Give chance a chance

How did I get to become a cell biologist? Or, more generally, why do things happen the way they do? The answer provided by the philosopher Democritus and later adopted by Jacques Monod is “everything existing in the universe is the fruit of chance and necessity.” While I read Monod''s book Chance and Necessity as an undergraduate student, little did I appreciate the accuracy of this citation and how much of my scientific trajectory would be guided by chance.     

NICE分型在结直肠癌诊断中的意义

结直肠癌发病率高,早期诊断困难,威胁着全世界人民的健康。近几年窄带成像技术(Narrow Band Imaging,NBI)发展迅速,大大改善了结直肠镜下图像的清晰程度,NBI辅助下的结直肠镜检查在早期诊治肠癌方面具有重要意义。为了进一步优化结直肠镜的诊断效能,多种NBI辅助的结直肠镜下的结直肠病变分型被提出。针对病变的表面形态、颜色分布以及微血管的形态与走形,Sano分型、Jikei分型、Showa分型、Hiroshima分型和NICE(Narrow-Band Imaging International Colorectal Endoscopic)分型相继被提出。其中NICE分型以良好的学习曲线和诊断效能被广泛认可和应用。     

载药纳米粒作为脑靶向给药系统的研究

血脑屏障使大部分的活性药物很难由血液进入脑内发挥作用。载药纳米粒具有脑靶向性,可显著提高药物在脑内浓度,成为药物突破血脑屏障的有效途径。本文综述了近年来载药纳米粒透过血脑屏障的研究进展,并对纳米粒载中药入脑提出展望。     

如何学好人体断层解剖学

断层解剖学作为解剖学与医学影像学等学科相结合的交叉学科,对现代化的影像技术及临床应用具有非常重要的意义。要学好断层解剖学:必须明确断层解剖学的重要性;培养学习的兴趣,注意临床针对性;抓好学习的重点,注意学习方法;打好局部解剖学知识的基础,始终贯彻断层标本与影像相结合的原则;并高度重视现代化多媒体资料的应用。     

Er-YAG 激光在牙体硬组织中的应用

随着科学技术的进步,激光技术正以惊人的速度向前发展。激光具有许多优异的性能,已被应用到人类生活的各个领域。伴随激光医学的进展,近来在口腔医学方面的研究已逐步开展起来,除了应用于口腔软组织处理外,激光用于牙体硬组织也得到了越来越多的关注。其中Er-YAG激光在口腔领域的实用性和安全性已得到多方面的认证。该文就激光在口腔医学特别是牙体硬组织中的应用作一综述。     

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.     

Maternal mortality and women's condition: “The distress in being a woman”

For millenaria, maternal mortality has been considered as a fatality inherent to women's condition. Thanks to the progress of the obstetric technology, the world M.M.R. fell from 2.000 to 400 per 100.000 births during the past 150 years. At the same time women's condition improved chiefly because of a better level of education. Is there any relationship between them: the decrease of Maternal Mortality and the amelioration of women's general status? Or, in other words, can the decrease of Maternal Mortality Rate be considered as an “indicator” of the situation of women? After a historical review of the importance of the maternal mortality drama as it occured in older times before the “obstetric era”, which began with the improvement of the obstetric technology, this paper will present the actual situation of maternal mortality in relation with the obstetric coverage, the female literacy level and some other socio-economic variables, and in relation with the Gross National Product (G.N.P.) as an indicator of governmental interest in the specific female problems of giving-life.     

