This research is based on Dr. Andras J Pellionisz, An Hungarian-American Genomics Pioneer in the Realm of Genomics and Genome Analytics.
Dr. Andras Pellionisz is a Hungarian-American Pioneer in Genomics. After completion of ENCODE project, he proposed “The Principle of Recursive Genome Function”. The illustrative mathematical approach used in the paper revealed that a repetitive self-similar process governs mathematical approaches in Biology, as how the fractal genome governs the fractal organelles and growth of fractal organisms.
The immediate resonance probably happened in Indian culture as our art, science and as well as mathematics are rather profoundly rooted in self-similar repetitions: the fractals. Indian temples are standing examples of “fractal architecture” since ancient times. Therefore, we naturally and immediately can embrace the “Pellionisz Principle”. I am an ardent advocate of his breakthrough in India, privy to his discovery in Fractal Genomics and his pioneering fractal approach.
With all that talk about “everything is fractal in India”, we are not ignorant of western cultures. Indeed, European mathematicians are much appreciated. Archimedes, Pythagoras, Euclid, etc. were admittedly of great influence to the minds of French philosopher and natural scientist Descartes even in the 1600-s. Newton’s Euclidean geometry and Einstein’s groundbreaking theories and observations were on par with philosopher Immanuel Kant. We know very little about Euclid, and way too little about Pythagoras. Along these lines some keen insights into Biology were shaped via Mathematics, namely, by Euler, Gauss, Jacobi, and David Hilbert, followed by physics giants Niels Bohr, Erwin Schrodinger and John von Neumann. Thinking machines were projected by Alan Turing.
Physicists with an interest in Biology and Genomics were common and Erwin Schrodinger’s book “Way to Life” is a proof of this. At this point emerged French Fractal giant Benoit Mandelbrot, who embraced the Fractals and Fractal theory, but stayed away from Life Science as he speculated that Biologists were not ready, even after the insistence of John von Neumann to apply Mathematics to Biology. Central dogma proposed by Susumu Ohno was published exactly 60 years ago and one decade ago BGI of China purchased Complete Genomics Inc of Silicon Valley.
Mathematics is the mother of all sciences. Norbert Weiner came up with a distinct discipline of Cybernetics centered on feedback, while Crick and Ohno marched ahead with “no feedback” notions of the central dogma and Junk DNA. The Pellionisz Principle reversed both mistaken axioms and thus liberated Molecular Biology.
What we do know is that in India’s Vedic period, speculated to be started by 5000 BC, Indian Mathematics and Astronomy were embedded in Vedic inscriptions. The principal scientist of his time was Dirgatamas Mamateya 4000 BC, a priest of king Bharata, who ruled ancient India and was a great scholar, and a saint. While the term “Fractal” was coined by Dr. Mandelbrot in the late seventies, the concept goes back to Shulba Sutras (Sutra means “Formula”). Arguably,the Sri Yantra diagram involves the application of two irrational numbers, Pi and Golden ratio. This “cultural globe-trotting” seems relevant to this originating from present India for Dr. Pellionisz and Dr. JC Perez another fractal researcher from Paris.
Prof. Janos Szentagothai was a great neuroscientist in Budapest, who trained an entire school of neurobiologists. Dr. Pellionisz was researching Purkinje cells and in a quarter of a century arrived at a mathematical explanation of the function of the cerebellar neuronal networks, by his Tensor Network Theory. Dr. Bela Bollobas, a fellow of the Royal Society at Trinity College, Cambridge, UK had a viewpoint of a global cultural perspective and recounted how Srinivasa Ramanujan a Madras city port clerk who was brought to Trinity College was awarded FRS, working with GH Hardy and Littlewood, 1920s giants in mathematics in the UK. Like Jacobi, Ramanujan also laid solid foundations for fractals in the 1900s.
Late Prof. Luc Montagnier and J C Perez could almost instantly alert the world that Covid-19 showed aberrant fractal properties. Dr. Andras Pellionisz being a biologist, biophysicist and computer scientist proposed what is now considered a reversal of two fundamental axioms, a double heresy, the notion of Junk DNA as proposed by Susumu Ohno and central dogma of Molecular Biology as proposed by Francis Crick.
Thus a postmodern era in genomics started with “The principle of recursive genome function”. The Pellionisz Principle overturned both mistaken axioms of Susumu Ohno’s “Junk DNA” and “Central Dogma” by Francis Crick.
Recognition of late Benoit Mandelbrot came very delayed. After 10 long years of its proposal his Principle is accepted unchallenged but not cited universally for its double-disruptive nature. It was called in as dark matter, but has controlling elements in them that reach far beyond the significant imagination of any Present-day genomics leader. The Fractal approach proposed by Dr. Pellionisz can be industrialized especially in countries like India and other countries in the East without regulatory hurdles that still keep the west handicapped. Third, the fundamental science of the dreaded disease cancer shows that these cells are considered and well established as fractal in nature.
