direct RNA sequencing, methylation, and protein translation.
[Technology of Pacbio - with Intel behind it - stands out from two viewpoints for "fractal defect" targeted search in full DNA. One is the much longer reads, compared to other competitive technologies; since with short reads precisely those repeats that are characteristic to the fractal distribution may remain "masked". Second, presently the PacBio (and Oxford Nanopore) technologies provide both the A,C,T,G full sequence information PLUS the degree of their methylation (with Oxford Nanopore not yet as advanced towards "assembly line mass production" as PacBio is). Theory of genome regulation by means of controlling fractal iterative recursion by methylation of perused auxiliary information (from what used to be "junk DNA") thus could be put to full DNA testing.
Pellionisz_at_JunkDNA.com]
Oral Cancer Study Shows Full Tumor Genome; Novel Method Speeds Analysis for Individualized Medicine
ScienceDaily (Feb. 24, 2010) — Mayo Clinic researchers along with collaborators from Life Technologies are reporting on the application of a new approach for sequencing RNA to study cancer tumors. Their findings from a proof-of-principle study on oral carcinomas appear in the current issue of PLoS ONE, the online science journal.
To explore the advantages of massively parallel sequencing of genomic transcripts (RNA), the researchers used a novel, strand-specific sequencing method using matched tumors and normal tissues of three patients with the specific cancer. They also analyzed the genomic DNA from one of the tumor-normal pairs which revealed numerous chromosomal regions of gain and loss in the tumor sample.
The key finding of this work was that alterations in gene expression which can arise from a variety of genomic alterations frequently are driven by losses or gains in large chromosomal regions during tumor development.
In addition to the specific tumor findings, this study also demonstrated the value of this RNA sequencing (RNA-Seq) method. It will allow researchers to measure strand-specific expression across the entire sample's transcriptome. This technology reveals far more detail about genome-wide transcription than traditional microarrays.
"This method allows us to investigate genetic changes at a level that we were never able to see before," says David Smith, Ph.D., Mayo Clinic genomics researcher and corresponding author of the study. "This provides us with much more information about alterations during cancer development that could reveal important therapeutic targets. We can more completely understand the relationship between an individual's genome and the alterations to that which result in disease.
This is a huge step in speed, detail and diagnostic power for the field of individualized medicine. This transforms how we are going to study cancer -- and how we're going to practice medicine -- in the very near future."
The urgency of this condition points to the need for more efficient technologies and methods. Head and neck cancers are the sixth most prevalent carcinomas in the world. Advanced stage oral and throat cancers have a five-year survival rate of only 50 percent in the United States. Information provided by these and continued studies will help to better characterize the molecular basis of cancer development. That information can hopefully define better therapeutic strategies for treating an individual's specific cancer.
Others involved in the research include co-first author Rebecca Laborde, Ph.D.; Kerry Olsen, M.D.; Jan Kasperbauer, M.D.; Eric Moore, M.D.; and Yan Asmann, Ph.D.; all of Mayo Clinic; and co-first author Brian Tuch, Ph.D.; Xing Xu, Ph.D.; Christina Chung, Ph.D.; Cinna Monighetti, Ph.D.; Sarah Stanley, Adam Broomer, Ruoying Tan, Ph.D.; Pius Brzoska, Ph.D.; Matthew Muller, Asim Siddiqui, Ph.D.; Yongming Sun, Ph.D.; Melissa Barker; and Francisco De La Vega, Ph.D.; all of Life Technologies, Foster City, Calif.
The research was supported by Mayo Clinic and Life Technologies. The funders had no role in study design, data collection, analysis or publishing. Some authors are or have been employed by Life Technologies, which makes technology and materials used in the study. Data and materials will be shared.
[Measuring the size of cancerous tumors based on full sequencing is of enormous significance. Observers watch with considerable anxiety the massive investments into affordable full DNA sequencing - since the "market" (what to do with them) is a much harder issue than searching with microarrys for "SNP"-s (single nucleotide polymorphisms). Searching for "fractal defects" (that are within 150-300 nucleotide sequences) were perhaps the first of such analyses that require full DNA sequencing; and clinical applications could not take off since full DNA sequencing is still too expensive ($5,000 at minimum by Complete Genomics, and they do not take yet "personal orders", but work with initial customers, e.g. Pfizer that can afford higher premium). Of course, the "supply-demand" equilibrium will work for a wider market, calling for more "mass production" and thus making full human DNA sequencing rapidly increasingly affordable.
Pellionisz_at_JunkDNA.com]
Junk DNA could provide vital clues to heart disease
Scientists have linked a region of junk DNA, the 98% or so of the genome that does not code for proteins, to the risk of developing at least one form of heart disease.
The research, published online in Nature, drew on previous genome-wide association studies that linked a non-coding stretch of chromosome 9p21 with coronary artery disease (CAD) and showed that people who carry certain single nucleotide mutations in this stretch of DNA have an increased chance of developing the disease.
Principal investigator and geneticist Len Pennacchio of the Lawrence Berkeley National Laboratory in Berkeley, California, based the study on the equivalent chromosome in mice and found a potential mechanism for how the region of non-coding DNA might increase the risk of heart disease.
Pennacchio said: "We were really interested in understanding how this purely non-coding interval leads to CAD, so we thought, 'Let's delete it and see what happens'."
He continued: "We did, and found that the expression of two genes nearly 100,000 base pairs away from the deletion dramatically decreased in mice."
But the expert pointed out: "How this translates into humans, we don't know yet."
Pennacchio added: "The fact that this non-coding region works on genes over 100,000 base pairs away goes to show that non-coding DNA can play important roles in common human disorders.
"We want to globally understand what fraction of human diseases are due to variation in the coding versus non-coding regions. That's a huge unanswered question as we continue into the post-genomic era."
Cardiovascular specialist Ruth McPherson of the University of Ottawa Heart Institute in Ontario, Canada, who led a genome-wide association study on CAD1, said: "This study brings the understanding of 9p21 and CAD risk to another level."
[Since the International PostGenetics Society was the first scientific international organization that declared officially "Junk DNA" as a non-scientific misnomer in 2006, 8 months before the US Government ENCODE results were published, the above news is novel only to those actively resisting a paradigm-shift (hope they don't have a heart-attack upon learning that not only nearby "promoters" to a gene play regulatory roles, known since the Operon theory of Jacobs and Monod (1961) - but those non-coding regions that are hundreds of bases away. "Facts don't kill theories - only more advanced theories kill obsolete ones", however. Thus is the significance that dismissing both obsolete axioms (the clearly ridiculous "Central Dogma" - just that its author confessed that he did not know what the word "dogma" meant, "prohibiting" recurse of information from proteins to DNA, as well as the "JunkDNA misnomer" that even if there were a recursion, it would only find "junk", devoid of information).
My paper "The Principle of Recursive Genome Function" will attain deserved appreciation NOT because I respectfully discarded obsolete axioms. I actually put forward the principle that genome function is suddenly seen as "recursive" - once the show-stoppers are discarded and one connects the dots of DNA>RNA>PROTEIN>DNA... in an unobstructed manner. Further, I specified an answer to the immediate question "okay, genome function is recursive - but what kind of recursion is taking place?" One can not write software if the algorithm of the recursion is not specified mathematically. I specified that genome function is based on a "Fractal Iterative Recursion", illustrated by the well-known hierarchical development of Purkinje brain cell arbors, following my pioneering notion of FractoGene (2002) that "Fractal DNA governs the development of fractal organelles (e.g. the Purkinje neuron), organs (e.g. the lung), and organisms (e.g. see Barnsley's fractal portrait of a human).
While my notion of recursion can be traced back to my 1989 fractal model of a Purkinje cell (explicitly calling for "re-visiting the DNA"), at that time both obsolete axioms and their authors ruled - and I lost an extension of my existing NIH grant for my "double heresy" - and an NIH grant based precisely on my fractal modeling work (see acknowledgement of the paper) was outright rejected.
By 2009 October 9th, Eric Lander et al. (Director of the Broad Institute and Science Adviser to the President) published on Science cover and lead-article experimental evidence that the STRUCTURE of DNA-strand-folding is fractal (ultra dense for packing a 2 meter long strand into a cell nucleus with 6 micron diameter, knot-free such as the entire DNA can be transcribed, and the fractal folding makes "linear distances" quite meaningless). The latter is particularly important, also in view of the present finding - see animation in lead-essay of this website - to make sure that Recursive Genome Function can have direct access to "innermost parts of the sequence".
This author has finished with "Junk DNA debates" quite a while ago. Of course it may be that "The Principle of Recursive Genome Function" harbors other than fractal iterative recursion. I would gladly serve as a referee of papers submitted for peer review who suggest an even better algorithmic (thus software enabling) theory.
Pellionisz_at_JunkDNA.com]
Three YouTubes later: Is IT ready for the Dreaded DNA Data Deluge?
This was the title of my personal Google Tech Talk YouTube on October 30, 2008. I followed up by presenting the Genome Computing in the Churchill Club Panel Format YouTube, 2009, and a month ago demonstrated implementation at the Personalized Medicine World Conference in Silicon Valley, YouTube. Dave Tribbett, a software developer for over three decades, has recently joined the fray of bloggers analyzing genome informatics from the key viewpoint of software-enabling algorithms. Visiting the "Genomics" chapter in his blog-site "Taste the Cloud" is highly recommended; e.g. his latest entry on Bioinformatics (at IBM). His blog entry will not be mirrored here, but I feel compelled to post here my enthusiastic reply, with some caveats:
It is for IBM to lose ...
by Pellionisz - 02/22/2010 - 15:02
I am very excited about Dave Tribbett' devotion to a series of deep analysis of postmodern genome informatics - as a core of critical mass, producing an explosion in the life sciences. I believe Dave’s present article is also great. Formally, there are only minor errors (for instance, to correct that Sun Microsystems is "now part of IBM" - actually on January 27, 2010 Sun was acquired by Oracle Corporation for US$7.4 billion, based on an agreement signed on April 20, 2009).
I more than agree to the "big picture" that "Life Science computing" is for IBM to lose - just as the PC was an "IBM PC"; just to be lost to Microsoft - that was a very young and aggressive company compared to perhaps too big and at time ossified IBM. I have written years ago a prediction of the "Big One"; and earthquake-like effect whenever the tectonic plates of "Big IT" pile up also private "Big Pharma" upon "Government Genomics". That predicted time is now.
Indeed, with great devotion and expertise, Caroline Kovac (recently retired) built a spectacular "IBM Life Science" program for at least a quarter of a Century - and as Dave’s embedded YouTube overviews shows, a huge array of activities in the Life Science Computing Program is thriving at IBM. I am particularly familiar with the trailblazing work of Isidore Rigoutsos and his colleagues; aiming at novel pattern recognition algorithms to address DNA structure.
Yet, I daresay, that the very enormity of the wide-spectrum Life Science effort of IBM might similarly result in IBM losing this game, the winner of which (just like in the early days of the "PC") just could not be predicted. In retrospect, a Monday Morning Quarterback "wisdom" might come to the crystal-clear "analysis" that the monstrous (and monstrously complex) IBM lost a singular focus. They wanted to accomplish holding both the key to the hardware architecture as well as (belatedly) gaining the upper hand of the PC OS (famed OS/2). They ended up with securing neither - and long time ago sold the entire IBM PC division for a token price. Likewise, what is the Government's slice in the pie of "PC"? - Just about zero.
Now take Genome Informatics. I was thrilled to hear about the IBM "Blue Gene" at the Monterey 50th Anniversary of the Double Helix (2003 February, exactly 7 years ago), from Caroline Kovac. Observing my surge of enthusiasm, she felt it necessary to utter some words of wisdom as a "caveat". She reminded me that the "Life Science Division" she was leading was NOT in control of Blue Gene at all - the World's fastest supercomputer (at that time) belonged to the IBM' "Computer Development Division"... Those of us who ever worked in huge operations like IBM (or the US Government), know that divisions of an entity are compelled AGAINST their cooperation, since in fact they pitch their efforts to COMPETE AGAINST EACH OTHER for one single pool of resources of the entity.
Thus, I am less than fully convinced that any single existing "Big Whatever" (including US Government...) is going to win "Genome Informatics". If history is any lesson, the winning combination is more likely to be laser-beam focused EMERGING entity (like Microsoft was, at that time) that grabs the singularly most crucial tenet (that was the OS and killer apps software for PC) and develops global alliances with just about all participating entities (minus perhaps IBM and Apple that decided NOT to take part in the cooperation). Far East manufacturers wisely opted in – and came out as winners of hardware production business, also Intel decided to focus on pure-play of CPU serial chip design and likewise became a big winner.
So what is the focus of "Genome Informatics"? Chances are that one answers: "DNA sequencing". Wrong! Affordably revealing the full human genome is a necessary, but not sufficient step. To take the cliche, "Genome Projects" are often compared to the "Moon Shot" (see e.g. Nobelist Sydney Brenner's very recent essay), in which comparison he says is quite literally true: "Getting a man on the Moon is relatively easy". "Getting the man safely back from the Moon is the harder part".
The AAAS grand annual meeting is wrapping up today - and Silicon Valley is teaming with not one but two most successful DNA sequencing Centers (Complete Genomics and Pacific Biosciences) rolling affordable full DNA sequences from the assembly line, like Ford T models avalanched the US from Detroit. (It had to be matched, for sustainability with an entire network of gas-stations…)
While I was not attending AAAS in San Diego, in the coverage I did not detect any major speech pinpointing that DNA sequencing does not reveal the "Language of Genome" at all. It does brings into plain view all the A,C,T,G “letters”, like when you obtain a copy of "War and Peace" with all Cyrillic letters of the Russian language on display - yet “readers” (except those who mastered the Russian language) will understand absolutely nothing of what the overwhelming number of letters might mean.
