UNDERSTANDING DOCTORS' ETHICAL CHALLENGES AS ROLE VIRTUE CONFLICTS

This paper argues that doctors' ethical challenges can be usefully conceptualised as role virtue conflicts. The hospital environment requires doctors to be simultaneously good doctors, good team members, good learners and good employees. I articulate a possible set of role virtues for each of these four roles, as a basis for a virtue ethics approach to analysing doctors' ethical challenges. Using one junior doctor's story, I argue that understanding doctors' ethical challenges as role virtue conflicts enables recognition of important moral considerations that are overlooked by other approaches to ethical analysis.     

Reputation,a universal currency for human social interactions

Decision rules of reciprocity include ‘I help those who helped me’ (direct reciprocity) and ‘I help those who have helped others’ (indirect reciprocity), i.e. I help those who have a reputation to care for others. A person''s reputation is a score that members of a social group update whenever they see the person interacting or hear at best multiple gossip about the person''s social interactions. Reputation is the current standing the person has gained from previous investments or refusal of investments in helping others. Is he a good guy, can I trust him or should I better avoid him as a social partner? A good reputation pays off by attracting help from others, even from strangers or members from another group, if the recipient''s reputation is known. Any costly investment in others, i.e. direct help, donations to charity, investment in averting climate change, etc. increases a person''s reputation. I shall argue and illustrate with examples that a person''s known reputation functions like money that can be used whenever the person needs help. Whenever possible I will present tests of predictions of evolutionary theory, i.e. fitness maximizing strategies, mostly by economic experiments with humans.     

OUGHT WE TO ENHANCE OUR COGNITIVE CAPACITIES?1

Ought we to improve our cognitive capacities beyond the normal human range? It might be a good idea to level out differences between peoples cognitive capacities; and some people's reaching beyond normal capacities may have some good side‐effects on society at large (but also bad side‐effects, of course). But is there any direct gain to be made from having ones cognitive capacities enhanced? Would this as such make our lives go better? No, I argue; or at least there doesn't seem to be any evidence suggesting that it would. And it doesn't matter whether we consider the question from a narrow hedonistic perspective, from a more refined hedonistic perspective, from a desire‐satisfaction view, or from some reasonable objective list view of what makes a life go well. Only an extremely perfectionist – and implausible – view of what makes our lives go well could support any direct value in cognitive enhancement. Finally, our sense of identity gives us no good reasons to enhance even our capacity to remember. So, cognitive enhancement as such would not improve our lives.     

The sanctity of life as a sacred value

The doctrine of the sanctity of life has traditionally been characterised as a Judeo-Christian doctrine that has it that bodily human life is an intrinsic good and that it is always impermissible to kill an innocent human. Abortion and euthanasia are often assumed to violate the doctrine. The doctrine is usually understood as being derived from religious dogma and, as such, not amenable to debate. I show that this characterisation of the doctrine is problematic in a number of ways, and I go on to rethink the doctrine. In doing so I follow in the footsteps of Ronald Dworkin, who offered a characterisation of the doctrine in his 1993 Life's Dominion, drawing on a conceptualisation of sacredness that is radically different from standard ones and not dependent on religious dogma. I'll argue that although Dworkin's efforts have much to recommend, his conceptualisation of sacredness is inadequate. Dworkin attempted to reconceptualise sacredness ‘from the armchair’. Here I explain how sacred values are thought of in anthropology and psychology and argue that the sanctity of human life should be understood in the same way. I'll explain how doing so allows us to resolve a number of conceptual problems that bedevil standard characterisations of the doctrine of the sanctity of life. I'll also consider the possibility of a compromise over the sanctity of human life, and as a consequence, compromise over the permissibility of abortion and euthanasia. I'll argue that such compromise is possible, albeit difficult to achieve.     

Joan Heath interviews Suzanne Cory and Joan Steitz: a female perspective of science in the swinging ‘60s

Prompted by the occasion of International Women''s Day, Joan Heath and DMM reunited Professors Suzanne Cory and Joan Steitz via Zoom to discuss their extraordinary careers and joint experiences in science. They also delve into past and present challenges for women in science, and discuss the role of scientists in a post-pandemic world.

Suzanne Cory, Joan Steitz and Joan Heath (from left to right) As one of Australia''s most eminent molecular biologists, with a school in Melbourne bearing her name, Professor Suzanne Cory has been both Director of The Walter and Eliza Hall Institute of Medical Research in Australia (WEHI) and President of the Australian Academy of Science. She earned her PhD at the Medical Research Council (MRC) Laboratory of Molecular Biology (LMB) in Cambridge, UK, with postdoctoral training at the University of Geneva. She continues her research at WEHI as an honorary distinguished research fellow, investigating the genetics of the immune system in the development of blood cancers and the effects of chemotherapeutic drugs on cancer cells.Joan Steitz – currently Sterling Professor of Molecular Biophysics and Biochemistry at Yale University, and for 35 years the recipient of a Howard Hughes fellowship – is best known for her seminal work in RNA biology. She was the first female graduate student to join the laboratory of James Watson at Harvard University and proceeded with her postdoctoral training at the MRC LMB in Cambridge. Her pioneering research delved into the fundamental mechanisms of ribosome and messenger RNA interactions, as well as RNA splicing, heralding the phenomenon of alternative RNA splicing. A recipient of many awards and honours, she is also involved in international projects aimed at supporting women in science.Host Joan Heath heads a laboratory at WEHI in Australia. She received her undergraduate degree from the University of Cambridge, followed by her PhD at the Strangeways Research Laboratory also in Cambridge, then just across the road from the MRC LMB. After postdoctoral positions in bone biology and osteoporosis research, Joan joined the Ludwig Institute for Cancer Research where she became a laboratory head, and changed her focus to cancer research using zebrafish to identify genes that are indispensable for the rapid growth and proliferation of cells during development. She joined the WEHI in 2012. There she showed that the same developmental genes are also required by highly proliferative, difficult-to-treat cancers, including lung, liver and stomach cancer, paving the way for translational research targeting these genes in novel cancer therapies. Joan H: How long have you two known each other? Suzanne: I was calculating that this morning and I was astonished because it seems like only yesterday, but it has been 55 years since we met in Cambridge. It has been a voyage in science and a voyage in the world because we have always made a point to meet up in beautiful places and go hiking. That is how we''ve been able to renew our friendship over all these years. Joan H: Where were you when you first met? Joan S: We both were working at the MRC LMB in Cambridge, England. Suzanne was doing her PhD and I arrived slightly later for a postdoc.Suzanne: We had a pre-meeting in the sense that Joan, Jerry Adams (my future husband) and Tom Steitz (Joan''s husband), were all graduate students together in Harvard. So, when Joan and Tom came to Cambridge, it was natural that we would all start doing things together. And Joan and I ended up sharing a lab bench.Joan S: The reason that I did a postdoc in the mecca of X-ray crystallography was that I had married a crystallographer – and there was no other place that he could possibly go. They very much wanted to have my husband at the Cambridge MRC lab, but there wasn''t a clear plan for me. Francis Crick suggested that I do a literature project in the library, but I knew that theory was not my forte in comparison to experiments. I started talking to the many people working in the lab and found a project that no one wanted, because it was so challenging. But it was a very interesting problem, so I decided to take it on – and it turned out to be a great project.Joan H: That''s amazing. You were obviously determined to overturn other people''s expectations of you.Suzanne, even now, it''s extremely unusual for a young person to leave their home country to do their PhD. It''s still a brave thing to do but all those years ago it was really courageous. You told me that you ended up there because you wrote a simple letter, which was a complete shot in the dark.Suzanne: It certainly was. During my master''s degree at the University of Melbourne, I became more and more interested in doing science and decided I would do a PhD. But I had a counteracting desire to travel and see Europe. So I decided that I would do my PhD overseas to give myself the opportunity of travelling. I had fallen in love with DNA during my undergraduate studies. So, I wrote a letter to Francis Crick in Cambridge, and asked if he would take me on as a PhD student. Much to my amazement, I eventually got a letter back saying yes. I think that my professor of biochemistry might have also visited Cambridge while he was travelling and spoken up for me. However, I was still extraordinarily fortunate that Francis had agreed because there weren''t many PhD students in the LMB at that time. It made such a difference to my entire life. I look back on that letter and think, “How did you have the audacity to write that letter and aim to go to that laboratory?”. I think it was partly naivety.Joan H: That''s a lesson for everyone, to go for your dreams, and don''t assume people won''t take notice of you. It is more difficult now, when scientists receive hundreds of e-mail applications from prospective PhD students in their inbox. You would have written a letter with a stamp on it that probably took three weeks to arrive, but it just shows you that you should be audacious. Did you have a different experience to Joan when you arrived? Was there a proper project already lined up for you?Suzanne: I was interviewed by Francis Crick and Sydney Brenner, who were the joint directors of the department. They decided that I would work on the structure of the methionyl-tRNA that puts methionine into internal positions in polypeptides. After they described the project – which involved doing counter-current distribution fractionation of bulk tRNAs, in which I had no experience whatsoever – Sydney in his very characteristic monotone said, “Do you think you''re up to it?”. I sort of gulped to myself and said, “Yes, I think I could do that”. I then went to Brian Clark''s laboratory, who was going to be my PhD supervisor, and started the project. Like always in life, if you learn from people and just go from one day to the next, you actually get there in the end.Joan H: So, persistence was key. Were there many other women at the LMB at the time?Suzanne: I don''t remember any female scientists who had official senior positions. There were certainly some strong female scientists there, but I don''t think they were given the recognition or the status that they actually deserved.Joan S: Later, some were given more recognition, crystallographers in particular, but not so much the molecular biologists.Suzanne: I think, as women, we both pioneered in that department.Joan H: Given the fact that you both agreed to take on projects you had very little previous experience with and that the male supervisors thought you weren''t going to have the mettle to carry it through, once you were there, did you feel that you had to work the whole time? Or did you still manage to have lots of fun and partake in opportunities that Cambridge had to offer at the time?Joan S: We certainly partook in a lot of those things. My husband and I got interested in antique furniture, antique paintings, and used to scour the countryside for little antique shops. We saw lots of England, then a little bit of Scotland and Wales. It was wonderful. A real adventure.Suzanne: I worked really hard most of the time that I was in Cambridge, as the work was very exciting. But I would take holiday periods, camping and youth hostelling all over Europe with a girlfriend from Melbourne and later, travelling with Jerry. We also would go to London for the opera and looking for amazing clothes on Carnaby Street and Chelsea Road (this was the Beatles era, late 60s). Jerry once came back with a purple velvet suit, which was his prized possession for many years. There was lots of fun but also lots of work.Open in a separate windowJoan Steitz, Tom Steitz, Jerry Adams and Suzanne Cory (from left to right) in the Swiss Alps, 1970. Image courtesy of Mark Bretscher. This image in not reproduced under the terms of the Creative Commons Attribution 2.0 Generic license. For permission to reproduce, contact the DMM Editorial office. Joan H: Can you remember the first moment in that part of your career that gave you the most pleasure? Joan S: I worked on a project for about a year, and it turned out that I was doing the wrong fractionation method to get the material that I needed to analyse. Then I had a conversation with Sydney Brenner telling him that I was going to give this one more try with a new method, and then I was going to give up. I remember Sydney saying, “Sometimes, like with a bad marriage, you have to give experiments one last try before you give them up.” Then I tried again, and it worked. This is often the case in science, that you try something new, that''s a little bit different, and it makes all the difference. Then you''re running.Suzanne: The same thing happened to me. I was labouring away on the counter current distribution machines fractionating methionine tRNA, with the goal of sequencing it by the laborious procedure recently published by Robert Holley. However, Fred Sanger, in the department upstairs, had invented a totally new method for sequencing using ³²P-labelled RNA. I desperately wanted to try this, so I managed to persuade my supervisor that we should change techniques. That change was key to my future because the approach was successful. I still remember to this day exactly where I was in Cambridge, walking on a Sunday afternoon, when the last piece of the puzzle dropped into place in my mind, and I had the entire sequence. In that moment, I was extremely joyful, because I knew I had my PhD and that I had succeeded. So that was my eureka moment.Joan H: Obviously, these were extremely productive years, and you''ve mentioned several Nobel Prize winners in your midst. It must have been the most inspiring environment, which I''m sure had a big impact on what you did next. By this stage in your career, were you already feeling ambitious or was it still your scientific curiosity that was driving your path?

