Myriad has lately made some concessions. A government deal now permits scientists doing NIH-funded research to use the test at a cut rate of $1,400. But critics have viewed this as a token gesture and remain particularly vocal in Canada and Europe. The European Parliament has passed a resolution expressing "dismay" at the actions of the European Patent Office and instructing the Parliament's staff to prepare challenges to Myriad's patents on both genes. Myriad's French partners in the BRCA2 sequencing – the Institut Curie and the Institut Gustave-Roussy – were particularly incensed about Myriad's BRCA2 patent and have filed a joint complaint to the European Patent Office. In any case, Myriad's monopoly may not be good for patients. The company's test fails to detect all possible cancer-causing changes affecting the gene, so people who test negative for the screened mutations may nevertheless still be at risk. Now when you're tested Myriad has you sign a waiver to the effect that a negative result does not necessarily indicate a clean bill of genetic health. Developing a more comprehensive test is difficult for technical reasons, but more breast cancer labs around the world would likely be trying it right now if not for Myriad's research-stifling patent.
Over the past dozen or so years, linkage analysis has also zeroed in on several other important cancer genes, including ones involved in neurofibromatosis ("Elephant Man disease," not commonly understood to be a form of cancer), colorectal cancer, and prostate cancer. But while effective, the gene-by-gene approach is slow and painstaking, with each study being dependent upon finding appropriate families for analysis. It is here that the Human Genome Project will prove its tremendous value. The DNA and protein micro-arrays we looked at in chapter 8 will furnish cancer-gene hunters with a powerful high-caliber weapon. When I first became interested in cancer research in the 1960s, we knew so little about the underlying genetics and relied on such primitive tools that I turned to viruses that cause cancer in animals. It was my hope that by studying such viruses – which, having very few genes, were manageable even then – we might glean some insight into human cancer. Nowadays, cancer research is no longer confined to viruses; the tens of thousands of genes in actual human tumors are within our powers to map and clone. An enormous wealth of knowledge awaits us as we discover, in greater and greater detail, all the minute biochemical deviations that contribute to turning a normal cell into a cancerous one.
Most linkage analysis studies depend on tracking one's genetic quarry through as large a pedigree as possible. But there is another strategy that looks at small populations with a high incidence of a disorder. And you can't get much smaller than the population of Tristan da Cunha.
A volcanic island rising steeply and inhospitably out of the sea, Tristan da Cunha is a speck of land – just forty square miles – in the middle of the South Atlantic, among the most remote places on the planet. The first permanent settlement was a British garrison established there in 1816 to prevent the French from using the island as a base from which to spring Napoleon from his exile on St. Helena, an island 1,200 miles to the north. Subsequent population growth was sporadic – a few settlers here, a few survivors of shipwrecks there – and as of the unofficial census of 1993, the total was only 301. That year a team from the University of Toronto went to the island to follow up on medical studies done on the islanders in 1961, when the entire population was evacuated to England because the island's dormant volcano had become temporarily active. The most surprising finding had been that about half of the evacuees had a history of asthma.
When the Toronto Genetics of Asthma Program examined 282 of the inhabitants in 1993, they found that 161 (57 percent) showed some symptoms of asthma. The Canadians prepared a genealogy of all the local families; it wasn't overly difficult since all the islanders are descendants of fifteen early settlers and so their lineages are closely interrelated. Asthma was apparently introduced into the island by two women who settled there in 1827. A population like this is a boon for gene hunters: the island is essentially an extended family, and so the genes causing any observable disorder are likely to be the same throughout the population – a best-case scenario for linkage analysis. In a larger, more mixed population, some people's asthma may be caused by one set of genes while that of others is caused by another set. Such heterogeneity is what makes nailing the genetic determinants of complex diseases so difficult.
The Toronto team collected blood samples and prepared DNA, but needed major funding to complete the study. It was then that they heard from Sequana, a company founded to hunt down disease genes. Sequana financed the study, immediately provoking charges that the company was exploiting the islanders, who did not perhaps fully appreciate their role in Sequana's business strategy. Canadian activists calling themselves the Rural Advancement Foundation International claimed that Sequana was "committing an act of biopiracy . . . violating the fundamental human rights of the people from whom the DNA samples are taken." Sequana claimed – in a move that was guaranteed to provoke more accusations of "biopiracy" – to have found two genes conferring susceptibility to asthma but refused to reveal them publicly until the European patent application was filed. The genes are located on chromosome 11, and subsequent studies of heterogeneous mainland populations have confirmed a role for chromosome 11 in asthma. It would thus seem that the genetic factors underlying the high incidence of asthma on Tristan da Cunha are not relevant solely to the isolated inhabitants of South Atlantic islands.
