A recent Freakonomics Radio podcast poses a question frequently heard these days: “Do you really want to know your future?” In our era of wildly proliferating genetic information, this question is on everyone’s lips: in labs and classrooms, in the media, at dinner parties. This particular podcast was about Huntington’s Disease, an oft-cited example of a disease that is purely genetic (as far as we know), dominant (one copy of the gene with the mutation suffices to cause the disease), adult onset, highly penetrant (if you have the genetic mutation, you are very likely to develop the disease), fatal (at present) and untreatable (at present.)
Nancy Wexler, Professor of Neuropsychology at Columbia University, President of the Hereditary Disease Foundation, and member of an HD family, is quoted extensively throughout the story, as is Emily Oster, an economist at the University of Chicago who studies the effect of life expectancy on investment choices. In closing, three women at risk for HD are briefly quoted on their viewpoints on getting tested.
All four of the women at risk for HD come out strongly against wanting to know their status. Add to this picture Emily Oster’s research, which points to lower investment in education and higher rates of divorce among those knowingly carrying the HD mutation, and the emotional message of this story is very stark. It is well summed up by this line from Nancy Wexler: “If you’re somebody who has a 50 percent risk as most people at risk around the world there is nothing, nothing whatsoever that you can do that makes any difference whatsoever, nothing, nothing, nothing, nothing, nothing, nothing.”
Grappling with a genetic disease in one’s own family is not easy, and my heart goes out to anyone who has abruptly found him or herself in this situation. Of course every individual must find their own way through this terrible emotional territory, and make their own decision.
But all the same, that is a lot of “nothings.”
I would like to submit a reminder that there is a second, less-discussed side to this debate. If the stance above can be summed up as the “ignorance is bliss” camp, there is also a “knowledge is power” camp. I’ve made my life in this latter camp, and I think it deserves, at the least, to be known and heard from – to be part of our ongoing social dialogue, as tricky genetic questions go from rare medical novelties to just one more dimension of twenty-first century human health.
Genetic prion diseases, like HD, are dominant, adult onset, fatal (at present) neurodegenerative diseases for which we do not currently have treatment options. When my husband Eric and I learned in fall 2011 that I was at risk for the genetic prion disease that had claimed by mother’s life the year before, we decided immediately to get me tested, and we have never looked back.
Our reasoning was that there was no going back to a time before I was knowingly at risk. We only ever move forward in life, and to our minds, the time of true ignorance was behind us. Choosing not to answer the question would not erase the question. And given that we would be thinking about it anyway, it seemed better to know what we were up against.
I tested positive for the mutation that causes Fatal Familial Insomnia. Up until the moment I received my results, I had no preconceived idea of what would happen either way – what effect the news, either good or bad, would have on the course of my life from that point on. So it was with total surprise that I watched the events of the next year unfold. From jobs in consulting and degrees in law and city planning, Eric and I set about transitioning into careers in neurodegenerative disease research. By summer 2012 we were both working in science and had founded Prion Alliance and cureffi.org. Today, in summer 2013, you can help us crowdfund our first therapeutic trial.
Ours is an extreme story of how genetic news can launch positive action. And it would not have been possible without a lot of luck, and a lot of help. Most exceptionally, we were lucky to meet outstandingly bright, thoughtful and open-minded scientists at every step of the way.
With that said, I do think that there are “somethings” – opportunities for positive action – that are broadly available to those facing genetic news, even if one has no interest in becoming a scientist, or an advocate. Below is a list of some that come to mind. Importantly, as I’ll note throughout, many of these opportunities can be accessed without knowing one’s own test results, if that is one’s personal preference.
These thoughts are composed with dominant, adult-onset, currently untreatable genetic diseases in mind, such as HD and genetic prion diseases. Their applicability to other types of genetic diseases may vary.