“I expected that I would go back to the United States and be a research associate in some man''s lab […]. Then it turned out that people were more impressed than I thought and started offering me junior faculty jobs.”

Joan S: I had gotten a lot of recognition for having sequenced a piece of mRNA, using the same methods that Suzanne used to sequence tRNA. However, I had no expectations, because I had never seen a woman as a science professor, or head of a lab. I expected that I would go back to the United States and be a research associate in some man''s lab, and maybe they''d let me guide a graduate student. Then it turned out that people were more impressed than I thought and started offering me junior faculty jobs.My husband had already secured a junior faculty job in Berkeley before we even went to England, so we went back there after two years. My husband went to the chair of the department in Berkeley and put down letters on his desk of job offers that both of us had received for independent, junior faculty positions from several universities. The Chairman then said to Tom, “But all of our wives are research associates in our labs, and they love it”. This tore at my pride, as there had been a couple of universities that offered us both faculty jobs, and Berkeley was only offering one. So, we didn''t stay at Berkeley, and we came to Yale, which was wonderful.Suzanne: It''s really amazing to think that they gave you up. How foolish they were.Joan H: They''ve lived to regret it a million times over. Suzanne, at that point were you ready to climb this very difficult ladder?Suzanne: Like Joan, I didn''t have any expectations. For me, it was a matter of being able to continue discovering things in science. Jerry had already arranged to start a postdoc in Geneva. So, I applied for a postdoctoral fellowship, and obtained one. We went off together to Geneva to start our married life, and that was the beginning of us doing science together, which we''ve done ever since. I think without Jerry guiding me at that stage in my life, I would have probably drifted out of science. I don''t think I had the scientific confidence to ever think that I would be running a lab. For me, it was just continuing a voyage of discovery; and being lucky to end up in a wonderful scientific partnership and, through that partnership, my confidence grew over the years. Joan H: How many years after your postdoctoral training was it before you looked around your environment and had the confidence to think that you could be a lab or department head or could run an Institute? Joan S: I would say that confidence just grew. Tom and I were part of a departmental overhaul that involved hiring about six new people at Yale. We all stuck together, supported each other and were very collegial even though we worked in different areas. I think the collegial nature of the department in Yale helped me gain confidence. It was very scary at first because I didn''t know if I could write grants or direct people.Suzanne: Cambridge had an incredible influence, certainly over me, and I''m sure over Joan, Tom and Jerry, too. We looked around and saw all these amazing Nobel laureates, but also all these very ambitious, talented postdocs from around the world. I don''t think anyone thought about being the head of a department at that stage. We were simply striving to make discoveries and we gave each other mutual confidence, and stiff competition, too.The other thing that Cambridge gave us, was a new technology. For Joan and me, it was RNA sequencing. Being able to do that technology opened doors all around the world. I now always advise young people to go to the best place in the world to train in your chosen subject and acquire a new technology, because that will open the door to many opportunities in the future.Jerry and I made some excellent discoveries in Geneva, which were published in front-rank journals. Then it was time to move to full independence. I really wanted to go back to Australia but, as Jerry is an American, it was not at all obvious that he should take the big leap of moving to the bottom of the world and starting a lab there. I owe him a tremendous debt because he decided that he would take that risk.Earlier, whilst on our honeymoon, we had visited various labs in Australia. Although WEHI was an institute for immunology, a field we knew little about at that stage, it had the same atmosphere as the LMB in the sense that everyone was striving at the frontiers of science and competing with the rest of the world. We decided this was the only place in Australia that we would work at and that we would attempt to persuade the new director Gus Nossal that he needed molecular biologists. We had an interview with him in Switzerland and he offered us jobs as postdocs. Again, we were probably very naive and audacious but we told him we didn''t want to be postdocs – we wanted to run our own lab. And he agreed and we launched our fledgling lab together in 1971. What drove us was always discovery, rather than career ambitions.Joan H: You''ve both described these amazing sets of circumstances that were challenging but, nevertheless, very satisfying. However, a lot of things have since changed. What do you think are the main remaining barriers to women in science?Joan S: There is an important phenomenon called social identity threat, or stereotype threat, that I think still impedes women in proceeding in their careers. The phenomenon is described by cognitive psychologists as a reaction that all people experience if they feel that they are part of an undervalued minority. And so, by definition, since there are fewer women in science than there are men, women are being subjected to stereotype threat. Cognitive psychologists have studied the physiological manifestations of this, including increased heart rate and perspiration but, psychologically, they''ve also documented that cognitive learning and memory are impaired when one has these feelings.I first learned about this in 2007 and I looked back and realized why, for 30 years, when I''d been on committees as the only woman amongst ten men, I wouldn''t dare say anything – because I was frightened stiff. Men undergo this response, too, if they''re put into the situation of being undervalued. If you understand why you''re reacting the way you''re reacting and know that this is a normal human response, I think it helps you to overcome your own feelings of insecurity and allows you to go ahead. I always tell young women who I''m rooting for in science about this, because I want them to know that they will very likely end up feeling this way, and it''s a normal human response.

“One thing I sometimes get frustrated about is that we often need men to change things […] but what we really need are women in those high-level positions, so that they can be the champions of change.”

