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By Rachel Horton, William Macken, Robert Pitceathly and Anneke Lucassen.
We’ve each got four to five million ways in which our DNA differs from the ‘standard’ or ‘reference’ genetic code. When our genome is looked at in a test, all these differences are logged. Most won’t affect our health at all, they’re just natural genetic variation, though they could be used to infer stuff ranging from where our recent ancestors probably lived, to what colour our eyes are likely to be. A few of these differences will have a clear impact on health – for example, they might influence our risk of developing cancer, or might mean that if we have children there’s a chance they could have a genetic condition like cystic fibrosis. For lots of these differences, we’ve got very little idea what they mean, or we know that they have slightly different effects in different people.
In getting from four to five million genetic differences per person to a clinical result from a genomic test, a huge amount gets filtered out along the way. This filtering is often seen as a very technical process, a way by which you find ‘the needle in the haystack’ – but that presupposes that we know what results look like and the challenge is simply to find them. In our article we talk through a case where genomic testing done to investigate muscle weakness found something off-target and uncertain: a genetic variation that possibly predisposes to kidney cancer, uterine fibroids and skin lumps. The ‘needle’ we were looking for was an explanation for the patient’s muscle weakness; what we saw instead wasn’t really needle or hay.
The variation in question isn’t causing the muscle weakness that led to the patient having a genomic test, and quite possibly it doesn’t really predispose to kidney cancer at all. It’s completely normal to have stuff that looks at least hypothetically concerning in your genetic code – on average, each person has 54 variations previously reported as disease-causing (i.e. in theory, we’re more confident than we are for the variation discussed here that they might cause trouble) in their genome. In practice, some of these might lead to disease in them or their family, but most won’t. However, in this particular case, a detailed family history asking about kidney cancer, uterine fibroids and skin lumps, and a careful clinical examination focussing on skin, might shed light on the meaning of this particular genetic variation.
So we argue that the variation should be discussed with the patient who had the test – not because it is medical information, but because further work might lead to its becoming so. But we reflect on some of the seemingly technical aspects of genomic testing that led to this variant being considered as a potential result – for example, the choice to examine the gene that the variant is in when exploring the cause of the patient’s muscle weakness, and how the person reviewing the genomic data happened to have a general genetics background rather than an exclusive focus on muscle conditions.
Our article suggests that when appraising genomic information, we should not leap to ask ‘what should we do about this result?’ before we have first questioned why and whether it constitutes a result. Ethical debates around genomics often focus on whether to look for, or how to respond to, genomic ‘results’, but finding results within a person’s millions of genetic variations is not a matter of waving a metal detector around and waiting for needles that make it beep – needle/hay distinctions are often in the eye of the beholder and the choices that need to be made as to why and when genetic variations should be viewed as results deserve more attention.
Authors: Rachel Horton (1, 2, 3), William Macken (4, 5), Robert Pitceathly (4, 5), Anneke Lucassen (1, 2, 3)
Affiliations:
Competing interests: None declared
Social media accounts of post authors: @rach_horton, @w_macken, @RobPitceathly, @annekeluc
The post When and why does a genetic variation become a result? appeared first on Journal of Medical Ethics blog.
Elon Musk, Mars, and bioethics: is sending astronauts into space ethical?
The recent crash of the largest-ever space rocket, Starship, developed by Elon Musk’s SpaceX company, has certainly somewhat disrupted optimism about the human mission to Mars that is being prepared for the next few years. It is worth raising the issue of the safety of future participants in long-term space missions, especially missions to Mars, on the background of this disaster. And it is not just about safety from disasters like the one that happened to Musk. Protection from the negative effects of prolonged flight in zero gravity, protection from cosmic radiation, as well as guaranteeing sufficiently high crew productivity over the course of a multi-year mission also play an important role.
Fortunately, no one was killed in the aforementioned crash, as it was a test rocket alone without a crew. However, past disasters in which astronauts died, such as the Space Shuttle Challenger and Space Shuttle Columbia disasters, remind us that it is the seemingly very small details that determine life and death. So far, 15 astronauts and 4 cosmonauts have died in space flights. 11 more have died during testing and training on Earth. It is worth mentioning that space flights are peacekeeping missions, not military operations. They are carried out relatively infrequently and by a relatively small number of people.