Reproductive decisionmaking. The one benefit of testing that occasionally gets some air time, this angle is briefly alluded to in the Freakonomics story. Armed with genetic information, for the first time in history, one can now make the decision to prevent a genetic disease from passing to the next generation. Chorionic villus sampling can be performed as early as 10-12 weeks and can identify genetic mutations of interest in a fetus. And a yet more proactive option is also now available: pre-implantation genetic diagnosis, in combination with in-vitro fertilization, is now a standard practice and has produced hundreds of healthy babies. Expense and inconvenience notwithstanding, the PGD/IVF parents who I’ve talked to seem to feel profoundly satisfied with their decision. (For more information, this HDBuzz post provides an excellent introduction to these topics.)
Notably, it is possible to go through PGD/IVF even without the parent at risk ever learning his or her own status.
Scientific progress. A person who knew he was at risk for a genetic neurodegenerative disease once said the following to me: “I just have to be optimistic, live my life, and trust that science will find the answers.” This was his explanation for why he was choosing not to get tested, and not to engage with the subject of his genetic risk at all.
There are many reasons to decide not to get tested – but this line of reasoning troubled me. Science does not move forward like a train on a track, destined inevitably for the future. Science moves forward because we gather information over time, and from it, draw the conclusions that allow us to sift through the crazy mysteries of human biology. We all benefit, every day, from medical discoveries that would not have been possible without the sharing of information on mankind’s many maladies.
It may sound ridiculous, and I do not say it to trivialize — but especially in the domain of rare diseases, the very fact of having a genetic mutation means that you have something worth sharing – something that can help science move forward. And there are many different levels on which one can make this kind of contribution.
The scarce data surrounding rare diseases makes it difficult to answer even basic questions that have real ramifications for patients: how many people in the population have this mutation? Of them, how many will develop the disease with which it is associated? When in life does this usually happen? What is the spectrum of symptoms? Are there genetic modifiers that affect when or how the disease presents? Are there environmental factors that affect disease progression? Are there biomarkers that can help us predict disease course prior to the onset of symptoms? The medical literature attempts to answer these questions, but is inevitably biased by which cases are reported, and which are not. Age of onset, for example, often skews young because disease in a younger person is more likely to strike us as strange and drive us to pursue medical answers.
The most comprehensive research studies seek to combine trait information, genetic information, and family history in one data set. Participating in a study like this, especially on an ongoing basis, is a large contribution that some people choose to make, for example the participants in UCSF’s diagnostic clinical study for prion diseases. But one-time donations, that carry no identifying information, can also be very valuable to researchers. And this is true even in the case of HD or other “less rare” (one in ten thousand, as opposed to one in a million) rare disease mutations. The search for genetic modifiers, for example, must cover the enormous search space of the genome in looking for secondary genes that might influence the course of disease. Thousands upon thousands of data points are needed to draw meaningful conclusions in this kind of analysis. And too often, the available data sets are simply too small.
Again, it is worth bearing in mind that it is possible to donate, for example, a blood sample to a research study without ever knowing one’s own status.
The case of the rare disease transthyretin familial amyloid polyneuropathy provides an extreme, and very beautiful, example of the kind of scientific good that can come from sharing genetic information. This disease was thought to be fully penetrant (those inheriting the mutation consistently developed the disease) until a physician noticed that in one family, it followed an atypical inheritance pattern. Further investigation revealed that several family members carried the mutation but remained healthy. Side-by-side genetic analysis of family members eventually uncovered the protective genetic modifier, the mechanism of which went on to serve as the template for Tafamidis – a novel drug that slowed the progression of the disease in a placebo-controlled trial and is now approved for use in Europe.
Being counted. Related to the above – science is expensive to do, and science funding is difficult to come by. The NIH, the major source of research grants in the health sciences in the US, makes awards based partly on “relevance” – how big an impact research may have. But the numbers of people who stand to benefit from treatments and cures are being systematically underestimated. Being counted – even through an anonymous donation, without receiving a test result – is one simple way in which we cast a vote for more therapeutic research to be staffed, funded, and shared.
Being proactive. Another thing troubles me about the idea of just waiting for science to find the answers. Even if a treatment for, for example, HD were to be available, it would likely not benefit – or at least, not maximally benefit – people who waited until they were experiencing symptoms to seek it out. Again, there are many valid reasons to choose not to know one’s status. But one cost of that choice is that it limits one’s ability to act preventatively. In the case of neurodegenerative diseases, a lot of damage is already done to the brain by the time clinical symptoms arise. Therapeutic studies routinely find that it is far, far easier to intervene early in disease course than to try to repair existing damage or replace lost cells.
