The Human Genome Project, whose results were announced in June of 2000 and published in full 10 years ago, took 13 years and $3 billion to complete. For biology, it was unprecedented in scale: it determined the sequence of three billion units, or base pairs, of human DNA. What life scientists wanted from the project was equally ambitious: they hoped sequencing our DNA would reveal the genetic causes of disease and lead to diagnoses, treatments, and cures for intractable illnesses like many forms of cancer.
In this issue of Technology Review, we explore what happened to those hopes.
Over the last 10 years, many advances in genomics have been made. As Jon Cohen explains in the introduction to our package of stories on the topic, “The price of sequencing DNA has dropped … to mere thousands [of dollars per person]. The number of single-gene aberrations known to cause disease … has jumped from 100 to nearly 3,000. The growing list of common diseases that have been traced to multiple genetic variants includes everything from types of blindness to autoimmune diseases and metabolic disorders like diabetes. Studies have linked more than 200 genes to cancer.”
But taken as a whole, it was a long, hard decade for genomics. Researchers and clinicians will disagree about how quickly they imagined the Human Genome Project would bear fruit, but no one will contest that the genome has turned out to be bafflingly complex and that genomic information has yielded few new cures. Cohen describes some of the difficulties in his introduction, and Stephen Hall provides more detail in “The Genome’s Dark Matter”: “Large-scale genomic studies … have mainly failed to turn up common genes that play a major role in complex human maladies. More than three dozen specific genetic variants have been associated with type 2 diabetes … but together they have been found to explain about 10 percent of the disease’s heritability … Results have been similar for heart disease, schizophrenia, high blood pressure, and other common maladies.”
In short, we have expended enormous energy on searching for disease genes, but it has become clearer that a variety of other factors, once thought minor, are in fact as important to our health as genes themselves. These include how much or how little of a protein is produced (gene expression); the degree to which gene expression can be influenced by mechanisms other than changes in the underlying DNA sequence (dubbed “epigenetics,” because the field studies mechanisms above—“epi”—the genome); and whether we have extra or missing copies of genes (copy-number variation).
This “missing heritability” problem—the fact that individual genes cannot account for much of a disease’s heritability—has significant implications for medicine. It turns out (as Hall explains) that “a person’s susceptibility to disease may depend more on the combined effect of all the genes in the background than on the disease genes in the foreground.” Therefore, mapping this complex nest of genetic relationships offers the best hope for turning genomics into therapies or cures.
Consider cancer. In “Cancer’s Genome” Emily Singer, Technology Review’s biomedicine editor, describes how research has proved that cancer genomics are “even more complicated than scientists had supposed.” We now understand that five to as many as 20 mutations are needed to trigger cancer’s cellular proliferation. But cheaper, faster sequencing technologies may, in the not-too-distant future, make personalized cancer medicine a real possibility. Singer reports on Foundation Medicine in Cambridge, Massachusetts, which wants to create clinical tests that reveal which mutations have caused a patient’s particular cancer, how severe that cancer is, and what drugs will affect it. According to Singer, early results from Foundation “suggest that about half the patient tissue samples analyzed would yield plausibly ‘usable’ information, meaning that the analysis might suggest a particular class of drugs or better define the type of cancer.” If readers are looking for hope that genomics can lead to cures for intractable diseases, companies like this are appropriate inspiration.
In Cohen’s introduction, Eric Lander, who was one of the leaders of the Human Genome Project and now directs the Broad Institute (and who is also a founder of Foundation Medicine), says we should not be surprised that the genome is so complicated. He counsels a historically informed patience as we work on new genomic medicines: after all, 60 years passed between the development of germ theory and the creation of antibiotics. Genomics is harder. Lander asks, “How simple did you think it would be?”
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