Joan H: There are other terms describing other relevant phenomena, such as unconscious bias, imposter syndrome and champions of change. One thing I really relate to is imposter syndrome. I''ve listened to webinars on this topic and they all reach a similar conclusion that we all feel the same. On the one hand, at the end of the webinar, you do feel somewhat elated to know that it''s not just you, and that it''s normal. But, on the other hand, it doesn''t really change things. It''s a recognition of what we feel, and we all get some help from that, but you really need opportunities to change things at a higher level. One thing I sometimes get frustrated about is that we often need men to change things, leading to this concept of male champions of change. I admire those men; but what we really need are women in those high-level positions, so that they can be the champions of change. Not having 50% of university departments and medical research institutes run by women still limits our full potential.Joan S: I certainly agree with you, Joan. It''s very important to have realistic role models. Suzanne being head of the WEHI for all those years has engendered all sorts of admiration.Joan H: During that period, Suzanne not only did fantastic science but our Institute doubled in size.It''s transformative when you have women making up 50% of people around the table. It''s no help just having a token female because that poor person''s not going to be able to change everything on her own. In American scientific institutions, are there any firm quotas for female scientists and other people that are underrepresented in science?Joan S: In recent years there has been a push in that direction. Sometimes it''s successful and sometimes it''s not. It is very different now compared to when there was no consciousness that this was unfair or that things could be better if we had real representation.Suzanne: I agree with both of you in everything that''s been said. While reflecting at this moment, what it says to me is that what''s really needed is societal change, and that we need to give courage to girls from the very earliest age. It should come naturally, they shouldn''t feel inferior, and others should not look at them as inferior. They should expect to have careers as well as families, be able to manage both and have somebody alongside them who helps them manage both.I think that affirmative action for women in science is necessary because the pace of change has been so slow. However, I also think quotas can be detrimental to the cause of women, in the sense that it''s then possible for people to say you only made it because there was a quota – which is very destructive. If I look back on our careers in science, it is clear that things have changed tremendously. Today there are more opportunities for women because many universities and institutes are bending over backwards to equalise things. The downside of this is that talented men may miss out on positions because of this policy and the pendulum could swing back.Joan H: The evidence shows that when more women are involved in things, those things go better. For instance, boards that have more women on them are more productive. Obviously, what you alluded to is there are lots of fantastic male scientists as well. The real issue here is there''s not enough funding to go round to support all the great men and women. But there are clearly enough good women around to be represented at the 50% level, without disproportionately disadvantaging male scientists.Joan S: Men and women are now operating on a more even playing field, which doesn''t mean that the men are missing out. They''re just in a more-competitive situation – as they should be. Joan H: Suzanne previously covered the specific advice she would give to young female researchers. Joan, do you have any other suggestions? Joan S: I encourage them to try lots of different things in science, and when they find something that really grabs them, then go for it and be persistent. We all know that science is very up and down. But if you keep pushing when you''re in a trough, it will always go back up again and you will succeed. That''s harder for a young person, who hasn''t experienced these troughs, to understand.Joan H: Yes, and the period when women scientists start having children is the hardest part. It''s still a choice that some women make, to take some years off and come back with a less ambitious plan for their career. Obviously, things like maternity leave payments and so on are improving but there''s no question that, in most circumstances, the research will slow down during that period.Suzanne: What I say to young women at that stage of their careers is that you have to be very focused, you must spend the time that you do have in a very focused manner, so that you can be the most productive you can be. But you have to be supported at home by your partner. If you''re both scientists it''s easier because you can appreciate why the other person is rushing into the lab late at night, for example, but for most people, that''s not true. So, what is really important is equal sharing of responsibilities from both partners when young families are around. And I think employers need to give both of those partners a longer time to achieve the kind of papers that they need to progress in their careers. That''s a period when it is much harder to be productive, and we need to continue to support people during that difficult phase of their careers because we''ve invested so much in them. They have so much to offer to science and to society, so to let them slip out at that stage is a great waste.Joan H: Let''s change tack a little bit and think about some of the broader challenges in science. What do you think the COVID-19 pandemic has taught us about the importance of clear scientific communication and real engagement with the community?Joan S: Whenever I talk to people about this, I very clearly make the point that it was decades of fundamental research that led to the development of the COVID-19 vaccine. If it hadn''t been for those fundamental discoveries in how cells and mRNA work, it would never have only taken 63 days from sequencing the virus to phase one clinical trials at Moderna. I try to point out to people that all the different discoveries coming in from different angles made that possible. I personally find it absolutely remarkable that all that knowledge could be harnessed, so very quickly. I''ve been doing fundamental research my entire life and I never expected to see it materialise in the way it has. It''s a wonderful reward. Joan H: Do you think this has resulted in the community appreciating scientists more? Joan S: I don''t think we''re far enough downstream to know that. In the US, there has been a congressional vote to abandon our maintenance of vigilance and preparedness for future pandemics – which seems ridiculous. Now we have all these procedures set up, all we have to do is maintain them for the next one. Whereas, if we just let go of these procedures, we''ll have to start over again for future pandemics. I guess we''re not good enough at communicating some of these things at this point.Joan H: Millions of people died from the virus and yet, if we hadn''t had the vaccines, the scale would have been even more horrific. If we were able to convey this information effectively to the public, then, hopefully, people would recognise that – as well as spending a fixed percentage of the gross domestic product on defence, for example – we should spend at least the same amount on science. Not only for pandemics but for tackling climate change and other pressing issues. I like to think this is an auspicious time but I don''t know whether we are really taking advantage of it.Suzanne: The pandemic has brought science and scientists to the forefront, and there has been a period of great respect for scientists having developed the vaccine. It''s an absolute miracle that it was done so fast and effectively. We''re very fortunate but, as Joan said, that was not luck. It was through investment in basic science for decades. We have to keep conveying this message, to our politicians in particular, so that they will keep supporting all kinds of scientists, because we never know what''s around the corner.Joan H: Certainly, people like Anthony Fauci in the US and Catherine Bennett in Melbourne, spoke eloquently and had a real talent for communicating things clearly and in a nutshell. That''s not something we''re all good at and it''s not something that is easy to train into people either. I think we all need to try to capture the attention of the community at large, by speaking plainly. I don''t think people understand that scientists are underfunded and could do so much more if funding was more generous.

“All I can say to young people is, if you really love science and have a passion for it, keep trying – because you will succeed if you put your whole heart and soul into this career path.”

Suzanne: I think the general public has no appreciation of how tenuous the life of a scientist can be, and how we are losing so many great minds entering the field because young people just finishing their PhDs look with dismay at how hard it is to support a career in science and get enough funding. There''s a tremendous waste of talent. All I can say to young people is, if you really love science and have a passion for it, keep trying – because you will succeed if you put your whole heart and soul into this career path.Joan H: This has been an absolutely fantastic discussion and it''s such a delight to talk to women who, after all these years, are still as passionate as ever and are pursuing their scientific subjects with the same vigour as they have all along.Suzanne: It''s been wonderful to talk with you, Joan, and I hope that we see each other soon, no matter what continent. And thank you, Joan Heath for getting us together and giving us this opportunity.     

Work life balance?

There is no perfect recipe to balance work and life in academic research. Everyone has to find their own optimal balance to derive fulfilment from life and work. Subject Categories: S&S: Careers & Training

A few years ago, a colleague came into my office, looking a little irate, and said, “I just interviewed a prospective student, and the first question was, ‘how is work‐life balance here?’”. Said colleague then explained how this question was one of his triggers. Actually, this sentiment isn''t unusual among many PIs. And, yet, asking about one''s expected workload is a fair question. While some applicants are actually coached to ask it at interviews, I think that many younger scientists have genuine concerns about whether or not they will have enough time away from the bench in order to have a life outside of work.In a nutshell, I believe there is no one‐size‐fits‐all definition of work–life balance (WLB). I also think WLB takes different forms depending on one''s career stage. As a new graduate student, I didn''t exactly burn the midnight oil; it took me a couple of years to get my bench groove on, but once I did, I worked a lot and hard. I also worked on weekends and holidays, because I wanted answers to the questions I had, whether it was the outcome of a bacterial transformation or the result from a big animal experiment. As a post‐doc, I worked similarly hard although I may have actually spent fewer hours at the bench because I just got more efficient and because I read a lot at home and on the six train. But I also knew that I had to do as much as I could to get a job in NYC where my husband was already a faculty member. The pressure was high, and the stress was intense. If you ask people who knew me at the time, they can confirm I was also about 30 pounds lighter than I am now (for what it''s worth, I was far from emaciated!).As an assistant professor, I still worked a lot at the bench in addition to training students and writing grant applications (it took me three‐plus years and many tears to get my first grant). As science started to progress, work got even busier, but in a good way. By no means did I necessarily work harder than those around me—in fact, I know I could have worked even more. And I’m not going to lie, there can be a lot of guilt associated with not working as much as your neighbor.My example is only one of millions, and there is no general manual on how to handle WLB. Everyone has their own optimal balance they have to figure out. People with children or other dependents are particularly challenged; as someone without kids, I cannot even fathom how tough it must be. Even with some institutions providing child care or for those lucky enough to have family take care of children, juggling home life with “lab life” can create exceptional levels of stress. What I have observed over the years is that trainees and colleagues with children become ridiculously efficient; they are truly remarkable. One of my most accomplished trainees had two children, while she was a post‐doc and she is a force to be reckoned with—although no longer in my laboratory, she still is a tour de force at work, no less with child number three just delivered! I think recruiters should view candidates with families as well—if not better—equipped to multi‐task and get the job done.There are so many paths one can take in life, and there is no single, “correct” choice. If I had to define WLB, I would say it is whatever one needs to do in order to get the work done to one''s satisfaction. For some people, putting in long days and nights might be what is needed. Does someone who puts in more hours necessarily do better than one who doesn''t, or does a childless scientist produce more results than one with kids? Absolutely not. People also have different goals in life: Some are literally “wedded” to their work, while others put much more emphasis on spending time with their families and see their children grow up. Importantly, these goals are not set in stone and can fluctuate throughout one''s life. Someone recently said to me that there can be periods of intense vertical growth where “balance” is not called for, and other times in life where it is important and needed. I believe this sentiment eloquently sums up most of our lives.Now that I''m a graying, privileged professor, I have started to prioritize other areas of life, in particular, my health. I go running regularly (well, maybe jog very slowly), which takes a lot of time but it is important for me to stay healthy. Pre‐pandemic, I made plans to visit more people in person as life is too short not to see family and friends. In many ways, having acquired the skills to work more efficiently after many years in the laboratory and office, along with giving myself more time for my health, has freed up my mind to think of science differently, perhaps more creatively. It seems no matter how much I think I’m tipping the balance toward life, work still creeps in, and that’s perfectly OK. At the end of the day, my work is my life, gladly, so I no longer worry about how much I work, nor do I worry about how much time I spend away from it. If you, too, accomplish your goals and derive fulfillment from your work and your life, neither should you.     

