It took an international consortium 13 years to map the first complete human genome, at a cost of $3 billion by the time it was done in 2003. Since then, improvements in sequencing technologies have cut the price of DNA analysis by at least five orders of magnitude, opening up a whole world of possibilities. Scientists have identified variants in several genes that are associated with health conditions like diabetes, heart disease and various cancers.
There are striking parallels to Moore’s Law, a function describing the relationship between the density of transistors on a chip and the cost over time. Computers that once took up entire rooms now fit in your pocket. And just as cheap processing power led to the creation of the personal electronics market, the falling cost of gene sequencing has given rise to a new industry: personal genetics.
Now, for about the price of a smart phone, you can have your own DNA scanned to learn what bugs might be lurking in your operating code. Genetic information pointing to potential health risks could one day inform the way doctors approach diagnosis and treatment, leading to more individualized care.
As enticing as the prospect of having this window into yourself may be, a little knowledge can be a dangerous thing. People may fail to grasp the technology’s limitations and take the wrong action based on false assumptions. And in this still largely unregulated landscape, what safeguards are there to ensure that your genetic information won’t be obtained or used without your consent? Stanford alums and faculty are involved in all aspects of the burgeoning field—scientific, commercial and ethical—and their views show directions the field may take.
Foster City-based Navigenics and Mountain View-based 23andMe are among the first personal genetics firms; both have faculty members on their advisory boards and alumni in key positions. The companies launched within a week of each other in the autumn of 2007 and provide similar services. Send one of them a vial of your saliva, and it will scan your DNA for markers associated with diseases and other traits.
Amy DuRoss, ’98, MA ’98, MBA ’03, employee No. 3 at Navigenics, now oversees policy and business affairs for the company. She says it’s no coincidence that the personal genetics industry largely is being created in the Bay Area. “Silicon Valley delights in paradigm shifting across many different sectors, whether it’s high tech or clean tech or biotech.”
The two companies differ slightly in their approach. Navigenics focuses on common health conditions—arthritis, eye diseases, diabetes, heart problems, intestinal disorders and breast, colon and prostate cancers—that in most cases can be prevented or at least mitigated through early intervention. 23andMe provides information on these conditions, but also reports on carrier status for less common genetic disorders and for a handful of traits that are more curiosities: alcohol flush reaction, bitter taste perception and earwax type, to name a few.
The underlying idea is the same. Nearly every cell in our bodies contains a complete blueprint, written in a chemical alphabet— A, T, C and G. It takes 3 billion pairs of these letters to spell out the recipe for a human being. The purpose of the Human Genome Project was to determine the precise arrangement of those letters.
At least 99 percent of the sequence is identical from one person to the next. It’s the last tiny bit, determining physical attributes like eye and hair color as well as susceptibility to particular diseases and responses to drugs, that makes each of us unique. Almost all human genetic variety arises from the occasional substitution of one letter for another at a particular location on the DNA molecule.
In most cases these typos—called single nucleotide polymorphisms, or SNPs (pronounced “snips”)—are inconsequential. But sometimes SNPs can alter cellular functions and increase the likelihood of your developing various illnesses. These are what the tests offered by Navigenics and 23andMe are looking for.
At the lab, your DNA undergoes a series of steps over several days. First, it’s broken up into smaller bits, and the pieces with SNPs are marked with fluorescent tags. Then the recombined DNA is stuck to an array—a tiny square with hundreds of thousands of sticky dots. A scanner reads the array to detect which dots are highlighted by fluorescent tags, and a computer then determines which version of the gene you have at each SNP location.
In six to eight weeks you’re invited to view your results via a secure website. Each company displays the results differently, but both tell you which SNP version—risk or non-risk, also called your genotype—you have at each location. They also present a summary score, which Navigenics calls “lifetime estimated risk” and 23andMe refers to as your “odds ratio.” This number is intended to reflect the contributions of all your SNPs for a given condition to your overall risk.
You may learn, for example, that your constellation of markers for breast cancer gives you a lifetime estimated risk or odds ratio of 25 percent, compared to 13 percent for the general population. Does that mean that you have a 1-in-4 chance of getting breast cancer? Not necessarily.
To find links between genes and complex diseases or other health-related conditions, scientists screen DNA samples from large groups of people with the disease or condition, looking for SNP variants that differ from an otherwise similar cohort without the disease or condition. Those markers that are significantly more common in the former group than in the latter are said to be associated with the disease or condition.
What those numbers really mean is that, statistically speaking, 25 out of 100 people who have the same SNPs as you will get breast cancer, while only 13 out of 100 people who have other versions of the genes will develop the disease. Both 23andMe and Navigenics expressly state in their consent documents that customers should not interpret their test results as an estimate of their personal risk of developing any of the conditions they report on.
