Gholson Lyon is a physician-scientist currently working at the Utah Foundation for Biomedical Research and the Center for Applied Genomics at Children’s Hospital of Philadelphia. He will be starting as an assistant professor in human genetics at Cold Spring Harbor Laboratory next month. I asked him to write this guest post to provide some personal context to his thought-provoking commentary in Nature (subscription required) on returning genetic findings to research subjects. [DM]
I have just published in Nature a commentary discussing the need to bring exome and genome sequencing into the clinical arena, so that these data are generated with the same rigorous clinical standards as for any other clinical test. This way, we can then easily return at least medically actionable results to research participants. In this day and age of consumer and patient empowerment, I can also see eventually returning all data, including the raw data, to any interested participants, as this can then promote crowd-sourcing for data analysis, with research participants controlling and promoting the relative privacy of and analysis of their own data.
As I described in my commentary, my thinking on this matter was prompted mainly by Max (see picture) and his family. The obituary for Max can be found here, and that of his cousin, Sutter, here. We described their condition here, and we named this new disease Ogden Syndrome in honor of where the first family lives. I am now trying to think about and discuss the human aspects of and lessons from this story. My thinking has also been influenced somewhat by the late James Neel, who wrote a very thought-provoking book called Physician to the Gene Pool.
To me, it was deeply disconcerting that I could not officially return any results to this family (or to another family in a different project discussed here) even when the papers describing the genetic basis of their disease were published, as this was considered “research” and was not performed in a clinically appropriate (CLIA-certified) manner. This was all the more painful when one of the sisters in the Ogden family became pregnant and asked me what I knew. I cannot predict whether it would have helped or hurt this woman to learn during her pregnancy that she was indeed a carrier of the mutation, with the associated 50% risk of her baby boy having the disease. I also do not know if she would have undergone any genetic testing via amniocentesis of the fetus prior to birth (with the associated ~1% risk of miscarriage from the procedure), nor do I know what decisions she might have made prior to the birth even if she had undergone such testing. All in all, it was certainly an ethical and moral dilemma for me not to be able to return the research result to her, given that the results were not obtained in a CLIA-certified manner. It is still an issue, as there are even now financial and systematic barriers for getting all women in the family tested with a CLIA-certified gene test for NAA10 (which was developed over a six month period by ARUP Laboratories). It would have been so much better if we had just done the entire sequencing up front in a CLIA-certified manner.
It is therefore my opinion that the current flood of human sequencing data is not being optimally generated, given that there is no regulation requiring the initial sequencing of each human to be performed in a clinical-grade manner, thus making it very difficult and unwise for anyone to return any research information to research participants. This is due to the fact that clinicians must “first, do no harm”, so returning less than clinical grade sequencing results to patients can potentially cause such harm, as noted above. Therefore, the natural corollary to this argument (to me at least) is that initial sequencing of human exomes and genomes should be performed in a CLIA-certified (or other clinical-grade) manner up front, so that the data can be returned to research participants and/or linked to their medical record. That way, as knowledge expands over the next few decades, we can constantly go back and re-analyze the genomes and update research participants on new unrelated findings, in the context of their biochemical individuality. Of course, one can always re-sequence using newer technologies and/or confirm any important results on a new DNA sample from each person, but there will no longer have to be rigorous development of a specific CLIA-certified gene test for each mutation, given that the exomes and genomes were sequenced up-front in a clinically proper manner.
What are the benefits?
The medical system in America is currently geared and financially rewarded to treat specific issues that people have when they are ill, whereas there are relatively few incentives in the system for counseling (genetic and otherwise) and keeping people healthy. This needs to change. A federal guideline mandating that the first exomes and genomes on each human be performed in a CLIA-certified or otherwise clinically appropriate environment could save substantial money in the long run, for many reasons, in my opinion, including in the area of preventive medicine. This of course includes beefing up the number of genetic counselors initially, but there is accumulating evidence that at least some people take corrective actions (some of which can be life-saving) when they learn of genetic predispositions. Also, preimplantation diagnosis and other preventive efforts may benefit readily from the increased carrier screening that will accompany the clinical sequencing of humans.