Moral Distress,Workplace Health,and Intrinsic Harm

Moral distress is now being recognized as a frequent experience for many health care providers, and there's good evidence that it has a negative impact on the health care work environment. However, contemporary discussions of moral distress have several problems. First, they tend to rely on inadequate characterizations of moral distress. As a result, subsequent investigations regarding the frequency and consequences of moral distress often proceed without a clear understanding of the phenomenon being discussed, and thereby risk substantially misrepresenting the nature, frequency, and possible consequences of moral distress. These discussions also minimize the intrinsically harmful aspects of moral distress. This is a serious omission. Moral distress doesn't just have a negative impact on the health care work environment; it also directly harms the one who experiences it. In this paper, I claim that these problems can be addressed by first clarifying our understanding of moral distress, and then identifying what makes moral distress intrinsically harmful. I begin by identifying three common mistakes that characterizations of moral distress tend to make, and explaining why these mistakes are problematic. Next, I offer an account of moral distress that avoids these mistakes. Then, I defend the claim that moral distress is intrinsically harmful to the subject who experiences it. I conclude by explaining how acknowledging this aspect of moral distress should reshape our discussions about how best to deal with this phenomenon.     

Walking between academia and industry to find successful solutions to biomedical challenges: an interview with Geoffrey Smith

Geoffrey W. Smith is currently the Managing Director of Mars Ventures. He actually started his studies with a Bachelor of Arts degree and a Doctorate in Law but then, in part by chance and in part by following in his family footsteps, he stepped into the healthcare and biotech field. Since then, he has successfully contributed to the birth of a number of healthcare companies and has also held academic positions at the Icahn School of Medicine at Mount Sinai and at The Rockefeller University in New York, teaching about the interface between science and business. During 2014 he served as Senior Editor on Disease Models & Mechanisms, bringing to the editorial team his valuable experience in drug development and discovery. In this interview, Geoff talks to Ross Cagan, Editor-in-Chief of Disease Models & Mechanisms, about how he developed his incredibly varied career, sharing his views about industry, academia and science publishing, and discussing how academia and industry can fruitfully meet to advance bioscience, train the scientists and stakeholders of the future, and drive the successful discovery of new therapeutics to treat human disease.Geoffrey W. Smith was born in 1965. He obtained a Bachelor of Arts degree from Williams College in Williamstown, MA. After a stint as a Research Associate at Harvard Business School, he graduated from the University of Pennsylvania Law School. Following a federal court clerkship and first job experiences in law, he joined a healthcare services start-up named Advanced Health as one of its first employees. Geoff then co-founded various healthcare and technology companies, including Interbind and Ascent Biomedical Ventures, and is still a Managing Partner at the latter. In 2012, he joined the Icahn School of Medicine at Mount Sinai, first as Professor in the Department of Population Health Science And Policy, and then as Director and co-founder of the Design, Technology, and Entrepreneurship PhD program. Until December 2014, he was a Senior Editor at Disease Models & Mechanisms. Geoff is now Managing Director of Mars Ventures.Let''s start with your background. You have a Bachelor of Arts degree and a law degree. How is it exactly that you ended up working in biotech and pharma?My career path has been anything other than linear. I was actually pursuing my legal career when two entrepreneurs turned up at the law firm I was working for with an idea for a new technology-based company focused on more effectively managing healthcare services. I was a new associate without much to do, so I got assigned to work with the start-up and after about a year they asked me to come and join the company, Advanced Health. I had grown up in a very medically oriented family – my father was a medical school professor, my older sister was a PhD, and my younger sister is a medical doctor – and so to a certain extent joining a start-up in the healthcare space was a bit like joining the family business.We had a fair amount of success with that company. A little less than 2 years after I joined it, we had a successful initial public offering, and that started me down the road of participating in the start-up environment around healthcare.It sounds like it was not a surprising path for you. Which key people influenced you?Actually, it is somewhat surprising in that I had really prepared for and expected a career in law. Certainly, the work I did in law school and the first jobs I had after that started me on a different career. I was really focused on international relations and international law. The twist was that I got brought back into the healthcare arena, and ultimately the biotech arena, by a serendipitous connection – one of the entrepreneurs who started Advanced Health had trained at Brigham Women''s Hospital where my father was the Chief of Cardiology. It was through this connection that I became more than just an associate drafting legal documents and really began to build a close relationship with the founders, which ultimately led to me joining that business. This taught me that you can spend much of your time preparing, and thinking that your schooling is going to take you in one direction, but individual relationships can change your path and take you somewhere else altogether. In my case, these particular relationships stemmed from my father, who clearly had an enormous influence on me. He was both a practising clinician and a basic researcher, studying basic biology related to the function of sodium and potassium in the heart, but he also did applied research. He helped develop a radioimmunoassay test to measure digitalis levels in the blood and ultimately was involved in developing a drug called Digibind, an antidote to digitalis toxicity, which was one of the first drugs to use antigen-binding fragments [Fab] as the basis for a drug. Watching him manage these different activities in his career had a big influence on me.

“This taught me that you can spend much of your time preparing, and thinking that your schooling is going to take you in one direction, but individual relationships can change your path and take you somewhere else altogether”

I think that each of my sisters – as I said, one of whom went down a PhD route and one of whom went down a medical training route – had a big influence on me, as well. Watching the challenges that they had to face in those areas in some ways pushed me to go off towards law school and take a different path. It also brought me back to one of the aspects that I think is the most rewarding in the bioscience field, which is that you can have a profound impact on a large number of people through your efforts, whether they be purely research-based, academic-based or commercially-based.One of the things I was constantly impressed by is that you always seem to have a good feel for the health field and the biology field. Is this because it is something of a family business?I think so. Growing up at my dinner table, I was just privileged to get to meet and interact with a lot of incredibly successful clinicians and researchers. For me those were comfortable conversations: these were friends and so there was a comfort level being involved in that environment. I didn''t feel a lot of intimidation from it, which I think sometimes people who come from the outside do.One of the aspects I really like about the bioscience field is the impact of ideas. Success is really about one''s ideas and ability to execute them, and that was very appealing to me. It wasn''t about how much money you had or where you went to school, it was really about the ability to think deeply about a problem or a potential advancement and figure out a way to find a way forward. It is also a very people-driven process because it is not only about thinking deeply yourself but also about thinking deeply with those in your field or adjacent to your field. Lots of different personality types can succeed in this field, but I think it is certainly easier for people who have an affinity for sitting with people and thinking about a common area of interest.To that point, you actually have walked between business and scientists. What do you see is the difference? Some of the priorities are obvious, but what are the differences in terms of what motivates people in the two? Are the personalities that you come across different between the basic science world, the translating science world and the business world?I don''t think the personalities are particularly different. I think you find introverts and extroverts and everything in between in each of these areas. I am not sure that personality is necessarily a good predictor of success. I think it''s a question of what toolset you are most comfortable using to get at a problem, and where in the lifespan of a problem you''re interested in working.For example, scientists in academia very often are interested in working at an early stage of a problem. They understand something fairly basic about a process or something earlier in the understanding of a field. People who gravitate towards industry, instead, are more excited about working on the later part of a process, so, rather than trying to understand what the fundamental working mechanism is, they want to understand how to work that mechanism in a way that is predictable and repeatable.Obviously people in the commercial realm are often highly influenced by money, but even that I don''t think is really particularly the differentiator. There are plenty of academics who are driven by money as well. I really think it has much more to do with where on the spectrum of understanding one is interested in working. Industry is geared to solving practical problems and, if a lot is understood about a problem, to getting down to the ability to repeatedly and safely intervene, whereas academia really lends itself more towards understanding the front end of a problem or of an unknown mechanism to understand it first and at a more basic level.What about working in teams versus individually? Do you see a difference there?I think that has changed over time. I think it is very hard in academia today to be the brilliant solo investigator. I''m not saying it''s impossible but, considering the increasing size of the data sets one is working with, the statistical methods one has to use, the complexity of different fields overlapping with each other, it''s just very hard to handle all the necessary aspects of modern science as an individual. Increasingly, working in teams isn''t a choice: I think it''s a necessity in order to be effective. The difference may be that, in academia, often the teams are teams of collaborators (meaning they have influence but not necessarily power over all people participating in the team) who may work for different institutions, whereas, more commonly in industry, teams are working within a single corporate structure. In industry more often there are hierarchical relationships, which may allow for more directive behavior. Again, I''m not sure I would draw as much distinction between team or not team and between industry and academia, but I might draw somewhat of a distinction between how those teams function and how one manages a team. I think they are a bit different between the two realms.