There are plenty of "Genome Sequencing Centers". To win "Genome Informatics" we need one more "Sequencing Center" as a hole in the head. Instead, we desperately need a private domain core-company that is totally focused in Genome ANALYSIS, such that a "Center of Genome Interpretation" emerges around it, reaching out to all R&D and business of the land.
Absolutely (just like Microsoft's OS and Killer apps), the core of this crucial fulcrum will not remain isolated, but will spread to virtually all hardware and software companies that are eager to grab a slice of the PostModern Genome Informatics market (as big as global Genome Based Economy is...).
Take the mentioned Intel. They bought into Genomics (now "Informatics") by contributing to $100 M investment to Genome Sequencing by PacBio (2007), plus put together a (small) "Downstream Data Analysis Group for Genomics" - that Intel disbanded when the global financial crisis hit us hard. The rationale might have been that "let's focus on sequencing first - the downstream analysis can wait; besides, as long as anybody does it with boxes with ‘Intel inside’ on them, the IntelVC investment in sequencing is safe". Moreover, technically it would take Intel just a few days, weeks or months (at most) to re-assemble an order of magnitude more potent "Downstream Genome Data Analysis Group". However, de facto, organizations of huge industries hardly ever move that fast, since decision-making is hierarchical and needs elaboration, submission and evaluation by committees of umpteen layers of corporate structure. Thus, it remains an open question if the huge freighter ship of IBM or Intel might turn tighter corners.
Meanwhile, Microsoft, Google, HP, Dell, Oracle could "cut in" - since all of them put together their Life Science programs, for readiness for "health-care business" - for the uncertain time when the Government might be ready with reforms accelerating e.g. digital health-data repositories. It might be debatable, though, if any of them singularly focus on "DNA Functional Analysis" - as it takes a quite unprecedented multiple domain expertise of disparate fields, that need a "psychological welding" (borrowing Nola Masterson's term) to get the two hemispheres of "genome informatics" together (my favorite term refers to the much drier anatomical structure of "corpus callosum"; the massive bundle of cable system connecting the right and left hemispheres of the brain).
So, where is the Government? Any Program at any of the countless branches of the organizations where "Algorithmic (software enabling) approaches to interpretation of genome function" are elevated into the role this issue ultimately will be?
Hardly.
The Government is not geared to take the enormous risk that scientist might THINK (as some, indeed, might not). The Government's role is to program of what contractors DO. But it is all right, since actually some "Genome Computing Architectures" (glimpsed e.g. in the first seconds of http://www.youtube.com/watch?v=mSRMCDCVg6Y ), a "Nurture server" (ingredients of what UPC barcoded nutrients contain) and a "Nature server" (knowledge-base of dietary consequences of genomic conditions and environments) are not only eminently doable "on the cloud" - but both USDA and OSHA are actually well under way of having implemented (part of) it. Since ALL government R&D (in the USA) is paid from our precious tax-dollars, it is just a simple mandate to issue that any/all government-funded research results pertaining to both "Nurture" and "Nature" aspects of genomics must be uploaded to a government-maintained cloud computing - and made available for US individuals and industries (sorry, not for Countries that don't pay taxes to support such repository of strategic value).
The author of this blog-reply, having decades of experience in Academia, Industry and Government (see bio at http://www.usa-siliconvalley.com) realizes full well that the above might be perceived (and even mis-labeled) as a "pipe-dream", like "the Manhattan Project" could be (wrongly) labeled as the "pipe-dream" of Albert, when he signed Leo's letter to the President Eisenhower on August 2nd, 1939. Yes, the "Plan" received an initial pittance of $4,000 from the Government to get going - but ultimately changed history.
Pellionisz_at_JunkDNA.com
Complete Genomics To Sequence A Million Genomes – CEO
January 26th, 2010 by keith kleiner
“We Are A Data Company” Cliff Reid, CEO Complete Genomics
Without a doubt the hottest company in the genomics sector right now is gene sequencing powerhouse Complete Genomics. In just the last four years the company has come out of nowhere to dominate the market for low cost sequencing of human genomes in large quantities. Although Complete Genomics is now slated to sequence an incredible 5,000 human genomes in 2010, this is nothing compared to what the company has in store for the years ahead. Just days ago, in a Singularity Hub exclusive interview with Complete Genomics CEO Dr. Cliff Reid, we have learned that the company is now hoping to sequence 50,000 genomes in 2011 and a whopping 1 million genomes by 2014. Considering that by the end of 2009 only about 100 or so human genomes had ever been sequenced, most of them by – you guessed it – Complete Genomics, this represents an enormous shift in the industry. In the rest of this post I will share with you the juicy details from the interview, followed by the full video of our conversation at the end.
Although companies like 23andme or Illumina have been hogging much of the headlines in genomics recently, the real story may be that Complete Genomics is about to rewrite the game for the entire industry. Simply put, Complete Genomics is the first company to realize that sequencing human genomes is a brute force computational problem that is best overcome through large scale centralization.
Traditionally if a research team wanted to sequence a human genome they would be forced to purchase expensive machines from the likes of Illumina to do the job. These machines, such as Illumina’s latest HiSeq 2000, might cost half a million dollars or more up front, require the hiring and training of several staff to operate and maintain the instruments, and require several different types of expensive, specialized materials as continuous inputs. What’s more, these expensive and wonderful machines might end up sitting around much of the time unused in between projects. In a world that demands the sequencing of millions of human genomes in the coming years, this model of distributing individual sequencing machines is simply too costly and inefficient.
Enter Complete Genomics: Master of Centralization and Scale
In the next decade we may sequence the genome of nearly every person in the developed world. With 6 billion people in the world and approximately three billion base pairs per genome we are talking about an enormous task of scale and computation. Years ago Complete Genomics realized that centralization in a dedicated sequencing facility was the answer to this challenge. Today they are bringing their vision to reality.
Instead of building individual machines that can be shipped off to laboratories, Complete Genomics is turning the traditional industry model upside down and doing the sequencing itself. Researchers send Complete Genomics a sample of human DNA in the mail, allow them to process it in their sequencing center, and shortly thereafter they will ship back the sequencing results at a cost and speed that is crushing the rest of the industry.
What do I mean by “crushing”? In November of last year Complete Genomics announced that they had sequenced 3 human genomes at an average cost of materials below $5000 apiece, shattering all previous records by nearly a factor of ten! Last year Complete Genomics was charging its customers $20,000 per genome and this year they will be charging $10,000 or less. We can expect the company’s costs and the prices it charges its customers to continue to drop dramatically in the next few years. The $1,000 genome is indeed within sight.
Complete Genomics is essentially turning genomic sequencing into an assembly line process with all of its associated advantages. Equipment can run pretty much 24/7 without interruptions, thereby maximizing the output and return from multimillion dollar investments. A small staff can be trained to run an entire facility of sequencing machines. This significantly reduces the human cost of training and labor. Reagents and other supporting materials can be purchased in bulk on the cheap.
Further streamlining the process and the costs, Complete Genomics is only sequencing human genomes. This is a huge differentiator that people often overlook, yet it is crucial to the competitive advantage of the company. When working with multiple organisms, there are unique factors such as reagents, read sizes, genetic coding idiosyncrasies, and preparation methods that must be accounted for. By focusing solely on human genomes Complete Genomics is further optimizing its operations for low cost and high efficiency.
Although originally slated to go live this January, Cliff Reid says that Complete Genomics’ first large scale sequencing center is now going to launch on April 1. It is because of this delay that Complete Genomics’ is only targeting 5,000 genomes this year instead of its original target of 10,000. Of course 5000 genomes is still nearly 50 times the number of genomes that have ever been sequenced to date by all companies/institutions combined. Not bad!
Can They Really Sequence 1 Million Genomes In 5 Years?
Although Complete Genomics is aiming for 1 million genomes by 2014, we need to take this target with a grain of salt. Given that the company is set to deliver only half as many genomes in 2010 as originally planned, who is to say that their 2014 roadmap won’t fall equally short? Yet to focus on a specific number really misses the point. The key takeaway here is that Complete Genomics is finally ushering in the long awaited era of cheap, high volume genomes through assembly line centralization and scale. The model seems to be a winner, and even if Complete Genomics were to somehow stumble, it is likely that competitors would be quick to follow suit.
A comparison to Henry Ford’s pioneering of the car assembly line with its hugely successful Model T naturally comes to mind, and this is not lost upon Cliff Reid. Ford famously said “Any customer can have a car painted any color that he wants so long as it is black.” In homage to Ford, Reid joked during the interview that “We’ll sequence any organism, as long as its human”. [Talking about Model T-s rolling off from the assembly lines of Detroit - they had to be matched by a network of gas-stations for the sustainability of business - see analysis above - AJP]
United States Today…Tomorrow The World
Over the course of the next year Complete Genomics will be creating plenty of waves in the industry with the world’s first human only large scale sequencing facility here in Mountain View, California. This facility will single handedly sequence on the order of 50,000 human genomes in the next 18 months. Impressive – yes – but to get to 1 million genomes in the next 5 years Complete Genomics is going to need more large scale sequencing facilities. Many of them will need to be in other parts of the world, such as Asia.
Can you say CAPEX? According to Reid, the current plan is to build up to 10 sequencing facilities in the next several years, each of them able to produce anywhere from 50,000 to 100,000 genomes per year. Although increased output and redundancy of operations is a key driver of these added facilities, Reid points out that political jurisdiction is an equally important driver. Governments will be reluctant to see their citizens’ genomic data crossing borders. If Complete Genomics wants to be in the game of sequencing genomes of major countries in Asia they are going to have to go inside those countries to get the job done, and that is indeed where they will go.
More Genomes, More Money – An IPO?
As we can see it is going to take a fair amount of capital for Complete Genomics to pull off its master plan. Last quarter the company secured $45 million in funding despite a very harsh economic environment. Yet this cash infusion is only a temporary measure to get the first facility or two up and running. More money will be needed to realize the company’s vision for ten or more sequencing facilities and 1 million genomes in the next 5 years. As Reid says in the interview “Fast growing companies like ours inhale cash”.
Of particular interest to many following this hot story is whether or not an IPO is in the company’s future. Although legally and strategically we can’t expect Reid to full out confirm an upcoming IPO, he does the next closest thing with the following comment “We also hear rumblings of the public offering market becoming open to certain companies and we would consider that a very attractive option”. Investors get your cash reserves ready – an IPO looks like a strong possibility.
What Will We Do With 1 Million Genomes?
One argument I often hear from people is that all this genome sequencing business is a big waste of time. After all, more than fifty genomes have already been sequenced and what do we have to show for it? Where is the medical revolution that genetics was supposed to unleash? Will there really be a demand for the sequencing of 1 million genomes in the next 5 years even if Complete Genomics can provide it?
Are you freaking kidding me! One million genomes is just the tip of the iceberg folks! Over the next decade or two we will probably sequence tens of millions of human genomes, and – yes – this data WILL be useful.
As with nearly all hot topics of the day – and genomics is no exception – our imaginations have gotten ahead of the technology. The medical revolution promised by genomics will indeed become reality, but it will take many more years than people thought. It turns out that by sequencing only a handful of human genomes there is only so much information that can be learned.
As Reid likes to say, there are only about 1,000 major human diseases out there. One million sequenced human genomes will allow us to study the genetics of each of these 1,000 diseases, each with a pool of 1,000 genomes for comparison. The information that will be teased out of this data will indeed produce the medical revolution that we have all been waiting for, but first we need tens of thousands of genomes to perform the required analysis. We need the data!
We Are A Data Company
One of the things I love most about Complete Genomics is their laser focus on doing only one thing: sequencing human genomes. This extreme focus on doing one thing well has been a proven secret to success for many of the world’s greatest companies. It will be no different with Complete Genomics.
Rat genomes, worm genomes, and the genomes of countless other organisms will need to be sequenced in the coming years, but Complete Genomics is going to ignore those. As Complete Genomics comes to dominate the market for human genome sequencing in the next several years, it may be the sequencing of non-human genomes that will provide a still enormous market for the Illuminas of the world. It is great when a field is so large that there is enough room for pretty much everybody to win. Genomics is one such field.
In the end Complete Genomics is a data company. Their gift to the world in the next several years will be to deliver the vast store of data that is locked within the individual genomes of each of us. Understanding this data, and converting this understanding into real world medical solutions, however, is not Complete Genomics’ game. They will leave that task to other companies. Complete Genomics is not the company that will directly give us the medical revolution that we have been waiting for, but indirectly their role is equally important. They are giving us the data.
But Who Are The Customers?
Although it is exciting to think of average citizens purchasing their genomes directly from Complete Genomics, at least for the next two years Reid explains that the real demand will come from research institutions and corporations. These organizations have the budgets, not to mention the desire to discover the next big medical breakthrough, to justify the purchase of thousands of genomes from Complete Genomics. Individuals will indeed be able to purchase there own genomes in the future, but at least for the next 2 years individuals will not be the key driver in this business.
The end of the deCODEme personal genomics service? [with comment -AJP]
Posted on: February 14, 2010 9:45 AM, by Daniel MacArthur
This piece in Newsweek is a neat summary of the rise and fall of Icelandic genomics giant deCODE Genetics. Regular readers of Genetic Future will be aware that the company has been steadily bleeding capital ever since its launch over a decade ago, and recently declared formal bankruptcy. Since then the company has been bought up by US-based company Saga Investments. (For an excellent analysis of the implications of this sale, see Dan Vorhaus' post on Genomics Law Report.)
