“I'll never understand what possessed my mother to put her faith in God's hands, rather than her local geneticist” - Vincent, the protagonist in the classic sci-fi flick GATTACA.
I had the pleasure of rewatching this film recently and offering some commentary on the scientific ideas it centres on at an event organised by Newstalk radio’s Futureproof program at Dublin’s Science Gallery. It was a very enjoyable evening, with a lively crowd and some thought-provoking questions. I had forgotten what a great film it is, and remarkably prescient in its vision of the possible future applications of genetic technologies.
Though released in 1997, when the Human Genome Project had only just begun, it imagines a world where access to everyone’s complete genetic information is routine, where most people are conceived in vitro and embryos are prescreened for all manner of perceived genetic defects, and where those remaining few who were conceived the old-fashioned way (with all the genetic baggage that comes along with that method) are actively discriminated against.
It is especially timely to consider these ideas, as cheap and routine whole-genome sequencing looks set to become a reality. This is already changing genetic research, leading to unprecedented breakthroughs in the genetics of conditions like autism, for example, and also fundamentally altering our conception of the spectrum of genetic variation in human populations. But as more and more people have their genomes sequenced, serious questions arise as to what we will do with all that new information.
One consequence of routine sequencing is that individuals may find out they are carriers for a number of genetic conditions. We all carry hundreds of potentially deleterious mutations, some of which are known to cause disease, though often only if both inherited copies of the gene are mutated. For very rare mutations, this will not be a major issue as the chance that one’s spouse will also carry it is vanishingly small (so potential offspring should never be affected). But many populations have certain disease mutations segregating at quite high frequencies, due to population founder effects, balancing selection or genetic drift. In Ireland, a particular mutation causing cystic fibrosis (the “deltaF508” mutation) is at very high frequency (as one of my parent’s carries it, I have a fifty percent chance myself). The carrier rate in the Irish population for this and a number of other specific mutations is 1/19. There are many other examples of high-frequency mutations causing a range of diseases in other populations – sickle-cell anemia in Africans, beta-thalassemia in Cyprus, Tay-Sachs disease in Ashkenazi Jews.
If you and your spouse know that you are both carriers of such a mutation, then in vitro fertilisation with preimplantation genetic diagnosis (PGD) becomes an attractive scenario. This is the method portrayed in GATTACA, though taken to the nth degree, by screening against vast numbers of mutations at once. In the present, the technique is used to diagnose inheritance of usually just one, very specific mutation, where one or both parents are known to be carriers. The diseases listed above are all commonly tested for – others include mutations causing Huntington’s disease, breast cancer, or other later-onset conditions.
With this technique, multiple embryos are generated by in vitro fertilisation and allowed to develop for several days. A single cell is carefully removed from each and the DNA extracted. This can then be molecularly analysed to determine which embryos have inherited the mutations causing concern. It is then possible to choose an embryo or embryos that have not inherited the mutation and implant those. The remainder are usually discarded.
To many, this smacks of playing God. To others, it is common sense – if a couple can choose to have a healthy child versus one with a serious disease, then why shouldn’t they? This is summed up by this exchange from the film:
Antonio: We were just wondering if, if it is good to just leave a few things to, to chance?
Geneticist: You want to give your child the best possible start. Believe me, we have enough imperfection built in already. Your child doesn't need any more additional burdens. Keep in mind, this child is still you. Simply, the best, of you. You could conceive naturally a thousand times and never get such a result.
The choice being made is to implant one embryo over another. IVF clinics do this routinely anyway, by “grading” embryos based on those which look most likely to lead to a successful pregnancy (based on a number of embryological criteria). This choice does remind me, though, of the “Wasn’t” in this poem (Happy Birthday to You) by Dr. Seuss:
"If we didn’t have birthdays, you wouldn’t be you.
If you’d never been born, well then what would you do?
If you’d never been born, well then what would you be?
You might be a fish! Or a toad in a tree!
You might be a doorknob! Or three baked potatoes!
You might be a bag full of hard green tomatoes.
Or worse than all that…
Why, you might be a WASN’T!
A Wasn’t has no fun at all. No, he doesn’t.
A Wasn’t just isn’t. He just isn’t present.
But you…You ARE YOU!
And, now isn’t that pleasant!"
The other main application of preimplantation genetic testing is to screen against possible chromosomal anomalies (or aneuploidies), such as trisomy 21, which causes Down syndrome or other abnormalities in the genetic complement. This is typically done with older women, where the chances of such anomalies arising is increased, or in couples that have had several miscarriages, which can also result from aneuploidies.
The prospect of routine whole-genome sequencing adds another angle to this kind of preimplantation screening and diagnosis, providing the means to select prospectively against embryos with any potentially harmful mutations (whether carried by the parents or new ones that have arisen in the egg or sperm). This starts to get closer to the scenario portrayed in GATTACA, and raises the ethical question of which kinds of conditions or genetic traits this procedure should be used for.