“Increasingly, working in teams isn''t a choice: I think it''s a necessity in order to be effective”

Let''s turn to Disease Models & Mechanisms [DMM], where you have been a Senior Editor. What did your experience at DMM teach you about science publishing that perhaps you hadn''t thought about, and has it made you think more deeply about what goes into a good scientific piece of work? What were some of the surprises?Watching the detailed process that is necessary to take a piece from an initial submission through to a published article gave me comfort and respect for the level of diligence and the level of attention that the reviewers brought to the vast majority of the pieces. It gave me a good feeling that the science community can be a strong self-reinforcing organization that takes its responsibility to heart and only publishes the best of the work available. I think that was very reassuring.An interesting question for me was: is there a different function that the publication process could play in helping to galvanize new ideas or new interactions among different fields? That seemed to be challenging because people don''t want to rush out there without their ideas and data being fully thought-out and fully vetted. But still, somewhere in my mind is this notion that there should be an option in the publishing world to play a little bit earlier in the generation of new ideas.Do you mean journals having an earlier relationship – earlier in the experimental process with a laboratory – to work with them to provide advice?I don''t know if it''s to provide advice. One of the things I was struck by at DMM is that there are these different siloed research communities – for example, the fly and the fish communities – in which interactions and relationships in the individual fields are so well established and routinized. And the outcome from a publishing standpoint is still the canonical academic paper that has been relatively unchanged over a long period of time. Yet, we have had these tremendous changes in information and communication technology such that the manner of knowledge production and the methods of communicating in other parts of society have changed dramatically. It feels like there hasn''t been nearly as big a concomitant communication change in the biomedical sciences, and so the silos and the standard paper remain the way things are done.The publication process, because of its preciseness, can take quite a long time, so the musing here is whether there is a way that the publishing industry could facilitate an earlier, more speculative communication of interesting results in a way that would positively impact the field by turning over new information sooner. If you look at an area like maths, for example, and their pre-print servers, there is more of a notion of putting ideas out in the community that acts as a kind of peer-review process and a way to get the community interacting on new ideas early. That doesn''t seem to get a lot of attention in the life sciences area. It seems to me that even journals like the PLOS journals that are pushing towards a more open world of communication are still ending up being pulled back into the canonical paper form to communicate.

“…the musing here is whether there is a way that the publishing industry could facilitate an earlier, more speculative communication of interesting results in a way that would positively impact the field by turning over new information sooner”

I guess one of the issues on the biology side is that there is a real emphasis on trying to get your paper into the most prestigious journal, so people don''t want to drop that paper until it is as far along as possible to aim at high-impact journals.That of course becomes a self-reinforcing system. If the yardstick used in the life sciences industry is publication in high-impact-rated journals, then you are going to get that behavior. But if you''re interested in the generation of new knowledge and in moving your field forwards, it is at least plausible that publishing in a quicker fashion or with at least some outlet to move more creative ideas ahead would be attractive.There are clearly challenges to that. But I do think it''s remarkable that if you look at almost every other media area there has been a huge amount of change since the advent of the internet era, but there really has been very limited change around life sciences publishing. It''s been surprisingly conservative to me. I am wishing there would be more experimentation to find other ways to communicate information sooner and in a way that could spur more creativity.Of course, when you tie publishing back to industry, for competitive and intellectual property protection reasons, industry tends to not really want to get out in the front with its most interesting work too early. I think that a lot of things being published out of industry are not the most interesting stuff that is happening. But again it seems to me that another area that science publishing should be thinking about is how they could come up with other solutions that might provide for a more creative interaction between publishing and industry.Talking about old models versus new models, let''s move to issues of training. Another area that you''ve been impressive at is the training of scientists. You''ve had your hand in creating a new PhD track at Mount Sinai called Design, Technology, and Entrepreneurship [DTE]. What is your view about how we train scientists, what we''re doing better these days and what you would like to see being done better to train them?It seemed to me that there was a remarkably small amount of experimentation in academia around thinking about how to train biomedical PhDs, and that academia had missed the opportunity to provide a better set of tools to PhDs to allow them to be effective across a wider range of potential career outcomes. The majority of biomedical PhDs are not ending up in tenure-track faculty positions but rather in the ‘alternative career track’. It seemed to be disingenuous to train them solely for the academic track if in reality the majority were going to some other career track.So what I was really excited about in putting together the DTE program was trying new ways to train PhDs to be effective askers of questions and proposers of solutions, and to create an environment where they could gain experience in how to solve a variety of problems effectively.

“…what I was really excited about in putting together the DTE program was trying new ways to train PhDs to be effective askers of questions and proposers of solutions, and to create an environment where they could gain experience in how to solve a variety of problems effectively”

This meant that our students had to be rigorously trained as scientists, but this was an ‘and’ opportunity and not an ‘or’ opportunity. In addition to being trained as excellent basics scientists, we wanted to give them some training in how engineers think about problems, how designers approach issues, what tools those people use and how that impacts how they try to solve a problem. Hopefully over time this would produce students that are better suited for interacting and influencing other parts of society – be it industry, government or policy – and better positioned to compete in what is a very competitive job market.What were some of the things you did in the DTE training to get at this?We really tried to teach theory in the context of real problems. Virtually all the classes of the DTE curriculum were problem-driven. We created a class that we called ‘The Q.E.D. Project’ that followed along from efforts at Stanford and elsewhere to teach students how to identify an unmet need. We then asked them to form a team to address the unmet need, and then helped them understand how to build a prototype to address that need. Along the way, we also talked about what kind of roles people in their team need to play. Should your team be very diverse or very deep in a given area? How do we integrate people who have different cultural backgrounds or how do we integrate medical students with PhD students? We brought in a lot of people out of the non-academic environment who were practitioners and experts in their various areas and we tried to get students to think about the full range of stakeholders they would have to engage with to bring a solution to bear.We did not want to spend a lot of time lecturing the students in a purely didactic way. We wanted to engage them in a process where they were solving important problems as part of the class. Whether that was a class on modelling or an engineering-focused class, or how to think about scientific problems, the core of DTE was built around getting the students to grapple with a real world problem and let all the learning hang off that.How did the students respond to that? Do you think you were successful?Based on the number of students signing up to take the courses and the student evaluations after the classes were over, I think we really struck a chord. I wouldn''t say it was necessarily the right answer for every student but I think there is clearly a group of students for whom this is a really effective and motivating approach.Let''s now move to drug discovery and development – the focus of the new online Special Collection from DMM. What would you say are some of the most urgent challenges in drug development that you have seen?I think one of the most urgent challenges is to begin to break free of some of our ‘old’ ways of thinking and take advantage of new scientific insights. For example, if you look at the traditional organization in a medical school environment, they are centered around departments devoted to organs (liver, heart, kidney). I think our increasing scientific understanding is that there are disease processes that may impact multiple organ systems but ultimately it is understanding the process, and drugging the process, that becomes important and not drugging the organ.I think that moving towards a process-oriented understanding of what common mechanisms are implicated in a given disease state or therapeutic challenge will help us be a little more creative and a little bit more interdisciplinary in how we think about these challenges.One of the difficulties with those new approaches is that pharmaceutical companies and academic institutions have not had a great track record of working together. Do you think that''s true? And why do you think it''s been so difficult to move ideas from the bench to the clinics?I think this is complicated. If you take the academic researchers'' point of view, their early identification of a problem and early identification of a potential solution feels like they have moved the ball very far forward towards the end solution. If you take industry''s point of view, the identification of the target or even the identification of a potential chemical compound is really just barely beginning to get to the starting line; the bulk of the time and the bulk of the dollars that will ultimately be needed to create a product come after the academic work and these will be spent by industry. I think that this differing point of view around where and how value is created has a lot to do with many of the challenges that arise when academia and industry are speaking to each other.Is it important to bridge this gap or is everybody playing their role?I think there''s an opportunity for academia to continue in its current role but to carry the potential solution further. I think in certain areas the access to tools and to patients allows academics to maybe carry projects further and closer to ‘proof of concept’ than they did historically, and that will continue to add value to the academic institution. That would ultimately help to bridge this gap because if you''ve taken something closer to proof of concept while still within the academic institution, you have created more value, you are able to engage with industry differently, and maybe the value perception gap is closed somewhat.What industry is really good at is organizing and managing late-stage research and clinical trials in an effective manner, and what academia is really good at is understanding basic questions, finding targets and sometimes finding early chemical compounds. Again, I think that the perception in academia of where value has been created is in part related to the fact that many academics haven''t been given the exposure or the training to actually understand the full breadth of the drug-development process. While they may have a general sense of it – we have all seen the same diagrams showing the steps and the funnel narrowing down from a million compounds to something getting onto the market – only those with real exposure to the work in industry understand it at a visceral or experiential level. One of the opportunities for academia is to find better ways to have some cross-talk, whether that''s internships for graduate students to get some experience in industry or other ways to get the students really exposed to the industrial side of drug development. Obviously, all the trained scientists on the industry side have been through academia because they had to go through it to get their PhDs, and thus they understand the academic side of the house pretty well. I really think the challenge is getting to people who have spent their whole career in academia to have a better understanding of what the drivers are on the industry side.

