January 12, 2009, 12:42 PM — In the 1997 science fiction thriller Gattaca, Ethan Hawke's character fights to make a life for himself in a world where pervasive genetic testing and manipulation has left the imperfect by the wayside. At the time, it was easy to dismiss the film as a futuristic flight of fancy, not an issue that people would be facing in the next 10 years. After all, the Humane Genome Initiative already had spent years trying to sequence a single man's DNA, and had years left to go.
But, as often happens in technology, the science of genomics followed a "hockey stick" curve. The initial breakthrough of a single sequenced genome required the development of new sequencing techniques, which have drastically reduced the cost and time required.
Currently, commercial services will deliver an entire sequenced genome in less than a month, and there is a concerted effort to reduce that price to under US$1,000. Meanwhile, several companies offer consumers the ability to get vast amounts of their genetic data for as little as $400. Personal genomics, so recently science fiction, is now a click away on the Internet. But while this information may offer new insights for individuals into their heritage and physical characteristics, the possibility of a Gattaca-like future suddenly doesn't seem so far-fetched.
The two best-known personal genomic services, 23andMe and deCODEme, both operated in essentially the same manner. After visiting their web site and paying for the testing ($1,000 for deCODEme, $400 for 23andMe), a kit is sent in the mail. The consumer either rubs a stick shaped like a large tongue depressor against the inside of their cheek, or provides a (somewhat voluminous) sample of their saliva. The kit is returned to the company, which then processes the sample.
After a few weeks, the customer's genetic data becomes available on the website. But what he gets is not his complete genetic sequence. Instead, he gains access to as much as a million of their Single Nucleotide Polymorphisms (SNPs). Human DNA is, on the whole, identical from person to person. It is in the small differences brought on by random mutations that all the differences we see between people occur. Many of these differences are a single letter chance in a portion of DNA, a G instead of a C, for example. Fortunately for the companies, these single letter changes are relative easy to detect, and there are now "Snip Chips" that can detect the values of hundreds of thousands of individual SNPs from a single sample at the same time.
"All genetic variation is a result of random mutation," explains Andro Hsu, Science and Policy Liaison for 23andMe. "A lot of SNPs are neutral, in that they don't seem to have any effect on phenotype, which is the physical characteristics of a person. When you have enough of these mutations, and they get spread out to children, then you get a natural set of variation across the population. Over 99.5 percent of the genome is identical between human beings, and it's that last 0.5 percent or so that's different. And SNPs make up a good deal of those differences."
Mining The Genome
Customers can do several things with the data, once available. For example, they can use it to get information about their geographic ancestry, although this is currently a rough estimate at best, broken down into mongoloid, Caucasian and negroid. However, the precision of this data will improve quickly, once more data is available, according to Hsu. He points to a recent study in which Smithkline Glaxo was able to pinpoint the country of origin for European samples with a fairly high degree of precision.
These tests can yield information about paternity and maternity, data that may lead to some awkward realizations. A child has half of his father's SNPs, and half of his mother's. If the child has SNPs that neither the father or mother has, he is either adopted or the father isn't really the father after all. In addition, a male child's Y chromosome is passed down unchanged from the father, and all children get their Mitochondrial DNA (a specialized piece of genetic information in the portion of the cell that produced most of the energy) directly from their mother. So a son or daughter who innocently gets an extended family tested may find skeletons in the closet.
But the use of SNP data that is most controversial is in its relationship to physical characteristics and predilections. Every day, researchers are discovering new associations between SNPs and characteristics such as physical endurance, as well as to potentially life-changing conditions such as diabetes and cancer. It may not be the SNP itself that causes the problem; but because genes tend to stick together through time, SNPs that are close to other defects can serve as markers for the faulty gene itself.
However, the degree to which they may affect an individual may be very weak, explains David Magnus, PhD, Director of the Center for Biomedical Ethics at Stanford. "Most of the traits that we have information about, from say an array that looks at SNPs... in the vast majority of the traits, those are not very predictive. So even if you have a gene for Type 2 diabetes, or that is positively correlated with heart disease, or for being tall, it contributes so little casually, that it doesn't really tell you much about the likelihood of the actually phenotype." This is in contrast to tests such as those for the BRAC1 and BRAC2 genes, which have a large probabilistic impact on the chances of a woman developing breast cancer. "Now [with the new tests] we're talking about things that have so little impact that it's just swamped by any number of other causal factors, including environmental ones."