The A to T of historical evidence

Geneticists and historians collaborated recently to identify the remains of King Richard III of England, found buried under a car park. Genetics has many more contributions to make to history, but scientists and historians must learn to speak each other''s languages.The remains of King Richard III (1452–1485), who was killed with sword in hand at the Battle of Bosworth Field at the end of the War of the Roses, had lain undiscovered for centuries. Earlier this year, molecular biologists, historians, archaeologists and other experts from the University of Leicester, UK, reported that they had finally found his last resting place. They compared ancient DNA extracted from a scoliotic skeleton discovered under a car park in Leicester—once the site of Greyfriars church, where Richard was rumoured to be buried, but the location of which had been lost to time—with that of a seventeenth generation nephew of King Richard: it was a match. Richard has captured the public imagination for centuries: Tudor-friendly playwright William Shakespeare (1564–1616) portrayed Richard as an evil hunchback who killed his nephews in order to ascend to the throne, whilst in succeeding years others have leapt to his defence and backed an effort to find his remains.The application of genetics to history is revealing much about the ancestry and movements of groups of humans, from the fall of the Roman Empire to ancient ChinaMolecular biologist Turi King, who led the Leicester team that extracted the DNA and tracked down a descendant of Richard''s older sister, said that Richard''s case shows how multi-disciplinary teams can join forces to answer history''s questions. “There is a lot of talk about what meaning does it have,” she said. “It tells us where Richard III was buried; that the story that he was buried in Greyfriars is true. I think there are some people who [will] try and say: “well, it''s going to change our view of him” […] It won''t, for example, tell us about his personality or if he was responsible for the killing of the Princes in the Tower.”The discovery and identification of Richard''s skeleton made headlines around the world, but he is not the main prize when it comes to collaborations between historians and molecular biologists. Although some of the work has focused on high-profile historic figures—such as Louis XVI (1754–1793), the only French king to be executed, and Vlad the Impaler, the Transylvanian royal whose patronymic name inspired Bram Stoker''s Dracula (Fig 1)—many other projects involve population studies. Application of genetics to history is revealing much about the ancestry and movements of groups of humans, from the fall of the Roman Empire to ancient China.Open in a separate windowFigure 1The use of molecular genetics to untangle history. Even when the historical record is robust, molecular biology can contribute to our understanding of important figures and their legacies and provide revealing answers to questions about ancient princes and kings.Medieval historian Michael McCormick of Harvard University, USA, commented that historians have traditionally relied on studying records written on paper, sheepskin and papyrus. However, he and other historians are now teaming up with geneticists to read the historical record written down in the human genome and expand their portfolio of evidence. “What we''re seeing happening now—because of the tremendous impact from the natural sciences and particularly the application of genomics; what some of us are calling genomic archaeology—is that we''re working back from modern genomes to past events reported in our genomes,” McCormick explained. “The boundaries between history and pre-history are beginning to dissolve. It''s a really very, very exciting time.”…in the absence of written records, DNA and archaeological records could help fill in gapsMcCormick partnered with Mark Thomas, an evolutionary geneticist at University College London, UK, to try to unravel the mystery of one million Romano-Celtic men who went missing in Britain after the fall of the Roman Empire. Between the fourth and seventh centuries, Germanic tribes of Angles, Saxons and Jutes began to settle in Britain, replacing the Romano-British culture and forcing some of the original inhabitants to migrate to other areas. “You can''t explain the predominance of the Germanic Y chromosome in England based on the population unless you imagine (a) that they killed all the male Romano-Celts or (b) there was what Mark called ‘sexual apartheid'' and the conquerors mated preferentially with the local women. [The latter] seems to be the best explanation that I can see,” McCormick said of the puzzle.Ian Barnes, a molecular palaeobiologist at Royal Holloway University of London, commented that McCormick studies an unusual period, for which both archaeological and written records exist. “I think archaeologists and historians are used to having conflicting evidence between the documentary record and the archaeological record. If we bring in DNA, the goal is to work out how to pair all the information together into the most coherent story.”Patrick Geary, Professor of Western Medieval History at the Institute for Advanced Study in Princeton, New Jersey, USA, studies the migration period of Europe: a time in the first millennium when Germanic tribes, including the Goths, Vandals, Huns and Longobards, moved across Europe as the Roman Empire was declining. “We do not have detailed written information about these migrations or invasions or whatever one wants to call them. Primarily what we have are accounts written later on, some generations later, from the contemporary record. What we tend to have are things like sermons bemoaning the faith of people because God''s wrath has brought the barbarians on them. Hardly the kind of thing that gives us an idea of exactly what is going on—are these really invasions, are they migrations, are they small military groups entering the Empire? And what are these ‘peoples'': biologically related ethnic groups, or ad hoc confederations?” he said.Geary thinks that in the absence of written records, DNA and archaeological records could help fill in the gaps. He gives the example of jewellery, belt buckles and weapons found in ancient graves in Hungary and Northern and Southern Italy, which suggest migrations rather than invasions: “If you find this kind of jewellery in one area and then you find it in a cemetery in another, does it mean that somebody was selling jewellery in these two areas? Does this mean that people in Italy—possibly because of political change—want to identify themselves, dress themselves in a new style? This is hotly debated,” Geary explained. Material goods can suggest a relationship between people but the confirmation will be found in their DNA. “These are the kinds of questions that nobody has been able to ask because until very recently, DNA analysis simply could not be done and there were so many problems with it that this was just hopeless,” he explained. Geary