entrePRECISIONeur: Sudhakaran Prabakaran Discusses Discoveries in the Dark Regions of the Genome

Sudhakharan Prabakaran
Sudhakaran Prabakaran
Founder, NonExomics

Editor in Chief Damian Doherty spent some time speaking with Sudhakaran Prabakaran about his company NonExomics and how he hopes to unravel the complexity of how cells achieve signalling specificity and subsequently translate these learnings into a better understanding of disease mechanisms.

 

What was the genesis of NonExomics?

I did my PhD at the University of Cambridge on ‘omics’ data analysis to understand schizophrenia and bipolar disorder but wasn’t entirely happy looking at snap shots of gene and protein expressions. So I joined Harvard University to understand the dynamics of gene and protein interactions using mathematical models to better understand cellular processes. Even this approach failed to really convince me because we were still missing something fundamental in the mathematical models. It was around about 2014, that next-generation sequencing datasets from different platforms were becoming available. So, putting all these datasets together we noticed that the entire human genome has the ability to make proteins and these novel regions couldn’t be defined as genes.

This observation created the underpinnings of the academic lab that I started in 2016 at the University of Cambridge. We started by systematically curating and cataloguing the human genome to identify all such possible novel gene regions and subsequently we identified around 250,000. This number is not set in stone and continues to increase. We showed that the proteins made by these novel genes are capable of forming structures, perform functions, and are disrupted in 1365 human diseases. More importantly, we showed that these novel proteins are druggable.

In 2021, I realized the enormous potential of this entirely new biology to aid in diagnosing and treating diseases that I filed for patents, quit my academic lab at the University of Cambridge, and co-founded NonExomics in Boston along with two colleagues, Dr. Ruchi Chauhan and Mr. Gary Magnant. NonExomics then licensed out all these discoveries from the University of Cambridge and has advanced the science and generated its own IP.

 

How important are these dark non-coding regions and what have you found thus far?

Through a series of publications in high-profile journals we demonstrated that proteins made from these noncoding regions are functional, disrupted in diseases, and more importantly are druggable. We used population scale datasets in our analysis to understand the significance of these new findings, such as the TCGA (for cancer, PsychENCODE (for schizophrenia and bipolar disorder), the UK biobank, and large- scale rare disease repositories.

We showed that mutations in these novel genes are not tolerated during the evolutionary process, which means that any mutations in these regions are deleterious and selected out. We showed that thousands and millions of mutations that we currently classify as benign or of unknown significance need to be reclassified based on this new evidence. Each and every one of our discoveries has the potential to become new diagnostics and therapeutics.

Taken together our findings have opened up an entire area of biology, the true significance of which, can only be realized if we are able to scale up the discovery process.

 

What tools and technologies are you using to interrogate the vast expanse of the genome that has hitherto been largely neglected?

We have developed a computational and machine learning based algorithm to identify these novel proteins. We have also developed a structural genomics-based algorithm to investigate the druggability of these novel proteins.

 

Are there other groups like the NIH ENCODE project that have helped generate interest in this particular area of research?

Just recently a consortium of 33 academic labs was announced to study these proteins entirely based on our work. I was a reviewer for an article for this consortium correspondence.

 

What is your growth strategy as a company beyond seed funding stage?

We would like to partner with as many interested collaborators (biotechnology and pharmaceutical companies) as possible to take our discoveries forward to develop therapeutics. Internally, we are interested in neurodegenerative and neuropsychiatry disorders and will initially develop targets in those areas, but we would like to see all of our other discoveries, including those that relate to cancer and rare diseases, be used for developing novel diagnostics and therapeutics.

 

You’re involved in the Illumina accelerator-how important is this recognition from a leading global sequencing powerhouse?

We are incredibly grateful to be part of the Illumina accelerator, it was a significant milestone for us. Their backing has given us a huge platform, enormous visibility, and has opened many doors.

Besides Illumina, AWS has been a trusted partner and supporter of our work. We are also grateful to our current investors, Formation Venture Engineering, LLC.

 

It seems the work you are doing in novel open reading frames is unchartered territory-are you pioneers in this space?

Yes, we started this work in my academic lab at the University of Cambridge. We encountered enormous resistance. My colleagues dismissed this work as noise in the initial stages and academic grants were difficult to get. But we persisted with our science and continued to demonstrate solid and irrefutable proof that these novel open reading frames (novel genes) make proteins that could perform biological functions. We continue to assert that investigating these proteins is critical; in understanding biological process and disease origins. We’re also behind a clarion call to redfine a gene based on our findings. Now there is a huge international consortium of scientists coming together to study this. It does feel great to have persisted with our efforts.

In addition to showing the importance of these novel proteins in biological process we outlined their role in speciation and evolutionary process. We demonstrated with a couple of scientific publications that not only human genomes but indeed all organisms are capable of making proteins pervasively and this process gives them the ability to evolve.

 

Are you looking to forge partnerships with academia and industry across different disease indications?

We are constantly looking for forging partnerships whether academic or industry and we have already initiated discussions with a number of entities. We cannot do it alone.

 

You’ve made some discoveries in schizophrenia and bipolar disorder-can you elaborate?

Our schizophrenia and bipolar disorder findings are very significant. These two disorders have always remained a genetic conundrum. We showed that novel proteins that are most disrupted in these diseases have emerged from the recently evolved regions of the human genome called the accelerated regions. These regions are entirely different from even our close relatives, the primates. Because schizophrenia and bipolar disorders are dysfunctions in higher order cognitive functions that are not found in primates, we suggested that perhaps the cure for treating schizophrenia and bipolar disorder should be based on these novel proteins that are recently evolved. Incidentally, the genetic hotspots for these two disorders map to the regions where these novel proteins emerge, thus supporting our hypothesis that we need to investigate these novel proteins to cure schizophrenia and bipolar disorder.

 

Why do you think it has taken two decades to come to the realization that 98% of the genome matters?

There are multiple reasons for this.

1.The technology was not there. The sensitivity of genomic, transcriptomic, and proteomics technologies have improved only recently

  1. These technologies were developed in silos. There was no cross talk between these technologies. Our analysis frame work started with the integration of these technologies.
  2. Algorithms were not there. We had to develop the algorithms over the last eight years to be able to do this.
  3. The computational power to deploy these algorithms were not there, we embraced AWS cloud infrastructure early on and built all our capabilities in a cloud framework.
  4. There was a huge conceptional barrier and inertia in dismantling our conventional notions of what a gene should be and what a protein should look like.

We have slowly overcome all these conventional and conceptual barriers.

 

How optimistic are you that precision medicine can be democratized for future generations?

It is indeed a possibility. Now we have a multitude of diagnostic capabilities based on molecular, clinical, and imaging technologies that can be acquired on wearable technologies. We have AI and computational capabilities to process all this data in real time and identify signatures that can inform a clinician to make more precise treatment programs. I believe the confluence of all of these areas will democratize precision medicine for future generations.

 

Damian Doherty has been in media and publishing for nearly 30 years, beginning in the early nineties at News Corporation. Damian has managed, edited, and launched life science titles in drug discovery and precision medicine. He was features editor of  Drug Discovery World for fourteen years and founded, established, and edited the Journal of Precision Medicine in 2014. In parallel, Damian founded and organized the Precision Medicine Leaders’ Summit, a global, immersive 3-day senior leadership conference that still runs today. He edited AIMed magazine in 2019 before launching Photo51Media, a platform for illuminating untold, compelling stories in precision healthcare. Damian joined Mary Ann Liebert in 2021 to help steer the new rebrand and relaunch of Clinical OMICS to Inside Precision Medicine.

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