This is a little bit of wishful thinking on my part, as there is no preventative treatment for HD, nor for any other neurodegenerative disease – at the moment. But surely we can agree that this is the best time in human history to be an optimist. And although we don’t know what the near future holds, I for one want to know as soon as it gets here.
Being linked to people working against a genetic disease – be they families, support groups, genetic counselors, physicians, or researchers – is one way of keeping abreast of new developments. Long before there is a cure, there will be clinical trials. This will be the earliest opportunity to receive a potential treatment. And related to the above about science needing us to move forward – only by recruiting from patient populations can treatments ever become approved and available for use.
Solidarity. This is to say nothing of the emotional and social benefits of being linked to a community that can relate to, or help provide context for a difficult genetic situation. Learning that I was at risk was the most profoundly isolating thing that has ever happened to me – and I was lucky to have a supportive spouse, and a wonderful relationship with my father. Some people living with uncertainty seek out support, but many choose to live with the secret. Again, it works for some. It could never have worked for me.
“Individually rare but collectively common” is the tagline of the National Organization for Rare Disorders. And in my experience, I’ve found it to be true. Statistically, I will never happen to run into another person with the FFI mutation walking down the street. However, since sharing my story with my friend network I’ve been amazed to find that many people I know are personally linked to someone who has a genetic disease. Perhaps it seems a paltry benefit in light of the heavy emotional costs of coming to terms with bad genetic news – but there is something to be said for learning both your own strength, and that of the strongest relationships in your life (spoiler alert: they may not be the ones you’d think they’d be.) We never know the strength within us, and around us, until we see it in action.
Adaptation. The psychological concept of adaptation captures another potential emotional benefit of knowing. Hundreds of studies have explored this phenomenon, by which people tend to respond to life events with largely transient dips or spikes in their happiness, before habituating to their new circumstances and returning more or less to baseline. The field of positive psychology is not without its controversies, but there is a principle here that seems to ring true of minor changes – how quickly, for example, a new purchase loses its luster – and may even provide insight into larger life changes. Emily Oster speaks to this effect when she says, “..[I]n the data we see evidence on whether people are depressed and we see people are initially, the first year after they get a bad test result they are somewhat more depressed, but then they basically return to baseline for quite a long time. Most people are kind of about the same amount of happy most of the time.”
When I consider the role of adaptation in my testing experience, what strikes me is the timing. For me, until the limbo of 50/50 risk was resolved, I was unable to adapt. The uncertainty had a different emotional flavor each time I focused on it. Both potential outcomes clamored for my attention, but not always equally. The subjective shifting of the risk made it hard for me to take my mind’s eye off of it. Not long after being tested, though – for me, it was less than a year – I could feel that I was acclimating to my new knowledge. Slowly but surely, as with other difficult things in life, the results became one more piece of furniture in my mind. The obsession ended, and my life resumed – perhaps on a different trajectory, but no longer on pause.
Clarity for families. I recently met a young woman who knew herself to be at 50/50 risk for a fatal (at present) genetic disease. She did not want to know her status, but also didn’t want to leave her family guessing in the event that she fell ill or passed away. She chose to get tested and, without seeing them herself, to have the results held in a file that her family has permission to access, under specific circumstances.
It makes sense that families struggle with how to communicate about a genetic disease. Everyone deals with risk differently, everyone deals with bad news differently, and family conflict around genetic diseases, sadly but understandably, seems to be very common. As I’ve read more genealogical accounts of families uncovering a history of disease in their lineage, I’ve been struck by how much confusion and strife can result from a seemingly neutral desire to avoid the topic. By burying the lead and obfuscating how loved ones passed away, families leave subsequent generations to re-encounter the same mysteries starting from scratch. This puts later generations at a disadvantage regarding relevant medical advances, and denies them the opportunity to choose a different approach to their own risk.