The storm over Sequana's "biopiracy" was nothing compared to the hurricane that was to envelop Kari Stefansson and his company, deCODE Genetics, a few years later. Recognizing that it was tedious and inefficient to look for a different Tristan da Cunha-like micropopulation for every disorder, Stefansson reasoned that what he needed was an isolated island but one with a much larger population, among whose members one could look for a number of disease genes at once. It just so happened that Kari Stefansson was born on such an island.
Iceland is about the size of Kentucky but its population of only 272,512 is one-fifteenth that of the Bluegrass State. The island was settled in the ninth and tenth centuries by the Vikings, who brought with them women kidnapped from Ireland during the voyage. Iceland offers several advantages for the enterprising gene hunter. First, the population is very homogeneous, derived almost entirely from the original settlers; there has been very little immigration since Viking days. Second, there are detailed genealogical records going back many generations; many Icelanders can trace their ancestry back five hundred years. This handy resource is supplemented by a detailed register of births begun in 1840 at the University of Iceland. Third, Iceland has had a nationalized health care service since 1914, so the entire nation's medical records are uniformly ordered and readily accessible – at least in principle.
A Harvard neurologist, Stefansson was interested in genetically complex disorders such as multiple sclerosis and Alzheimer disease. Recognizing his own people as a nearly perfect population for genetic research, he devised a project to link the genealogical and medical records to create a database for gene-hunting. Despite the project's worthy purpose, local privacy statutes stood in the way until the Althingi (the Icelandic Parliament, founded in A.D. 930) passed the Law on a Health Sector Database in 1998. The legislation authorized "the creation and operation of a centralized database of non-personally identifiable health data with the aim of increasing knowledge in order to improve health and health services."
In 2000, deCODE was awarded a twelve-year license to build and run the Icelandic Healthcare Database at its own expense in exchange for an annual fee payable to the national government. The genealogical component of the database contains information in the public domain, but access to the medical records database is more restrictive, operating on a basis of "presumed consent" – information about people's health is entered into the database unless they take the initiative to opt out. The genotype component is most restrictive, relying on informed consent – individuals must actively agree to give tissue samples for DNA extraction. Here's the hot spo
t: although deCODE has a system in place to protect donor privacy, critics argue it is inadequate. Since a person's DNA must be correlated with genealogical and medical records, samples are not taken anonymously; instead the source's identity is encrypted. In theory such encryption could be broken. Word might get around, especially in such a small population, that one family or another is carrying "bad" genes, opening up the possibility of gene-based discrimination. The deCODE project crystallized in microcosm many of the issues concerning genetic privacy that had been discussed rather more hypothetically elsewhere. Nevertheless, despite the controversy, most Icelanders were in favor of the company, viewing it as a means of combining a noble mission – fighting genetic disease – with the happy prospect of serious money swelling the country's small economy. Caught up in the excitement, many Icelanders invested heavily in the company, snapping up shares for as much as sixty-five dollars long before deCODE was officially floated on NASDAQ. But the economic downturn has not been kind to biotech in general, or to deCODE in particular. At the time of writing, shares are worth around two dollars. Many Icelanders have been left to rue those heady buy!-buy!-buy! days. Still, deCODE has undeniably brought money into Iceland through its lucrative collaborations with both Hoffmann-La Roche and with Merck. But with the government of Iceland willing to provide a $200 million loan guarantee and the company forced to lay off a substantial proportion of its workforce, the financial reality is that deCODE may yet prove to be less of an economic boon to the country than had been hoped.
The real test of deCODE, however, lies not in the vagaries of the stock market, but in the science it produces. Here unfortunately the commercial imperative of non- or delayed disclosure makes evaluation difficult. The company, we learn via press releases, is now carrying out linkage analysis on forty-six disorders, including asthma, depression, cancer, osteoporosis, and hypertension. It has found linkage markers for twenty-three of these disorders, and it has isolated genes contributing to peripheral blood disease, stroke, and schizophrenia. But with few of the details published in scientific journals, it is too often difficult to distinguish science from hype. Still, deCODE has certainly shown itself capable of making useful contributions: in June 2002, deCODE researchers published a new map of the human genome with significantly higher resolution than that of the old CEPH map. In addition, the long-anticipated publication of the company's research on schizophrenia hints at a scientifically – and commercially – productive future for the company.
Whatever the years to come hold for deCODE, it's clear that its overall approach – a three-way marriage of medical, genealogical, and genetic records for a well-defined population – has great potential. The company is, therefore, not alone in subjecting the population of a whole country to genetic scrutiny. Finland, for example, has a population of 6 million and notable incidence of some thirty-five genetic disorders, some unique, others simply more common there than in other European countries. The Finns have duly attracted considerable interest among human geneticists. Other countries, too, are leaping on the genetic database bandwagon. In April 2002, Britain launched its "Biobank" program, and the government of Estonia is promoting a comparable nationwide effort as well. Large-scale population studies like these will ultimately help us track down even the most elusive of genes.
