Lost on the Gene Map

Scientists hoped the Human Genome Project would deliver a road map for personalized medicine. But we are still unequipped to deal with its ethical and medical implications

Illustration by Alain Pilon

A tiny dot of DNA, thousands of times smaller than a pinhead, exists in almost every cell of our bodies. Stored in its tightly wound double helix is the wisdom of nearly four billion years of evolution—the hereditary information that decides our hair colour, whether we might stutter, or if we have the potential to win an Olympic gold medal. Human DNA is typically divided into forty-six chromosomes, twenty-three inherited from each parent; the DNA on one chromosome includes hundreds, sometimes thousands, of genes. These gene segments of DNA (deoxyribonucleic acid) encode data that the cell expresses as proteins to build and operate the various parts of the body. The seven billion faces in the world, all different, reveal individual differences in our genetic makeup. But so much of our collective DNA is the same that we share a common genetic heritage: the human genome.

To comprehend genomes is to begin to unlock the mysteries of life. One of the aims of the Human Genome Project, an international research program launched in 1990, was to map and then sequence every bit of DNA in a composite human genome. The project was heralded as the first step toward personalized medicine, a new age in health care when prevention and treatment of illnesses would be guided by examining a person’s genome and genetic predispositions. Understandably, expectations for the Human Genome Project ran high, and in 1996 President Bill Clinton glowingly foretold a not-too-distant future in which parents, armed with a map of their newborn’s genetic structure, could identify the risks for illness. In his vision, the fruits of the project would help “organize the diet plan, the exercise plan, the medical treatment that would enable untold numbers of people to have far more full lives.”

When the HGP was completed in 2003, that vision was still out of reach. Thanks to technological advances, it’s now on the horizon. The expense of genomic sequencing is falling fast; in Canada today it costs $10,000 to sequence an individual genome. “Once a whole genome costs $1,000 or less, entire families will get their genomes sequenced,” says Michael Hayden, director of the Centre for Molecular Medicine and Therapeutics at the University of British Columbia. “But what will they do with that information? ” Whole-genome sequencing generates enormous amounts of raw data that must be analyzed by highly qualified medical geneticists and genetic counsellors, both in short supply (Canada has about eighty medical geneticists and 230 genetic counsellors). “DNA Sequencing Caught in Deluge of Data,” ran one recent headline in the New York Times, reflecting a common view that modern medicine doesn’t yet have the expertise to tell us what this data means, much less how to act on it.

Meanwhile, some people are already circumventing the medical system and turning to cheaper and less comprehensive direct-to-consumer genetic testing technologies. Just spit in a bottle or scrape the inside of a cheek, send the sample to a service such as DNA Testing Centres of Canada, and for a few hundred dollars the company will detail your risks for a menu of diseases. Many clinicians and researchers such as Hayden are concerned that the results may be used without a doctor’s advice. Yet Robert Green, a medical geneticist at Harvard Medical School and Boston’s Brigham and Women’s Hospital, sees advantages in direct-to-consumer testing. “People are taking more responsibility for their own health,” he says. “Many are extremely comfortable empowering themselves with genetic information without the guidance of conventional medical care practitioners.”

The demand will continue to grow. Earlier this year, the federal government pledged $67.5 million toward projects in areas of health care that will benefit from approaches based on genomics and personalized medicine. And as the use of genetic testing expands, the ethical considerations multiply as well. For instance, who should be tested and why? How should patient confidentiality be protected? How much genetic information should be revealed to patients, potential employers, or health insurers? Ultimately, what limits, if any, should we impose on this rapidly advancing technology?

Genetics has long been an ethical minefield. When Gregor Mendel’s pioneering work on genes was recognized at the start of the twentieth century, the pseudo-Darwinian philosophy of eugenics (controlled human breeding for desirable characteristics) was in full flight. When eugenics culminated in the Nazis’ horrifying promotion of Aryan racial supremacy, the new science of human genetics became tarnished. Later in the century, recombinant DNA technology led to the controversial use of gene splicing in agriculture. The most common genetically modified foods are soybeans and corn, which can be engineered to generate their own insecticides. Several European Union countries, including Germany, have applied safeguard clauses to ban genetically modified organisms, and have at times refused to import North American food products that may contain them. Opponents in North America claim their use has been approved by regulatory bodies without sufficient independent, evidence-based testing of their long-term effects on the food chain, and particularly on produce for human consumption.