has already collected some ancient DNA samples and plans to collect more from burial sites north and south of the Alps dating from the sixth century, hoping to sort out kinship relations and genetic profiles of populations.King said that working with ancient DNA is a tricky business. “There are two reasons that mitochondrial DNA (mtDNA) is the DNA we wished to be able to analyse in [King] Richard. In the first instance, we had a female line relative of Richard III and mtDNA is passed through the female line. Fortunately, it''s also the most likely bit of DNA that we''d be able to retrieve from the skeletal remains, as there are so many copies of it in the cell. After death, our DNA degrades, so mtDNA is easier to retrieve simply due to the sheer number of copies in each cell.”Geary contrasted the analysis of modern and ancient DNA. He called modern DNA analysis “[…] almost an industrial thing. You send it off to a lab, you get it back, it''s very mechanical.” Meanwhile, he described ancient DNA work as artisanal, because of degeneration and contamination. “Everything that touched it, every living thing, every microbe, every worm, every archaeologist leaves DNA traces, so it''s a real mess.” He said the success rate for extracting ancient mtDNA from teeth and dense bones is only 35%. The rate for nuclear DNA is only 10%. “Five years ago, the chances would have been zero of getting any, so 10% is a great step forward. And it''s possible we would do even better because this is a field that is rapidly transforming.”But the bottleneck is not only the technical challenge to extract and analyse ancient DNA. Historians and geneticists also need to understand each other better. “That''s why historians have to learn what it is that geneticists do, what this data is, and the geneticists have to understand the kind of questions that [historians are] trying to ask, which are not the old nineteenth century questions about identity, but questions about population, about gender roles, about relationship,” Geary said.DNA analysis can help to resolve historical questions and mysteries about our ancestors, but both historians and geneticists are becoming concerned about potential abuses and frivolous applications of DNA analysis in their fields. Thomas is particularly disturbed by studies based on single historical figures. “Unless it''s a pretty damn advanced analysis, then studying individuals isn''t particularly useful for history unless you want to say something like this person had blue eyes or whatever. Population level studies are best,” he said. He conceded that the genetic analysis of Richard III''s remnants was a sound application but added that this often is not the case with other uses, which he referred to as “genetic astrology.” He was critical of researchers who come to unsubstantiated conclusions based on ancient DNA, and scientific journals that readily publish such papers.…both historians and geneticists are becoming concerned about potential abuses or frivolous applications of DNA analysis in their fieldsThomas said that it is reasonable to analyse a Y chromosome or mtDNA to estimate a certain genetic trait. “But then to look at the distribution of those, note in the tree where those types are found, and informally, interpretively make inferences—“Well this must have come from here and therefore when I find it somewhere else then that means that person must have ancestors from this original place”—[…] that''s deeply flawed. It''s the most widely used method for telling historical stories from genetic data. And yet is easily the one with the least credibility.” Thomas criticized such facile use of genetic data, which misleads the public and the media. “I suppose I can''t blame these [broadcast] guys because it''s their job to make the programme look interesting. If somebody comes along and says ‘well, I can tell you you''re descended from some Viking warlord or some Celtic princess'', then who are they to question.”Similarly, the historians have reservations about making questionable historical claims on the basis of DNA analysis. Geary said the use of mtDNA to identify Richard III was valuable because it answered a specific, factual question. However, he is turned off by other research using DNA to look at individual figures, such as a case involving a princess who was a direct descendant of the woman who posed for Leonardo Da Vinci''s Mona Lisa. “There''s some people running around trying to dig up famous people and prove the obvious. I think that''s kind of silly. There are others that I think are quite appropriate, and while is not my kind of history, I think it is fine,” he said. “The Richard III case was in the tradition of forensics.”…the cases in which historians and archaeologists work with molecular biologists are rare and remain disconnected in general from the mainstream of historical or archaeological researchNicola Di Cosmo, a historian at the Institute for Advanced Study, who is researching the impact of climate change on the thirteenth century Mongol empire, follows closely the advances in DNA and history research, but has not yet applied it to his own work. Nevertheless, he said that genetics could help to understand the period he studies because there are no historical documents, although monumental burials exist. “It is important to get a sense of where these people came from, and that''s where genetics can help,” he said. He is also concerned about geneticists who publish results without involving historians and without examining other records. He cited a genetic study of a so-called ‘Eurasian male'' in a prestige burial of the Asian Hun Xiongnu, a nomadic people who at the end of the third century B.C. formed a tribal league that dominated most of Central Asia for more than 500 years. “The conclusion the geneticists came to was that there was some sort of racial tolerance in this nomadic empire, but we have no way to even assume that they had any concept of race or tolerance.”Di Cosmo commented that the cases in which historians and archaeologists work with molecular biologists are rare and remain disconnected in general from the mainstream of historical or archaeological research. “I believe that historians, especially those working in areas for which written records are non-existent, ought to be taking seriously the evidence churned out by genetic laboratories. On the other hand, geneticists must realize that the effectiveness of their research is limited unless they access reliable historical information and understand how a historical argument may or may not explain the genetic data” [1].Notwithstanding the difficulties in collaboration between two fields, McCormick is excited about historians working with DNA. He said the intersection of history and genomics could create a new scientific discipline in the years ahead. “I don''t know what we''d call it. It would be a sort of fusion science. It certainly has the potential to produce enormous amounts of enormously interesting new evidence about our human past.”     

