Ten year retrospectives are a popular form of gazing at near history. So it is with looking at the results of the first complete sequencing of the human genome (first draft released June 26, 2000). The Human Genome Project was a three billion dollar multi-year program that finally achieved the long sought genome-wide catalog of human genes. It was hailed as a mighty achievement (which it was), that it would revolutionize biology (which it did somewhat), and would signal a beginning to a new era of medical cures based on the genomic information (which it didn’t). It’s this last point that’s attracting much of the attention. Sequencing the human genome has had many important effects, but creating new medicines to cure major diseases has not been one of them.

This aspect of the consequences of the Human Genome Project hasn’t been a secret. As the pharmaceutical researcher/blogger Derek at In the Pipeline puts it:

…there was already a deep sense of nervousness among the people searching the sequences for disease clues – not to mention the nervousness among the people who had given them huge piles of money to do so. When the total estimated number of genes came out far lower than most people expected, there was a collective “Hmmm. . .” across the field. That number meant that the simpler possibilities for gene sequence-protein-disease linkage could already be ruled out – complicated things were clearly going on in transcription, translation, and further downstream.

[Source: In the Pipeline]

Now, a June 12th article by Nicholas Wade, A Decade Later, Genetic Map Yields Few New Cures in the New York Times brings the issue (if it can be called an issue) to broader public attention.

It’s not so much that the sequencing of the human genome didn’t create possibilities for medical advances; it’s that they were consistently oversold (in part to encourage funding and public support). The Times article quotes a couple of high-profile figures, for example, then President Clinton: “[sequencing the genome will]…revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases.” But the payoff hasn’t arrived, at least not yet. The pharmaceutical industry has pumped billions into researching the secrets within the genome, but has found little reward. A quote from the Times article stands out: “Genomics is a way to do science, not medicine,” according to Harold Varmus, soon to be director of the U.S. National Cancer Institute.

The reason few new medicines have been guided by the association of genes with disease – greater complexity – is also the reason that sequencing the human genome has been a watershed for biology. As Wade puts it in the Times article:

But while 10 years of the genome may have produced little for medicine, the story for basic science has been quite different. Research on the genome has transformed biology, producing a steady string of surprises. First was the discovery that the number of human genes is astonishingly small compared with those of lower animals like the laboratory roundworm and fruit fly. The barely visible roundworm needs 20,000 genes that make proteins, the working parts of cells, whereas humans, apparently so much higher on the evolutionary scale, seem to have only 21,000 protein-coding genes.

The slowly emerging explanation is that humans and other animals have much the same set of protein-coding genes, but the human set is regulated in a much more complicated way, through elaborate use of DNA’s companion molecule, RNA.

Little, if any, of this research could have been done without having the human genome sequence available. Every gene and control element can now be mapped to its correct site on the genome, enabling all the working parts of the system to be related to one another.

[Source: New York Times]

From the medical perspective, an excellent article by Orac at Respectful Insolence covers many of the details, including the main points of what is sometimes called the GWAS (Genome wide association studies) controversy, for example:

…whenever you look at large numbers of anything and try to link them to something, there will be many false positives, and there will be a lot of noise. Because of the enormous amount of data generated in GWAS, it’s not at all surprising that, statistical tests notwithstanding, that most of the associations detected would be due to chance or to statistical flukes. This is particularly true since scientists don’t actually sequence the genomes of people in these studies. Rather, they look for sites in the genome where many people have a variant bit of DNA, known as the single nucleotide polymorphism, or SNP. When you start looking for differences in 1.2 million SNPs, you will find them. Lots of them. It isn’t the SNPs per se that tell us a lot, but rather the genes implicated by the SNPs, and, more importantly, the biological pathways and functions of the networks of genes implicated by them.

[Source: Respectful Insolence, The Human Genome Project: Hype meets reality]

Three observations:

1. The hopes for the medical benefits derived from genome sequencing were overhyped. Put another way, the expectations were unrealistic.
2. Typically the benefits from major shifts in medical knowledge take not one but several decades to develop. Time will tell us more.
3. The stark claims for medical benefits from genomic analysis dissolved into something much more subtle and complicated. The complications opened a door into another view of biological reality, much as physicists found a different world when it became known there was something more than atoms.

For those in the medical research community, the frustration of finding mostly questionable correlations between genes and disease has only been compounded by the realization that the road to treatments goes through more complicated genetic pathways than previously thought. This same realization has been the stimulus for biologists to dig ever deeper into the way genes and their expression actually work. Eventually, their basic research will provide keys to many medical treatments – just not in this past ten years; in the next ten years, maybe.