Currently, some countries (the UK, Canada and Germany, for example) have laws limiting its use to screening for serious genetic conditions. Others are more loose, however. In many American states it is legal to screen and select on the basis of sex, for non-medical reasons. In fact, a 2006 study (see below) found that 9% of PGD procedures carried out in IVF clinics in the U.S. were performed for this reason. Other reasons include screening for an embryo with the same immune type (“HLA type”) as a current child who is ill and requires a transplant of some sort. Screening for these “savior siblings” was done in 1% of PGD procedures. And 3% used it for a reason I personally find jarring – to specifically select embryos with a mutation causing a genetic condition. This is usually in cases where both parents have either deafness or dwarfism and they want their child to be similarly affected. This gets into the political movement objecting to society labelling conditions as “disabilities”. I can sympathise with that to some degree – more for some conditions than others – but I think, if it were my child, I would still rather he or she could hear.
In any case, these applications illustrate the range of possibilities that will arise as we get routine access to the entire genomes of prospective parents and of embryos generated in vitro. Genetic testing can also obviously be done post-implantation, of a fetus in utero. For example, screening by amniocentesis for conditions like Down syndrome is routine, and in some countries, the majority of such diagnoses result in the decision to terminate the pregnancy. Remarkably, it is now possible to screen a fetus’ DNA without the invasive procedure of amniocentesis, by sequencing the entire fetal genome from DNA that enters the maternal bloodstream from dying placental cells. (Independently sequencing the mother’s genome provides a reference to distinguish fetal from maternal DNA).
Once genome sequencing becomes both cheap and fast (as recent announcements of new technologies suggest may happen very soon), it will change the game when it comes to these reproductive technologies. Not only will we all have more knowledge of mutations we may carry and wish not to pass on, we will also have greater access to the complete DNA information of embryos or fetuses. Different societies will have to decide what level of intervention they deem permissible.
The prospect envisioned in GATTACA is not just that individual embryos are routinely prescreened and selected, but that that process has led over time to the progressive weeding out of mutations in the gene pool. This is the grand vision of eugenics realised through molecular technology and not just selective breeding. Should we be concerned that this might become a reality? Will this kind of selection change gene frequencies in specific populations? Would that be a bad thing?
In fact, this is already happening. A program has been in place in Cyprus since the 1970s where all prospective couples must be genetically tested for the mutation causing beta-thalassemia (a serious and life-threatening disease). Remarkably, the Greek Orthodox Church is one of the strongest supporters of this program and will not marry coupes who have not had the test. This has led many couples who find they are both carriers to not get married, decide not to have children or decide to prescreen, either in vitro or in utero, to detect the inheritance of two copies of the mutation, permitting embryo selection or termination of a pregnancy. Collectively, these actions have led the rate of live births affected by beta-thalassemia to decrease from 1/158 to effectively zero. On the one hand, the “eradication” of the disease can be seen as a good thing. On the other, the selective termination of pregnancies of individuals who will inherit what is now a more treatable disease than in previous years may be troubling to many.
This is, in a sense, the ultimate form of genetic discrimination. I am not arguing against this program, not saying that it should not happen and not saying I would not avail of these technologies in that situation myself. Where abortion without a medical reason is legal, it’s certainly hard to argue against it when there is a medical reason. But as our potential information increases – as we learn more about how various mutations can affect a person’s phenotype – these issues will arise in more and more cases, many in much grayer areas than those discussed above.
What about mutations causing conditions like autism, for example, maybe only in a percentage of people who inherit them? Is that information prospective parents would want or would act on? There is a question of personal choice there, but also whether society wants that choice (i.e., one based on genetic information) to be available. Should screening for sex be allowed? This is a different proposition when selecting embryos in vitro than in prenatal testing and selective termination of a fetus based on sex. The latter has been common in China and India for years and has resulted in a massively skewed sex ratio in some areas. The United Nations Population Fund concluded that “if the continent’s overall sex ratio was the same as elsewhere in the world, in 2005 Asia’s population would have included almost 163 million more women and girls.”
These are just some of the possible ramifications of increased access to genetic information that society will have to figure out how to deal with. One final note: in the film, our hero overcomes his genetic destiny, proving the predictions wrong in his case. That is a timely reminder to remember both the limits of our current knowledge and also the more fundamental limits of phenotypic prediction based on genetic data. The fact that monozygotic (“identical”) twins are really not identical for many traits (or in affected status for many disorders) shows directly the limits of genetic determinism and reinforces the fact that the individuality of each person goes far beyond their genome.
Baruch S, Kaufman D, & Hudson KL (2008). Genetic testing of embryos: practices and perspectives of US in vitro fertilization clinics. Fertility and sterility, 89 (5), 1053-8 PMID: 17628552