20 years ago the Human Genome Project was declared complete and the global media trumpeted the beginning of a new era of scientific discovery. In this blog Dr Peter Attia describes, both, why much of optimism about the HGP was misplaced and yet how the HGP is genuinely opening up pathways to new medical discoveries.

He starts by explaining that the misplaced over-optimism regarding the HGP was due to scientists’ incorrect understanding about genes actually work: “…in looking back, these pie-in-the-sky predictions about the HGP’s potential immediate benefits reveal just how little we truly knew about our own genetics and biology before this project began…
The “central dogma” of biology states that genes “work” by being expressed – that is, they are transcribed into RNA, which in turn is translated into proteins, which then carry out countless cellular functions. Prior to the HGP, it had been thought that the complexity of an organism would therefore correlate positively with its number of genes: more genes = more proteins = more functions.

Given this logic, one of the most shocking results of the HGP was that the human genome contained far fewer genes than previously thought – only around 20,000, or roughly the same number as are found in a sea sponge (or ~one-third of the number found in soybeans). Further, it was discovered that this “functional” DNA accounted for only a tiny minority of the total human genome. Approximately 98% of our DNA does not code for proteins at all, and scientists were at a loss for how to interpret this genomic “dark matter.” The research also revealed that our genetics are remarkably similar to that of other species. For instance, mainstream media has popularized the knowledge that humans are 50% genetically identical to bananas, while the fact that we share 99% of our DNA with chimpanzees illustrates just how little of our genetic material defines all of our many uniquely human qualities. Together, these surprises signaled that our understanding of how genetics influence our biology was woefully simplistic…

The Human Genome Project mapped out the sequence of letters that make up the human genetic code, but the task of deriving meaning from that sequence was not as trivial as many had hoped. The relatively small number of genes implied (correctly) that they – and their eventual protein products – could be modified or regulated in myriad ways which would alter their expression and function. To some, this meant that the project was a failure and that research ought to shift away from genetics and toward environmental influences on disease. One particularly pessimistic journalist went as far as to call the HGP a “map to nowhere” and expressed the belief that deciphering such a complex system would never be possible.”

Then Dr Attia moves on to the good news: “…the HGP led to the 2003 launch of the Encyclopedia of DNA Elements (ENCODE) Project, aimed at determining the function of all genomic material, whether protein-coding or not. ENCODE has since reported that over 80% of the genome demonstrates some form of functionality, with much of the “dark matter” DNA involved in regulation of gene expression in various cell types – a critical link between the genetic code and biological relevance. However, the task of deciphering which genes are regulated by which non-coding elements and under which circumstances is ongoing…

Another undertaking that arose in the wake of the HGP was the 1000 Genomes Project, an international collaboration to catalog common genetic variations across humanity.”

In short, 20 years on from the supposed culmination of the HGP, we now actually know how genes work and scientists are now trying to figure out the precise mechanics of how just 20,000 genes (of which 98% do not code for proteins) determine how physical and mental make-up.

Then Dr Attia points out a big issue with how gene research is progressing: “In order to use genetic information to gain insights into personal health risks, we must learn how genetic sequences vary in certain locations across individuals, and how each of those different variations correlates with disease. (For example, I’ve frequently discussed how the APOE4 variant of the APOE gene is associated with elevated risk of Alzheimer’s disease.) But we can only study risk for the variants we know exist, and we only know they exist if they’ve been documented before.

Analysis has revealed that around 70% of the original HGP genome derived from a single individual, providing a reference for comparison but virtually no information on variation. Since then, the cost of human sequencing has plummeted, facilitating expansion of sampling for the purpose of identifying and studying variants. But this process has been heavily biased in its representation: a 2019 study found that around 80% of all participants in genetic studies have been of European descent, a group which represents around 16% of the world’s population. This disparity is a problem for two reasons.

First, it means that underrepresented groups are far less likely to benefit from genetic risk assessments, as they are more likely to possess variants for which we do not have enough data on possible associations with disease. This in turn is likely to heighten racial and geographical inequalities in quality of medical care.

Second, it deprives us of a source of knowledge which might benefit all populations. Certain variants are only present in specific populations and are therefore more likely to be discovered by sampling from a broad spectrum of humanity. But the insights these variants provide on health may be applicable to many. An excellent example of this scenario is the identification of a rare variant, present primarily in African Americans, that results in loss of function of the PCSK9 protein. As I explained in a previous newsletter, these individuals have low cholesterol levels and are largely protected from atherosclerotic cardiovascular disease – a discovery which inspired the development of a class of lipid-lowering PCSK9 inhibitor drugs, which have proven highly effective in reducing cardiovascular risk across broad populations.”

Given the incredible amount of genetic diversity in the Indian sub-continent’s population and given the highly developed pharma & science ecosystem in India, gene based research seems to be a commercial opportunity crying out of an ambitious Indian scientist.

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