The Human Genome Project Wasn’t Overhyped. The Payoff Just Took Time
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the full range of human genetic information at the highest level of resolution—the single nucleotide. Whereas the first-draft human sequence cost nearly $3billion to produce, we can now sequence an entire human genome for a cost approaching $1,000. This allows comparisons at maximum sensitivity across thousands; in due time, millions of genomes from individual people. It is the greatest increase in output of any technology in human history, including the computer chip. At last, we are within sight of the greater promise offered by human genetic variation studies —a vista into the physiology of the most common and devastating diseases, leading to novel therapies for patients who now lack good options.
To realize the full benefit of this potential, comparisons among affected and unaffected persons are essential. We know from twin studies that genes determine many human traits, including disease risk, but pairwise comparisons, in isolation, have little power to delineate which of the roughly 25,000 human genes influence which of the 100-plus most common diseases.
Using New Genomic Technologies to Hunt For New Medicines
A more powerful approach is to search for rare variants that convey a large fluctuation in disease risk. We know that these rarer variants can be much more informative for guiding development of new medicines. An excellent example is the PCSK9 locus that impacts heart disease risk—identified originally by analysis of rare individuals with abnormally high cholesterol levels. The protein encoded by the PCSK9 locus is now the target for innovative targeted therapies under development by several companies, including our company (Amgen) as well as Sanofi and Regeneron Pharmaceuticals. This type of genetic insight had been relatively infrequent because of the limited tools available, but now, virtually any disease is accessible to this approach because we have the power to integrate large clinical datasets with detailed DNA sequence information across a population.
Harnessing the Power of Human Genetic Variation and De-risking Drug Development
Human genetic variation is nature’s gift to medical science. Without it, drug discovery would remain at the mercy of disease models in animals and drug development would remain a high-risk enterprise marked by frequent, expensive failures caused by our limited knowledge of valid human disease targets.
We don’t know exactly how this genetic gift will appear when fully unwrapped, but we have a sense of where we are headed. Eventually, we will be able to sample almost the entire spectrum of gene differences by comparing human diversity at the scale of tens of millions of people. Such scope is now within our line of sight.
Our society values basic knowledge about the biological world as much as practical applications, and we have a history of investing in our future, even if the returns are long-term. The Human Genome Project was such an investment. Genetic data that flow from this initial work promises to ease the shortage of insights into the complex biology of human diseases and novel therapeutic mechanisms that may afford large effects without undue sacrifice of safety and tolerability. The new human genetics, built on the foundation of the genome project, lights the path.