“One of the opportunities for academia is to find better ways to have some cross-talk, whether that''s internships for graduate students to get some experience in industry or other ways to get the students really exposed to the industrial side of drug development”

Between target identification and clinical trials of course there is another piece. At what point does the researcher in academia put down his pipette, walk out and start a biotech company? Should that happen?That''s a fraught question because I think it is an enormous undertaking to start a biotechnology company. Fundraising, intellectual property, regulatory affairs, company management – there are a whole number of disciplines that biotech companies have to take on. It is very rare that an academic scientist is going to have the training, the time and the motivation to do all of those things while also continuing to pursue their academic career in a very challenging funding environment. I think it comes back to this point that we were talking about with teams. I think it is really important for a scientist who is excited about their work and thinks it may be the basis of a company to go out and begin to form a team that is going to increase the likelihood of success. They have to accept the fact that science is a critical component, but it is just a component, and many different disciplines along with many different people are needed to make a successful company. If a scientist can bring that sort of collaborative view point and is open to working closely with an intellectual property attorney, with a business development person and with whomever their funding source is, that will increase their likelihood of success. They have to do it with a certain amount of humility, which is to say that it isn''t just going to be the science that drives the success: all the given pieces have to come together to be successful.You''ve watched a lot of technology coming through, including at your new position at Mars. Which technology excites you?We all have to pay a lot of attention to CRISPR and the gene-editing technologies. There is certainly a number of intellectual property issues that have to get sorted out but that''s clearly an area that will have a huge impact not just on human health but on animal health and plant health as well.The other area I''ve been thinking a lot about lately is the microbiome. As sequencing technology has altered in cost and time, we have begun to be able to explore the microbiome in a way that historically was not possible. And it feels like we are moving towards a tipping point where the explosion of understanding is going to open up a lot of interesting opportunities for us to intervene. Whether that''s through traditional drug modalities or through altered nutrition or through changing the microbial community in soil to produce crops that have higher nutrient value or other approaches, I think that''s another broad area that seems poised to begin to offer really interesting results.Were you surprised that a company like Mars, which has not been a basic research company at all, is now giving you an opportunity to build something that is much more research-orientated?The reality of Mars is that they have actually had a very deep fundamental research program for a number of years. They got involved in the sequencing of the cacao genome and contributed it to the public domain, and they are now also involved in the sequencing of the genomes of a large number of orphan crops in Africa. So they have been very active in their research both in the company and in collaboration with academic scientists around the world. The nature of the company has meant that the work is perhaps not as obvious as others, but it is a remarkably science-driven company in much of what it does.You have done a myriad of things. What are the one or two things that you are most proud of?I am most proud of my efforts to keep a hand in both the commercial and the academic world. It certainly has not been easy but I have received enormous satisfaction from the opportunity to work with bright students at each of the schools I have had the opportunity to teach at. I am not sure there is anything more satisfying than the opportunity to work with students and feel you have helped them towards their goals.At the same time, I think I''ve been effective in doing that because I have managed to keep an active role in the applied world. In some ways, my greatest achievement has been finding a way to balance those two interests in a way that seems to have worked for the various organizations I''ve been affiliated with.How do you relax away from work? Do you have a family?I am married. My wife is a securities litigator so has a very active career of her own. We have two children, one in high school and one in middle school. I''ve had the privilege to coach both of them on their various soccer teams since they were each about 4 years old so that''s been a lot of fun.The other thing that many people will not find relaxing – but for some reason my family does – has been taking backcountry ski trips annually for a number of years. Worrying about navigating through the snow and finding shelter before darkness falls has a way of clearing the mind.     

After the year of the dumpster fire

2020 has been one of the craziest and strangest years we have lived through. Now that it’s over, it’s an opportunity to show gratitude for all the good things. Subject Categories: S&S: History & Philosophy of Science

I moved to New York City the year of the attacks on September 11, 2001, one of the bleakest moments in the history of the United States. I was also in New York City when Superstorm Sandy hit in 2012. Luckily, much fewer people died due to the storm, but it was incredibly disruptive to many scientists in the affected area—my laboratory had to move four times over a period of 6 years in the storm’s aftermath. These were awful, tragic events, but 2020 may go down in the record books as one of the most stressful and crazy years in modern times. Not to be outdone, 2021 has started terribly as well with COVID‐19 still ravaging the world and an attack on the US Capitol, something I thought I’d never see in my lifetime. The unnecessary deaths and the damage to America’s “House of the People” were heartbreaking.While these events were surely awful, nothing will be as crushing as the deaths of family members, close friends, and the children of friends; perhaps, it is these experiences—and the death of a beloved dog—that prepared me for this year and made me grateful, maybe even more than usual, for what I have. But in the age of a pandemic, what am I particularly grateful for?I''m ridiculously grateful to have a job, a roof over my head, and food security. The older I get, the more I see illness and injury affect my colleagues, family, and friends, I increasingly appreciate my good health. I am grateful for Zoom (no, I have no investment in Zoom)—not for the innumerable seminars or meetings I have attended, but for the happy hours that helped to keep me sane during the lockdown. Some of these were with my laboratory, others with friends or colleagues, sometimes spread over nine time zones. Speaking of which, I’m also grateful for getting a more powerful router for the home office.I''m immeasurably grateful to be a scientist, as it allows me to satisfy my curiosity. While not a year‐round activity, it is immensely gratifying to be able to go to my laboratory, set up experiments, and watch the results coming in. Teaching and learning from students is an incredible privilege and educating the next generation of scientists how to set up a PCR or run a protein gel can, as a well‐known lifestyle guru might say, spark serious joy. For this reason, I’m eternally grateful to my trainees; their endless curiosity, persistence, and energy makes showing up to the laboratory a pleasure. My dear friend Randy Hampton recently told me he received a student evaluation, thanking him for telling his virtually taught class that the opportunity to educate and to be educated is something worth being grateful for, a sentiment I passed onto a group of students I taught this past fall. I believe they, too, were grateful.While all of the above things focus on my own life, there are much broader things. For one, I am so grateful to all of those around the globe who wear masks and keep their distance and thereby keep themselves and others safe. I am grateful for the election of an American president who proudly wears a mask—often quite stylishly with his trademark Ray‐Ban Aviators—and has made fighting the COVID‐19 pandemic his top priority. President Biden''s decision to ramp up vaccine production and distribution, along with his federal mask mandate, will save lives, hopefully not just in the United States but worldwide.This Gen‐X‐er is also especially grateful to the citizens of Generations Y and Z around the world for fighting for social justice; I am hopeful that the Black Lives Matter movement has got traction and that we may finally see real change in how communities of color are treated. I have been heartened to see that in my adopted home state of New York, our local politicians ensure that communities that have been historically underserved are prioritized for COVID‐19 testing and vaccinations. Along these lines, I am also incredibly encouraged by the election of the first woman who also happens to be of African and Asian heritage to the office of vice president. Times are a changin''...While it is difficult to choose one, top thing to be grateful for, I would personally go for science. I am stoked that, faced with a global crisis, science came to the rescue, as it often has in the past. If I had to find a silver lining in COVID‐19—albeit it would be for the darkest of clouds—I am grateful for all of our colleagues, who despite their usual arguing, quickly and effectively developed tests, provided advice, epidemiological data and a better understanding of the virus and its mode of infection, and ultimately developed therapies and vaccines to save lives. The same can be said for the biotech and pharmaceutical industry that, notwithstanding its often‐noted faults, has been instrumental in developing, testing and mass‐producing efficient and safe vaccines in blistering, record time. Needless to say, I have also much gratitude to all of the scientists and regulators at the FDA and elsewhere who work hard to make life as we once knew it come back to us, hopefully in the near future.Once again, thank you for everything, Science.     

Decoding the genetics of rare disease: an interview with Monkol Lek

Monkol Lek, Assistant Professor at Yale University School of Medicine, and Associate Editor at Disease Models & Mechanisms, dedicates his research to finding a genetic diagnosis and improving treatments for rare disease patients. As he originally studied computer engineering at the University of New South Wales in Sydney, Australia, he now utilises computational methods to optimise large-scale genetic studies, provide globally accessible resources for genetic research communities and, importantly, resolve diagnostic odysseys for rare disease patients. Monkol completed his PhD in Prof. Kathryn North''s lab at the University of Sydney, studying the genetics of muscle strength and performance, and then continued his investigation of muscle disease in Prof. Daniel MacArthur''s lab at Massachusetts General Hospital and the Broad Institute. During his postdoc, he led several large-scale studies aimed at distinguishing pathogenic from benign variants, including the Exome Aggregation Consortium (ExAC) project ( Lek et al., 2016). Monkol established his own lab at Yale University School of Medicine, which continues to improve the diagnosis and treatment of rare muscle disease, and also focuses on underserved populations, whose genetic mutations are not as well characterised as those of European ancestry. In this interview, Monkol discusses how his own diagnosis with limb girdle muscular dystrophy has shaped his career and what he envisions for the future of genetic research in rare disease.