云南楚雄发现绿孔雀繁殖巢

正绿孔雀(Pavo muticus)在我国主要分布于云南省中部、南部及西部地区,国内关于其在野生状态下的繁殖生物学资料较为缺乏,仅郑作新(1979)、杨岚等(1995)对绿孔雀的巢与卵等有简单描述记录,但迄今为止,中国境内尚无确切的野外绿孔雀巢的影像资料发表。2017年5月20日,在元江上游绿汁江流域的楚雄市双柏县(23°25′55″N,101°11′13″E,海拔1 132 m)境内进行样线调查时惊飞绿孔雀,从而发现1处绿孔雀繁殖巢(图1、2)。该巢简陋,无明显边界,几乎无巢材,仅     

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.     

神经外科重症监护室发热及其治疗

发热是神经外科重症监护室(Neurosurgical intensive care unit,NICU)最常见的症状之一,它是人体对损伤的保护性反应,但同时又加重了机体的负担,从而恶化临床结局。NICU发热起因复杂并相互交错,仅少部分有特异性表现,并且总上而言处理困难。因此系统地了解发热的起因、处理以及预后是非常重要的。尽管过去的文献对于发热已有很好的研究,然而缺乏对NICU发热的系统性描述。我们通过回顾文献系统性地总结了NICU发热,旨在进一步增进对NICU发热的认识从而有利于临床诊治。     

Doctor,you're in tobacco sales!

The director of British Columbia''s Doctors'' Stop-Smoking Project says that, whether they recognize it or not, doctors have the best and most competitive position within the tobacco industry because they have the best product line. Dr. Frederic Bass says physicians'' products—health and freedom from addiction—will win against the competition, which can offer only smoke, addiction to nicotine and ill health. “We offer the better deal,” he says, “but are we selling like we could? That''s the issue.”     