The advent of GMOs raised the distinct possibility that once the nascent Human Genome Project provided a complete genetic road map, biotechnology could enhance humans, too. Those who found the idea objectionable weren’t reassured by pre-implantation genetic diagnosis, another new form of biotech wizardry. This involves vetting a newly fertilized egg for genetic mutations that might indicate a disease such as cystic fibrosis, and electing not to implant the egg if the variants point to potentially catastrophic outcomes. Although most North American testing companies use PGD solely to detect diseases, rejecting an embryo because of its gender is commonplace in a handful of countries, among them Turkey, China, and India. The prevailing concern, however, is that PGD will lead to the creation of “designer babies”: once genomic medicine advances sufficiently, it could grant parents’ every whim, from blue eyes or bulging biceps to musical talent or exceptional intelligence.

At the turn of the millennium, HGP plus GMO plus PGD added up to a robust fear of—or, in some cases, a desire for—“playing God,” which contributed to President George W. Bush’s decision to establish a council on bioethics. At its first meeting in 2002, chairman Leon Kass asked the members to read “The Birthmark,” Nathaniel Hawthorne’s short story about a scientist obsessed with a blemish on his beautiful wife’s face. Determined to perfect her, he removes it—killing her in the process. Kass used the story to encourage his colleagues to frame the ethical issues raised by advances in biotechnology, such as the HGP, within the broader philosophical perspective of how far humanity should aspire to perfection, and at what price.

In reality, gene enhancement in humans remains a theoretical proposition; the most popular candidate gene so far is one that encodes for the protein hormone erythropoietin, which stimulates the production of red blood cells, and until now has been used (and abused) by athletes only in its synthetic form. Still, reproductive technologies such as PGD have revived the possibility of “good” eugenics: Julian Savulescu, a neuroethicist at the University of Oxford, evangelizes for it at every opportunity, most recently in an iPad app. In his view, once a technology like PGD becomes available to all, parents and health care providers will have a moral obligation to create children with the best genes possible.

The enhancement debate highlights the fact that genomic research has vastly expanded the range and impact of long-standing ethical conundrums. One can understand rejecting an embryo identified by early testing as carrying the mutation for a fatal genetic disorder such as Tay–Sachs disease; from there, the ethical choices get thornier. For decades, prenatal tests have given parents the option of aborting a fetus with Down’s syndrome. But many people with Down’s enjoy satisfying lives with support from the health care system. As PGD and other prenatal technologies become more prevalent, should limits be placed on which conditions and diseases are screened for? And how should parents decide whether they can manage to raise a child with a disability?

The choices about Down’s are based on a biological understanding of the syndrome that dates back more than fifty years. But as genome research progresses and makes new discoveries, our knowledge about other disorders keeps shifting, complicating choices about rejecting an embryo. Until recently, autism was considered an incurable genetic disorder and under this definition could have justified prenatal termination. Now it has been redefined as a spectrum of disorders, to capture its variety of physical and behavioural manifestations; on the plus side, these often include heightened cognitive and creative abilities. In the world of genes, very little is black and white.

With whole-genome sequencing providing so much data that is so little understood, making the best ethical choice is more difficult than ever. But long before the sequence data arrives, the right of the patient or volunteer to know—or not know—the results must be established. In Canada, outside of some direct-to-consumer testing, individuals applying to have their genome sequenced sign a consent form to acknowledge that they understand the process. If they volunteer for a research project, they agree to permit use of their personal data and are assured privacy in return. But what if the sequencing data reveals the presence or a clinical sign of a disease the participant was not being screened for? To address this, the federal government requires researchers to consult with subjects beforehand about incidental findings that may be disclosed to them.

In a clinical situation, however, informing a patient about incidental findings complicates a doctor’s responsibility. What if testing reveals that a person’s biological father is not his or her mother’s partner? In which circumstances should the doctor reveal that information?

Another ethical concern is the patenting of genes or smaller stretches of DNA for the purpose of diagnostic testing. For example, Myriad Genetics of Salt Lake City holds a patent on the BRCA1/2 genes, which protects its breast cancer diagnostic test while preventing other companies from developing similar tests on the same DNA sequence. According to criteria in patent law requiring that inventions must be new, not obvious, and useful, some experts estimate that 20 percent of the human genome is already under patent. However, the US Supreme Court may hear an appeal against Myriad’s patent, and has already heard one against another diagnostic patent that opponents (including the American Civil Liberties Union) claim should be revoked, on the grounds that the human genome constitutes an exception requiring revision to the standard criteria of patent law.