A reader emailed me to point out that buried towards the end of the Newsweek article is an ominous paragraph for customers of the company's personal genomics arm, deCODEme. Despite earlier promises that the personal genomics service will be continued, the article gives the strong impression that the days of the service are well and truly numbered:
A few weeks ago, meeting with Stefánsson in Boston, he proved his point. The two were mulling the fate of deCODEme, the consumer diagnostic test. Stefánsson said he still hoped to be "very modestly marketing" the test as of next year. Collier raised his eyebrows and said, "If you want one, you'd better buy it now." In other words: forget it.
The loss of deCODEme would mean the end of one of the "Big Three" personal genomics companies out there right now; and there are also increasing signs of financial strains on the other two competitors (23andMe and Navigenics). It looks as though 2010 will be a year of turnover for the industry, as some of the early players are replaced by newcomers offering quite different services and business models (such as the extensive carrier testing offered by the recently launched company Counsyl).
What will happen to the customer data generated by deCODEme if the service is abandoned? No-one knows for sure, but those interested in this question should revisit the excellent posts by Dan Vorhaus and Lawrence Moore on this topic
---
[comment by AJP on February 15, 2010]
The end of the (deCODEme) personal genomics service excellent entry is actually a double question (when parentheses are used).
I would refrain from commenting on the "end of deCODEme" as a single company, even if it was the first, and part of the "top three".
Daniel McArthur (and just about everyone) point out that survival of any DTC hinges on a better business model. As such, the other leading two (Navigenics and 23andMe) are no different. Their "growth pains" are substantial, e.g. the inevitable upgrade from microarrays, interrogating the tiny (up to 1.6 M bases out of 6.2 Bn bases) "SNP-tests", towards a targeted (algorithmic) search for structural variants over the affordable full human DNA are contingent only on time/money (to the extent that they are convertible, with limitations). Organizational issues are also very frequent and are eminently solvable.
The key questions are, therefore, if genomic testing service has a future at all - and if yes, what is the business model that will sustain it.
Francis Collins' book, fresh off the shelves, "The Language of Life - DNA and The Revolution in Personalized Medicine" effectively and definitely answers the naysayers. Futurists who may still voice their doubts about the future of genomic testing simply have not done their homework. Most likely did not get a chance yet to read Chapter I., page 1. of the [above] book with the title "The Future Has Already Happened".
In all fairness, those behind the curve lag only a few months, perhaps up to two years. The book appeared early this year, and as we learn on page 84 Francis Collins in 1996 "found the idea of direct-to-consumer genetic testing completely unimaginable in my lifetime". Moreover, his turn-around only happened a mere two years ago (page XVII)- and the final conviction (as usual) was due to his own genomic testing by all three companies last Spring. Proclivities found were in line with his family history (as far as elevated risk for macular degeneration was concerned), but did not apparently occur in his family (as far as diabetes type II is concerned). Dr. Collins, an MD/PhD, head of NIH, immediately went on prevention program for both, modifying his diet, body weight (visible on his before and after portraits), etc; he apparently found DTC results "actionable". Conclusion of his chapter "So Personal Genomics is here..." reads "Given the early stage of DTC genetic testing, there are [those]...arguing that it is premature for this kind of information to be made available for consumers. I am not one of them" (pp. 89)
The "open question" remains, therefore, in what business model can such testing pay for itself in a manner (like the first rudimentary OS; "DOS", followed by "Apple OS" and "Windows" and killer apps) promising a hyper-escalation in a business sense.
One of the answers is given by (full disclosure; my new venture) HolGenTech, see YouTube where the heretofore "open" DTC-loop (not closing on empowerment of consumers) becomes a "closed business model" by both tooling up consumers for personal and participatory prevention programs, as well as providing interoperability of their genomic- and health-data, all overridden by their personal preferences.
pellionisz_at_junkdna.com
Art Communicates Better than Science ...
The significance of recursion ("regulatin genes") gets over 100,000 views well within a single year of a rap by Stanford Students how "regulatin genes is crucial for development" . For a stunning visual presentation how simple rules through constant recursion generate utterly complex results, see this YouTube: The Secret Life of Chaos Part (5 - 6) [The original BBC video has been withdrawn]:
http://www.youtube.com/watch?v=wc0IYJm5-mE
:
Simple rules generate fractal complexity [also true for DNA, see FractoGene]
Looking at the 100,000+ views in less than a year it should be clear that "regulating genes is crucial for development". Looking at the utterly convincing case that nature's geometry is fractal, the notion of FractoGene (Pellionisz, 2002) that fractal DNA governs development of fractal organelles, organs and organisms becomes "obvious".
The Principle of Recursive Genome Function Blogged by a Software Developer
Thomas Kuhn's classic book on "The Structure of Scientific Revolutions" expects naysayers at every paradigm-shift. Accordingly, PRGF had its own share. Lately, however, some refreshing appreciation make PRGF almost "obvious" - how come I did not think (or write...) the article?
Here are some screenshots from a fresh one. It is free to visit, have to register only if you want to rate, comment the entry. For full coverage with proposed extensions, see the blog here, and the full free paper here.
[See more on the blog, and beyond the dry science paper see YouTube explaining it in 58 minutes and YouTube featuring a practical application in 7:44 minutes - Pellionisz_at_JunkDNA.com]
Procter and Gamble Invests in Navigenics
By Bio-IT World Staff
February 3, 2010 | Navigenics has raised approximately $18 million of funding thanks to the addition of Procter and Gamble to its existing portfolio of investors.
“I welcome the partnership of Procter and Gamble," said Vance Vanier, Navigenics President and CEO, in a press release today. "Their extraordinary track record of consumer understanding provides Navigenics with an unparalleled opportunity to understand and serve the needs of our customers. When combined with their commitment to developing innovative consumer health and wellness products and an expanding focus on health services, P&G’s insight and brand will strengthen Navigenics’ position to embed personal genomics into the prevention dialogue of everyday health care.”
“Navigenics represents an exciting opportunity for future innovation for P&G,” said Nathan Estruth, Vice President of Procter & Gamble FutureWorks and board member of MDVIP, a national network of primary care physicians focused on personalized, preventive care. MDVIP has initiated a collaborative effort with Navigenics, making their genetic test available as a service to MDVIP-affiliated physicians. “Based on their strong science and clinical foundation, Navigenics promises to change the shape of health care as we know it. Personalized genetic testing can have significant meaning in helping consumers focused on prevention and wellness live better, healthier lives – something that P&G has always been committed to.”
“This Series C financing will help ensure that Navigenics has the ability to continue our groundbreaking research into the impact of genomics on preventive health care, expand our clinical offerings into exciting new areas and lead the way in making personal genomics an integral part of employer-sponsored preventive health and wellness programs,” said Vanier.
Kleiner Perkins Caufield and Byers and Mohr Davidow Ventures who also participated in this financing round.
[I commented on my FaceBook page on the fast-breaking news that Procter and Gamble just invested in Navigenics. Last May, at "First Ever" Consumer Genetics Conference in Boston, HolGenTech introduced the "shopping for consumer products by Personal Genome Assistant barcode system", using 2 pairs of products for genomic preference preference (all from Procter and Gamble…) Meanwhile, DTC was “blessed” by Francis Collins (NIH Chief) in his book. Maybe time to peek into YouTube “Shop for Your Life” (below) as it appears in the immediate future. See below “Boonsri Dickinson”, played by an actress, holding “The Language of Life” book by Francis Collins, and explaining how Dr. Collins’ DTC testing resulted in his immediate decisions to improve his consumer choices. – Those whishing to comment may do so in the FaceBook of “Andras Pellionisz” or drop an email Pellionisz_at_JunkDNA.com .
Once the underlying science was accepted at Cold Spring Harbor without a single word of opposition, that Proteins are NOT the "dead end" of DNA>RNA>PROTEIN "straight arrow dogma" but "The Principle of Recursive Genome Function" supersedes obsolete dogma and immediately opens up specific applications, the blogosphere responds differently, too. Though it might require your registration, one can ponder over pages after pages of appreciation here - thanks for the analysis!]
Genomic Advances of the 2000s Will Demand an Informatics Revolution in the 2010s
Xconomy
January 14, 2010
Eric Schadt 1/14/10
We have witnessed some of most striking technological and scientific innovations in humankind during the first decade of the new millennium. While such claims perhaps seem cliché in an age where the media constantly report on new findings that really do not warrant our full attention, several discoveries and innovations in the recent history of genomics were truly groundbreaking and will have long-lasting implications.
The expanding applications of genomic technology that will help us better understand causes and treatments of common human diseases, global warming, and hunger will become clear in the coming decades. The innovations most impressive to me in the past decade were those that have begun to shake many of the foundations upon which the life sciences and biomedical research have been built. Here are what I consider four of those more impressive discoveries:
1) The discovery that environmental stress can induce heritable DNA-based changes.
2) The maturation of highly parallel sequencing and genotyping technologies that have revolutionized our ability to associate changes in DNA with disease.
3) The discovery of whole new classes of RNA that do not carry out instructions from genes, yet are still critical to cellular and higher order biological processes.
4) The development of third-generation DNA sequencing that will lead to greater insights about underlying biology.
As our ability to capture data from entire genomes increases exponentially, this is creating a huge software and computing challenge. Life sciences and biomedical researchers will need novel solutions (a yet to come fifth innovation):
5) The translation of the deluge of data coming from the new discoveries and technologies into actionable results that can impact human wellbeing.
This will be a big trend to watch in the coming decade, but more on that later. First, I want to explain a little about why I’m singling out these four particular discoveries and technologies as groundbreaking:
1. Environmental stresses can induce heritable DNA-based changes.
In 2005 Michael Skinner, a professor at Washington State University, published a paper in Science demonstrating that in response to exposure to an endocrine disruptor (a common environmental toxin), DNA can be chemically modified in certain locations and that these modifications can affect the ability of the biological machinery within the cells in every bodily organ to read the modified DNA. Reading DNA is a necessary first step for cells to manufacture the proteins needed to drive normal biological processes. Chemical modifications of DNA induced by environmental toxins have been shown to influence many of the common human diseases that are of significant public health concern today, such as type 2 diabetes and cancer.
While this finding on its own was not so surprising, the astonishing observation was that these chemical modifications to DNA can be transmitted to subsequent generations, even after exposure to the agents inducing the changes were stopped. Skinner later demonstrated that these types of environmentally induced changes could affect fundamental behaviors like mate selection, demonstrating a potentially more rapid evolutionary selection mechanism that does not require mutations in the actual DNA sequence.
A recent related discovery published in Nature by Decode Genetics, an Icelandic company that has helped lead the way in establishing how changes in DNA associate with disease, demonstrated that mutations in the sequence of DNA that are inherited from, say, a mother, can have very different consequences relating to disease risk and progression than the very same mutations inherited from the father.
2. Highly parallel sequencing and genotyping technologies have revolutionized our ability to associate changes in DNA with disease.
The maturation of second generation, highly parallel DNA sequencing and genotyping technologies, along with the completion of the sequencing of the human genome, has enabled an astonishing wave of discoveries about how the specific forms of DNA inherited from our parents can cause disease or differences in our response to treatments. While hundreds of examples of rare, single gene mutations in our DNA that cause disease have been discovered over the past 30+ years, finding common changes in DNA that affect our risk of disease turned out to be incredibly difficult. Before this past decade, only a handful of examples of genetic risk factors existed for common human diseases. However, technologies able to fully characterize all of the common DNA variation in the human genome at lower cost have dramatically increased the number of causal genes identified. Scientists now have catalogued nearly a thousand genes in which common DNA changes affect the population risk of more than one hundred different disease associated phenotypes, including those associated with type 2 diabetes, heart disease, multiple different types of cancer, arthritis, Crohn’s disease, schizophrenia, and Alzheimer’s disease, as well as other human traits like height, eye color, and hair color.
While this wave of discovery has been truly impressive, few of the DNA changes were found to directly affect the function of proteins directly implicated in diseases like Alzheimer’s. In fact, most changes in DNA associated with common human diseases appear to be affecting the rate at which genes represented in the DNA are transcribed into RNA and then translated into proteins (as opposed to directly affecting the function of the protein). Further, these findings actually turned out to explain very little of the disease variation in the human population. That is, while these DNA variations were associated with disease, they were unable to explain very appreciable amounts of the overall disease variation in the human population. This has prompted a new search in the life sciences for the “missing heritability” relating to human disease. Given the low percentage of variation explained by common, simple variations in DNA, the hunt is on for other types of variation (including the environmentally induced changes mentioned above) that had not been thought to play a key role in disease, but that now may represent some of its significant explanations.
3. Whole new classes of RNA discovered to be critical to cellular and higher order biological processes.
Emerging from recent genetics research is a greater appreciation that in order to understand and treat disease, we will need to fully characterize the role that whole new classes of non-coding RNA discovered over the last 10 years play in biological processes. While non-coding RNAs like ribosomal RNA were discovered long ago and shown to be responsible for translating protein-coding RNAs into protein, completely new classes of non-coding RNA have been discovered that are widespread and have been shown to have regulatory roles for entire networks of genes associated with disease. In fact, one particular class of non-coding RNA known as microRNA has not only been well demonstrated to affect processes that cause disease, but is now being pursued as a way to treat it as well. Despite hundreds of thousands of copies of some microRNAs existing in our cells, it was not until this past decade that we discovered these molecules and their effect on critical biological processes.
