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Junk DNA Revisited Silicon Valley startup claims to have unlocked a key to its hidden language Hal Plotkin, Special to SF Gate   Thursday, November 21, 2002 When the human genome was first sequenced in June 2000, there were two pretty big surprises. The first was that humans have only about 30,000-40,000 identifiable genes, not the 100,000 or more many researchers were expecting. The lower -- and more humbling -- number means humans have just one-third more genes than a common species of worm. The second stunner was how much human genetic material -- more than 90 percent -- is made up of what scientists were calling "junk DNA." The term was coined to describe similar but not completely identical repetitive sequences of amino acids (the same substances that make genes), which appeared to have no function or purpose. The main theory at the time was that these apparently non-working sections of DNA were just evolutionary leftovers, much like our earlobes. But if biophysicist Andras Pellionisz is correct, genetic science may be on the verge of yielding its third -- and by far biggest -- surprise. In addition to possessing a doctorate in physics, Pellionisz is the holder of Ph.D.'s in computer sciences and experimental biology from the prestigious Budapest Technical University and the Hungarian National Academy of Sciences respectively -- institutions that together have produced nearly a dozen Nobel Prize winners over the years. In a provisional patent application filed July 31, Pellionisz claims to have unlocked a key to the hidden role junk DNA plays in growth -- and in life itself. Rather than being useless evolutionary debris, he says, the mysteriously repetitive but not identical strands of genetic material are in reality building instructions organized in a special type of pattern known as a fractal. It's this pattern of fractal instructions, he says, that tells genes what they must do in order to form living tissue, everything from the wings of a fly to the entire body of a full-grown human. Another way to describe the idea: The genes we know about today, Pellionisz says, can be thought of as something similar to machines that make bricks (proteins, in the case of genes), with certain junk-DNA sections providing a blueprint for the different ways those proteins are assembled. The notion that at least certain parts of junk DNA might have a purpose appears to be picking up steam. Many scientists, for example, now refer to those areas with a far less derogatory term: introns. Other investigators are also looking into introns from a variety of perspectives. A group at UC Berkeley, for example, recently won $14 million from the National Institutes of Health to study the role introns might play in cardiovascular disease. Other researchers have begun looking at similar questions, with most focusing on intron strands located near genes whose functions are better understood. Scientists at UCLA, for example, recently made a promising association between what appears to be an intron abnormality and spinocerebellar ataxia, which is similar to Huntington's disease. What makes Pellionisz' approach different is his suggestion that fractals will be found to play a critical role not only in these conditions but also in tens of thousands of others that have not been studied yet. His patent application covers all attempts to count, measure and compare the fractal properties of introns for diagnostic and therapeutic purposes. "It's certainly possible that such a patent could be granted," says C. Anthony Hunt, Ph.D., a holder of nine patents who heads the Hunt Lab in the Department of Biopharmaceutical Sciences and Pharmocogenomics at the University of California at San Francisco. To win a patent, Hunt notes, all an inventor must do is describe or teach some new skill that is not obvious. "And this would certainly qualify as non-obvious," he says. "If it works, [fractal intron analysis] could become a very important tool." Hunt adds that most biologists simply don't know enough about fractals or the advanced math behind them to understand how they might apply to the field of genetic medicine. "We need someone to tap us on the shoulder and explain it to us," he says. "But if it clicks as a tool, we would be more than happy to use it." "Overall, we know very little about what is referred to as 'junk DNA,'" he adds. "But every year that goes by, there are more insights into the possible role they might play." Staking His Claim Pellionisz hopes his patent application will help him launch his company and make him one of the field's key players. The provisional application lets him put the words "patent pending" on any related creations for one year, after which he must file a complete application. Like other inventors, he's also free during that time to disclose his concept through other means, such as in professional journals or at scientific gatherings. In a move sure to alienate some scientists, Pellionisz has chosen the unorthodox route of making his initial disclosures online on his own Web site. He picked that strategy, he says, because it is the fastest way he can document his claims and find scientific collaborators and investors. Most mainstream scientists usually blanch at such approaches, preferring more traditionally credible methods, such as publishing articles in peer-reviewed journals. Scientists who don't follow that tradition are usually treated with suspicion. But Pellionisz' credentials and prior accomplishments make him much harder to dismiss than the average cyberspace