Whether or not one chooses to be tested, delineation of one’s end-of-life wishes can provide a tremendous gift of clarity to a confused and grieving family in a terrible moment. Anyone who has watched a loved one struggle on life support will recognize the ability of this uniquely stressful moment to divide even the closest clan. No test result is required to set forth one’s intentions should different possible scenarios arise. And along similar lines, no test result is needed for one to pledge tissue to science after death, should it prove to be of interest.
Reform and de-stigmatization. An oft-cited reason for not getting tested is fear about discrimination and stigma. There is a not-unfounded sense that predictive genetic testing is too new – that in today’s world, one can’t be sure how the information will affect one’s social or financial life, and that given the uncertainties, the risk-minimizing option is to avoid receiving any information.
I’ve wrestled with these concerns myself, and the uncertainties are real. It is true that despite positive developments, there remain some tricky questions about discrimination, insurance, and stigma surrounding genetic diseases. But I’ve come to believe that no better world is owed to us, destined to arrive at some point in the enlightened future. Like scientific progress, social and legal progress will arise from actions taken today, and from the collective strength of determined individuals. History tells us that stigmas don’t erase themselves – this happens over time through the raising of a chorus of voices that say: We are here, and we want to live a good life.
In Massachusetts, a genetic bill of rights was proposed in 2011. Among other things, if it passed this bill would have supplemented GINA (the federal Genetic Nondiscrimination Act) by providing protection against discrimination in life, disability, and long-term care insurance for carriers of genetic mutations, in addition to the protection against health insurance discrimination that GINA confers. To my knowledge, neither this bill nor any similar state initiative has yet become law. For the moment this may be for the best, as in addition to the admirable goals above, the MA bill proposed new genetic privacy measures that would have made genetic research more cumbersome and expensive to conduct. From my perspective, a law making genetic research (which is already tightly regulated) harder to do would work squarely against the interests of those living with genetic risk – for whom treatments and cures that hinge critically on the pace of research are the ultimate goal.
All of that said – it is my hope that an improved version of this measure will come back around, and surface in other states, offering broad protections against insurance discrimination in all of its forms, while ensuring that research is not jeopardized. This is precisely the sort of legal change that would help us build that better, de-stigmatized world. And it would be great if we could count on de-stigmatizing legal movements to build themselves – but as we all know from observation, perceived need and demand are critical to moving history along. We can incrementally speed the process by adding one more voice to the chorus, whether it be by lobbying and letter-writing, or simply by being counted and being cognizant.
Every time someone at genetic risk chooses to share that fact, on any scale, rather than keeping it a secret, the circle of people who are plugged into these issues grows.
I can only speak for me. But with that caveat, here is what I can say: Getting tested was one of the best decisions I’ve made. The hardest time by far was when we were waiting for results, holding our breath, waking up scared every morning. Now, far from waking up every day worrying about my status, I rarely think about my genetic test results per se. I’ve made a kind of peace with them, and to the extent they now enter my thoughts, I have a scientific framework within which to consider them – a framework that excites my curiosity, fills me with optimism, and motivates me every day. I know I am doing what I can, and with that knowledge, I feel more empowered now, and prouder of how I spend my time, and better about myself in all regards, than I ever did in any previous phase of life.
Compare that to this excerpt from Nancy Wexler, discussing people who know their positive HD status:
“People think, I think, everyone thinks really that in some secret soul of their bodies or their minds that they’re truly unattractive and that nobody if they know this, they won’t love them… And especially, you know, when the outside world is saying this is repugnant, this is repulsive, then we act it out in bad ways. It is toxic knowledge, it is difficult.”
This observation is based on a career spent studying HD. But it is important to remember that this isn’t the only story out there.
Whether to get tested is a profoundly personal decision. No one piece of advice will work for everyone. Above I’ve tried to capture some of the reasons that it was a good decision for me, some of the benefits of knowing, and some of the empowering and proactive steps one can take without ever learning one’s own test results.
Even in the face of the most arbitrary of arbitrary life events – a 50/50 coin flip for a life-altering genetic accident – I submit that there remain important ways in which we can control, if not life’s random events, the stories that we tell with the lives that we build around those events, every day.