Straight Dope on Medicine: The Dark Genome

Author

Scott Ganser
September 11, 2023

Dark Web

noun

  1. the part of the World Wide Web that is only accessible by means of special software, allowing users and website operators to remain anonymous or untraceable.

"the Dark Web poses new and formidable challenges for law enforcement agencies around the world"

I’m not a computer geek. My specialty is medicine.

We’ll have to be satisfied with exploring the biological equivalent: The Dark Genome.

The human genome is divided into a "coding" genome containing approximately ~23,000 protein-coding genes and a "dark" genome that does not encode proteins. Although non-coding genome regions do not provide instructions for making proteins, they contain key hereditary information from a regulatory point of view.[i]

Regulation is the key word.

These regulators are called silencers, promoters, enhancers and repressors. They determine how much you get of a protein, or if you get any at all.

It constitutes about 98% of the genome.

Why the sudden interest?

On the surface, the dark genome isn’t the center of interest. It doesn’t make anything.

But it sure can screw things up!!

It is believed that it is implicated in 650 haploinsufficiency diseases, as well as autoimmune diseases, neurodegeneration, cancer and aging.[ii]

They are also finding out that it CAN make something, given special circumstances.

About ROME Therapeutics

ROME Therapeutics is developing novel therapies for cancer and autoimmune diseases by illuminating the role of the dark genome in human health and disease. Leveraging the company’s unprecedented data sciences platform, ROME has built a deep pipeline of therapies targeting the dark genome. To lead this exploration, ROME has assembled a team of world-class leaders across oncology, immunology, virology and machine learning. ROME is based in Boston, Mass.

About Enara Bio

Enara Bio’s purpose is to shine a light on unconventional T cell targets to develop the next generation of cancer immunotherapies designed to treat broad patient populations. Enara’s proprietary EDAPT® platform enables the discovery of Dark Antigens®, a novel source of shared, tumor-specific T cell targets derived from genomic dark matter. We are pioneering approaches to exploit these Dark Antigen targets with a range of immunotherapeutic modalities, including bispecific T-cell engagers, adoptive cell therapies and cancer vaccines. Based in Oxford, UK, Enara Bio is backed by RA Capital, Samsara Biocapital and SV Health Investors.

It is now increasingly clear that the functional importance of the dark genome tails in its regulatory non-coding RNAs (ncRNAs) and Transposable Elements (TEs), which were largely overlooked in genetics studies.

New Frontier

Newer technologies finally have allowed scientists to sequence pieces of DNA and apply artificial intelligence and machine learning approaches or computational approaches to extract information. This has led to remarkable discoveries in the dark genome with implications for several human diseases.

One such example is the research of Sudhakaran Prabakaran, a former faculty member at the University of Cambridge and now Executive Officer and Chief Technology Officer of NonExomics, Inc., in Boston[iii]

“My research (at Cambridge) demonstrated that the entire human genome makes proteins pervasively and not necessarily just from the regions that we call ‘genes’,” says Prabakaran. “We showed that ‘novel’ proteins from the so-called dark matter regions of the genome are capable of forming structures, performing functions, and [that these proteins] are disrupted in a number of diseases, including schizophrenia and bipolar disorder.”

Schizophrenia and bipolar disorders are known to have genetic causes. Current treatments are ineffective and have adverse side-effects, likely because they only target proteins encoded by the “known” 1-to-2 per cent of genes.

Conclusion
Initially the Dark Genome was cast aside as “junk DNA.” Now, the thought process is changing. It has uses, and we are discovering them day by day.

Now, two decades on, we have the first inklings of the role of the dark genome. Its primary function appears to be regulating the decoding process, or expression, of protein-making genes. It helps to control how our genes behave in response to all the environmental pressures our bodies face throughout our lives, ranging from diet to stress, pollution, exercise, and how much we sleep, a field known as epigenetics.[iv]

Panay in the Philippines is best known for shimmering white sands and a regular influx of tourists, but this idyllic setting hides a tragic secret. The island has the highest number of cases in the world of an incurable movement disorder called X-linked dystonia Parkinsonism (XDP). Like Parkinson's disease, people with XDP develop a range of symptoms affecting their ability to walk, as well as their capacity to respond quickly to various situations.

Since XDP was first discovered in the 1970s, it has only ever been found in people of Filipino descent, something which had long been a mystery until geneticists found that these individuals all have the same unique variant of a gene called TAF1. The onset of symptoms seems to be driven by a transposon (a Dark Genome element) in the middle of the gene, which is able to regulate its function in a way which causes harm to the body over time.

"The TAF1 gene is an essential gene, meaning it's required for the growth and multiplication of all cell types," says Boeke. "When you tweak its expression, you get this very specific defect that manifests as this horrible form of Parkinsonism."

In the field of cancer vaccines, where companies conduct DNA sequencing on a patient's tumor sample to try and identify a suitable target for the immune system to attack, the majority of approaches have focused only on the protein-coding regions of the genome. However, German-based biotech CureVac is pioneering an approach where they analyze the non-protein coding regions as well in the hope of finding a target which can disrupt the cancer at its source.

Ounzain's company, Haya Therapeutics, are currently pursuing a drug development program targeting a series of non-coding RNAs which drive scar tissue formation, or fibrosis, in the heart, a process which can lead to heart failure. One of the hopes is that this approach could minimize the side effects which come with many common medicines.

With the Dark Genome, we are going to continue to explore, learn and apply. Perhaps, at the end of it all, the Dark Genome won’t be so dark anymore. It could use a more enchanting name, nomen. How about the Enchanted Genome?