人组织激肽释放酶4在激素依赖性肿瘤中的研究进展

人组织激肽释放酶基因家族由KLK1-KLK15构成,编码一组丝氨酸蛋白酶。研究发现KLK基因家族涉及癌细胞的多种生物学功能,且其表达受类固醇激素的调节。人组织激肽释放酶4是丝氨酸蛋白酶家族的一个成员,在多种激素依赖性肿瘤如卵巢癌、前列腺癌、乳腺癌、子宫内膜癌中高表达,且表达量受雌激素、孕激素、雄激素不同程度的调节。近年来很多文献报道人组织激肽释放酶4涉及癌细胞的增殖、上皮间质转化及细胞外基质的降解等过程,可能促进了肿瘤的发生、发展,且与激素依赖性肿瘤的预后不良有关。这些研究显示人组织激肽释放酶4与激素依赖性肿瘤关系密切,是其潜在的肿瘤标记物和治疗靶点,随着研究的进一步深入,有望应用于激素依赖性肿瘤的早期诊断、病程监测和治疗。     

READER REACTION

M. Y. Kim , X. Xue , and Y. Du 929 Cai et Zeng (2004) ont récemment proposé une méthode pour déterminer la puissance d'une étude de cohorte, lorsqu'il n'y a qu'une seule variable d'exposition, qu'elle est binaire et que le taux d'événements est faible. Nous montrons ici que l'on obtient quasiment les mêmes valeurs de puissance avec une méthode usuelle pour étude cas‐témoins. Or, avec l'approche cas‐témoins, les calculs de taille d'échantillon peuvent être menés avec les logiciels courants, ce qui constitue un avantage. Par ailleurs, nous proposons une formule pour calculer la puissance associée à une étude de cohorte lorsque l'événement étudié n'est pas un événement rare. H. Holzmann , A. Munk , and W. Zucchini 934 Nous étudions l'identifiabilité des modèles de mélange utilisés dans le contexte de l'estimation d'effectifs par capture‐recapture en population fermée. Ce type de modèles permet de tenir compte de l'hétérogénéité des probabilités de capture entre individus, mais leur validité a récemment été remise en cause par Link (2003) [Biometrics 59, 1123‐1130], en raison de leur non‐identifiabilité. Nous donnons un critère général d'identifiabilité de la distribution de mélange, et nous l'appliquons pour déterminer l'identifiabilité dans des familles de distributions de mélange couramment utilisées dans ce contexte, notamment les mélanges de lois finies et de Beta. Notre analyse concerne aussi les cas binomial et à distribution géométrique. Dans un exemple, nous soulignons la différence avec les problèmes d'identifiabilité rencontrés dans les modèles classiques de mélanges de lois binomiales.     

Genomic Imprinting of Grb10?: Coadaptation or Conflict?

Mammalian development involves significant interactions between offspring and mother. But is this interaction a carefully coordinated effort by two individuals with a common goal—offspring survival? Or is it an evolutionary battleground (a central idea in our understanding of reproduction). The conflict between parents and offspring extends to an offspring''s genes, where paternally inherited genes favor demanding more from the mother, while maternally inherited genes favor restraint. This “intragenomic conflict” (among genes within a genome) is the dominant evolutionary explanation for “genomic imprinting.” But a new study in PLOS Biology provides support for a different perspective: that imprinting might facilitate coordination between mother and offspring. According to this “coadaptation theory,” paternally inherited genes might be inactivated because maternally inherited genes are adapted to function harmoniously with the mother. As discussed in this article, the growth effects associated with the imprinted gene Grb10 are consistent with this idea, but it remains to be seen just how general the pattern is.     

Using a Generalized Mean as a Measure of Location

In Taylor (1985 a) a measure of location, akin to a generalised mean was proposed, it's properties were studied for a particular family of skew distributions. The measure of location is essentially the retransformed mean after first transforming the observations to an approximately symmetric scale. Here it's properties are investigated for more general skew distributions. In particular, we study whether it satisfies the axioms for measures of location given in Bickel and Lehmann (1975). We show that it is estimating approximately the distribution median and through simulations we show that it is more efficient than the sample median.     