4. Third-generation DNA sequencing will enable greater insights about underlying biology.
Technologies brought to market in the last decade have enabled amazing discoveries, but they have also shed light on how much we still don’t know and need to learn in order to develop more effective strategies for preventing and treating disease. In order to truly make a difference to improving patient care, scientists need access to fast, accurate and comprehensive snapshots of the underlying biology of living systems. One of the more impressive technologies developed this past decade toward this end was single molecule, real time (SMRT) sequencing.
SMRT sequencing was invented by a group of scientists at Cornell University and is now being developed and commercialized by Pacific Biosciences (a biotechnology company formed by Stephen Turner and some of his colleagues from Cornell University, which I joined this year as chief scientific officer). The technology employs waveguide transmission below cutoff technology to directly observe the activity of DNA polymerase as it sequences DNA. This technological advance enables the observation of nature’s own amazing sequencing engine as it very rapidly sequences DNA. Observing DNA polymerase as it sequences DNA stands in contrast to the heavily engineered second generation systems that have relied on brute force approaches to sequencing rather than nature’s own highly evolved and efficient approach.
SMRT sequencing will enable sequencing of an individual’s complete DNA sequence very quickly and for little cost over the next decade. For example, current technologies take roughly one hour to sequence a single letter from a fragment of DNA, whereas SMRT sequencing can sequence roughly 20,000 letters of the fragment in the same period of time. The system has been designed to observe many of these DNA polymerase molecules at the same time, sequencing many fragments simultaneously, which will ultimately enable the observation of hundreds of gigabases of DNA per hour. This level of unprecedented speed and efficiency in genome sequencing is expected to finally make personalized medicine a reality.
5) Needed: Informatics innovation to translate the data deluge.
Third-generation technologies will enable sequencing every individual in large populations and that will create unprecedented amounts of data, rivaling all other areas of science with respect to quantity and complexity. So the real challenge in the next decade will be informatics based. How will petabyte scales of complex data be managed and integrated so that predictive models of disease can be constructed and routinely applied? While companies like Google routinely play in the space of petabyte scale data sets, the problem they have solved is far simpler than understanding how all DNA variations, RNA levels and isoforms, metabolites, and proteins interrelate to one another across all of the different environments that give rise to life.
Only by marrying information technology to the life sciences and biotechnology will we realize the astonishing potential of the vast amounts of biological data we will be capable of generating. Such data, if properly integrated and analyzed, will enable personalized medicine strategies that lead to every one of us making better choices on how we not only treat disease, but prevent it altogether.
Eric Schadt is chief scientific officer of Pacific Biosciences, and a consultant to Sage Bionetworks, a nonprofit organization that aims to start an open source movement for genetic data.
[A strikingly similar view was advocated in YouTube - Pellionisz_at_JunkDNA.com]
Fractals and DNA - The Old, the Young and the Ugly
Some notes may be helpful amidst the new “Fractal Frenzy”.
While some of us focus on making “Personal Genome Computing” immediately useful for consumers through the very visible “Personal Genome Assistant” (See YouTube PGA), HolGenTech maintains that the “Personal Genome Computer” needs an algorithmic approach to understanding recursive (fractal) genome regulation.
According to FractoGene (2002) the basic tenet is that “fractal DNA governs fractal growth of organelles, organs and organisms”. The basic insight was provided in 1989 by the “Fractal Model of the Purkinje Brain Cell” – suggesting an at that time doulbe-heretical notion of recursion of protein information to the repository of auxiliary DNA information (formerly “Junk DNA”).
The latest round was blown open by the paper I dubbed “Mr. President, the DNA is Fractal” – the cover article I often refer as by “Eric Lander et al., 2009” (Science 326, 289 (2009); Erez Lieberman-Aiden, et al. Human Genome Interactions Reveals Folding Principles ...). Lately, even Jean-Claude Perez of France threw his hat into the ring with reference to his early work on Fibonacci-numbers in DNA quoted in French in his 2009 book.
For the “Old” part, the masterful article quotes on Science cover the Hilbert-curve (1891), to make a point that what Benoit Mandelbrot coined as “fractals” in his book “The Fractal Geometry of Nature (1977) has long existed before – indeed, it could be what Francis Collins calls “God’s language” (the DNA and mathematics) existed from the beginning of evolution. The paper makes tangential reference to the origin of their core-concept by Alexander Grosberg et al. (1993) or even to their earlier paper in 1988. As elaborated by this author in a joint paper with Dr. Simons (2006), the wave in the past century of “DNA and fractals” roughly coincided with the Buldyrev et al. paper (with Eugene Stanley) in 1993 and Mantegna et al (1993) – with Flam (1944) short paper in Science (1944), risking a patently arbitrary breakdown of non-coding DNA into “words” of 3-8 A,C,T,G bases, and based on an arbitrary premise hinting “a language in junk DNA” (1994). Because of their arbitrary premise, that wave could be shot down by Bonhoeffer et al (1997), “No signs of hidden language in noncoding DNA”.
It is noteworthy that Mandelbrot’s classic book (1977) at the very same time re-ignited the “fractal notion” by his musing in the book that “the Purkinje brain cell may be fractal”. This was taken up by my actual fractal model (1989), with the heydays of our paradigm-shift from “AI to Neural Networks”. Since all neural net algorithms including mine in Tensor Network Theory were recursive, I was truly astounded by the rigidity of the wall of the mostly not very mathematically minded NIH establishment at that time, with my “double heresy” of not accepting either the falsehood of Crick’s “Central Dogma” (forbidding recursion) and Ohno’s “Junk DNA misnomer” (that would render such recursion useless if 98.7% of non-genic DNA were truly what he mislabeled as “Junk”).
Though the establishment inflicted unbelievable (well documented) harm on me, I was unshaken and proceded by my scientific conviction. First “connected the dots” that the fractality of DNA is the basis of fractal growth in biology (FractoGene, 2002) – and emboldened by experimental evidence in support (Simons and Pellionisz, 2006) and by the release of ENCODE results, rendering “Junk DNA anything but junk” (2007) I again, now publicly “connected the dots” by The Principle of Recursive Genome Function and subsequent Google Tech Talk YouTube for the world (both 2008). Further, once the first author of the paper “Eric Lander et al., 2009” made his public speech (see below), I could present the scientific underpinning of my fractal approach by showing at Cold Spring Harbor (2009) that an entire DNA complies with the “Zipf-Mandelbrot Fractal Parabolic Distribution Curve” – when the “words” are not arbitrary, but are “Pyknon-like short repeat elements”.
So this is the “Old”. Where is the “Young”?
Before we answer that meaningful question, let’s put a side-issue, nothing but noise, to rest:
Where is the “Ugly”?
Gone with the wind. Though in complience with Thomas Kuhn’s “Structure of Scientific Revolution” naysayers must be expected in every paradigm-shift, at this point true scientists frankly don’t give any consideration to dense minds who might be petrified that their expertise in biochemistry killed all their comprehension of advanced abstract thinking - and thus might convert their profession to baby sitting to their grandchildren. (Baby Zoe does not look “full of Junk” as her Lonely Moron grand-dad is likely to remain, for the rest of his life, hallmarked by habitual intolerance and the lowly darkness of ad hominem attacks).
For the “Young”,
while I quote their landmark paper “Eric Lander et al.” – since among the 19 authors (from Boston and Seattle), as the Director of the Broad Institute as well as a Science Adviser to the President of the US Dr. Lander is unquestionably the strongest authority to have delivered the message “Mr. President, the DNA is Fractal!”, the first author is grad-student Erez Lieberman-Aiden with his spectacular youth. With immense forces behind him, the straightforwardness of his Cold Spring Harbor is astounding – clearly he does not have to even consider that his NIH or other supporting grants would be recalled:
Hi-C Talk by Erez Lieberman-Aiden at Cold Spring Harbor Laboratory from Erez Lieberman on Vimeo.
Viewing his video, it is remarkable that the findings of the structure (folding) of DNA into tiny chromosomes actually happens in a way that the folding is ultra-dense yet linearly very remote parts of the DNA-strand can be functionally neighbors. For the mathematically minded (like Eric Lander with his first degree in mathematics) the conclusion and the message to the President is that the folding is consistent with the Hilbert-curve (after coining the word “fractal” acknowledged as an early fractal paradigm), Erez Lieberman-Aiden shows the word that he could talk biology not once mentioning the word “fractal” (the “dirtiest” word he used was “eigenvector”).
Contrary to paralyzing fears of old and rigid minds, “biochemistry is not dead” – and in fact can be looked from the very refreshing new angle of “genome informatics” by the flood of young, willing, able and available.
The Potential Of Personalized Medicine
Life Science Leader, February 2010
Written by: Cliff Mintz Ph.D.
Personalized or individualized medicine is the latest life sciences innovation that is poised to transform medicine and delivery of healthcare to patients. While some describe personalized medicine as a technology of the future, others contend that personalized medicine is already influencing and having an impact on the way patients are being treated today.
Generally speaking, most experts agree that the era of personalized medicine began in earnest in 2003 after sequencing of the human genome (and publication of a genetic map) was completed by the U.S. Department of Energy and the National Institutes of Health. Prior to 2003, physicians and healthcare providers primarily relied on patients’ memories and family histories to assess personal disease risks. Now, advances in genomics and bioinformatics are revolutionizing science and allowing consumers to acknowledge disease risk factors more accurately, pursue appropriate treatment options, and possibly maintain better health.
Access to the entire human DNA sequence has allowed investigators to begin to identify: 1) genetic defects and gene polymorphisms associated with disease initiation and progression, 2) effectiveness of specific treatment regimens, 3) predictions of patient drug responsiveness and clinical outcomes, 4) likelihood of adverse events and tolerability issues with certain drugs, and 5) fine tuning of dosing requirements. Activities linking the performance and pharmacology of drugs with genomics is collectively known as pharmacogenomics. Pharmacogenomics introduced the concept of using molecular markers (biomarkers) to assess drug efficacy and safety and the risk of disease — or its presence — before the appearance of clinical signs and symptoms.
While Ray Woosley, M.D., Ph.D., president and CEO of the Critical Path Institute, agrees that recent advances in pharmacogenomics may have accelerated interest in personalized medicine, he warns that patients’ needs — not science itself — should drive the adoption of personalized medicine. “There is no question that exciting changes are under way,” he said. However, he added, “I think the science is moving much faster than medical practice at this point. Personalized medicine isn’t going to happen overnight; we are currently experiencing a scientific logjam of sorts. I think a carefully planned scientific and regulatory-compliant approach is warranted before personalized medicine is fully embraced and adopted by the healthcare community.”
What Is Personalized Medicine?
The term personalized medicine is frequently bandied about in both scientific and lay literature, but its precise definition has been elusive. An April, 2008 article in the U.S. News and World Report defines personalized medicine as “a young but rapidly advancing field of healthcare that is informed by each person’s unique clinical, genetic, genomic and environmental information.” Similarly, a description of personalized medicine on the Personalized Medicine Coalition’s website suggests that it “uses new methods of molecular analysis to better manage a patient’s disease or predisposition to a disease.”
In contrast, Critical Path’s Woosley contends that while molecular testing and pharmacogenomic analyses may be important, they aren’t always the most critical aspects of personalized medicine. “High tech solutions aren’t always the answer. Sometimes the most important part of personalized medicine — the patient — may be overlooked or, in some instances, left out of the equation,” he said. “Integration of clinical findings and results from pharmacogenomic analyses will be required before the full benefits of personalized medicine will be realized.” Nevertheless, there is general consensus among scientists, healthcare providers, and patient advocacy groups that personalized medicine will help to improve patient health outcomes in the future. To that end, personalized medicine is likely to have a major impact in three primary areas: 1) determining the safety and efficacy of an experimental new drug prior to regulatory approval, 2) establishing an individual’s genetic predisposition to certain disease states, and 3) identifying possible adverse drug reactions and tolerability issues in large patient populations.
The Promise
Despite some recent advances and early successes, the field of personalized medicine is still in its infancy. While most Americans have already heard about the promise of personalized medicines, there are only a handful of commercially available products on the market today. Nevertheless, Michael Cantor, director of healthcare informatics at Pfizer, and Cecelia Schott, personal healthcare manager at AstraZeneca, believe that personalized medicine will benefit physicians and patients alike. Some of the likely benefits include:
• improved ability of physicians and patients to make informed medical and healthcare decisions
• selection of optimum treatment regimens and a reduction in trial-and-error prescribing practices
• safer dosing options
• reduced probability of negative drug side effects and tolerability issues
• a shift in emphasis to disease prediction and prevention rather than a reaction to it
• better diagnoses and earlier, more effective disease intervention
• reduced healthcare costs and medical expenditures.
The therapeutic areas most likely to benefit from personalized medicine include oncology, cardiovascular disease, neurodegenerative disease, psychiatric disorders, and metabolic diseases such as diabetes and obesity. “Things are advancing most rapidly in cancer diagnostics and treatment option determinations,” said Pfizer’s Cantor. “The greatest challenge we face in personalized medicine is determining whether or not the tests we are developing will have a clinical impact or provide patients benefit,” he added.
AstraZeneca’s Schott agrees that the field of oncology will greatly benefit from personalized medicine. She also contends that infectious diseases are another area likely to benefit from advances in personalized medicine. For example, AstraZeneca is currently developing a diagnostic test to identify patients with bacterial infections who may be at risk for developing sepsis, a disease that has mortality rates approaching 90%.
In addition to potential medical and clinical benefits to patients, many drug makers believe personalized medicine will help expedite the time required and reduce the costs associated with new product development. Pfizer’s Cantor offered, “Many of our products in development have a biomarker strategy and plan associated with them. This is necessary because many new drugs in the future will likely be packaged with companion diagnostic tests to determine the safest and most effective treatment options and to optimize dosing.” AstraZeneca’s Schott concurs and suggested that many of her company’s oncology drugs in development will likely be commercialized with companion molecular diagnostic tests.
