Skepticism about the feasibility of the Human Genome Project (HGP) was laid to rest by its completion. But skepticism about its value in clinical medicine persists. As Leroy Hood, who created the first DNA sequencer, noted, the HGP gave us a genetic parts list but did not explain how all the parts interact. Neither did it factor in the combinatorially explosive product of 30,000 genes, 300,000 proteins and countless environmental factors. If we could do that and explain the interactions — creating effective tests for diseases and predispositions, as well as effective prophylactic and therapeutic countermeasures — its value would be much clearer.
Several more ongoing, HGP-sized projects that have required government financing and leadership include:
- the approximately $1 billion Cancer Genome Atlas project to map the molecular basis for cancers.
- the Human Epigenome Project, a European private-public consortium building a map to show how environmentally caused changes to an individual's genome relate to disease.
- the International HapMap Project that groups people who have similar genetic differences into "haplotypes" that provide around 90 percent of the information that would be obtained by looking at individual genetic differences. A given group may be more susceptible to a given disease, for example, as is the case with Ashkenazi Jews, whose haplotype makes them more susceptible than others to Tay-Sachs and Gaucher diseases. The HapMap helped to reveal an environmental as well as an inheritable component to genetics, thus contributing to the birth of epigenetics.
- the Human Connectome Project, a five-year, $30 million project begun in 2009 to draw a wiring diagram of the healthy adult human brain.
- the Human Microbiome Project that uses "metagenomics" to describe and analyze the effect on human health and disease of the microbes that live within us and that outnumber our own cells by 10:1.
Even these projects do not tell the whole story. They do not address the proteome (the system for the creation, transformation and interactions of proteins, workhorses of the cell); the spliceosome (the proteomic subsystem that enables a single gene to order up thousands of different proteins); the glycome (the system of sugars that help stabilize and determine the function of proteins); or any other layer of the onion to be revealed.
The HGP and similar projects were like the early space program. There was no clear and immediate payoff and, even if there had been, the private sector would have been incapable of financing it. But once the heavy financial lifting was done, the profit potential made clearer and more immediate, and the capital costs reduced, the private sector was bound to get to work, as it is in developing space vehicles today. In genomics, equivalent private-sector-driven projects include:
- the 1000 Genomes Project, which aims to sequence the genomes of at least 1,000 people to produce a catalog of genetic variations, and their impacts, present at 1 percent or greater frequency in the human population. Project data are being made available free of charge to the worldwide scientific community.
- the Personal Genome Project, which goes even further. As of this writing, the genomes of the first 13 of as many as 100,000 volunteers have been sequenced and analyzed against a database of over 20,000 (and growing) genomic "markers," and cell lines have been created from their tissue samples. Both the database and the cell lines are available online to researchers and the public. The project website carries stripped-down, de-identified versions of each volunteer's medical record. Together with the genome data, the medical records will facilitate research into links between genotype and phenotype. In contrast, the 1000 Genomes Project collects genetic information only.
- projects started at individual health systems, such as a Massachusetts General Hospital program to look for known cancer genome signatures in all new cancer patients to predict whether drugs already on the shelf or in development might work for them.
Rise of Genomic Medicine
The value to clinical medicine of these various projects was first felt in 2006. That year, the acne drug Aczone, which targets patients with a particular enzyme deficiency, was added to the pharmacogenomic formulary; gene therapies for chronic granulomatous disease and advanced melanoma were protecting patients after 18 and 24 months of trial, respectively; gene therapies were reported to have cured more than two dozen patients in Europe suffering from three rare immune disorders; new techniques made gene therapy safer and more effective; and more than 300 gene therapy trials were under way around the world.
Today, the number of genetic therapies at some level of development (including a handful of therapies that have reached the market) is much larger and growing exponentially. They include, for example, a more potent version (thanks to our understanding of glycomics) of the red blood cell booster drug erythropoietin.