But some observers like David Magnus, PhD ’93, director of Stanford’s Center for Biomedical Ethics, worry that these reports may be misleading. The biggest concern, he says, is that people’s expectations of what these tests will reveal about their health and risk for disease exceed the current capabilities of the science.
To the extent that most of us learned about genes in school, we were taught simple Mendelian patterns of inheritance for dominant and recessive genetic traits, named for 19th-century monk Gregor Mendel, who first described them. Mendel cross-bred pea plants to study how physical attributes governed by single genes were passed on to subsequent generations. His results fit neatly in a two-by-two grid.
Of course, human genetics is far more complicated. With the exception of a handful of traits that are controlled by a single gene—dimples (dominant), albinism (recessive), free (dominant) or attached (recessive) earlobes—most human traits for which there is a genetic component will likely involve hundreds, if not thousands, of genes, with no clear pattern of inheritance.
Take height. We know from twin studies that your genes are about 80 percent responsible for how tall you are. Environmental factors, such as nutrition, make up the remainder. More than 20 genes have been identified that contribute to height. However, collectively they explain only 4 percent of the differences among people.
Similarly, what does it mean when you learn from a Navigenics or 23andMe test that 36 percent of people with your combination of SNPs for type-2 diabetes develop the disease, compared to 25 percent in the rest of the population?
Not much, says Magnus, given that the 16 locations, or loci, in the genome that are implicated in type-2 diabetes together contribute just a few percent to the genetic component of the disease—not to mention the problem of interpreting what it means when you have a mixture of “good,” “bad” and neutral markers. But people rooted in a deterministic way of thinking about genes may overinterpret the significance of DNA findings about complex traits that are fundamentally non-Mendelian. Magnus fears that may lead them to take actions that are not in the best interest of their overall health.
“There’s been an apocryphal amount of fear in the field that patients may not be ready for this information, that they’ll jump off a bridge or whatever if they have a certain gene,” says Vance Vanier, ’95, MBA ’06, Navigenics’s chief medical officer. But, he says, evidence paints a different picture.
An ongoing study with the Mayo Clinic so far shows that patients don’t experience undue anxiety or depression after receiving information about possible genetic risk factors—as long as they have a doctor or genetic counselor to talk to. A much more comprehensive study in collaboration with the Scripps Institute will test 10,000 patients then follow them for 20 years to more fully understand the impact of giving people this kind of insight into their genes.
Most states require that a physician be involved in ordering medical tests. Last summer, the California state health department decided that the services provided by personal genetics companies fall into that category. Thirteen “cease and desist” letters were sent to companies operating in the state mandating that a physician oversee the ordering of DNA tests. A physician’s involvement means test results go into your medical record, protected under federal regulation from being used against you by health insurance companies or employers.
Nearly all states bar health insurers from using genetic information to determine eligibility or rates; more than half prohibit genetic discrimination in the workplace; and a third expressly protect genetic privacy. In May 2008, President Bush signed the Genetic Information Nondiscrimination Act, to take effect this year. It bars discrimination by health insurers and employers on the basis of what’s in your genes.
However, the law does not cover disability, long-term care or life insurance plans—which, Magnus points out, are far more likely than an employer-sponsored health insurance plan to deny you coverage because of risk factors revealed by a genetic test.
Still, many people feel it is their fundamental right to know what their genes have to tell them, with or without a doctor’s blessing. “People have made the analogy to the freedom of the press, that this information should be out there,” Magnus says. “And even if it turns out people misunderstand, and because of those misunderstandings people get harmed, that the information shouldn’t be encumbered.”
The difference, in his view, is that genetic information is not like news but rather like medical diagnostic results, such as an MRI. “We generally don’t believe that there should be restrictions on the ability of information to flow,” he says. “On the other hand, we do think that if you’re going to practice medicine you need to have a license.”
Magnus worries that people are not giving enough consideration to the future consequences of obtaining information about their genes—or of sharing that information. Our understanding of the genetic basis of disease is evolving so rapidly, he says, “information that right now seems banal or innocuous could later turn out to be stigmatizing.”
Another startling scenario to consider is the potential for misappropriation of DNA. “We leave bits of ourselves all over the place. Every time you lick a stamp, you’ve left your DNA,” Magnus points out. It would be easy enough to swab the spittle from a Coke can, pass the sample off as your own and scan someone else’s genes, without them knowing about it. 23andMe and Navigenics collect a substantial amount of saliva from customers for testing, but it is possible to run some kinds of tests using a smaller DNA sample like a cheek swab.