Recent reports estimate that, on average, newly approved drugs work for only 50% of the people who take them. By using pharmacogenomic data about a new molecular entity and corresponding information about how patients’ genes may affect drug responsiveness, drug makers may be able to identify subsets of clinical trial participants who are most likely to respond or least likely to experience side effects. This would likely reduce the number of patients required to conduct clinical trials, which in turn would reduce the time and costs associated with garnering regulatory approval. While this may be a boon to drug manufacturers, patient advocacy groups argue this approach may limit and hinder new drug development to only molecularly well-characterized diseases. “Not so,” said Pfizer’s Cantor. “In the not-so-distant future, personalized medicine will be necessary to differentiate one company’s product from another in smaller patient populations and markets. The ability to compete in smaller, competitive markets will likely, in turn, foster new drug development in specialty areas including orphan diseases. Also, personalized medicine will allow companies to demonstrate that the products they develop have a clear clinical impact on the patients who use them. This will be necessary to justify premium prices and reimbursement costs for news products.”
Moving Toward Commercialization
The results from the human genome project indicated that humans possess 20,000 to 25,000 genes. To date, over 1,500 disease-related genes have been discovered. At last count, an estimated 1,300 genetic tests exist for conditions ranging from hearing loss to sudden cardiac arrest.
A recent report by PricewaterhouseCoopers predicts that the personalized medicine market for pharmaceutical, medical devices, and diagnostic companies is expected to grow 10% annually and reach $42 billion by 2015. However, in the past five years, about 10 personalized medicine tests have won regulatory approval in the United States and elsewhere. Of interest, most of these tests were developed in the areas of oncology, cardiovascular, and infectious diseases.
Most experts agree that the “poster child” of personalized medicine is the HER-2 gene, which produces a protein that causes a form of breast cancer. If a woman tests positive for the HER-2 gene, she is a good candidate for treatment with Herceptin, a breast cancer drug developed by Genentech. Herceptin treatment has been shown to reduce the risk of recurrence of HER-2 positive breast cancer by almost 50%. Similar diagnostic tests used to determine the effectiveness of certain treatment regimens have been developed for other oncology drugs, including Gleevac (chronic myeloid leukemia), Iressa (nonsmall cell lung cancer), Rituxan (non-Hodgkins Lymphoma), and Camptostar (colorectal cancer). A new diagnostic test is also in the works for another colon cancer drug called Erbitux.
Researchers also have found that two genes can affect how patients respond to the widely used anticlotting drug warfarin. Determining the appropriate treatment dose of warfarin is extremely challenging, and the test was developed to help fine-tune dosing regimens. However, while the test may have helped to improve warfarin dosing in some cases, there is still limited data on whether or not it has led to improved safety and efficacy. And, perhaps more importantly, even with the test, about 45% of the variability in responsiveness to warfarin remains unexplained and is likely due to other factors, including diet, exercise, and patient compliance (taking the medication).
Roche Diagnostics recently developed an FDA-approved diagnostic that assesses the level of activity of a person’s drug-metabolizing cytochrome P450 (CYP450) enzyme system. CYP450 enzymatic activity is known to affect the effectiveness of certain medications, most notably, antidepressants and cardiovascular drugs. The test allows physicians to fine-tune drug dosing based on a person’s metabolism rather than cruder indicators such as body weight or body mass index. However, like the warfarin test, it isn’t clear whether or not the CYP450 diagnostic is any better than trial-and-error with regard to clinical utility. Another new molecular diagnostic test was developed for Ziagen (abacavir), a drug used to treat HIV infections.
Although abacavir is an effective treatment for HIV, one of its main drawbacks is the risk of a hypersensitivity reaction, which has been reported to be fatal in some instances. Recently, a predictive test, based on the relationship of abacavir sensitivity with the human leukocyte antigen allele HLA-B*5701, was developed to reduce the incidence and risk of adverse events among patients taking abacavir. This test is now widely used to determine whether or not abacavir should be used to treat individual HIV-infected patients.
Despite these early successes, Pfizer’s Cantor cautions that personalized medicine may not make sense for drugs in all therapeutic areas. “Only tests that are likely to have a clinical impact on prescribing habits, treatment selection, and patient safety ought to be developed,” he said. Cantor added, “I think it makes sense in the oncology area but do we really need a test to help to determine the correct dosage for a statin?” Critical Path’s Woosley echoed similar sentiments. “There is no question that some of the new biomarker tests are worthwhile,” he said. “But, much more work needs to be done to verify and validate the relationship with certain biomarkers and diseases before tests are ultimately commercialized and used in clinical settings.”
What’s In Your Genome?
Completion of the human genome project and advances in automated DNA sequencing and analysis have given rise to so-called personal genomics companies such as 23&Me and Complete Genomics. These companies provide direct-to-consumer (DTC) genetic analyses services to individuals interested in learning more about their genetic makeup or ancestry. While these companies — also known as personal genomics companies — currently don’t offer whole genome DNA sequencing services, many industry experts believe it is only a matter of time before they become available. To that end, Complete Genomics recently announced it expects to be able to sequence an entire human genome for $5,000 or less by the end of 2010!
Alan McHughen, Ph.D., a faculty member at the University of California-Irvine and personalized medicine advocate, has “no doubt that whole genome sequencing will be used and useful for people.” But he worries that lay consumers don’t truly understand the implications of the personal information contained in their DNA and is concerned about access and privacy issues for whole genome sequence data. “If I donate or pay to have my DNA sequenced, and the data is subsequently used for beneficial purposes, then I have no problem. However, if that data is inappropriately shared, misused, or stolen, there may be serious personal consequences for individuals who provided their DNA,” he warned. Others worry that the DTC genome analysis trend may lead to unnecessary medical interventions, possible false assurances, and missed diagnoses in patients. Because the clinical value of most personal genomics tests remains unproven, most personalized medicine experts agree that additional research will be necessary to assess their predictive value and potential to improve the use of clinically effective interventions and therapies.
The Five Challenges To Personalized Medicine
There is no question that personalized medicine has the potential to revolutionize medicine and transform healthcare. However, before the full potential of personalized medicine can be realized, there are several formidable challenges that must be overcome. First, while there is little doubt that some of the new molecular biomarker tests are worthwhile, many potential biomarkers have yet to be verified and qualified for use in personalized medicine products. According to some estimates, there currently may be as many as 200 molecular biomarkers in various stages of commercial development. Woosley and other experts believe the real challenge of personalized medicine is finding relevant biomarkers and then matching them with an actual medical condition of interest. To that end, the Critical Path Institute submitted and received FDA approval for use of seven biomarkers in a variety of therapeutic areas. Woosley indicated that the Institute will submit FDA applications for 18 new biomarkers (including several for Alzheimer’s disease) later this year. Nevertheless, other biomarker researchers contend that more than half of the published biomarker studies have been compromised by factors such as sex and age mismatches of sample donors and variations in the handling and storage of donor samples. “Despite the hype and all of the promises that have been made, much work needs to be done before personalized medicine can be fully realized,” said Woosley.
Second, despite approval of a handful of personalized medicine diagnostic tests, the FDA has yet to clearly define a regulatory approval pathway for this new class of products. Although the agency has been collecting biomarker data for the past five years or more, it has yet to issue useful guidance on the subject. This means that each regulatory submission for a personalized medicine product is handled on a case-by-case basis by regulators. This process is time-consuming, labor-intensive, and costly. Further, industry insiders and personalized medicine advocacy groups contend that FDA regulators lack the knowledge and training to critically evaluate prospective new personalized medicine tests. Further, many believe that the agency’s personalized medicine program is grossly underfunded and understaffed. According to Woosley, more than $1 billion has been budgeted for a personalized medicine program at the European Medicines Agency, whereas only $18 million was allocated for a similar program at the FDA.
Despite the problems at the FDA, several important regulatory questions pertaining to personalized medicine must be addressed in the near future. For example, a pressing question is how narrowly should clinical trials be designed to include/exclude trial participants based on the results of certain genetic screening tests? Another question pertains to whether drug efficacy and safety are defined in different ways for different genetic subgroups within patient populations. Finally, FDA regulators must craft a clearly defined and interpretable regulatory framework for the validation and verification of molecular biomarkers.
Third, the success of personalized medicine is contingent upon the ability of scientists and healthcare providers to capture, manage, store, and provide access to large amounts of data and medical information. This will require the use of high-speed computer networks and large databases composed of electronic health records (EHRs). At present, most medical records in the United States are almost exclusively paper-based. While billions of dollars of U.S. stimulus funds have been allocated to convert paper records into EHRs, no consensus has been reached on software standards that will be used to create, store, or share EHRs. Further, linking clinical data and genomic data sets is likely to present formidable integration challenges, and superimposing treatment algorithms on this data may be even more daunting. Consequently, it will be difficult to begin to practice personalized medicine on a large scale (despite a growing number of commercially available tests) until the software standards are adopted and the supporting IT infrastructure is better defined and constructed.
Fourth, in order for personalized medicine to succeed, healthcare providers, patients, and insurers must learn how it works. This will require substantial sums of money to develop instructional materials, continuing medical education programs, and public outreach campaigns. At present, it isn’t clear how these programs will be funded or whether or not government, medical organizations, private sector companies, or academic institutions will assume responsibility for training and educational initiatives.
Finally, and perhaps most importantly, there are many privacy, confidentiality, and fair-use concerns about personalized medicine. Mark Rothstein, J.D., at the University of Louisville Center for Health Policy and Bioethics, believes that the advent of personalized medicine coupled with the federal initiative to digitize healthcare records will invariably raise privacy issues. “For the first time, medical and genetic information about individual patients [collected and stored over long periods of time] will be linked and centrally located. This raises the likelihood of potential confidentiality, privacy, and access concerns,” he said. Rubenstein added, “The number one concern that individuals have today is that information about past health or prediction of future health based on genetic tests may be used by a health insurance company to increase rates or deny healthcare coverage. Also, people are concerned that employers might use genetic information to make decisions about hiring, firing, and job assignments.”
Personalized medicine advocates contend that the Genetic Information Nondiscrimination Act (GINA) enacted in May 2008 would shield patients from potential “genetic discrimination” by either health insurance companies or employers. While this may be true, GINA does not cover life, disability, or long-term care insurance, and the potential for genetic discrimination still exists in these areas. For example, a person at genetic risk for developing Alzheimer’s could be denied long-term healthcare insurance because Alzheimer’s patients have been known to live for long periods of time, and their care is costly.
Surprisingly, at present, it isn’t clear who owns or ultimately controls a person’s genetic information and DNA sequence data after it is generated. For example, it is likely (but not certain) that a consumer who purchases whole genome sequencing services from a personal genomics company owns and controls his/her sequence data. However, as whole genome sequencing continues to enter the mainstream, individuals will likely receive complete or partial genomic sequence information from a variety of sources. Ownership and control of the information isn’t likely to be straightforward or easily defined until rules and regulations are crafted to clarify how genomic information is owned, stored, and accessed by individuals and third parties.
Faster Drug Discovery, Less Cost
Personalized medicine has the potential to fundamentally change the way U.S. healthcare is practiced and delivered in the 21st century. While there is much work to be done, personalized medicine promises to expedite drug discovery, cut development costs, improve diagnoses, and provide patients with more effective and safer drug treatments. However, its success depends on the ability of drug and diagnostic manufacturers, healthcare providers, medical educators, information technology professionals, policy makers, and payors to work together to create an integrated framework that meets the healthcare needs of all Americans.
[While at NASA (to automate landing of an F15 with one wing, based on Neural Net algorithms implemented by parallel HPC) I was also involved the Government's "Blue Book" to envision development of the Internet - just as the Private Sector took it over in 1994. In just a few fast years, our Blue Book became almost laughable compared to the catapulting "Internet Boom". While it is difficult to make predictions, especially about the future, I risk to say (backed by PMWC2010 that we've just wrapped-up in Silicon Valley) that Personal Genomics, the core of Personalized Medicine, will similarly be taken over by Private Sector. In the video below, while the focus appears to be on the "glitzy" appearance of Genome-Based Product Recommendations, in the beginning and towards the end one can spot the sheer ("afterburner") power of Genome Computing Architecture (with HPC both at the Personal Genome Computer of the destop, and scaled for the future Genome Analysis Center either in Silicon Valley or other winner region). The architecture completes the presently "open loop" Business Model of DTC by connecting the dots through consumers (not just "patients" but also those consumers who are impatient enough to possibly never becoming patients through Prevention). Also, as shown by syncing the PGC with PGA, the integration of personal health- and genomic data must become under the control of the Person, with her/his Personal Preferences and Decisions overriding the rest. - Pellionisz_at_JunkDNA.com]
Knome Challenged to Keep in Step with Falling Genetic Sequencing Prices
Ryan McBride 1/20/10
Knome, the personal genomics startup co-founded by leading Harvard geneticist George Church, is navigating rapid change in its business. The Cambridge, MA-based launched in 2007 to make whole-genome sequencing and analysis a personal luxury item rather than just a marvel of modern science, but now it’s facing more competition on the sequencing side of its business and a dramatic decline in fees for its bread-and-butter consumer services.
About two years ago the startup announced that it was charging its first three wealthy customers $350,000 to sequence their entire genomes and then have its scientists interpret and analyze the data for each person. A year or so ago the firm dropped the price for that service to around $100,000, due in large part to a sharp decrease in the cost of sequencing. Last June, that price was then dropped again, to $68,500, where it has stayed, says Jorge Conde, the firm’s co-founder and CEO.