尼泊尔生态系统质量评估与时空格局变化——基于参照条件的评估方法

良好的生态系统质量是维持人类社会供给需求和可持续发展目标实现的重要保障。针对尼泊尔自然地理环境复杂多样,区域间气候差异明显的特点,结合基于参照条件的评估方法可以得到生态系统质量的相对水平值,其结果能够反映出不同的变化信息。植被是区域生态系统质量变化的重要指示器,利用尼泊尔五大地理区以及四种主要植被生态系统类型划分出20个生态评估区,从表征植被生态系统的水平结构、生产功能和垂直结构3个方面计算生态参数相对密度指标（RVI）,结合主成分分析法构建植被生态系统质量指数（VEQI）,并以其国家自然保护区为参照,构建基于参照条件的生态系统质量评估模型,计算了尼泊尔2016和2020年基于参照条件的植被生态系统质量指数（VEQI''）并分析其生态系统质量的时空格局变化。结果表明：（1）2016至2020年,尼泊尔生态系统质量现实值VEQI的平均值增加了3.49%,总体上,在参照生态系统质量（VEQI_ref）提高（约1.41%）的背景下,生态系统质量相对水平值VEQI''增加了1.42%;（2）对于尼泊尔地区,评估区89%分位数的VEQI与其对应的国家自然保护区的参照值具有很强的相关性,总体差异较小,可以代替作为参照值;（3）从空间格局变化趋势来看,尼泊尔生态系统质量变好、基本稳定和变差的面积分别占植被生态系统总面积的74.16%、14.25%和11.59%。与数量不足、较难收集利用的野外观测台站数据相比,国家自然保护区更接近理想参照生态系统的假设,通过有限的自然保护区确定生态评估区的参照值,实现生态系统质量的快速评估,其结果具有更好的时空可比性,可以为区域生态质量变化评估及量化分析等方面提供参考。     

脊柱损伤的法医临床学鉴定研究进展

随着社会和现代交通、建筑事业的发展,脊柱损伤的病人发病率呈上升趋势,尤其道路交通事故为其损伤的首要原因。脊柱损伤的现场急救、临床诊断与治疗为人们所关注。然而,伴随着事件的进一步处理,对病人的损伤进行法医学鉴定显得尤为重要。目前,有关脊柱损伤的鉴定标准仅仅是确定的标准,没有规定标准的适用条件。同时,也易导致鉴定人对标准的理解与应用存在差异,由此导致了鉴定结论的争议。本文对脊柱损伤的法医临床学应用研究进展作一综述。     

神经母细胞瘤免疫治疗研究进展

神经母细胞瘤是最常见的儿童肿瘤疾病之一,对患者及其家属来了巨大的精神痛苦和经济损失,传统治疗方法对该疾病的预前及术后都效果极差,对该肿瘤的治疗一直是医学界研究的热点和难点。免疫治疗近年来在肿瘤疾病治疗中体现出来的有效、安全、毒副作用小等特点越来越引起临床科学界的重视,科学家对通过免疫疗法治愈神经母细胞瘤的研究进展迅速,并已经取得部分有效的治疗性研究结果,值得进行综述,但目前尚未有对该方面研究的综述出现。本文就近年来神经母细胞瘤治疗研究的热点——免疫逃逸的机理研究、神经母细胞瘤疫苗、免疫类药物开发等进行综述。可以预见,未来神经母细胞瘤免疫治疗的前景广阔,也将有越来越多的针对神经母细胞瘤的商品化免疫性药物、肿瘤疫苗出现,这些药物将对该疾病的治疗具有显著的疗效。     

Growth of a Molecular Base for Feeding: The Mind Body Dualism

It is often difficult to identify the ‘who, when, and where’ of advances in medicine and surgery because it's a rare advance indeed (such as the use of digitalis by William Withering) that can be clearly related to the astuteness of one person at one time and place.