2006 was also the year when the market for genomic tests began to take off, and with it the era of genomic or personalized medicine. Genetic testing and biomarker identification was a $5 billion business, growing by 25 percent annually. Insurers did not rush to pay for the tests, though some test makers got a foot in the reimbursement door. The tests also had a foot in the door among practitioners who did not conform to the conservative norm. One Mayo Clinic physician already used pharmacogenetic tests "very regularly."
These were tests intended for use by doctors, but do-it-yourself tests were being sold directly to patients in 2006, notwithstanding advice to avoid them. They included tests for hereditary hemochromatosis and BRCA genes associated with breast and ovarian cancer. One company offered tests for a problem on one gene for $250, or a battery of tests on four genes for $800, and four U.S. retailers began testing over-the-counter sales of $99.99 home test kits for bone health, heart health, insulin resistance, inflammation and antioxidant/detoxification.
The identification of disease-contributing genes or biomarkers on which such tests rely has continued. It was discovered in 2008 that the deletion of seven genes could trigger a wide variety of cognitive problems, including autism, mental retardation and developmental delay. Not only can we identify gene deletions with disease, as in the cases of autism and prostate cancer, but we also can manipulate them to control disease, including the disease of aging — at least in common yeast, whose normal one-week lifespan was extended tenfold by the deletion of two genes and the imposition of a calorie-restricted diet.
New methods contributing to our understanding of disease processes have led to a proteomic breakthrough in treatment for women who become resistant to breast cancer drugs, which in turn has meant that resistance to the breast cancer drug tamoxifen is in some cases preventable and reversible. Proteomics also may help reduce the ravages of aging: Genetic modifications to mice have delayed the age-related decline in cellular protein recycling that results in cell death.
Projects such as these generate a data tsunami, which swells and accelerates with each new generation of DNA sequencer. In 2008, prototype sequencers that could read single strands of DNA in real time were much faster and cheaper than earlier sequencers. Today, new sequencing technologies such as nanopore and nanotile sequencing continue the exponential advance to the point where sequencing a whole genome costs as little as $4,000 and soon will be less than $1,000.
Harvard geneticist George Church, who started the Personal Genome Project, sees the future of genomic medicine as fused with regenerative medicine — in particular, the use of induced pluripotent stem (IPS) cells to repair damage. He intimated in an interview that in less time than it took to complete the Human Genome Project (13 years), medicine will combine genomics, epigenetics, synthetic biology, stem cells and other postmodern (as we call them) aspects of medicine, and he noted that many people are quite unaware of how quickly advances are being made. (See George Church on the Future of Stem Cells, by David Ewing Duncan, in a September 14, 2011, blog on Technology Review.)
IPS cells already can be used to reprogram genomes genetically and epigenetically. In fact, an entire mouse has been grown from IPS cells, and Church does not doubt that eventually the technique will be used to grow humans. He wants to establish an IPS line for every single person who gets sequenced in the Personal Genome Project, and then initiate small projects such as treating patients who have diseased bone marrow with synthetic bone marrow created from IPS derived from the patients. It will take (he thinks) a brave sick person to be the guinea pig, given (we take him to imply) that no animal or clinical trial would be possible without a population of genetically identical patients. But the results could be better health than the patients had even before they became sick, and the publicity from such results would mean that this form of medicine will spread like wildfire.
That may sound like hype or at least wishful thinking, but there is no denying that the Human Genome Project has put us on the road to new forms of medicine. Our duty, it seems to us, is to ensure that it develops ethically and is distributed ethically. To do that, we need enlightened policy and regulation, adequate funding and changes in medical education. Surely, given the reward and our investment in the HGP and daughter projects to date, it's not too much to ask.
David Ellis is a futurist, author, consultant and publisher of Health Futures Digest, a monthly online discursive digest of news and commentary on long-range, leading-edge technological innovations and their consequences and implications for health care policy and practice. He is also a regular contributor to H&HN Daily and a member of Speakers Express. Ramesh Babu Batchu, Ph.D., is an assistant professor of surgery at Wayne State University and associate director of surgical oncology and the Developmental Therapeutics Laboratory at the Karmanos Cancer Institute. He specializes in the development and viral delivery of microRNA-based therapies for cancer.