If you had your entire genome sequenced just five years ago, you might have been considered a pioneer on par with the first handful of astronauts who ventured into outer space. But there have since been a series of technological advances in tools used to map DNA, innovations that have brought down the price of whole genome sequencing from about $1 million dollars per genome a few years ago to less than $5,000 today.
Conde says the falling costs of genomic sequencing are a positive development for human health and science. He’s even confident that the lower costs of sequencing opens up a much larger market for Knome than possible at its original $350,000 price tag. Still, the company operated profitably in its early days when its small staff of around five full-time employees served clients who paid six figures for their services. Today, the company is trying to find a way to get back in the black with a larger staff of closer to 20 people and a premium service that costs the same as a fancy Mercedes rather than a nice condo near Kendall Square.
“I think the biggest challenge for us has been in clearly communicating the difference between sequencing and interpretation,” Conde says. He adds that while the price of whole-genome sequencing has fallen sharply, the costs of employing teams of scientists to interpret the data have not decreased nearly as much. The firm is spending more money today on salaries, given that its staff is larger than it was two years ago.
Conde says that the greatest value that his firm brings customers is in the analysis and interpretation of genomic data, for which it employs geneticists, bioinformatics experts, and clinicians. (Indeed, co-founder Church, in addition to heading the non-profit Personal Genome Project, stays involved in the business as a chief scientific advisor.) The actual genomic sequencing is handled by the startup’s partners at the Beijing Genomics Institute in China and SeqWright, a genomic analysis lab in Houston, TX. Indeed, plain genomic sequencing has become a commodity business, with firms such as Mountain View, CA-based startup Complete Genomics advertising whole genome sequencing for less than $5,000 per genome.
Fairly or unfairly, Knome is also often compared with the personal genomic analysis services of firms such as Foster City, CA-based Navigenics, and Silicon Valley startup 23andMe, which was started by a team that includes Google co-founder Sergey Brin’s wife, Anne Wojcicki. Both firms offer DNA tests, not sequencing, for $1,000 or less to tell people whether they have genes for certain diseases. 23andMe also gives customers clues about their ethnic roots based on the genes detected in the firm’s genotyping service. (Rather than sequencing a person’s genome to uncover all the genes in their DNA, those firms get a person’s DNA from their saliva and use test chips to find out whether the person has certain genes for diseases related to diseases or heredity. Conde notes that such DNA tests don’t uncover many genes or variants that give people a more complete picture of their genetic makeup, making it difficult to predict whether a person is at risk of developing, say, heart disease.
Even for those who do get their entire genome sequenced, there are limits to what scientists can tell them about the data because there are vast regions of the genome that are not yet fully understood. But that is expected to change as the U.S. government’s investment in genetic research leads to new discoveries about what the reams of genetic data really mean for human health. The National Human Genome Research Institute, a division of the NIH, received a windfall of $113 million from the federal economic stimulus last year to invest in genetic research, in addition to its normal annual budget of $367 million. The goal of the institute is advance the understanding of our genes to prevent, diagnose, and treat human illnesses.
Conde expects the government research dollars and the reduced costs of sequencing to provide more data to help his firm inform its clients about their health. Their clients can use the software to get updated on how the discoveries impact their health, without the company having to reanalyze their genomes.
To get back into the black, Knome is diversifying its service offerings to appeal to more potential customers. In May, the firm began offering to sequence and interpret a person’s exome, which is the 1 percent or 2 percent of the genome that is most functional for making proteins, for $19,500-$24,500. Then in December, it formally rolled out a service for researchers to provide sequencing and analysis for $12,000 per exome, making sequencing services available to scientists who may not have the infrastructure to perform that work themselves, Conde says.
Interestingly, the lower prices for Knome’s services have dramatically changed the profile of its typical customer, Conde says. The first few people who came through the door back when the price tag was $350,000 were wealthy individuals who saw themselves as genetic pioneers. (Essentially, he says, they wanted to have their genomes sequenced because, for essentially the first time ever, they could.) Many of the firm’s recent customers are people with means, yet they often come to the table with specific questions about their health or genetic composition. For example, one family worked with the firm to help identify genetic signals linked to an aggressive form of Parkinson’s disease that appeared to be prevalent in that family. Others want to find genes for certain physical traits that are common in their families.
The firm has a proprietary browser application that enables its clients to view their genetic information as it relates to certain indicators for diseases or physical traits. The application is updated as new discoveries are made. Conde says that the software side of the business offers his firm the opportunity to get recurring revenue from its customers who pay for software subscriptions to stay abreast of how new findings in genetic research impact their health (The company does not disclose details about revenue, sales figures, or how much capital it has raised.) Conde says that the company is internally funded by the founders, but he hasn’t ruled out raising venture capital in the future. The founders include Conde, Church, and company chairman Sundar Subramaniam, an IT and life sciences entrepreneur who has founded five tech companies that have gone on to complete IPOs, according to his bio.
“Because of the incredible improvements on the sequencing side and all the innovation that has taken place,” he says, “now there’s going to be a tidal wave of genetic data, and we think we’re as well-positioned as anyone to help people begin to wade through that increasing flood of data.
[I was involved - while at NASA - with the "Blue Book" of how the Government envisoned to build the "Internet boom" - until the Private Sector took it over in 1994. In retrospect, our Blue Book is almost laughable, compared to the Private Sector Internet Boom. Although it is difficult to make predictions, especially about the future, I risk to say (backed by PMWC2010 that we've just wrapped up in Silicon Valley) that Personal Genomics, the core-driver of Personalized Medicine will be fueled by the Private Sector. The video below focuses on how the consumers (not those who are already "patients", but also those impatient enough never to become patients, by prevention) will close the presently open Business Model of existing DTC. In the very beginning and towards the end, behind the consumer-focus lurk the High-Performance Computing architecture (both for the consumer's Personal Genome Computer, synced with Personal Genome Assistant, PGA, as well as scaled for the future Genome ANALYSIS Center). Also, the much-desired integration of personal health- and genomic data from various sources must be under the governance of the individual, whose personal preferences and decisions must be ultimate - Pellionisz_at_JunkDNA.com]
Google, Microsoft May Help Usher in Personalized Medicine Wave, Says George Church
Luke Timmerman 5/12/09
The genomic era hasn’t yet produced a revolution in personalized medicine, but it’s coming, says Harvard University geneticist George Church. Major tech companies like Google and Microsoft are making it their business to help people keep track of their health data—side-by-side with their genome sequence data (if they’ve got it). The adoption of these technologies has been slow to date, but combined with a new policy push for electronic medical records in Washington D.C., it just might move medicine away from one-size-fits-all approach that’s been the standard for so long, Church says.
That was the most interesting idea I picked up from talking with Church after he spoke at the Xconomy Forum on biotech innovation that we held recently at Biogen Idec headquarters in Cambridge, MA. People perked up their ears when Church talked about genomics and personalized medicine, since he’s one of the world’s leading thinkers on those topics, and has also worked hard to apply his ideas at a number of emerging biotech companies. The list includes Cambridge, MA-based Knome, a provider of genomic interpretation services; South San Francisco-based LS9, a renewable fuel company; and Mountain View, CA-based Complete Genomics, a gene sequencing company that has brought down the price of a genome to $5,000.
Here’s an edited account of my conversation with Church after the forum:
Xconomy: You mentioned earlier that you think Google and Microsoft are doing interesting things in terms of fostering greater usage of genomic data. How is that?
George Church: It’s not really about genomics so much as it is about personally controlled health records.
X: Ok, so what kind of impact does this have on your work?
GC: To the extent that these things are a controlled vocabulary, that’s important. To the extent that it makes people feel like they own their medical records, they can then share them more easily than filling out a form or asking the physician to give them something, and then getting a bunch of photocopied sheets that need to be transcribed onto a computer. This makes it much easier for people to share it for research.
I would love to see a wave of enthusiasm where people say ‘I’m going to share my genome and my medical traits, so that we can all benefit.’ Because right now it’s largely uninterpretable. But if everybody shares, it becomes interpretable. It greatly changes the ability to do research if the genome and the traits are both in the hands of the individual, and it really costs them nothing to push a button. But they need to think very deeply …Next Page »
Luke Timmerman is the National Biotechnology Editor for Xconomy. You can e-mail him at ltimmerman@xconomy.com, call 206-624-2374, or follow him on Twitter at http://twitter.com/ldtimmerman
[HolGen Technologies integrates for the Consumers: - Pellionisz, Jan 19-20, 2010, Personalized Medicine World Conference, Silicon Valley. While neither Google nor - literally next door - Microsoft Research participated, HolGen laid out the Genome Computing Architecture suitable for integration of genomic- and health-data, DTC genomic tests, all overriden by Personal Decisions and Preferences - and there results made available for user-friendly (smart phone) barcode shopping. The YouTube (7:44 minutes) starts showing the integration at 5:20 minutes:
[See YouTube through Press Release by HolGen Technolgies.
The Genome Computing Architecture (proprietary to HolGen) is shown in the very beginning of this YouTube, implemented from the already protected architecture shown 14 months ago in Google Tech YouTube. The architecture is scalable. Immediately available stage features the Personal Genome Computer (PGC) as any PC or laptop (synced presently with Google Android PDA/GPA). Genome-aware individuals, such as researchers will soon phase-in for PGC High Performance Computer desktops as DRC hybrid was featured at PMWC2010. The Genome Analysis Center planned by Dr. Pellionisz will use a massive grid of such hybrids for analysis of Full DNA sequences for early structural variants (SNP-s, indels, CNV-s, etc), as well as proprietary search for fractal defects in the regulatory sequences - AJP]
^ back to topNavigenics names Vance Vanier, MD, to serve as President and Chief Executive Officer
January 20, 2010
Posted 09:16 PM PDT
Today, Navigenics made an important leadership announcement. Here is the text of the official press release:
Navigenics, a leading personal genomics company, announced today that Vance Vanier, MD, has been appointed by the Board of Directors to serve as President and Chief Executive Officer of the firm.
Dr. Vanier joined Navigenics as Chief Medical Officer in April of 2008 and has been instrumental in growing the company’s clinical offerings as well as institutional research and corporate partnerships. Prior to joining Navigenics, he was a partner at venture capital firm Mohr Davidow Ventures where he spent years in the molecular diagnostics industry bringing new genomic technologies into clinical practice. Vanier also serves as a clinical faculty member of Stanford University Medical Center.
“Navigenics has defined preventive genomics and its potential to enable prevention and motivate behavior change, and I look forward to leading the company as it continues to pioneer in this emerging industry,” said Dr. Vanier. “Interest in wellness and prevention is briskly increasing and I am confident that the company is well positioned for the opportunities that lay ahead.”
As the number one personalized genetic testing provider recommended by physicians, in the last year Navigenics has also become the personal genomics testing service of choice for corporate health programs. According to the management team, the company has a considerable pipeline of corporate accounts and has begun introducing preventive genomics-based health to increasing numbers of people through employer-based partnerships. To date, the company has successfully integrated into the health and wellness programs of large, self-insured employers by offering large scale preventive genomic programs in order to increase employee motivation to improve lifestyle, enhance participation in existing employee wellness offerings, and improve medical compliance.
“It was Vance’s vision that guided Navigenics into the physician and employer wellness markets, and he has been critical to Navigenics’ success over the past two years,” said Dana G. Mead, Jr., partner at Kleiner Perkins Caufield & Byers and member of Navigenics’ Board of Directors. “As the company evolves its corporate strategy, forging deeper relationships with physician groups and employer-sponsored health and wellness programs, Vance’s clinical experience and exceptional leadership make him a natural choice to lead the company.”
“Vance has displayed an impressive commitment to getting at the heart of one of the biggest obstacles to preventive healthcare – motivating people to engage in healthy lifestyles,” said Pam Hymel, M.D., Medical Director of Cisco Systems and President of the American College of Occupational and Environmental Medicine. “But when it is successful, we have seen that every dollar spent on prevention yields three dollars in benefits. I believe that any behavior change that Navigenics can accomplish is consequently very valuable.”
ABOUT NAVIGENICS
Navigenics, Inc. is a privately held company based in Foster City, Calif. The company was founded by David Agus, M.D. and Dietrich Stephan, Ph.D., with the goal of improving health outcomes in individuals across the population. Navigenics educates and empowers individuals and their physicians with knowledge of their genetic predispositions, and then motivates them to act on the information to prevent the onset of disease, achieve earlier diagnosis, appropriately manage disease, or otherwise lessen its impact. Navigenics’ lead investors are Kleiner Perkins Caufield and Byers, Sequoia Capital and MDV-Mohr Davidow Ventures. More information can be found at http://www.navigenics.com.
Why Your DNA Isn't Your Destiny
Time Magazine,
January 6, 2010
By John Cloud
[Time Magazine Cover, January 06, 2010]
The remote, snow-swept expanses of northern Sweden are an unlikely place to begin a story about cutting-edge genetic science. The kingdom's northernmost county, Norrbotten, [No, it isn't a Saint Olaf' story... AJP] is nearly free of human life; an average of just six people live in each square mile. And yet this tiny population can reveal a lot about how genes work in our everyday lives.
Norrbotten is so isolated that in the 19th century, if the harvest was bad, people starved. The starving years were all the crueler for their unpredictability. For instance, 1800, 1812, 1821, 1836 and 1856 were years of total crop failure and extreme suffering. But in 1801, 1822, 1828, 1844 and 1863, the land spilled forth such abundance that the same people who had gone hungry in previous winters were able to gorge themselves for months.