It is also worth noting the upcoming longer and more complex human missions in the near future, such as the mission to Mars. The flight itself, which is expected to last several months, is quite a challenge, and disaster can happen both during takeoff on Earth, landing on Mars, and then on the way back to Earth. And then there are further risks that await astronauts in space.
The first is exposure to galactic cosmic radiation and solar energetic particles events, especially during interplanetary flight, when the crew is no longer protected by both Earth’s magnetic field and a possible shelter on Mars. Protection from cosmic radiation for travel to Mars is a major challenge, and 100% effective protective measures are still lacking. Another challenge remains being in long-term zero-gravity conditions during the flight, followed by altered gravity on Mars. Bone loss and muscle atrophy are the main, but not only, negative effects of being in these states. Finally, it is impossible to ignore the importance of psychological factors related to stress, isolation, being in an enclosed small space, distance from Earth.
A human mission to Mars, which could take about three years, brings with it a new type of danger not known from the previous history of human space exploration. In addition to the aforementioned amplified impact of factors already known—namely microgravity, cosmic radiation, and isolation—entirely new risk factors are emerging. One of them is the impossibility of evacuating astronauts in need back to Earth, which is possible in missions carried out at the International Space Station. It seems that even the best-equipped and trained crew may not be able to guarantee adequate assistance to an injured or ill astronaut, which could lead to her death—assuming that care on Earth would guarantee her survival and recovery. Another problem is the delay in communication, which will reach tens of minutes between Earth and Mars. This situation will affect the degree of autonomy of the crew, but also their responsibility. Wrong decisions, made under conditions of uncertainty, can have not only negative consequences for health and life, but also for the entire mission.
“It is worth raising the question of the ethicality of the decision to send humans into such a dangerous environment.”
Thus, we can see that a future human mission to Mars will be very dangerous, both as a result of factors already known but intensified, as well as new risk factors. It is worth raising the question of the ethicality of the decision to send humans into such a dangerous environment. The ethical assessment will depend both on the effectiveness of available countermeasures against harmful factors in space and also on the desirability and justification for the space missions themselves.
Military ethics and bioethics may provide some analogy here. In civilian ethics and bioethics, we do not accept a way of thinking and acting that would mandate the subordination of the welfare, rights, and health of the individual to the interests of the group. In military ethics, however, this way of thinking is accepted, formally in the name of the higher good. Thus, if the mission to Mars is a civilian mission, carried out on the basis of values inherent in civilian ethics and bioethics rather than military ethics, it may be difficult to justify exposing astronauts to serious risks of death, accident, and disease.
One alternative may be to significantly postpone the mission until breakthrough advances in space technology and medicine can eliminate or significantly reduce the aforementioned risk factors. Another alternative may be to try to improve astronauts through biomedical human enhancements. Just as in the army there are known methods of improving the performance of soldiers through pharmacological means, analogous methods could be applied to future participants in a mission to Mars. Perhaps more radical, and thus controversial, methods such as gene editing would be effective, assuming that gene editing of selected genes can enhance resistance to selected risk factors in space.
But the idea of genetically modifying astronauts, otherwise quite commonsensical, given also the cost of such a mission, as well as the fact that future astronauts sent to Mars would likely be considered representative of the great effort of all humanity, raises questions about the justification for such a mission. What do the organizers of a mission to Mars expect to achieve? Among the goals traditionally mentioned are the scientific merits of such a mission, followed by possible commercial applications for the future. Philosophers, as well as researchers of global and existential catastrophes, often discuss the concept of space refuge, in which the salvation of the human species in the event of a global catastrophe on Earth would be possible only by settling somewhere beyond Earth. However, it seems that the real goals in our non-ideal society will be political and military.
By Gabriel Watts and Ainsley J. Newson.
Data obtained from genomic sequencing has an interesting quality. Unlike most other kinds of health results, the stored information remains accurate over time, because it reflects a largely stable property of our bodies: our DNA.