Both 23andMe and Navigenics were already operating in compliance with California’s requirement to have a doctor in the loop. In addition, Navigenics had genetic counselors on staff and a genetic counseling advisory board. Kelly Ormond, an associate professor of genetics at Stanford who serves on that board, applauds the company’s commitment to making genetic counseling an integral part of their service. “If you don’t automatically offer it, people aren’t going to think to ask,” she says.
Navigenics’s three counselors are available to guide people through the process, from answering questions about whether the test is right for them to helping them make sense of their results. About 60 percent of counselors’ time is spent bringing doctors up to speed, says Vanier. Although medical schools are increasingly incorporating genetics into their curriculum, most primary care physicians in the United States have no formal genetics training. Genetic counselors, on the other hand, have to understand “all the molecular stuff, all the medical stuff and also the psychology, how to talk to people,” Ormond says.
In the late 1960s, around the time that prenatal diagnosis really began, genetic counseling as a profession got its start. Because it was officially recognized as a primary medical specialty in 1991, the number of genetic counselors nationwide has grown from fewer than 500 to more than 2,000. But as direct-to-consumer genetic tests become more mainstream, that may not be enough.
In a 2008 survey, of the 91 percent of consumers who said they would take a genetic test for one or more disease conditions, most would whether or not their doctor was involved. And Time magazine named the retail DNA test “Invention of the Year” for 2008. Given all that, it’s not surprising that genetic counseling was on U.S. News & World Report’s list of the best careers for 2009.
There are 30 training programs nationwide, producing a total of 250 graduates each year. Stanford’s master’s program in human genetics and genetics counseling, which welcomed its first cohort of seven students last September, received 80 applications this spring, up from 51 the previous year. The two-year program is one of only four in the western United States.
Ormond, the program’s director, previously ran the genetics counseling program at Northwestern for 10 years. She says one of the challenges is giving students the tools they need to adapt to this rapidly changing field.
“One of the biggest transitions I’ve seen is just the sheer number of genetic tests that are available,” Ormond says. With tests for more than 1,000 conditions—and more being developed all the time—counselors really have to stay on top of the literature. “A lot of what we have to teach our students is how do you critically assess information and where do you go to find it.”
Personal genetics companies face this challenge, too. Navigenics customers can receive updates (for an additional annual fee) as tests for new markers and conditions become available. Vice president of genetics Michele Cargill’s group is responsible for determining which conditions the company’s test will cover. “We have a really small filter for what we let through.”
Navigenics’s curatorial team of epidemiologists and geneticists scours the scientific literature for newly reported SNPs from large genome-wide association studies. Not only must studies come from well-respected journals, explains Cargill, PhD ’96, but they must relate to conditions that are common in the population and that people can do something about. Fewer than 5 percent of the markers published make the cut.
Ormond says another skill would-be counselors have to learn is how to effectively communicate information that may impact people’s health. “What I don’t want to have happen is for me to say, ‘All right, you have an increased risk for lung cancer and colon cancer and skin cancer,’ and for you to go, ‘Ugh, I’m totally going to get cancer. Screw this, I’m going to go smoke in the sun!’” Ideally, she says, the goal is to empower people to lessen their risk for health conditions that have an environmental basis, which most do.
Navigenics’s Vanier says he’s seen evidence that there’s something uniquely compelling and motivating when you show people their genes. He points to the case of a 37-year-old woman with a vague family history of cancer—both grandfathers had died fairly young from the disease, but details were sketchy. She took the Navigenics test and it revealed that she had markers associated with a heightened risk for colon cancer. She elected to get a colonoscopy—some 13 years earlier than she might have otherwise—which revealed a precancerous polyp she was able to have removed. Had she waited until she was 50, the age at which the American Cancer Society generally recommends beginning regular colon screening, the disease might have advanced. (Guidelines for when someone should have a mammogram or test for prostate cancer are mostly based on average rates of disease within a population.)
“In medicine today, you try to treat the average person,” says Russ Altman, a scientific adviser to 23andMe who also chairs Stanford’s bioengineering department. “But nobody’s average.” The effective dose of the anticoagulant warfarin, for example, can vary tenfold from one person to the next. Doctors have to resort to trial and error to find the sweet spot, and that can be dangerous: too little and a patient may clot; too much and he may hemorrhage.
Researchers led by Altman, PhD ’89, and Teri Klein, a senior research scientist in genetics at the School of Medicine, recently showed that by combining genetic information with demographic and clinical information, they could devise an algorithm to predict the ideal dose for individual patients within a narrow margin. “It’s really an amazing story,” Altman says. “This shows conclusively that including a patient’s genetic information yields a far superior prediction. It’s a vast improvement over the guessing game physicians play now.”
Ultimately, the hope is that as genetic testing is integrated into standard medical practice, one-size-fits-all medicine will give way to a tailored approach. Although we’re not there yet, we need only look back to see how far we’ve come.