In the 1980s, Dr. Lars Olov Bygren, a preventive-health specialist who is now at the prestigious Karolinska Institute in Stockholm, began to wonder what long-term effects the feast and famine years might have had on children growing up in Norrbotten in the 19th century — and not just on them but on their kids and grandkids as well. So he drew a random sample of 99 individuals born in the Overkalix parish of Norrbotten in 1905 and used historical records to trace their parents and grandparents back to birth. By analyzing meticulous agricultural records, Bygren and two colleagues determined how much food had been available to the parents and grandparents when they were young.
Around the time he started collecting the data, Bygren had become fascinated with research showing that conditions in the womb could affect your health not only when you were a fetus but well into adulthood. In 1986, for example, the Lancet published the first of two groundbreaking papers showing that if a pregnant woman ate poorly, her child would be at significantly higher than average risk for cardiovascular disease as an adult. Bygren wondered whether that effect could start even before pregnancy: Could parents' experiences early in their lives somehow change the traits they passed to their offspring?
It was a heretical idea. After all, we have had a long-standing deal with biology: whatever choices we make during our lives might ruin our short-term memory or make us fat or hasten death, but they won't change our genes — our actual DNA. Which meant that when we had kids of our own, the genetic slate would be wiped clean.
What's more, any such effects of nurture (environment) on a species' nature (genes) were not supposed to happen so quickly. Charles Darwin, whose On the Origin of Species celebrated its 150th anniversary in November, taught us that evolutionary changes take place over many generations and through millions of years of natural selection. But Bygren and other scientists have now amassed historical evidence suggesting that powerful environmental conditions (near death from starvation, for instance) can somehow leave an imprint on the genetic material in eggs and sperm. These genetic imprints can short-circuit evolution and pass along new traits in a single generation.
For instance, Bygren's research showed that in Overkalix, boys who enjoyed those rare overabundant winters — kids who went from normal eating to gluttony in a single season — produced sons and grandsons who lived shorter lives. Far shorter: in the first paper Bygren wrote about Norrbotten, which was published in 2001 in the Dutch journal Acta Biotheoretica, he showed that the grandsons of Overkalix boys who had overeaten died an average of six years earlier than the grandsons of those who had endured a poor harvest. Once Bygren and his team controlled for certain socioeconomic variations, the difference in longevity jumped to an astonishing 32 years. Later papers using different Norrbotten cohorts also found significant drops in life span and discovered that they applied along the female line as well, meaning that the daughters and granddaughters of girls who had gone from normal to gluttonous diets also lived shorter lives. To put it simply, the data suggested that a single winter of overeating as a youngster could initiate a biological chain of events that would lead one's grandchildren to die decades earlier than their peers did. How could this be possible?
Meet the Epigenome
The answer lies beyond both nature and nurture. Bygren's data — along with those of many other scientists working separately over the past 20 years — have given birth to a new science called epigenetics. At its most basic, epigenetics is the study of changes in gene activity that do not involve alterations to the genetic code but still get passed down to at least one successive generation. These patterns of gene expression are governed by the cellular material — the epigenome — that sits on top of the genome, just outside it (hence the prefix epi-, which means above). It is these epigenetic "marks" that tell your genes to switch on or off, to speak loudly or whisper. It is through epigenetic marks that environmental factors like diet, stress and prenatal nutrition can make an imprint on genes that is passed from one generation to the next.
Epigenetics brings both good news and bad. Bad news first: there's evidence that lifestyle choices like smoking and eating too much can change the epigenetic marks atop your DNA in ways that cause the genes for obesity to express themselves too strongly and the genes for longevity to express themselves too weakly. We all know that you can truncate your own life if you smoke or overeat, but it's becoming clear that those same bad behaviors can also predispose your kids — before they are even conceived — to disease and early death.
The good news: scientists are learning to manipulate epigenetic marks in the lab, which means they are developing drugs that treat illness simply by silencing bad genes and jump-starting good ones. In 2004 the Food and Drug Administration (FDA) approved an epigenetic drug for the first time. Azacitidine is used to treat patients with myelodysplastic syndromes (usually abbreviated, a bit oddly, to MDS), a group of rare and deadly blood malignancies. The drug uses epigenetic marks to dial down genes in blood precursor cells that have become overexpressed. According to Celgene Corp. — the Summit, N.J., company that makes azacitidine — people given a diagnosis of serious MDS live a median of two years on azacitidine; those taking conventional blood medications live just 15 months.
Since 2004, the FDA has approved three other epigenetic drugs that are thought to work at least in part by stimulating tumor-suppressor genes that disease has silenced. The great hope for ongoing epigenetic research is that with the flick of a biochemical switch, we could tell genes that play a role in many diseases — including cancer, schizophrenia, autism, Alzheimer's, diabetes and many others — to lie dormant. We could, at long last, have a trump card to play against Darwin.
The funny thing is, scientists have known about epigenetic marks since at least the 1970s. But until the late '90s, epigenetic phenomena were regarded as a sideshow to the main event, DNA. To be sure, epigenetic marks were always understood to be important: after all, a cell in your brain and a cell in your kidney contain the exact same DNA, and scientists have long known that nascent cells can differentiate only when crucial epigenetic processes turn on or turn off the right genes in utero.
More recently, however, researchers have begun to realize that epigenetics could also help explain certain scientific mysteries that traditional genetics never could: for instance, why one member of a pair of identical twins can develop bipolar disorder or asthma even though the other is fine. Or why autism strikes boys four times as often as girls. Or why extreme changes in diet over a short period in Norrbotten could lead to extreme changes in longevity. In these cases, the genes may be the same, but their patterns of expression have clearly been tweaked.
Biologists offer this analogy as an explanation: if the genome is the hardware, then the epigenome is the software. "I can load Windows, if I want, on my Mac," says Joseph Ecker, a Salk Institute biologist and leading epigenetic scientist. "You're going to have the same chip in there, the same genome, but different software. And the outcome is a different cell type."
How to Make a Better Mouse
As momentous as epigenetics sounds, the chemistry of at least one of its mechanisms is fairly simple. Darwin taught us that it takes many generations for a genome to evolve, but researchers have found that it takes only the addition of a methyl group to change an epigenome. A methyl group is a basic unit in organic chemistry: one carbon atom attached to three hydrogen atoms. When a methyl group attaches to a specific spot on a gene — a process called DNA methylation — it can change the gene's expression, turning it off or on, dampening it or making it louder.
The importance of DNA methylation in altering the physical characteristics of an organism was proposed in the 1970s, yet it wasn't until 2003 that anyone experimented with DNA methylation quite as dramatically as Duke University oncologist Randy Jirtle and one of his postdoctoral students, Robert Waterland, did. That year, they conducted an elegant experiment on mice with a uniquely regulated agouti gene — a gene that gives mice yellow coats and a propensity for obesity and diabetes when expressed continuously. Jirtle's team fed one group of pregnant agouti mice a diet rich in B vitamins (folic acid and vitamin B12). Another group of genetically identical pregnant agouti mice got no such prenatal nutrition.
The B vitamins acted as methyl donors: they caused methyl groups to attach more frequently to the agouti gene in utero, thereby altering its expression. And so without altering the genomic structure of mouse DNA — simply by furnishing B vitamins — Jirtle and Waterland got agouti mothers to produce healthy brown pups that were of normal weight and not prone to diabetes.
Other recent studies have also shown the power of environment over gene expression. For instance, fruit flies exposed to a drug called geldanamycin show unusual outgrowths on their eyes that can last through at least 13 generations of offspring even though no change in DNA has occurred (and generations 2 through 13 were not directly exposed to the drug). Similarly, according to a paper published last year in the Quarterly Review of Biology by Eva Jablonka (an epigenetic pioneer) and Gal Raz of Tel Aviv University, roundworms fed with a kind of bacteria can feature a small, dumpy appearance and a switched-off green fluorescent protein; the changes last at least 40 generations. (Jablonka and Raz's paper catalogs some 100 forms of epigenetic inheritance.)
Can epigenetic changes be permanent? Possibly, but it's important to remember that epigenetics isn't evolution. It doesn't change DNA. Epigenetic changes represent a biological response to an environmental stressor. That response can be inherited through many generations via epigenetic marks, but if you remove the environmental pressure, the epigenetic marks will eventually fade, and the DNA code will — over time — begin to revert to its original programming. That's the current thinking, anyway: that only natural selection causes permanent genetic change.
And yet even if epigenetic inheritance doesn't last forever, it can be hugely powerful. In February 2009, the Journal of Neuroscience published a paper showing that even memory — a wildly complex biological and psychological process — can be improved from one generation to the next via epigenetics. The paper described an experiment with mice led by Larry Feig, a Tufts University biochemist. Feig's team exposed mice with genetic memory problems to an environment rich with toys, exercise and extra attention. These mice showed significant improvement in long-term potentiation (LTP), a form of neural transmission that is key to memory formation. Surprisingly, their offspring also showed LTP improvement, even when the offspring got no extra attention.
All this explains why the scientific community is so nervously excited about epigenetics. In his forthcoming book The Genius in All of Us: Why Everything You've Been Told About Genetics, Talent and IQ Is Wrong, science writer David Shenk says epigenetics is helping usher in a "new paradigm" that "reveals how bankrupt the phrase 'nature versus nurture' really is." He calls epigenetics "perhaps the most important discovery in the science of heredity since the gene."
Geneticists are quietly acknowledging that we may have too easily dismissed an early naturalist who anticipated modern epigenetics — and whom Darwinists have long disparaged. Jean-Baptiste Lamarck (1744-1829) argued that evolution could occur within a generation or two. He posited that animals acquired certain traits during their lifetimes because of their environment and choices. The most famous Lamarckian example: giraffes acquired their long necks because their recent ancestors had stretched to reach high, nutrient-rich leaves.
In contrast, Darwin argued that evolution works not through the fire of effort but through cold, impartial selection. By Darwinist thinking, giraffes got their long necks over millennia because genes for long necks had, very slowly, gained advantage. Darwin, who was 84 years younger than Lamarck, was the better scientist, and he won the day. Lamarckian evolution came to be seen as a scientific blunder. Yet epigenetics is now forcing scientists to re-evaluate Lamarck's ideas.
Solving the Overkalix Mystery
By early 2000, it seemed clear to Bygren that the feast and famine years in 19th century Norrbotten had caused some form of epigenetic change in the population. But he wasn't sure how this worked. Then he ran across an obscure 1996 paper by Dr. Marcus Pembrey, a prominent geneticist at University College London.
Published in the Italian journal Acta Geneticae Medicae et Gemellologiae, Pembrey's paper, now considered seminal in epigenetic theory, was contentious at the time; major journals had rejected it. Although he is a committed Darwinist, Pembrey used the paper — a review of available epigenetic science — to speculate beyond Darwin: What if the environmental pressures and social changes of the industrial age had become so powerful that evolution had begun to demand that our genes respond faster? What if our DNA now had to react not over many generations and millions of years but, as Pembrey wrote, within "a few, or moderate number, of generations"?
This shortened timetable would mean that genes themselves wouldn't have had enough years to change. But, Pembrey reasoned, maybe the epigenetic marks atop DNA would have had time to change. Pembrey wasn't sure how you would test such a grand theory, and he put the idea aside after the Acta paper appeared. But in May 2000, out of the blue, he received an e-mail from Bygren — whom he did not know — about the Overkalix life-expectancy data. The two struck up a friendship and began discussing how to construct a new experiment that would clarify the Overkalix mystery.
Pembrey and Bygren knew they needed to replicate the Overkalix findings, but of course you can't conduct an experiment in which some kids starve and others overeat. (You also wouldn't want to wait 60 years for the results.) By coincidence, Pembrey had access to another incredible trove of genetic information. He had long been on the board of the Avon Longitudinal Study of Parents and Children (ALSPAC), a unique research project based at the University of Bristol, in England. Founded by Pembrey's friend Jean Golding, an epidemiologist at the university, ALSPAC has followed thousands of young people and their parents since before the kids were born, in 1991 and 1992. For the study, Golding and her staff recruited 14,024 pregnant mothers — 70% of all the women in the Bristol area who were pregnant during the 20-month recruitment period.
The ALSPAC parents and kids have undergone extensive medical and psychological testing every year since. Recently, I met an ALSPAC baby, Tom Gibbs, who is now a sturdy 17-year-old. I accompanied him as clinicians measured his height (178 cm, or 5 ft. 8 in., not including spiked blond hair), the bone density of his left femur (1.3 g/sq cm, which is above average) and a host of other physical traits.
All this data collection was designed from the outset to show how the individual's genotype combines with environmental pressures to influence health and development. ALSPAC data have offered several important insights: baby lotions containing peanut oil may be partly responsible for the rise in peanut allergies; high maternal anxiety during pregnancy is associated with the child's later development of asthma; little kids who are kept too clean are at higher risk for eczema.
But Pembrey, Bygren and Golding — now all working together — used the data to produce a more groundbreaking paper, the most compelling epigenetic study yet written. Published in 2006 in the European Journal of Human Genetics, it noted that of the 14,024 fathers in the study, 166 said they had started smoking before age 11 — just as their bodies were preparing to enter puberty. Boys are genetically isolated before puberty because they cannot form sperm. (Girls, by contrast, have their eggs from birth.) That makes the period around puberty fertile ground for epigenetic changes: If the environment is going to imprint epigenetic marks on genes in the Y chromosome, what better time to do it than when sperm is first starting to form?
