The Coronaviral lie detector

Posted on March 1, 2020 by Steve Caplan

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Coronavirus cover from the Journal of Biological Chemistry’s virtual issues.

Back in Oct. 2019, the Washington Post’s Glenn Kessler had counted 13,435 lies or false claims by President Donald Trump. They came in all shapes and sizes, large and small, significant and irrelevant. Some likened Trump’s mendacity to his breathing—simply a way of life, or philosophy of being. And for the most part, he seems to have escaped relatively unscathed from his behavior. Despite the Mueller Report and impeachment, he seems to have retained a similar level of support since his unfortunate election to the presidency. Whether due to the sheer massive volume of the lies, or the propensity of supporters to ignore them while believing “the end justifies the means,” little political price or any other price seems to have been paid. At this point in time, most people now believe that aside from the large democratic gains in the House of Representatives in 2018, only time will tell whether the lies would eventually lead to his removal from office in the 2020 elections.

And along came the Coronavirus. Out of the blue—or rather out of Red China. Scientists have been predicting possible pandemics for years, in the wake of HIV/AIDS, SARS, MERS, ZIKA, not to mention the fears back in the early 2000s of anthrax and other biological infectious agents. But this president, who cut funding for the Centers for Disease Control (CDC), and requested cuts for funding both to the World Health Organization (WHO) and National Institutes of Health (NIH) in his most recent budget proposal, had already dismissed the pandemic experts in the White House that were put in place by (his nemesis) President Obama, precisely to prepare for such a potential catastrophic event. Why? Because he is a “small man” who is intensely jealous of Obama’s success and achievements, and simply wants to try and erase everything the former president has done—whether or not it is good for the country.

Unfortunately, viruses do not respect borders. Walls do not block them. They infect immigrants and national citizens alike. And they don’t care what falsehoods and spin are being spouted from the President’s mouth.

Unlike the president’s son claim, Donald Jr., who maintained that democrats want to see millions of Americans die so that the President’s “winning streak” is blocked, I can’t envision a single person, democrat or republican, who wants to see anyone die in this pandemic. I think the country is united in hoping that the virus can be slowed, contained, stopped—that a vaccine can be developed, that effective anti-viral drugs be made. No one that I know wants schools closed, sports events and performances shutdown, the workforce quarantined—all so we can blame the president. That is not only ridiculous—it’s warped and disgusting.

However, this does not mean absolving the president or abstaining from criticism for the poor preparedness and lack of a scientific approach. This does not mean that scientists and doctors from the top health agencies should be muzzled so that a positively-spun message out of the White House is the only one voiced. It’s time to rehire a pandemic preparedness team—better late than never. It’s time to turn over handling of the crisis to health experts so that they will brief the public and provide the truth and credibility that has been so sorely lacking. If the president thinks that the stock market slide into a tail-spin—the one sensitive spot for this president who seems to care more about the stock market than anything else—will be mollified by untrue statements that the infections are soon-to-be wiped out in the US, then perhaps he will get his first taste of the price of his mendacity. Unfortunately, this is a high price for citizens in the US to pay.

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Does it pass the smell-test? Review of “The DNA of you and me”

Posted on January 18, 2020 by Steve Caplan

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Moving into 2020, I realize that this is now my 10th year of blogging, a sport that I never really signed up for. In 2010, my daughter was 13 years old; now she is preparing for a series of interviews for graduate programs in the biosciences. Time flies! And in the meantime, she is now suggesting books for me to read, rather than the other-way-round. One such book was a new LabLit novel called “The DNA of you and me” by Andrea Rothman.

I am a sucker for this genre, and basically will read any science or lab-related fiction, just for the curiosity of seeing how my profession is perceived in someone else’s eyes. My daughter, who seems to have picked up similar interests, was not overly positive. And in truth, having read the novel, nor am I. But I do suggest that interested readers pick up a copy and decide for themselves.