Problems with the current system
Some researchers have suggested that the “easy” thing would be to “simply” re-sequence the research samples for each mutation of importance in an already CLIA-certified lab. However, this overlooks many things, including 1) not obtaining the blood/saliva or isolating, storing and tracking the DNA in any sort of specified and reproducible manner, 2) not developing an official CLIA-certified Sanger-sequencing test for this particular gene, and 3) not interpreting the Sanger sequencing in any sort of CLIA-certified manner. It is not enough to just place a sequencing machine in a “CLIA-certified lab” and then simply declare that all DNA, no matter how that DNA was obtained, stored, or tracked, nor how the sequencing data were analyzed, will suddenly now yield “CLIA-certified” results, deliverable back to research participants. What about the real risks of sample mix-up and incorrect results? In addition, are researchers really going to take the time to develop CLIA-certified tests for each and every one of the possible medically-actionable mutations that they uncover now?
Even though it is very likely that whole genome sequencing will become a routine part of clinical care in 10-20 years, it is far from certain what the path and process toward this goal will be. In science, much as in public policy, there is sometimes Brownian motion, whereby there are many small steps forward and backward, with many people losing perspective on the overall progress being made. Thirty years ago, very few people would have predicted that in vitro fertilization and test tube babies would become a routine part of medicine, even garnering a Nobel Prize for one of the champions of this technology. Furthermore, targeted carrier screening and pre-implantation genetic diagnosis is also becoming a routine part of medical care, particularly in some communities with an excess burden of recessive genetic diseases. So, the real question is: where we will be in two years? And in five years? The current sequencing will certainly lead to many scientific papers and discoveries, but the question is whether any of this sequencing, genetic discoveries, or unrelated findings will actually directly benefit anytime soon the actual families who took the time to donate their blood and other tissue samples? Will results, including unrelated findings, be returned to these families so that they can take preventive measures? Will the genomic data be returned directly to research participants so that they control the privacy of and access to their own genomic data? If so, how will this be done to minimize error and misinformation?
Hopefully, one day soon, each person will possess a copy of their own clinically certified genome, and they will then have the option to link their genome to their medical record and/or to provide their own genome data to other researchers. Indeed, some people could even contribute to the analysis as citizen scientists, akin to what is described in the new book Reinventing Discovery: The New Era of Networked Science by Michael Nielsen. Many researchers and interested participants can then together analyze the genome of each person repeatedly, as our collective knowledge expands. The consent process could also follow the model being proposed by the Sage Bionetworks Common Genomic Research Project, including a version of “portable legal consent“. Right now is hopefully a revolutionary time in medicine, as discussed by Eric Topol in his new book The Creative Destruction of Medicine, so we should seriously consider doing the right thing now, before we have gone down this current path far too long.
I am struck by the following quote in a recent Nature editorial:
What kind of work deemed as accepted today will be denounced by future generations? The question is one that all researchers should bear in mind, because history may judge them more harshly than their peers do.
Currently, it is the wild West for human genome sequencing. Many researchers are sequencing as many exomes and genomes as possible, using a range of methods. However, I am struck by the question of whether we are really thinking through the ethics of this. In the 1940’s, there was a huge rush to find a cure for syphilis and other venereal diseases, and this led many prominent researchers to conduct experiments on humans that we now look back on as being morally repugnant. Are we repeating the same mistake when we sequence live humans in research environments in which we are not able (or perhaps willing) to inform and counsel these people concerning potentially very deleterious mutations in their genomes? Are we keeping these people “in the dark” and thereby taking away from them the chance to take preventive measures for highly penetrant mutations running in their families, i.e. their “clan genomics”?
Acknowledgements: First and foremost, I would like to thank the families with whom I have had the pleasure to work. The Ogden Syndrome family also graciously consented to the publication of the photograph.
Conflicts of Interest: I do not have any obvious conflicts of interest to declare. I have had informal discussions with representatives from Illumina, Sage Bionetworks, ARUP, Golden Helix, Complete Genomics and Omicia, Inc., but I have not had any formal consulting role, nor have I received financial compensation from these or any other companies performing DNA collection or sequencing.