sci-fi wacko. A biophysicist by training, the 59-year-old is a former research associate professor of physiology and biophysics at New York University, author of numerous papers in respected scientific journals and textbooks, a past winner of the prestigious Humboldt Prize for scientific research, a former consultant to NASA and holder of a patent on the world's first artificial cerebellum (a part of the brain), a technology that has already been integrated into research on advanced avionics systems. Because of his background, the Hungarian-born brain researcher might also become one of the first people to successfully launch a new company by using the Internet to gather momentum for a novel scientific idea. The Hidden Fractal Language of Intron DNA To fully understand Pellionisz' idea, one must first know what a fractal is. Fractals are a way that nature organizes matter. Fractal patterns can be found in anything that has a non-smooth surface (unlike a billiard ball), such as coastal seashores, the branches of a tree or the contours of a neuron (a nerve cell in the brain). Some, but not all, fractals are self-similar and stop repeating their patterns at some stage; the branches of a tree, for example, can get only so small. Because they are geometric, meaning they have a shape, fractals can be described in mathematical terms. It's similar to the way a circle can be described by using a number to represent its radius (the distance from its center to its outer edge). When that number is known, it's possible to draw the circle it represents without ever having seen it before. Although the math is much more complicated, the same is true of fractals. If one has the formula for a given fractal, it's possible to use that formula to construct, or reconstruct, an image of whatever structure it represents, no matter how complicated. Basically, Pellionisz' idea is that a fractal set of building instructions in the DNA plays a similar role in organizing life itself. Decode the way that language works, he says, and in theory it could be reverse engineered. Just as knowing the radius of a circle lets one create that circle, understanding the more complicated fractal-based formula that nature uses to turn inanimate matter into a heart might -- in theory, at least -- help us learn how to grow a living heart, or simpler structures, such as disease-fighting antibodies. At a minimum, we'd get a far better understanding of how nature gets that job done. The complicated quality of the idea is helping encourage new collaborations across the boundaries that sometimes separate the increasingly intertwined disciplines of biology, mathematics and computer sciences. Thinking about whether junk DNA has a purpose "is a rather obvious question for scientists to ask," says UC Berkeley mathematics Professor Jenny Harrison, a world-renowned expert on fractals. When Harrison examined the strings of amino acids involved, the idea that had also dawned on the mathematically inclined Pellionisz, in addition to several other theorists, immediately jumped out at her: If junk DNA really is junk, some of it is certainly organized in a pretty peculiar pattern, one that looks amazingly like a fractal. "This is a fractal form of nature that must stop at some stage," Harrison says simply, adding that the fractal pattern looks exactly like others that appear in nature. She's been batting the topic around with Pellionisz recently, and is continuing to think about it. Pellionisz has been working on understanding the possible linkages between math and physiology since his earliest days as a college student in Hungary, when he first decided to devote his life to understanding how the brain works. It's that pursuit that has helped lead him to his latest ideas, he says. "When you consider how the brain tells the fingers to pick up a pencil -- all the many different muscles involved, the senses, vision, touch, the distances involved, and how it is all managed by the brain -- you quickly realize there has to be some form of math involved to coordinate everything," he explains. "I always knew from my earliest days that it had to be math, and I knew it wasn't calculus, because of the distances involved [e.g. from the brain to the tip of the finger]. So it had to be a form of geometry, but it had to be a very special kind of geometry." Pellionisz has dubbed his new company Helixometry Inc. The name ("helix" refers to the unique spiral folded-over shape of the DNA molecule) alludes to what he says is the fractal math at work inside DNA. His theory is highly speculative. But there is at least one other important piece of anecdotal evidence that he might be on the right track: As organisms become more complex, they seem to have more intron DNA. "It's not a perfect correlation," says UCSF's C. Anthony Hunt, "but it is a trend. It's as if the more advanced organisms had made a larger number of steps to get to where they are now." In other words, although people are made up of the same basic stuff as other organisms, the instructions for making a person should in theory be more complex, which could account for the large amount of intron DNA found in humans. What's Next While they remain generally cautious, a number of top biomedical researchers and other scientists say Pellionisz might be onto something really big. Experts generally agree that a breakthrough in figuring out the role junk DNA plays, if any, would represent a spectacular advance in our understanding about how DNA in general turns inanimate matter into living organisms. If that happens, humanity would take a giant