In case, dear reader, you elect to read the novel, I will not give away too much. The narrator of the story and heroine is Emily, who begins the tale as a Principal Investigator who studies and maps how the brain perceives our sense of smell, and has just received notification of winning the Lasker Prize, an award that often has served as a precursor for the Nobel Prize. However, most of the story returns 11 years earlier to the start Emily’s postdoctoral studies in a prestigious New York lab, detailing her interactions with her manipulative mentor and a torrid but heart-rending relationship with a fellow postdoc and project co-worker. So far so good? Well, to a point…

Science, intrigue, prestigious prizes, love affairs—what could possibly be wrong with that formula?! Trying to put my finger on perhaps what I perceive as the main drawback, the word “authenticity” pops up. While labs come “in all flavors” with regards to the vast types of social interactions between those doing the research, the interactions and situations that come up in this novel simply don’t ring true for me. Yes, the Principal Investigator (my position at this point in my career) can be immoral and a bad person. That’s not out of the realm of believability. But it’s pretty much inconceivable that a Principal Investigator would or even could hide the project, and names of the genes that some postdocs in the lab are working on from others in the lab. Especially, as in the novel, if the goal was to prevent one postdoc from starting to work on that project. As a Principal Investigator, all he/she would have to do would be to say: “that’s their project, they are already working on it, this is yours.” No need to have people hiding things from one another. That simply doesn’t pass the smell test.

In addition to many additional smaller points that just don’t mesh including real-life interactions between people in any of the research labs that I’ve ever encountered, I found some issues with the scientific descriptions. Scientists love to talk about their science, and a common problem is that many of us typically forget that the general public does not have the same specialized knowledge, and that when presenting our work to lay-people, it is necessary to carefully explain our science and not go into superfluous detail. I took that point very seriously in the 4 LabLit novels that I wrote, wanting more to provide a flavor of the lab experience than a primer in the science itself. The author of “The DNA of you and me” launches rather heavily into scientific descriptions, but surprisingly I found some to be less than accurate. As an example, for those of you who are interested in the science, while searching for proteins potentially involved in neural pathfinding in the olfactory system in the novel, the author (who is speaking for Emily as a postdoc) on several occasions mentions finding good candidate genes based on DNA motifs—and yet, it would make a lot more sense that Emily would identify functional protein motifs, rather than DNA sequences, that might account for some specific pathfinding function.

Given the anomalies noted above, I wondered a little about where the author obtained her information—and whether she had scientific research experience herself. Perhaps she simply had an unqualified adviser who gave poor advice? Upon searching for the author’s background, I found that she described herself as a researcher who received two grants from the National Institutes of Health (NIH) to study the sense of smell. But that didn’t seem to mesh with the descriptions of the lab, research and some of the science. The reason, of course, is that someone who has received two NIH grants would be a Principal Investigator and obviously someone with a lot of experience and expertise.

Unfortunately, I can be like a bull in a China shop, or a dog worrying a bone. I had to know—was she really a Principal Investigator before turning to writing? Enter a scientist’s tools—PubMed and NIH Reporter. Through the PubMed, I found that Dr. Rothman had indeed published several; scientific papers—one as a first-author (indicating that the work was driven by her), and had 3 additional collaborative papers. One, I might add, with a group of Israeli researchers led by a Principal Investigator at the Hebrew University, Jerusalem, Israel, who taught me part of a course in physiology in 1987. Small world….

Returning to the author and her scientific productivity—in my experience, although there can be great variability in individual systems, her output would have more reflective of a graduating student rather than a postdoc, and certainly not the head of a lab conducting independent research. A quick check on the other website—NIH Reporter—indeed showed that one of the “grants” held by the author was a predoctoral fellowship, indeed one of my own students currently holds that very fellowship. While certainly prestigious for a student, I would be hard-pressed to call, it a “grant.” The second award was a grant of sorts, but a small award and not indicative of an independent researcher.

Without spoiling things “The DNA of you and me” does not paint a very flattering portrait of scientists and their ethics and behavior. Are there “rogue scientists” who are unethical and behave badly? Obviously. Are they representative of the entire scientific community? From my experience, absolutely not. So why, then, do such stories come to the forefront in fiction related to science? “Intuition” by Allegra Goodman is another example. Is it purely to provide tension and excitement in the story? Or is it possible, just possible, that the smell of sour grapes, and a career that hasn’t rocketed forward is leading some LabLit authors to bash science and career scientists a little? I leave it to you, dear reader to decide whether The DNA of you and me” passes the smell test.

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The changing face of science

Posted on December 15, 2019 by Steve Caplan

This past week, I attended the American Society for Cell Biology (ASCB) & European Molecular Biology Organization’s annual meeting in Washington, DC. This is a meeting that I have been attending since 1997, almost every year since then—for 22 years.

ASCB

When I first attended in 1997, it was at the end of my PhD at the Hebrew University in Jerusalem, and it was my first big international conference outside of Israel. It was an especially exciting meeting, because it was also in Washington, DC, and very near the National Institutes of Health (NIH) in Bethesda, MD, where I intended to do my post-doctoral studies. So the meeting not only allowed me to present my research at an international forum, but also gave me an opportunity to come to the US and interview at a number of NIH labs, as well as to “scout the landscape” and look for a potential apartment to rent, a daycare for my then-embryonic daughter (who incidentally has just applied for a slew of graduate programs in the biomedical sciences…). A lot can happen in just 22 years!