GINA To The Rescue?
While some see personal genomics as ushering in a new era of personalized health care, it also raises the specter of discrimination on the basis of genetic data. Conceivably, health insurance companies could start to consider a positive SNP test for a disease to be a pre-existing condition, for example. Or an employer might not hire someone who carried an increase risk of a mental illness, according to their genetic data. To answer some of these concerns, Congress passed GINA, the Genetic Information Nondiscrimination Act, in 2008.
But as Hsu points out, it's only a first step. "As it stands, it only applies to health insurance coverage and to employer discrimination based on genetic information. It doesn't currently apply to life insurance or long term care insurance, things that people's decisions might be effected by because of genetic information." He also points out that GINA only deals with the approval or denial of health care coverage, leaving insurance companies and health plans free to charge higher premiums for those they deem risky.
The issue of employment discrimination is particularly complex, according to David Magnus. Imagine that a certain subgroup in the general population is likely to become ill in the presence of some pathogen which is otherwise well-tolerated by people. If there was a test for that variation, a company might very well want to screen potential employees for it, if the work environment would expose the employee to the pathogen. "But then that raises questions about who has the authority to make those decisions," Magnus says. "Can you force that testing on people against their will? If they decided that they needed the job, that it was much better paying than any other job in town, could they decide that it's worth it to get exposed to the risk? These are all the kinds of concerns that people have been very worried about."
Magnus also points out that the medical community may not be prepared to deal with this flood of new data. "This is a huge problem, because then what are you supposed to do with this data? If you can't understand it, and a clinician can't understand it, what are we going to do with it? I'm very concerned that people are going to believe that they are at increased risk or decreased risk [for a disease], when they aren't."
Brave New World, V2.0
Although discrimination on the basis of genetic information could be a serious issue, there is another use for genetic testing that's starting to emerge, with disturbing implications: designer babies. Prenatal screening for genetic abnormalities in high-risk parents, such as those who carry the genes for Tay-Sachs disease, is commonplace these days; although the moral dilemma that a positive result can create is still a difficult issue. But as more and more traits are testable through SNPs and other genetic markers, it is becoming possible to design the child you want.
In its more benign form, this takes the form of sampling a cell from in-vitro fertilized (IVF) embryos and choosing which one to implant based on the results. So, if the parents want a blue-eyed child, only blue-eyed embryos would be implanted. Parents can already choose the gender of the child to be implanted, sometimes to prevent a gender-linked disease from being passed on, and sometimes to create "family balance."
The more sinister scenario is the use of amniocentesis or ultrasound studies of a fetus to abort undesirable children. This is not science fiction; it's a growing problem in India and China. Selective abortion of girls has led to an increasingly out of balance gender ratio, with 20 percent more boys than girls being born in China.
As the price of genome testing falls, and more and more traits are identified, we face the possibility that other traits, such as blond hair or green eyes or height could be similarly skewed. Today, very few children are born by IVF, but the allure of creating the "perfect" baby may be hard to resist.
David Magnus points out that some IVF couples already practice a version of this, by selecting egg and sperm donors with traits they desire. But he's less worried about skewing the genome than he is about the welfare of the children, and what is called "The right to an open future." "If you allow prenatal testing, if you allow selection of these sorts, if you allow newborn testing, you do worry about the kind of impact that it could have on the children, and the likelihood that they will be as free to make decisions about themselves as they otherwise would. From the kid's point of view, imagine if the parent says 'Look, I got this egg from someone who's very musically inclined... we did a genome scan when you were born and you have several of these genes that have a very small casual associations with musical ability, so we expect you to become a very gifted musician.' But the kid wants to play football."
Magnus doubts it will become a serious problem though, at least in the United States. "The idea of a Gattaca world, where most people do IVF in one form or another to procreate, I think is very unrealistic. As long as there is alcohol and youth and indiscretion, people will continue to have children the old fashioned way."