Dr. Pellionisz is a genius in suggesting his seminal paper that so called junk DNA has signals encoded to determine the recursion of DNA, a sort of limit to which the fractals iterations can occur. This is truly a seminal idea. His observation of Mycoplasma genitalia the smallest free-living genome obeys the Zipf-Mandelbrot fractal parabolic distribution hyperbolic curve, itself a sign of fractal nature and thus will play a pivotal role in the early detection of cancer and diagnosis of autism. Having said, how fundamental this breadth is, it is intriguing not to believe its modern applications, like statistical diagnosis, probabilistic prognosis and Precision Medicine.
In 2006 Dr. Andras J Pellionisz showed the smallest DNA of free-living organisms (mycoplasma Genitaliae) contains repeats that conform to the Zipf- Mandelbrot Fractal Parabolic distribution Curve and he presented this at the Venter Institute. Later, in 2009 he presented these results at the invitation of George Church at the Cold Spring Harbor Institute (http://www.junkdna.com/pellionisz_csh.html).
Nobel laureate Hamilton Smith, when he saw the Zipf-Mandelbrot Fractal Parabolic Distribution curve, asked a very good question. “How would the distribution look like if the DNA would be replaced by an identical number of random A, C, T, G-? His response was, I will do the analysis”. Instead of the Zipf-Mandelbrot Fractal Parabolic
Distribution curve for random A, C, T, G-s the curve of repetition- distribution did not appear at all. At that time he did not publish this result, but Ram M V Ramanujam pointed out its timeliness. Going beyond that mathematical comparison, there are two further pieces of analysis one could do.
As it is known, the Venter Institute came up with a seemingly brilliant idea. While the DNA of no living organism can be patented (though synthesizing a small DNA is astonishingly inexpensive), a DNA that does NOT exist in Nature can be patented. Thus, they reduced by about 10% the number of A, C, T, G-s, thus creating a “new and patentable organism” (a stripped-down version of Mycoplasma).
The problem was that for 15 long years, they could not bring the “new DNA” to life! To him, it was obvious that the original DNA had 7% “regulatory” (non-coding) DNA – and while the JCVI did reduce somewhat the number of genes, they did not know how to change the regulatory DNA to kick the reduced set to live! After 15 years they claimed “it lives!” put it in the freezer and abandoned the project.
Thus, one could look into a comparative analysis of the Zipf-Mandelbrot Fractal Parabolic Distribution Curve of the pristine versus reduced genome. It would be most significant to deploy the very powerful analysis by Jean-Claude Perez to see if the Golden Ratio of the pristine versus reduced genome is altered. Both full A, C, T, G sets are available, and we believed the project is very doable. Their rationale could be that overlooking the significance of repeats cost Craig and the Venter Institute very dearly, in three different instances. When Celera assembled the human genome first, contrary to popular belief it was left incomplete, since the “shotgun” assembly could not deal with short repeats. This was most likely a factor why there was no Nobel for “full human DNA sequencing”. The above-mentioned “synthetic life” did not work for 15 long years, again most likely for a lack of sufficient understanding of the role of repeats. Venter had an episode with prostate cancer about a few years ago – and since his very own full DNA was sequenced for 15 years, in retrospect he attributed his cancer to an “extremely few” repeats at a given locus (only 6 instead of the very common 22)
What we consistently believed is an affordable, low-cost outlet of genome editing, led to cures for genetic disorders, to begin with, which was based on a serendipitous discovery by Y Ishino and Monica, in 1987 and 2002, followed by Jennifer Doudna and Emmaneul Charpentier’s reprogrammed tool CRISPR. What ensued was a beautiful collaboration mind in Genomics and the mathematization of Genomics, and a proposal gene editing requires first, the deciphering of fractal defects, in disease genomes but our current limitations and understanding lead to just determining commas and full stops like a spell checker scanning for grammatical error failing to specify smaller to larger deletions and additions which we know are fractal defects like that of copy number variations. Lung cancer is the most prevalent killer in the USA along with breast, colon and prostate cancers. The lung, simply put is the fractal signature. So is a cancerous tumor. In retrospect, the Pellionisz Principle putting the DNA fractal in a cause-and-effect relationship with the organismal the fractal seems almost obvious. The work by Dr. Pellionisz emphasizes the fact that fractal measurements and their correlation established will certainly yield an early detection mechanism. It is proposed that one part of the equation is well established now that we are not clear about what to edit, but we have as scientists are racing and have embarked on germline editing. While mechanisms of action of CRISPR-CAS9, is just getting established, our scientists in a race to gain name and fame are editing genes, but sadly not knowing what or where to edit in cancer-type complex diseases, and also limited off targets effects, they have to be minimized otherwise. The point that we are making in India is, that Dr. Pellionisz has steadfastly and successfully faced a colossal challenge. His revolutionary principles are recommended for India, and also the industrialization of genome editing done with care and proper scientific edifice. What we have is a cross-road approach, biologists have not really fully accomplished even the analytics of the T2 to T2 genome sequenced. People are just sequencing, with no full interpretations of genome sequences, yet we continue pouring big data at an astonishing rate. Dr. Pellionisz asked already in 2008 in a Google talk, “Is IT ready for dreaded DNA data deluge?” His provocative question went not been totally answered or even listened to for over 13 years now. Thus we embarked on our rather treacherous path of a bed of thorns trying to convince scientists and the commercial world to follow low cost affordable Genomic solutions for India and East and other developing LMIC countries where regulatory hurdles can be minimized. However, that path has proven more Himalayan than Everest height is now. Dr. Pellionisz thus proposed “the future pharma will be IT-led” and smartphones will revolutionize genomic medicine as embraced by Dr. Eric Topol, in his famous book Creative Destruction of Medicine.