leap toward gaining control of the machinery of life itself, which would open up a wild new frontier in medicine and science that could lead to everything from growing new organs designed for specific patients to preventing and curing any health- or age-related problems that have a genetic origin or component. Pellionisz says his main goal is to set the stage for the next and even more promising generation of research into genetics. Given the fact that he may be the first person to assert a patent on intron fractal counting and analysis, it's also conceivable that Pellionisz could wind up with related commercial rights worth billions of dollars. If he's wrong, of course, any patent he might receive will be worthless. And even if he's right, he could have to contend with other inventors who may also have recently filed similar patent claims that, like his, have not yet been fully disclosed. Meanwhile, Pellionisz has several additional patent applications in the works that he says will build on and further protect his original claims. At the same time, he's also looking for the investments he says he needs to move forward more quickly, including completing his formal patent application by the deadline, as well as ramping up his company's first commercial applications, which other researchers would use. Wary of all the startup horror stories Pellionisz has heard, he's hoping to avoid working with a traditional venture-capital company. Instead, he says he's looking for a single "angel" investor, ideally someone knowledgeable and connected in the biosciences and database worlds who can help him develop his patent portfolio and formulate a business plan that links his efforts with those of some larger organization in a related field. Pellionisz even has a short list of names of specific people who he thinks would be ideal partners at this stage. He is, he says, more interested in building a successful company than in selling the idea for a quick buck. Given the stakes, additional competitors seem certain to join the fray. It could be years, even decades, before the dust settles and Pellionisz learns whether his patent application has any real merit, as well as whether someone else beat him to the punch with an earlier enforceable patent claim. "All I know is that I'm in a race," Pellionisz said last week. "And the clock is already ticking." [Comment by Dr. Pellionisz on March 21, 2010] The above article appeared in the electronic version (SF Gate) of the San Francisco Chronicle on Nov 21, 2002. Today, over 7 years after introducing the concept that "The genes we know about today, Pellionisz says, can be thought of as something similar to machines that make bricks (proteins, in the case of genes), with certain junk-DNA sections providing a blueprint for the different ways those proteins are assembled" requires some explanation why it was filed to a US patent application, rather than the usual "peer reviewed science publication". It was certainly not because Dr. Pellionisz was not familiar with science publications, having written well over 100 by that time. The reason was that Dr. Pellionisz' "FractoGene" concept had its origins with his 1989 paper "Neural Geometry; Towards a Fractal Model of Neurons"; invoking a recursion from proteins to DNA. At that time not only Crick's (false) "Central Dogma of Molecular Biology" (that mistakenly claimed since 1956 that such recursion of information "never happens", but also the "Junk DNA" erroneous theory by Ohno since 1972 still ruled. Moreover, both leading scientists still lived and dominated genomics, and never in their life recalled their mistaken axioms. Thus, the 1989 publication could only appear in the Proceedings of the Coppenhagen meeting of the Neural Net community (just breaking through with another paradigm-shift from AI to Neural Nets), and peer-review was done by Neural Net pioneer colleagues to whom such recursion was "taken for granted". Moreover, published by Cambridge University Press in the UK, the occasionally overbearing US scientists could not prevent publication. Nonetheless, the existing NIH grant to Dr. Pellionisz was discontinued, and a new NIH proposal (acknowledged in the publication) was flatly denied for the double lucid heresy of violating both cardinal axioms of genomics. Though Ohno passed away in 2000, Crick still lived in 2002 when Dr. Pellionisz conceived FractoGene (and at odds with Crick also on the turf of Neural Nets, where Dr. Pellionisz brought out his highly mathematical "Tensor Network Theory" explaining the space-time coordination of existing cerebellar neural networks, while Crick attempted to explain consciousness by theoretical biology without the benefit of any mathematics at all) Dr. Pellionisz saw zero chance that FractoGene would pass peer review of the establishment. Thus, filing FractoGene to USPTO served not for undue financial gains, but to establish Dr. Pellionisz' priority - and perhaps to help sustaining his efforts and that of his like-minded colleagues. While it is unfortunate that the two obsolete axioms set back genome informatics by half a Century (1956-2006 when Dr. Pellionisz' "International PostGenetics Society" officially abandoned the misnomer "Junk DNA"), still one more year was needed when the ENCODE results concluded similarly. Answering Dr. Collins' call that "the scientific community will have to re-think long-held beliefs", Dr. Pellionisz could publish his peer-reviewed paper "The Principle of Recursive Genome Function"; specifying that the protein-to-DNA action sets off a "fractal iterative recursion". ..   · ·