Of course, during this time, sequencing methods themselves are likely to have advanced further such that new sequence data will be of better quality. Much in the same way that the resolution on a phone camera picture from 2013 is not as good as one from today – indeed, we are already seeing changes to high-throughput DNA sequencing quality with the advent of long-read sequencing. But still, that present day sequence data can retain diagnostic validity for as long as a decade is already exceptional. In our paper in the Journal of Medical Ethics, we refer to this property as the ‘diagnostic durability’ of genomic data.
Another important aspect of genomic information is that while the sequencing data itself is stable, the interpretation of that data can be quite dynamic, and may change within a short space of time. This means a result delivered to a patient at one point in time may have a different interpretation later on.
For patients who receive results such as ‘no pathogenic (disease-causing) variant identified’ or who are told they have a ‘variant of uncertain significance (VUS)’, the changing status of this result can be significant. If a finding is re-graded, it may open up new treatment options that they couldn’t previously access. A result can also go the other way, to benign from VUS.
These attributes of genomic data have important implications for the responsible implementation of genomic testing in health. One question is: should laboratories or clinicians routinely go back to the data they hold for patients with null or VUS results, to see if a new interpretation is possible? We consider this question in our paper.
An immediate issue here is whether routine reanalysis is even feasible. On the one hand, doing this is known to increase the ‘diagnostic yield’ of genomic testing: more patients receive definitive information that can inform their treatment. Yet on the other hand, until automation of reanalysis is in place (and this is coming) this process is time- and resource-intensive, and likely beyond the majority of health systems to provide at large scale.
One way around this limitation is to only provide reanalysis to those who ask for it. But this is likely to limit this benefit to those who know to do it, or to ask for it, and so raises equity concerns.
One part of reanalysis, however, is reinterpretation of variant classifications. This process can achieve increased diagnostic yields in a comparable way to a detailed individual reanalysis. But it is more sustainable because it occurs at the level of classes of variant rather than individual patient DNA sequences. As such, routine reinterpretation of variant classifications may be more feasible at scale, at least in the short to medium term.
Given this, do laboratories or clinicians have an obligation to undertake routine reinterpretation of variant classifications as a part of the responsible implementation of genomic health care?
In our paper we argue against the existence of any general duty to reinterpret genomic variant classifications. Yet, we contend that a restricted duty to reinterpret ought to be recognised.
Our initial motivation was drawn from the intuitive pull of the position we argue against. It is undoubtedly ideal that diagnostic laboratories routinely reinterpret all their variant classifications, in order to keep up with the rapid changes in our understanding of genomic testing results.
It is a different question, however, whether there is a moral duty to do so. At issue here is whether the potential benefits of routinely reinterpreting genomic variant classifications is likely to lead to a valid diagnosis for any particular patient. If not, then it is arguably better to invest resources in preparing patients for the high likelihood that genomic testing will produce results that are uncertain, and that are statistically unlikely to become clinically relevant in the future, than to hold out of hope of a statistically unlikely diagnosis through regular variant reinterpretation.
To be clear, we are not arguing that we should not aim to develop diagnostic systems on which all genomic variant classifications are routinely reinterpreted. For instance, developing diagnostic systems that automate the various elements of reanalysis – including reinterpretation of variants classifications, but also the re-prioritisation of previously unanalysed sections of a patient’s genome, as well as the re-annotation of sequence data – is a morally laudable aim.
What we do argue is that the best healthcare systems need to be developed within the limits of what is currently or imminently feasible. As automation expands, the obligation to reanalyse may become actual. Our point is that we best not confuse this with an obligation arising from certain peculiar properties of genomic sequencing data. For any obligations here only stretch so far, and better warrant investment in patient counselling concerning the inherent uncertainty of genomic testing than investment in the routine reinterpretation of all variant classifications.
Paper title: Is there a duty to routinely reinterpret genomic variant classifications?
Authors: Gabriel Watts, Ainsley J Newson
Affiliations: Sydney Health Ethics, University of Sydney – Australian Genomics
Competing interests: None declared
The post Should we routinely reinterpret genomic results? appeared first on Journal of Medical Ethics blog.
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