As the demand for whole-genome sequencing grows, so will profits, but the big money in personalized medicine will come from the development of treatments. Progress to date has been slow and confined to monogenic diseases such as Huntington’s, whose origin lies in a mutation on a single gene inherited from one parent. Because monogenic diseases are relatively rare, sequencing the genomes of those affected generates a manageable amount of data. Yet only 10 percent of monogenic diseases have yielded to treatment. On the other hand, multigenic disorders, such as cancer, diabetes, or Alzheimer’s, result from a complex interplay of genetic mutations and environmental factors. A given mutation on a person’s genome may not necessarily express as a malignant disease, so identifying the probability of a multigenic disease is extremely challenging. Traditional indicators such as family history, diet, and lifestyle may still be far more predictive than genetic testing for individual risk.

Compounding the problem, the bodily pathway of a multigenic disorder is complex and difficult to trace, and each person’s metabolism responds in a highly idiosyncratic way to the conditions that cause disease. To discover how individuals’ systems respond to the genetic risk for a multigenic disease requires comparing data gathered from the genomes of thousands of test subjects, ideally involving research findings and tissue samples from bio-banks worldwide. And once potential treatments for these disorders are identified, they require long-term clinical trials.

Convincing governments and other funders to support these kinds of initiatives rather than searching for a magic bullet to cure a disease such as cancer presents a challenge. “Getting population cohort studies launched in Canada is very difficult,” says Tom Hudson, president and scientific director of the Ontario Institute for Cancer Research. “It’s less sexy than funding basic human genome research.” Hudson has made consulting with clinicians and assessing their requirements a high priority. “We need to turn the question around,” he says. “We have to identify the medical need and make sure our research programs create paths to address those clinical questions. It’s like starting a puzzle from the end.”

More problematic is the reality that the human genome is still a vast catalogue of the unknown and scarcely known. The Human Genome Project’s most startling finding was that human genes, as currently defined, make up less than 2 percent of all the DNA on the genome, and that the total number of genes is relatively small. Scientists had predicted there might be 80,000 to 140,000 human genes, but the current tally is fewer than 25,000—as one scientific paper put it, somewhere between that of a chicken and a grape. The remaining 98 percent of our DNA, once dismissed as “junk DNA,” is now taken more seriously. Researchers have focused on introns, in the gaps between the coding segments of genes, which may play a crucial role in regulating gene expression, by switching them on and off in response to environmental stimuli.

Gene regulation, whether by introns or by regulator genes, forms one aspect of the burgeoning field of epigenetics, which concerns itself with the process of differential gene expression. In a classic study published in 2004, biologists at McGill University in Montreal identified a regulatory sequence in rat pups that lowered stress hormone production when the mother groomed them; their production of the hormone stayed low throughout their lives. Moreover, the researchers could adjust the gene in healthy adults to increase their stress, and in agitated adults to lower it. Though not their intention, the study provided the genetic evidence to prove Freud right: what happens in childhood has a lasting, though theoretically reversible, biological effect on adult behaviour.

Epigenetics is just one of many disciplines supercharged by the Human Genome Project. Another is proteomics, which focuses on the structure and function of proteins within an organism. It shows us more clearly how our genes and proteins coexist and interact with the genes and proteins of the trillions of microbes each of us hosts. Indeed, our bodies contain ten times more microbial cells than human cells. Human microbiomics studies the approximately three million microbial genes in the human body, a genetic load so massive it is almost nonsensical to talk about “our” bodies at all. The food we eat, the drugs we consume, our emotional and social environments, or whether we get vaccinated (“vaccinomics,” of course)—all these factors affect how our genes are expressed. Each action sets in motion a Rubik’s cube of metabolic variables we have only begun to comprehend.

As medical science struggles to apply these new discoveries to society’s benefit, human genome research, now unstoppable, continues to evolve. Ironically, though, this initiative to tailor health care to the individual genome—the touchstone of the Human Genome Project and personalized medicine—increasingly reveals that our genes, and we as individuals, do not function in isolation from other life forms and the environments we all inhabit. Whatever secrets genes contain, our book of life and that of a microbe remain written in the same language.

This appeared in the May 2012 issue.

Mark Czarnecki
Mark Czarnecki has previously discussed evolutionary psychology and male shame in The Walrus.
Alain Pilon
Alain Pilon has drawn for such publications as The Atlantic and the New York Times.