You have a very unique career path – could you tell us a little bit about that? My first degree was in computer engineering. When I first went to university, I studied the hardware and software of computers. I really liked the software aspect of the degree, and so I worked for IBM as a software developer when I finished university. However, during the last few years of university, I noticed that my muscles were getting weaker. My university was on a big hill, with classes at the bottom and top of the hill, and I had to stand up for about 3 h a day while commuting on public transport. It started becoming obvious that I had something wrong with my muscles because I felt totally exhausted at the end of the day. It was frustrating, because I felt that my performance at university was impacted by something that had nothing to do with my ability to think. So, I went from doctor to doctor to try to find out what was wrong with me. As a lot of doctors are not trained in rare diseases, they didn''t consider a rare disease diagnosis. Then one doctor did a blood test for creatine kinase (CK), which is leaked into the bloodstream when muscle is damaged. In healthy people, high levels of CK are detected in the bloodstream after they''ve done intensive exercise, like a marathon. If someone hasn''t done something like that, but they have high levels of circulating CK, it could be an indication that there''s something wrong with their muscles. As I had high levels of CK in my bloodstream, I then went to a neurologist, which was when I got a clinical diagnosis. At that point, they didn’t know the root cause of the problem, but they knew that I have a muscle disease based on several tests, including a nerve conduction test.I received this clinical diagnosis during my time in IBM, and that''s when I became dissatisfied with my job, because I felt that I was using all my talents to make a very big, international company richer. I was also becoming frustrated when visiting the neurologist every 6 months, as all they would tell me was that my muscles were getting weaker, which I already knew. I began to think that not much was happening in the neuromuscular disease field if that''s the best they could offer me. I wanted to know what the root cause of my disease was and if there were any treatment options. I came to the conclusion that no one would care about my disease more than I would, because I''m the one that has lived with it every day of my life.That''s when I decided to leave IBM and pursue a career in researching muscle disease. It didn''t go down well with my parents and friends, because I was leaving a well-paid job to go back to university to get paid nothing for an unknown number of years. If I had known my chances of success – completing a meaningful PhD, doing a meaningful postdoc and landing a faculty position – I wouldn''t have gone on this journey. I have been very fortunate, but I wasn''t always in the right place at the right time.When I finished my undergraduate degree in bioinformatics and physiology at the University of New South Wales, I started a PhD in Melbourne, but it didn''t work out, because not all supervisors are perfect. My wife and I then returned to Sydney, where my wife bumped into one of the professors from our undergraduate degree. She explained that we''d had a bad experience in Melbourne with our PhDs, but our passion was still to do muscle research. The professor''s daughter was researching muscle disease in Kathryn North''s lab at the University of Sydney, and she invited us to visit the lab. I was offered an opportunity to do my PhD in Kathryn''s lab, but I was initially reluctant as it was a diagnostic lab, and I was more interested in developing therapies for people with muscle disease. However, I thought I could still learn a lot about muscle physiology and, in the long term, I''m glad that I received training and mentorship from Kathy''s lab. Also, if I hadn''t done my PhD there, I wouldn''t have met Daniel MacArthur, my future boss. He was a very talented student in Kathy''s lab, who taught me a lot about scientific communication among other things, and I taught him some coding skills. He left to work on the 1000 Genomes Project in Cambridge, UK, but I kept in contact with him to get his advice on my project.When I was finishing my PhD, Daniel asked if I wanted to join the lab he was setting up in Massachusetts General Hospital and the Broad Institute. His lab was going to study common loss-of-function mutations in human populations using large datasets from the 1000 Genomes Project, but he offered me a project investigating neuromuscular diseases. As soon as I submitted my PhD thesis, I started working in his lab. This was perfect timing, because it was 2012, when exome sequencing had recently been published in the context of rare diseases (Ng et al., 2010) and, more importantly, it was becoming affordable, in terms of research. I waited over 10 years for a genetic diagnosis, so my goal was that no one should have to wait that long in the future.Through collaboration with our former PhD lab, Daniel and I used samples from undiagnosed patients to find answers for Australian families. The first family had two affected girls with undiagnosed nemaline myopathy, who had been on a diagnostic odyssey for about 9 years. It was amazing how quickly we progressed from receiving the samples to identifying the novel gene, LMOD3, associated with their disease (Yuen et al., 2014). This was part of my main project during my postdoc – working on gene discovery in neuromuscular diseases and finding answers for patients that have been waiting years and years to get a genetic diagnosis (Ghaoui et al., 2015; O''Grady et al., 2016).The project that most people know me for is the ExAC project, which was initially my ‘side’ project during my postdoc. The idea was to create a big database of all rare variants that we see in the general population, so we can better interpret the rare variants that we see in rare disease patients. When we were creating it, we thought that it may be useful to other researchers around the world. Therefore, we tried to ensure, through data-use agreements and consent processes, that we could share as many of our findings as possible. I''m happy to say my side project was quite successful. After that, I led other projects, including an analysis group in the Centre for Mendelian Genomics, to expand that framework and idea across all rare diseases, not just neuromuscular diseases (Baxter et al., 2022).I was having a lot of fun at the Broad Institute, and I was co-author on a lot of high-impact papers. However, the reason I left the Broad Institute was that I wanted to be involved in the full journey for the patients. Sometimes scientists don''t understand that getting a genetic diagnosis is not the end of the journey for a patient. After the diagnosis they want to know what treatment options are available. Yale gave me the opportunity to continue doing the gene discovery and analytical work that I was doing at the Broad Institute, plus the capability of doing experiments with mouse models to investigate gene replacement therapies and other therapeutic approaches.

“I waited over 10 years for a genetic diagnosis, so my goal was that no one should have to wait that long in the future.”

How has being both a researcher and a patient affected your career? When I was first diagnosed, there was a neurologist who discouraged me from researching my own disease and this became the basis of my TEDx talk, because I thought it was very condescending. I thought, “Just because I have this disease, it doesn''t mean that I have a low IQ”. However, this experience motivated me more. I discussed it with Kathy before starting my PhD, and her encouragement and enthusiasm was refreshing. At the time, in the early 2000s, people hadn''t accepted the idea of patients researching their own disease. Things have changed since then, mainly because there are more examples of it now (Branca, 2019), but at the time, it was really hard for me to progress in science. I always thought that people were looking at me with sympathy, and I felt like I had to achieve twice as much to get the same respect as someone else who wasn''t as talented or didn''t work as hard as me. It was frustrating, but in everyday life people still correlate physical disability with intellectual disability. For example, if my wife is pushing me in the wheelchair in public, no one ever directs a question to me because they assume that the physical disability comes with mental disabilities. There are well-known examples of scientists with physical disabilities, like Stephen Hawking, but it is still challenging in academia when you have a physical disability and people make certain assumptions about you.On the other hand, just before starting at Yale, my collaborators at the University of Massachusetts took a skin biopsy from me. With this skin biopsy, they created induced pluripotent stem cells, and, using CRISPR, they corrected my disease-associated gene variant in the cultured cells. They then published this in a Nature article, in which fig. 1 is the experiment in which they corrected my mutation (Iyer et al., 2019). Are there specific skills or knowledge you learned while working in computer engineering that have helped shape and develop your research today? When I started my PhD, there was an increase in how much genetics research, and biological research in general, relied upon big data. It can be very challenging to work with big data if you''re a biologist without a background in computer science. You can go online to teach yourself to an extent, but it gives you an advantage to learn the theory behind a lot of algorithms and other aspects of software engineering, in a formal setting. It makes the difference between building tools that take a week to analyse a set of data and building tools that take a few minutes to analyse the same data. If you can analyse the data more quickly, you can explore different possibilities and ideas much more quickly. You can''t learn everything online, and having a firm foundation of knowledge can enable you to work with big data in an efficient way.The other thing that you learn from computer science is a certain mindset when approaching problem solving. This is because you have to debug code frequently and, due to this fast pace, you learn quickly. This helped me to troubleshoot problems in biological research quickly.

“Getting a genetic diagnosis is not the end of the journey for a patient. After the diagnosis they want to know what treatment options are available.”

What do you think are the key challenges for rare disease research and diagnosis moving forward? I now have a greater appreciation of the challenges because I see it from two points of view: one as a researcher in a group and one as a PI, who leads the research. The diagnosis rate for rare disease is about 50%, so there are still 50% of patients with a disease that has an unknown genetic cause. The gold standard requirement for associating a new disease gene with a novel phenotype is that it presents in multiple unrelated families (MacArthur et al., 2014). However, when you work with rare diseases, there is the issue of small sample numbers. One challenge for basic scientists is creating good collaborations with physician scientists across the world to enable you to create a large enough dataset.The other challenge is the cost of research for these diseases with unknown genetic cause. The 50% of cases for which we know the genetic cause are no longer considered an area of research, as clinical genetic services can now diagnose these patients. To diagnose the remaining patients, you have to use more expensive technologies, such as long-read sequencing.The last thing is the interpretation of rare variants. Although the ExAC project helped with this, there is still a challenge. For example, if a patient has a rare genetic variant, this doesn''t necessarily mean it is the cause of their rare disease. This is because even healthy people have rare variants. So, we have a massive interpretation challenge in rare disease genetics, which can be overcome by creating a laboratory model system with that genetic variant to investigate it further. However, if you had 1000 variants to consider, it''s not going to scale as an animal model. So, an important question is how can we interpret these variants in a scalable manner? This is one of the main driving forces behind the new Subject Focus, ‘Genetic variance in human disease: decoding diversity to advance modern medicine’, that we are launching in DMM. You have led and coordinated several studies involving very large cohorts. From your experience what are the key components of a successful study? I think the key to a successful large cohort study with unsolved rare disease patients, is the amount of structured phenotype data you can collect. This requires a good collaborator, who has the time to prepare that data in a meaningful way, which makes it easier to find other families with the same rare disease. The other thing is to have the ability to recontact patients and collect different samples from them, because we''re moving to a more multi-omics world. Therefore, we need the ability to go beyond just collecting DNA samples. Also, we''re in a world where we''re starting to link data to electronic health records, which allows the collection of deeper and richer phenotype data that enable associations to be made between families.In addition, you can''t work in isolation. In order for us to make a meaningful impact, we need to work with groups that have specialties outside of our own. For instance, we collaborate with groups that specialise in the interpretation of non-coding variants. This is important as variants in these regions could hold the answers for some of those unsolved cases.Another key aspect to a successful study is collaboration with statistical geneticists because some of the more complicated questions are best asked by them. Some of these questions go beyond monogenic diseases. We are seeing convergence between genome-wide association studies, looking for many variants, each with very small contributions to a disease, and studies of Mendelian disease that are looking for one gene that causes disease. The field has to start looking at diseases in the middle of this spectrum, which requires statistical geneticists. This is because you need to make sure that your conclusions are correct. For instance, if you''re asking whether a rare disease is caused by a combination of two genes, then you must have a robust statistical model to show that these variants aren''t presenting together by chance. You have to prove that those two variants are acting in concert, instead of independently, to cause this disease. My colleagues at Yale published a great paper that demonstrated this concept (Timberlake et al., 2016).Lastly, it is important to forge meaningful collaborations beyond academia. A lot of my colleagues are being funded by industry collaboration, and a lot of these companies have access to more samples than we do in academia. You can also collaborate with large biobanks, such as the UK Biobank, which has a rich set of phenotype data and also the ability to recontact patients (Glynn and Greenland, 2020). The FinnGen project is a recent public–private collaboration that combines genetic data with electronic health records from Finnish biobank participants to improve disease diagnosis and treatment (Kurki et al., 2022 preprint). So, working with biobanks and industry is another way of increasing sample numbers, which is the biggest challenge in rare disease research.