Human genetics has a long history, starting with our early ancestors' curiosity about how certain characteristics were passed down through generations. But for virtually all of that history, the scientific foundation of the inquiry was weak at best. Charles Davenport's attempts to bolster his eugenics program by searching for the genetic basis of what he called "feeblemindedness" scarcely rate as science. As a measure of just how slow the field was to develop, it's worth noting that for a long time the accepted figure for a fundamental genetic parameter defining our species was wrong. It was not until 1956, three years after the discovery of the double helix, that the number of human chromosomes was determined correctly to be forty-six, and not forty-eight, as had been supposed without question since 1935. But the flood of knowledge let loose in the twenty years since RFLP linkage studies began has, with fantastic speed, created a fertile field from formerly barren ground. Having completed the sequencing of the human genome, we will likely soon find the genes underlying virtually all important genetic diseases. The question then becomes: What do we do with them?
CHAPTER TWELVE
DEFYING DISEASE:
TREATING AND PREVENTING
GENETIC DISORDERS
From the moment he was born, David Vetter never felt the direct touch of another human being. David suffered from an inherited condition called severe combined immunodeficiency disorder (SCID). The failure of his body to develop B and T cells, both crucial elements in the immune response to disease, left him susceptible to the slightest infection.
David's parents knew before he was born that he might have SCID: their firstborn son had died of it. The Vetters and the doctors were ready. They decided early on that if the infant should prove to have SCID, he would be isolated in a germ-free environment until a treatment could be developed – surely it would not be long given the rate of progress in medicine. David was delivered by cesarean section in September 1971 and immediately placed in a sterile incubator. All contact with him was made using latex gloves built into the little chamber. As he grew older he was transferred into larger and larger sterile environments, plastic "bubbles," but one constant remained: the gloves. They would continue to be his only way of feeling anyone or anything in the outside world (see Plate 55).
The hoped-for cure proved elusive. David remained in his bubble, where he drew national attention. NASA tried to help him with a Mobile Biologistical Isolation System, essentially a space suit permitting the boy the freedom to venture beyond the bubble. But a space suit is really only a bubble of a different kind.
Advances in transplantation methods looked promising, and in October 1983, a month after his twelfth birthday, David received a bone marrow transplant from his older sister. Unfortunately, her marrow proved to contain a virus that caused a pernicious lymphoma to develop in David's defenseless system. By February 1984, he had to forsake his bubble and be placed in intensive care. He died soon after, but at least in those final days he was able to experience at last the warmth of human touch.
We can be thankful that SCID is rare, but genetic disorders are surprisingly common among children. In fact, about 2 percent of all babies are born with some kind of serious genetic abnormality. It's estimated that genes are directly responsible for one-tenth of admissions to children's hospitals, and indirectly implicated in about half. David Vetter's case is sadly representative of where our knowledge stands regarding most genetic diseases: we can understand what's wrong and we can diagnose them, but there is relatively little we can do to treat, much less cure, them.
It is interesting to chart the image of SCID in popular culture. In the seventies the condition inspired a made-for-television tearjerker called The Boy in the Plastic Bubble. By the nineties, the Bubble Boy had become a figure of fun in the sitcom Seinfeld. And in 2001, Disney released a tasteless film reimagining as a series of goofy adventures the life of a boy confined in a bubble on account of an unnamed but unmistakable condition.* This enduring powerlessness of science in the face of such a horrific illness must to some degree account for this trajectory from sentimentalism to farce. But the same powerlessness makes the diseases only harder to bear for the afflicted and their families. Especially with diseases that cause a progressive and inexorable decline, a diagnosis is virtually a death sentence. In the absence of treatment, some would prefer not to know their awful fate, particularly if they have witnessed its ravages in loved ones. In the previous chapter we met Nancy Wexler; with a 50 percent chance of developing Huntington disease, the scourge that had claimed her mother and uncles, Wexler worked so long and so hard at Lake Maracaibo and in genetics laboratories in the United States to track down the genetic culprit. But even though her extraordinary crusade resu
lted in isolating the gene and identifying the lethal mutations, a cure is still nowhere in sight. And although she has done so much to make a diagnostic genetic test available, Wexler herself has said that she will not be tested – at least, not until a viable treatment seems near. She would prefer to live with a huge uncertainty than discover the truth in a 50-50 gamble: the odds are even that she will face a mental and physical decline leaving her a shell of the dynamic woman she is now.
* The Disney ending: The movie's bubble inhabitant turns out to be healthy after all.
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