This is the second of three guest posts from panellists in the Race to the $1000 Genome session tomorrow at the Cheltenham Science Festival. Yesterday we heard from Oxford Nanopore‘s Clive Brown about the disruptive effects of genomic technology; today’s instalment is from science broadcaster Adam Rutherford, presenter of the recent BBC series about the genome, The Gene Code. Tomorrow we’ll hear from Genomes Unzipped’s own Caroline Wright.
There are known knowns; there are things we know we know. We also know there are known unknowns; that is to say we know there are some things we do not know. But there are also unknown unknowns – the ones we don’t know we don’t know. –Donald Rumsfeld.
The expectations of the Human Genome Project were Rumsfeldian. This much-mocked statement that the then US Secretary of Defense Donald Rumsfeld made in response to the continued absence of evidence for weapons of mass destruction was made almost exactly a year after the publication of the first results of the Human Genome Project (HGP). His oddly profound cod-philosophy resonates with that grand endeavour. The announcement, initially in June 2000, and the publication, were met with triumphalism in the media, fanned by our and its glorious leaders. President Clinton stood on a platform, flanked by Craig Venter and Francis Collins at the White House, and declared that:
Without a doubt this is the most important most wondrous map produced by human kind…
Today we are learning the language in which God created life.
Whatever your religious disposition, that is a bold statement. He and others went on to speculate that soon we would understand and be on the path to curing many, if not all, diseases. Geneticists bristled at this hubris. The fundamental problem was unknown unknowns. It turned out that humans have far fewer genes than we expected. The vast majority of the genome does not contain genes. So what is it doing?
Culturally this was and is a big deal: the history of genetics has conspired to reveal a simplistic view of inheritance. In the 19th century, Mendel revealed the rules of inheritance with his pea experiments: traits such as flower colour are carried by discreet units, genes, one from each parent. At the beginning of the 20th, Thomas Hunt Morgan cross bred fruit flies and showed that these genes sat on chromosomes. Crick and Watson revealed the mechanism of genetics in the iconic DNA double helix. Crick went on to formulate the so-called central dogma, that DNA makes RNA makes protein. In the 1980s, with DNA sequencing in its infancy, the first human diseases to be understood genetically were ones that slavishly followed simple Mendelian inheritance patterns: cystic fibrosis, Huntington’s disease, Duchenne muscular dystrophy.
But humans are not simple. The unknown unknowns of human genetics in 2001 were that we didn’t know that these disorders were the outliers, and we didn’t know what was hidden in the rest of the genome. Whilst all of the tenets of genetics are still correct, we can’t currently account for human heritability or complexity using the straightforwardness of those models. To characterise this, as some have done, as a “crisis” in genetics is absurd. This is a perfectly valid scientific issue, which will be resolved with science.
This is why the drive for the conceptual $1000 genome is important. While we’re keen to point out that humans are unique, we’ve been slow to point out that that uniqueness will be reflected in our genomes. The HGP was a brilliant and necessary step in elucidating human complexity and disease. Characterising rare genetic differences between individuals, rather than the broad similarities, is a crucial step on that path, and this can only be achieved by sequencing many more people’s genomes. As such, the drive to reduce the cost of sequencing is absolutely critical. This is the process of science: converting unknown unknowns via known unknowns, into known knowns. Who knew Donald Rumsfeld was such a clear thinker?