“We don''t want to create disparity in terms of health, especially in the context of genetics, which will continue to become more prominent in modern medicine.”

You dedicate a lot of your research towards patients in underserved populations, such as East Asian populations, whose genetic mutations are not as well characterised as those of European ancestry. Can you explain the importance of this? One of the reasons that it took over 10 years for me to get a genetic diagnosis was because the gene that causes my disease was first reported as not commonly associated with disease in populations of European ancestry. The problem with biomedical research is that when people read that, they think it applies to everyone, even patients who have non-European ancestry. Although the gene that causes my disease aligned with my muscle disease phenotype, it wasn''t sequenced because of this assumption. They only decided to sequence this gene once they did linkage analysis of my family, and this was the only gene associated with neuromuscular disease in the linkage region they identified. This is the reason why we need to have good data on all populations. The ExAC and gnomAD studies that I worked on acknowledged that we need good allele frequency data for populations of East Asian, South Asian, Latino and African ancestry, because we don''t want to create disparity in terms of health, especially in the context of genetics, which will continue to become more prominent in modern medicine.If you want to deliver the best healthcare, you have to realise that some variants and diseases are more common in certain populations, such as Tay-Sachs disease, which is common amongst the Jewish community, and sickle cell anaemia, which is more prevalent in populations of African ancestry. By understanding these differences, we can actually find a genetic diagnosis a lot quicker. If it''s not a de novo variant, and is instead a variant inherited in the population, and if you''ve made the discovery in East Asians, there is a better chance of identifying more incidences of this variant in the population in which it was first discovered.I think it''s also good for validation of data, because if you had discovered a potential disease-causing variant and you find that this variant has a frequency of 1% or higher in a non-European population, then it''s impossible for it to be the cause of a rare disease, regardless of its frequency in a European population (Lek et al., 2016).     

A Passion for Parasites

I knew nothing and had thought nothing about parasites until 1971. In fact, if you had asked me before then, I might have commented that parasites were rather disgusting. I had been at the Johns Hopkins School of Medicine for three years, and I was on the lookout for a new project. In 1971, I came across a paper in the Journal of Molecular Biology by Larry Simpson, a classmate of mine in graduate school. Larry''s paper described a remarkable DNA structure known as kinetoplast DNA (kDNA), isolated from a parasite. kDNA, the mitochondrial genome of trypanosomatids, is a DNA network composed of several thousand interlocked DNA rings. Almost nothing was known about it. I was looking for a project on DNA replication, and I wanted it to be both challenging and important. I had no doubt that working with kDNA would be a challenge, as I would be exploring uncharted territory. I was also sure that the project would be important when I learned that parasites with kDNA threaten huge populations in underdeveloped tropical countries. Looking again at Larry''s paper, I found the electron micrographs of the kDNA networks to be rather beautiful. I decided to take a chance on kDNA. Little did I know then that I would devote the next forty years of my life to studying kDNA replication.     

WHAT DOES RESPECT FOR THE PATIENT'S AUTONOMY REQUIRE?

Personal autonomy presupposes the notion of rationality. What is not so clear is whether, and how, a compromise of rationality to various degrees will diminish a person's autonomy. In bioethical literature, three major types of threat to the rationality of a patient's medical decision are identified: insufficient information, irrational beliefs/desires, and influence of different framing effects. To overcome the first problem, it is suggested that patients be provided with information about their diseases and treatment choices according to the objective standard. I shall explain how this should be finessed. Regarding the negative impact of irrational beliefs/desires, some philosophers have argued that holding irrational beliefs can still be an expression of autonomy. I reject this argument because the degree of autonomy of a decision depends on the degree of rationality of the beliefs or desires on which the decision is based. Hence, to promote patient autonomy, we need to eliminate irrational beliefs by the provision of evidence and good arguments. Finally, I argue that the way to smooth out the framing effects is to present the same information in different perspectives: it is too often assumed that medical information can always be given in a complete and unadorned manner. This article concludes with a cautionary note that the protection of patient autonomy requires much more time and effort than the current practice usually allows.     

AIDS and medical confidentiality.

In summary, I have argued that the arguments offered or hinted at in favour of doctors'' breaking medical confidentiality by passing on information about their patients'' HIV state to others, including other doctors, when this is against the patient''s considered wishes are generally unconvincing. Although in highly exceptional cases there may be justifications for overriding confidentiality, the requirement of medical confidentiality is a very strong, though not absolute, obligation. Patients, their contacts, doctors and their staff, and the common good are most likely to be best served if that tradition continues to be honoured.     

Is the repeated prisoner's dilemma a good model of reciprocal altruism?

Axelrod and Hamilton (1981) used the repeated prisoner's dilemma game as a basis for their widely cited analysis of the evolution of reciprocal altruism. Recently, it has been argued that the repeated prisoner's dilemma is not a good model for this task. Some critics have argued that the single period prisoner's dilemma represents mutualistic rather than altruistic social interactions. Others have argued that reciprocal altruism requires that the opportunities for altruism occur sequentially, first one individual and then after some delay the other. Here I begin by arguing that the single period prisoner's dilemma game is consistent with the definition of altruism that is widely accepted in evolutionary biology. Then I present two modified versions of the repeated prisoner's dilemma, one in which behavior is sequential, and a second in which behavior occurs in continuous time. Each of these models shares the essential qualitative properties with the version used by Axelrod and Hamilton.     

Health as Normal Function: a Weak Link in Daniels's Theory of Just Health Distribution

Drawing on Christopher Boorse's Biostatistical Theory (BST), Norman Daniels contends that a genuine health need is one which is necessary to restore normal functioning – a supposedly objective notion which he believes can be read from the natural world without reference to potentially controversial normative categories. But despite his claims to the contrary, this conception of health harbors arbitrary evaluative judgments which make room for intractable disagreement as to which conditions should count as genuine health needs and therefore which needs should be met. I begin by offering a brief summary of Boorse's BST, the theory to which Daniels appeals for providing the conception of health as normal functioning upon which his overall distributive scheme rests. Next, I consider what I call practical objections to Daniels's use of Boorse's theory. Finally I recount Elseljin Kingma's theoretical objection to Boorse's BST and discuss its impact on Daniels's overall theory. Though I conclude that Boorse's view, so weakened, will no longer be able to sustain the judgments which Daniels's theory uses it to reach, in the end, I offer Daniels an olive branch by briefly sketching an alternative strategy for reaching suitably objective conclusions regarding the health and/or disease status of various conditions.     

Bergmann's Rule – what's in a name?

Despite the great interest it generates, the definition of Bergmann's Rule is vague and often contested. Debate focuses on whether the rule should be described in terms of pattern or process, what taxa it should apply to and what taxonomic level it should be associated with. Here I review the historical development of studies of Bergmann's Rule. I suggest that Bergmann thought that his rule should be strongest at the intra‐specific level, rather than between closely related species as is usually thought. I argue that the rule is a pattern that can be studied regardless of mechanism in any taxon and at any taxonomic level.     

The child's best interest in gamete donation

Procreation with donor gametes is widespread and commonly accepted, but it involves ethical questions about the child's best interest. Understanding the historical structures of the moral discussion of gamete donation may contribute to reflecting on the child's best interest. This is why I have analysed the debate on gamete donation in the Netherlands, and this analysis has uncovered some striking discontinuities. Notions of the child's best interest have undergone a radical swing. In the past, it was considered acceptable to conceal the truth about the child's biological origin, but in the past two decades the general opinion has changed to the common belief that this information should be shared with the child. This changed notion of the child's best interest will be analysed using a framework encompassing three views of the child, which derive from the debate on children's rights. These three views each provide a different interpretation of the child's moral and political status. I conclude that the changed notion of the child's best interest results from a view of the child that focuses on autonomy and citizenship, and which frames the child's interests according to its legal status. I comment on this view and I champion an alternative one, namely ‘the embedded child’. This is a relational view based on care ethics that goes beyond what can be articulated in law, and that will help to establish a more balanced interpretation of the child's best interest at the practice and policy levels of gamete donation.     

Non-therapeutic modification and self-interest: reply to Schramme

In this article I reply to Thomas Schramme's argument that there are no good reasons for the prohibition of severe forms of voluntary non‐therapeutic body modification. I argue that on paternalistic assumptions there is, in fact, a perfectly good reason.