I have attended the ASCB meeting once as a graduate student, 3-4 times as a postdoc, and roughly 12-13 times as a principal investigator. In the latter capacity, sometimes I have even had the pleasure of coming with a contingent of 4-5 students/post-docs, all bearing posters and excited to present at the meeting. This year, for a variety of reasons (including the birth of a baby, someone leaving the lab shortly, and so on), I arrived with a single student who presented her poster. However, coming from our semi-isolated geographic location at the edge of nowhere (at least scientifically) here in Nebraska, this meeting is critically important to show my students how large and well-represented our basic cell biology community is in the rest of the US and internationally. Indeed, the meeting is often a real eye opener for students who at our relatively small and focused medical center have been accustomed to being “outsiders” in their basic science amongst a strong cadre of “translational researchers” in cancer, HIV, and other more disease-oriented areas. Suddenly, in one fell-swoop, a student who has felt on the fringes of modern science can feel a deep sense of belonging in a large and incredibly successful scientific community.

For me, the ASCB meeting has evolved greatly over the years in a number of ways. First, as a student, post-doc and junior PI, I was keen to get to every poster, hear every talk and maximize this week of cell biology, “getting my fill” of “breathable cell biology air” to keep me excited and involved and focused on my basic research. I was there primarily to gather information, see what new studies were being done, and keep abreast of new developments. However, now as a more experienced PI, who spends a lot of time reviewing new grants and manuscripts, as well as reading, I find that while the new advances are fun to hear and see, it’s really the opportunity to catch up with old contacts (and make new ones) that I enjoy most. In a short couple of hours in a poster session, I might (and have) run into my post-doctoral mentor, a colleague from the lab next door from my post-doc days who now has a lab back in Israel, a colleague who I invited to give a seminar a couple years ago, a colleague who invited me to give a seminar a few years ago, former students, collaborators, friends and more. Often I don’t even manage to get to all the posters that I had listed, but that’s okay, because as long as I am networking and discussing science with friends and colleagues, that is the point.

One of the things that I have noticed over the past 10 years in particular, are the changes in the annual ASCB meeting. When I first attended in 1997, there were relatively few graduate students in attendance. We had special name-tags identifying us as “those undesirable students”—although I suppose the rationale was to highlight that we were at an early career stage. Most of the talks then in the symposia were given by PIs, with occasional post-doc talks. Student talks were virtually unheard of. We were thankful to present posters. But all this has changed, as the ASCB has become more inclusive and desires to incorporate students and post-docs at earlier career stages into the fold. Now I’m told that 1/3 of all poster presenters also present short talks! I heard several undergraduate and post-bac students give terrific talks at a mini-symposium. And the difference in attendance is evident—while I still run into and bump into many old colleagues and friends at the poster sessions, it’s not nearly as frequent as it used to be—because there are so many new faces. It seems as though many established investigators are starting to feel that since their students and post-docs are being asked to present and give talks, that they need not attend.

I am all in favor of the new policies supporting the participation of junior scientists at ASCB, and will continue to attend and support the annual meetings and society as long as I have funding and can do so—it benefits my science and I come back to my lab with new ideas to assimilate and incorporate, both technically and conceptually, and it is a breath of fresh air for me—whether I present a talk or not does not matter. But I do hope that ASCB can find ways to encourage more senior and established investigators to continue to attend and enjoy this exciting venue in future years.

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Important Takeaways from “The Discovery of Insulin” for Today’s Scientists

Posted on October 20, 2019 by Steve Caplan

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Back in 2013 I visited the University of Toronto for a seminar and was given a very special gift by my gracious hosts: a copy of “The Discovery of Insulin” by Michael Bliss, which tells the fascinating story of the people and research that led to the finding that pancreatic extracts contain biologically active material that reduces blood sugar levels, and paved the way for the identification of insulin. Unfortunately, I managed to bury the book on my bedside table underneath an avalanche of other books, and completely forgot its existence over the last 6-7 years. Fortunately, a recent excavation led me to rediscover the book, and I have just completed reading this rich and interesting story of an important chapter of science history.