When Pembrey, Bygren and Golding looked at the sons of those 166 early smokers, it turned out that the boys had significantly higher body mass indexes than other boys by age 9. That means the sons of men who smoke in prepuberty will be at higher risk for obesity and other health problems well into adulthood. It's very likely these boys will also have shorter life spans, just as the children of the Overkalix overeaters did. "The coherence between the ALSPAC and Overkalix results in terms of the exposure-sensitive periods and sex specificity supports the hypothesis that there is a general mechanism for transmitting information about the ancestral environment down the male line," Pembrey, Bygren, Golding and their colleagues concluded in the European Journal of Human Genetics paper. In other words, you can change your epigenetics even when you make a dumb decision at 10 years old. If you start smoking then, you may have made not only a medical mistake but a catastrophic genetic mistake.
Exploring Epigenetic Potential
How can we harness the power of epigenetics for good? In 2008 the National Institutes of Health (NIH) announced it would pour $190 million into a multilab, nationwide initiative to understand "how and when epigenetic processes control genes." Dr. Elias Zerhouni, who directed the NIH when it awarded the grant, said at the time — in a phrase slightly too dry for its import — that epigenetics had become "a central issue in biology."
This past October, the NIH grant started to pay off. Scientists working jointly at a fledgling, largely Internet-based effort called the San Diego Epigenome Center announced with colleagues from the Salk Institute — the massive La Jolla, Calif., think tank founded by the man who discovered the polio vaccine — that they had produced "the first detailed map of the human epigenome."
The claim was a bit grandiose. In fact, the scientists had mapped only a certain portion of the epigenomes of two cell types (an embryonic stem cell and another basic cell called a fibroblast). There are at least 210 cell types in the human body — and possibly far more, according to Ecker, the Salk biologist, who worked on the epigenome maps. Each of the 210 cell types is likely to have a different epigenome. That's why Ecker calls the $190 million grant from NIH "peanuts" compared with the probable end cost of figuring out what all the epigenetic marks are and how they work in concert.
Remember the Human Genome Project? Completed in March 2000, the project found that the human genome contains something like 25,000 genes; it took $3 billion to map them all. The human epigenome contains an as yet unknowable number of patterns of epigenetic marks, a number so big that Ecker won't even speculate on it. The number is certainly in the millions. A full epigenome map will require major advances in computing power. When completed, the Human Epigenome Project (already under way in Europe) will make the Human Genome Project look like homework that 15th century kids did with an abacus.
But the potential is staggering. For decades, we have stumbled around massive Darwinian roadblocks. DNA, we thought, was an ironclad code that we and our children and their children had to live by. Now we can imagine a world in which we can tinker with DNA, bend it to our will. It will take geneticists and ethicists many years to work out all the implications, but be assured: the age of epigenetics has arrived.
[This is a brilliant breakthrough article for a popular (not even scientific) leading global Journal; Time Magazine. Congratulations! The gap suddenly narrowed to a mere 14 months between October 30, 2008 as a scientist on Google Tech Talk YouTube I would daresay much of the above (and a bit more; that The Principle of Recursive Genome Function specifies that it is a fractal iterative recursion, FractoGene, in which the Genome through Epigenomic channels constitutes the HoloGenome). Now, 14 months later we have actually just presented the Genome Computer Architecture (with high-performance computing for Personal Genome Computer linked with the mobile device of Personal Genome Assistant), how consumers can act for their own preventive health benefit, once they flipped from the now ancient and gloomy mode of "The Genome is Destiny" to the postmodern, bright and hopeful "Ask what you can do for your genome" - Pellionisz_at_Junkdna.com, January 22, 2010]
At Personalized Medicine World Conference 2010, HolGentech contributes the only proprietary Genome Computing Architecture
Silicon Valley weighed in on "Genome Computing Architecture" - an absolute must for processing not just SNP files by DTC to employ in personalized shopping, but as an integrator of various sources of genomic- and health information, all controlled by personal preferences (SNP raw files and eventually Full Genome Sequences by Complete Genomics and Pacific Bioscieces, integrated with health information on servers of major IT companies2) The only company (of course, from Silicon Valley) was HolGenTech (founded by Andras Pellionisz) that came forward with a proprietry computing architecture to befit the oncoming challenge of affordable full genome sequences. If Ford would have only turned out affordable transportation rolling off from assembly-lines in mass-production available to all, but NO GAS STATIONS were built, their business mode would have been untenable. Likewise, the huge business of molecular genome sequencing (Complete Genomics, Pacific Biosciences) would become untenable - unless algorithmic (not "brute force") software pinpoints the "fractal defects" that shuld not be in the recursive and interative genome function.
Preview of A Personal Genome Assistant
Tech Start Ups
Jan 19, 2010
By Staff Writer – Boonsri Dickinson (@boonspoon)
LACTOSE - Boonsri, do not use!!!
HolGenTech is using my DNA in their demo at the Personalized Medicine World Conference in Silicon Valley. Before the conference, I emailed my raw DNA file from 23andMe to Dr. Andras Pellionisz and he uploaded it onto a hand-held personal genome assistant.
This morning, I finally got to see the device. I’m lactose intolerant and was looking for something I could eat this morning. By scanning barcodes on food and medications, the device can let me know if it has lactose in it. If it does have lactose, it says “Boonsri, do not use!!!”
According to HolGenTech:
“A Genome Based Economy is upon us. Soon, awareness of our genome will allow us to use our genome to live in a way that constantly promotes personal health and well being. As we are aware of our genome, we realize that the genome is not our destiny, but rather it is affected by our choices. In the HolGenTech genome computing architecture we perform the analysis and provide the user tools to discover and make the best genomic and personal choices,” said HolGenTech founder Dr. Andras Pellionisz. “Through the HolGenTech genome computing architecture, we can provide answers as consumers respond to the compelling new paradigm and its imperative: Ask what you can do for your genome!”
In the future, it might help me shop for the best food and products to fit my genome
[The Real Boonsri Dickinson [right] also had a chance to meet Isabel Matick [left] who enacted her in the YouTube - AJP].
HolGenTech YouTube for Funding Round at PMWC2010
It is not very often that a Company seeks a funding round not only at the largely extended Personalized Medicine World Congress in SiliconValley; PMWC2010 on January 19-20, but uses both the regular Press Release - and a simultaneous YouTube. I the 21st Century, communication is different. A major change from "Sick Care" to "Health Care" by Personalized Prevention is promoted, also as a government program in Francis Collins' NIH Director's newly released book (see below, with the top praise coming from President Barack Obama).
In the same spirit of rapid communication, HolGenTech' pitch for a funding round is presented in "the old ways" - as well as globally telecast via YouTube (see via Press Release link above). Presentations in the HolGenTech booth by Founder will include HPC (Personal Genome Computer, PGC) and mobile application for barcode shopping (Personal Genome Assistant, PGA). In addition an ALZtrek mobile application will also be presented by CTO-designate of HolGenTech.
Times are changing.
The Language of Life - Book on Personalized Medicine by Francis Collins
The Language of Life - DNA and the Revolution in Personalized Medicine, by Francis Collins
This book is not only a "game changer" in genomics - it is a "life changer" for everybody who cares about health - AJP
“From New York Times bestselling author and world-renowned doctor and geneticist Francis Collins, [this is] a book that will forever change how you think about your body, your health, and the future of medicine”.
The readership thus includes every body - a guaranteed bestseller. It is not a textbook in Medicine for those who (pretend to) understand genomics. Francis Collins knows best that "The discoveries of the past decade, little known to most of the public, have completely overturned much of what used to be taught in high school biology. If you thought the DNA molecule comprised thousands of genes but far more "junk DNA", think again." Francis Collins is very upfront not only about his successes, but tells us straight that other of his assumptions were off the mark:
In 1999 scientists were guessing how many genes would be found in the human DNA. “The range of guesses extended from 30,000 to 150,000; my own guess was 48,004. (Okay, I was trying to avoid a round number.) Imagine the surprise and consternation of the scientific community when the ultimate answer was a mere 20,000 protein-coding genes”. …”It turns out that only about 1.5 percent of the human genome is involved in coding for protein. But that doesn’t mean the rest is “junk DNA””. Likewise, “in 1996 Donna Shalala, the United States Secretary of Health and Human Services, asked me whether I thought it would ever be possible for individuals to obtain direct analysis of their genome for prediction of future medical risks, without the involvement of a health provider. …I found the idea of direct-to-customer genetic testing completely unimaginable in my lifetime”.
Francis Collins is critical not only about himself, but his book leaflet points out: “Just in the past decade, most of what you think you know about DNA has been overturned. Much of the advice given routinely by health care providers is ill informed, so you need to educate yourself about this raidly moving area of medicine”.
“Now, with a simple home test, costing a few hundred dollars, you can learn the secrets of your own DNA”
Francis Collins has been at the forefront of this revolution”.
[HolGenTech contributes to this revolution essentially in two fronts. First, results of Direct-to-Customers genome testing need to be deployed into an automated, user-friendly system; thus the Personal Genome Assistant “Smart phones” will enable consumers to conveniently tell apart what is “naughty or nice” for our genome via barcode shopping, the PGA synced with a Personal Genome Computer.
Second, in another book, Francis Collins said that the DNA and mathematics are “God’s languages”. He also mentions there that as a Ph.D. (before his M.D.) he focused on thermodynamics and quantum theory – but did not think that in his lifetime major new achievements will be reached with advanced mathematics of chemistry or biology. At that time, the present forefront was looming in a distant future …
The Language of Life is written in brilliant, lucid English, with a permanent imprint for all. But it does not actually tell the Language of Life. As the cover article of October 9th issue of Science (by Eric Lander et al., Director of the Broad Institute and Science Advisor to the President), the mathematical language of the DNA is most likely to be fractal geometry - and our scientifically solid hope that "the genome is not our destiny" will hinge on the principle that the hologenome is a thermodynamically open system.
Hopefully it will not remain symbolic that the top praise for this book of Francis Collins (Director of the NIH) comes from a leading "team-player":
“His groundbreaking work has changed the very ways we consider our health and exemine disease” - President Barack Obama - AJP]
"What Recession in Genomics ??? Triple-Digit Stock Price Increases !!!
Eight Firms in GWDN Index Return Triple-Digit Stock Price Increases in '09
January 06, 2010
By a GenomeWeb staff reporter
NEW YORK (GenomeWeb News) – Of the 33 firms that are included in the GenomeWeb Daily News Index of life science tools and molecular diagnostics makers, eight of those had stock price gains exceeding 100 percent for full-year 2009.
As was the case with tech stocks in general in the market, many of the firms in the Index had double-digit returns, with only six firms having a drop in their stock price compared to the close of 2008.
The biggest gainer for the year, by far, was Compugen, whose shares climbed in the second half of the year, culminating in a late-year spike. Compugen's shares closed 2009 up over 1,000 percent for the year. [I guess this is 4-digits... a tenfold growth in a single year - not exactly a "recession" - AJP].
Shares of the Israel-based computational biology firm had already risen 367 percent in the first half of 2009, and its shares rose even further over the last two weeks of December, as two news items served as catalysts.
Exact Sciences also produced a massive gain in 2009, with its shares up 495 percent for the year. Like Compugen, Exact had a strong first half of the year — its shares were up 365 percent at the midway point — and continued to climb through the back half of '09.
Exact, which traded at only $.57 per share at the close of 2008, rose early in the year after the firm announced that it had sold to Genzyme certain intellectual property assets related to the fields of prenatal and reproductive health in a deal that is expected to provide the firm with a cash infusion of $24.5 million. In addition, the Marlborough, Mass.-based firm sold to Genzyme three million shares of its common stock for $2 per share. The deal ended Sequenom's bid to acquire Exact Sciences for around $41 million.
Broad Institute's Revenues Rose 9 Percent in FY '09
January 05, 2010
By a GenomeWeb staff reporter
... Broad finished MIT's 2009 fiscal year with $166.3 million in research revenues, up 17 percent from the previous 12 months, Theresa Stone, MIT executive vice president and treasurer, said in the MIT Report of the Treasurer for the Fiscal Year Ending June 30, 2009.
The report also recorded a 23.5 percent year-over-year jump, or $23 million, in the Broad Institute's direct spending for sponsored research, which rose during FY 2009 to $121.3 million from $98.2 million in FY '08.
Total revenues for the Broad Institute as reflected in MIT financial statements rose 9 percent during the recently-concluded fiscal year, to $206 million from $188.9 million. Total expenses climbed 4.5 percent year-to-year, from $206.9 million in FY '08 to $215.4 million in FY '09.
Until July 1, 2009, the Cambridge, Mass., genomic medicine research institute was governed jointly by MIT and Harvard, though the institute was legally an MIT entity. MIT and Harvard provided financial support and services for the institute's initial 2004 launch, which followed the first of two $100 million commitments by Los Angeles philanthropists Eli and Edythe Broad.
In October, Broad named its first board of directors, a 14-member panel, capping a process toward independence that began in September 2008, when Eli and Edythe Broad announced their intent to donate $400 million for use as a permanent endowment, in addition to their initial pair of gifts totaling $200 million.
At the time of its separation from MIT and Harvard, according to the FY '09 report, the Broad Institute accounted for $199.5 million in assets and $106.2 million in liabilities reflected in MIT's Statements of Financial Position....
[The fact of Genome Revolution resulting in an explosion of private profits is not at all surprising - some of the most successful companies started in the recession of the seventies, and e.g. Google catapulted exactly in the days of "Internet Bust". What may surprise some that even non-profit "Venture Philantropy" showed significant growth in the year of one of the most severe recession - but it had to be in Genomics, and with the best donors and leadership. - AJP]
Personalized Medicine World Conference, Silicon Valley, January 19-20
[The year starts in earnest in Silicon Valley by the "first ever" Personalized Medicine World Conference 2010, in the Computer History Museum; register here. HolGenTech, announced on Google Tech Talk and Churchill Club YouTube-s will be participating - HolGenTech_at_gmail.com]
