P4 Medicine Era- Fractal Organs grow Fractal Organisms:  Fractality Of The  Human Genome.

~ Ram M V Ramanujam, President-Founder &CEO, Propinquity Therapeutics, Bangalore, India.

“The Principle of Recursive Genome Function” (PRGF) upon completion of ENCODE project by Hungarian American Genomics Pioneer and mathematical approaches in Biology are illustrative as the paper revealed that a repetitive self-similar process governs how the fractal genome governs growth of fractal organs and organisms.

During 70s emerged French fractal giant Benoit Mandelbrot, who embraced the Fractals and Fractal theory, but stayed away from life sciences as he speculated that biologists were not ready, even after insistence of John von Neumann to apply mathematics to biology. Central dogma by Susumu Ohno proposed was published exactly 60 years ago and one dacade ago BGI of China purchased Complete Genomics Inc of silicon valley.

While the term “fractal” was coined by Dr.Mandelbrot in the late seventies, the concept goes back to Salbustra (Sutra means “Formula”).Arguably, the Sri Yantra diagram involves application of two irrational numbers, Pi and Golden ratio. These “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 scientists in neurobiology. Dr Pellionisz was researching Purkinje cells and in a quarter of Century arrived at a mathematical explanation of the function of the cerebellar neuronal networks, by his Tensor Network

Theory. Incidentally from the viewpoint of a global cultural perspective, Dr. Bela Bollobas,who become a Fellow of the Royal Society in Trinity College, Cambridge, UK. Prof. Bollobas 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 UK. Ramanujan he compared with the likes of Jacobi, also laid solid foundations for fractals in 1900s Late Prof Luc Montagnier and JC Perez could almost instantly alert the world that Covid-19 showed aberrant fractal properties.

Pellionisz being a biologist, biophysicst 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 “Junk DNA” and “Central Dogma” by Francis Crick.

Recognition to Late Benoit Mandelbrot came very delayed.

After 10 long years of its proposal his Principle is accepted unchallenged but not universally cited for its double-disruptive nature. Called in as Dark Matter, but has controlling elements in them that reaches far beyond the imagination as significant, by any present day genomics leader would have realized. 98 percent junk and 80 percent functional. First, The Genome is Fractal. Second, the Fractal approach proposed by Pellionisz can be industrialized especially in countries like India and East without regulatory hurdles that still keep in the west handicapped. Third, it is fundamental to science, in doing away with the dreaded disease cancer, as these cells are considered and well established as Fractal Nature. Dr Pellionisz is a genius in suggesting 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 genitaliae the smallest free living genome obeys the Zipf-Mandelbrot fractal parabolic distribution hyperbolic curve, itself a signature for fractal nature and thus will play a pivotal role in 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 presented at the Venter Institute, showing that the smallest DNA of free-living organisms (Mycoplasma Genitaliae) contains repeats that conform to the Zipf- Mandelbrot Fractal Parabolic Distribution Curve (later, in 2009 he presented these results by the invitation of George Church at the Cold Spring Harbor Institute, see http://www.junkdna.com/pellionisz_csh.html

Nobelist 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, 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 life!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, at 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 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), see https://www.xconomy.com/san-francisco/2016/12/08/craig- venter-used-own-posh-health-clinic-to-diagnose-his-cancer/

What we consistently believed is an affordable, low cost outlet of genome editing, led cure 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 minds in Genomics and Mathematization of Genomics, and proposal Gene editing requires first, the deciphering of fractal defects, in disease genomes but our current limitations and understanding leads 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 a most prevalent killer in USA along with breast, colon and prostate cancers. The lung, simply put is fractal signature. So is a cancerous tumor. In retrospect, the Pellionisz Principle putting the DNA fractal in a cause and effect relationship with organismal fractal, seems almost obvious. The work by Pellionisz emphasizes the fact that fractal measurements and their correlation established, will certainly give 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 germ line editing. While mechanisms of action of CRISPR-CAS9, TALENS is just getting established, are 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, that have to be minimized otherwise.

The point that we are making in India is, that 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 T2 to T genome sequenced. People are just sequencing, with no full interpretations of genome sequences, yet we continue pouring big data at an astonishing rate. Pellionisz asked already in 2008 in a Google talk, “Is IT ready for dreaded DNA data deluge?” His provocative question went not totally answered or even listened to over 13 years now.

Thus we embarked on our rather treacherous path of bed of thorns trying to convince scientists and commercial world to follow low cost affordable Genomic solution for Indian 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 smart phones will revolutionize the genomic medicine as embraced by Dr Eric Topol, in his famous book Creative Destruction of Medicine.

I thus strongly and full-heartedly address Pellionisz and JC Perez for their fractal contributions first PRGF, principle of Recursive Genome Function by Pellionisz and JC Perez’s and 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, Food security. In addition to treatingthe 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 Pellionisz’s ground- breaking path is going to be embraced or going to be remembered like the Discovery Epitome of 20th century the 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 one 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 minute killer, a natural enemy, and can cause a 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 arepossible.

Intelligence circles cannot disregard the caveats and potential as remote possibility of as 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 what to edit first, then the perils of misuse are at least far from reality at present. When designer babies are not a welcome, and germ line editing is a contentious issue subject to regulation, one can assume genome editing for during diseases is the real potential for next decade and Genetic Engineering of 21st Century.

As a collaborator in Fractal Genomics, we have assumed for assuming leadership in fractal algorithmic approaches since they are software-enabling Approach. 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.

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. Its a rare opportunity for India to claim a space in word genomics enterprise.The symbolism of Lindenmeyer fractals have been absorbed by myself the author of this piece and India has to enter its metal in the world Genomics enterprise to carve out a niche place.