I thus strongly and full-heartedly address Dr. Pellionisz and Dr. Jean-Claude Perez for their fractal contributions first PRGF, the principle of Recursive Genome Function by Dr. Pellionisz and Dr. JC Perez’s and Dr. Luc Montagnier deciphering the COVID genome exogenous sequences with fractal aberrations. Mathematization of Genomics and genome editing will pave the way for the agricultural revolution, production and food security. In addition to treating the debilitating single-cell mutative Mendelian disorders, to extend diagnosis and therapy for autism to cancer. My vision is global and scalable.
Time will tell whether Dr. Pellionisz’s ground-breaking path is going to be embraced or going to be remembered like the discovery epitome of 20th century Indian maize fame Barbara McClintock. For the History of Science it may not matter much. For doing away with cancer it will be a life-or-death issue for mankind. We in India, a select few in 1.45 billion who have stood with him in the test of times for the past decade would only wish his recognition for a humble Hungarian born, American Scientist’s pure and unadulterated persistence to seek truth, in the name of curing cancer, an enemy of the planet and there cannot be a plan B in this aspiration, but his unrelenting march towards to the fight against cancer, a minute by a minute killer, a natural enemy, and can cause havoc in destabilizing the stability and wellness of the nations.
One last geo strategy note about genome editing. Many in security and Intelligence circles believe that genome editing is a cause for worry as they can inflict not only destruction at a mass level but genome-engineered designed soldiers are possible. Intelligence circles cannot disregard the caveats and potential as
The remote possibility of a mildly potent genome-engineered version of bio arsenal. While it is certainly not a garage-style DIY science, it should be no secret that scientists are already working on it. If the so-called skilled in the art hardly can decipher the fact of what to edit first, then the perils of misuse are at least far from reality at present. When designer babies are not welcome, and germline editing is a contentious issue subject to regulation, one can assume genome editing for diseases is the real potential for the next decade and the Genetic Engineering of the 21st Century. As a collaborator in Fractal Genomics, we have assumed leadership in fractal algorithmic approaches since they are software-enabling approaches. We hope this effort should be funded by investors to start a foundation in India for curing the dreaded genetic and rare disorders. Our ideation from scratch, in the last 13 years deserves an accolade. Both myself from Bangalore and Prof EG Rajan from Hyderabad; would like to very strongly advocate for investments in fractal approach in this part of the world. We herald this Principle as a path-breaking discovery. Dr. Pellionisz shouldered the burden of dislodging genomics from a half-a-century deadlock by mistaken axioms. Fractal genomics would make sense, making a home run for India and developing nations since fractals are deeply embedded into ancient Indian culture and architecture and mathematics now computer science and Software. It’s a rare opportunity for India to claim a space in the world of Genomics enterprise. The symbolism of Lindenmeyer fractals have been absorbed by me the author of this piece and India has to enter its metal in the world Genomics enterprise to carve out a niche place.
Acknowledgements:
I thank Prof Dr Andras Jeno Pellinisz for his immense coaching since 2010 on Fractal Science and Prof Dr Jean-Claude Perez for enhancing the learnings during the past very many years. I thank my Computer Science guru Prof Dr EG Rajan, Hyderabad for his guidance in the past 25 years not only as a teacher but as his immediate family. I am indebted to Prof Dr Sergey Petoukhov for introducing me to the world of Genetic Music and Symmetry, along with Fractal Genome. I am very much thankful to my Maternal Uncle Prof Dr Rajan Varadarajan for 40 years of mentorship in my Scientific career.
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