The discovery of insulin did not emerge from a vacuum; instead, for many years researchers and physicians understood that the pancreas likely held “secretions” that might be able to alter or regulate carbohydrate metabolism and thus control blood sugar levels. The Bliss depiction, a historian’s very carefully documented and thoroughly analyzed sequence of events, clearly shows that previously, a number of researchers in Europe and also in the US had tried valiantly (but overall unsuccessfully) to use pancreatic extracts on patients. The difference was that in Toronto in 1922, nearly a century ago, work mostly propelled by Banting, Best, Macleod and Collip, led to an actual pancreatic extract that could be used successfully on diabetic patients, some of whom were almost starved to death on diets with as little as 500 calories a day—the only known way of somehow extending life for Type 1 Diabetics at the time. A very uplifting portion of the book tracks some of the patients whose lives were saved and extended by the discovery.

In the book, Bliss tells the story of how physician/surgeon Frederick Banting, a shy and not particularly articulate World War 1 veteran was frustrated with his attempt to establish a clinical practice in London, Ontario. He had few patients, rent and debt were piling up, and his childhood sweetheart and fiancé was not pleased. As told by Bliss, Banting was looking for change, and he found two potential options: 1) to do some research on an idea he had related to pancreatic extracts, or 2) to go on an expedition with a group of people up north as a medical officer. Apparently unable to choose between these radical changes in career, he flipped a coin—and thus decided to go on the expedition. According to Bliss, Banting would have gone up north if the expedition leader hadn’t called him at the last moment to say that they decided not to include a medical officer in the group. And thus, by default, Banting ended up coming for the summer to the lab of Macleod for his research.

By all descriptions, Macleod was a very competent and qualified physiologist with broad knowledge of carbohydrate metabolism and physiology in general. Based on records of his early conversations with Banting, he was not impressed by Banting’s knowledge of physiology or of the current literature regarding pancreatic extracts. Depending on whom one believes, he either cautioned or discouraged Banting, but nonetheless agreed to give him space and resources, as well as a student, Charley Best, to do the work. Banting’s initial hypothesis was that other researchers had been unsuccessful in obtaining pancreatic extracts with the “internal secretion” that later became known as insulin, because he thought that the “external secretions” (all the gastric enzymes produced by the pancreas) were digesting the insulin, rendering it inactive. His plan, therefore, was to ligate and tie off the ducts that generated the “external secretions,” thus allowing those areas of the pancreas to atrophy, and leaving the remining pancreas (and its extracts) more likely to maintain an active “internal secretion/insulin.”

The book exquisitely details the methodologies employed by Banting and Best, with some guidance, cautionary and sometimes more directly useful, by Macleod, over the summer of 1922 and on to December 1922. The work was done primarily with dogs, rabbits, and later pancreases obtained from slaughterhouses. At some point when there was a modicum of success in obtaining preparations with potential benefit for actual patients, Macleod introduced Banting and Best to a biochemist colleague from Alberta who was in Toronto at the time, and his expertise in working out biochemical methods for extraction of the active insulin-containing extracts seems to have further propelled the project forward.

Bliss highlights scientists who nearly 100 years ago, just as they do today, bickered, and fought about the scientific credit for their research. In truth, as per Bliss, assigning credit was no simple matter. Each researcher involved had certain contributions, but for various reasons, it appears that no one person was wholly responsible. In the end, a contentious Nobel Prize decision was made to award the honor to both Banting and Macleod, whereas Best and Collip were not included. Banting was outraged that Best did not receive his due credit, claiming that “Macleod never did a single experiment.” Macleod, on the other hand, being the head of the lab, not only provided the resources, some of the key ideas for successful extraction, and the biochemist Collip to the team, but supported and promoted the research through his talks and help with articles (where he did award equal credit to Banting and Best). So while Banting gave half of his award money to Best, Macleod was upset that Collip did not receive his recognition, and he shared half of his prize with the latter researcher.

I highly recommend that every student in the biomedical sciences read this book (and not bury it under other books as I did!). Importantly, there are some key takeaway points that I think will enrich every scientist and anyone interested in science and discovery:

1)   For many years I have been a strong proponent of basic research, maintaining that (in particular) the serendipitous discoveries are historically often the most significant. And while one might argue that in this instance, a clear “translational research goal” was defined and led to the big advance, the discovery of insulin, I will argue that again it is basic science in the background that is, in part, the unsung hero of this story. Why did Banting and his colleagues succeed in Toronto in 1922 whereas 10-20 years earlier, Zuelzer and others remained unsuccessful? My read on that from Bliss’ book is that by 1922, advances in basic science had reached a level whereby assays had been worked out to accurately and efficiently measure various biochemical parameters, such as the level of glucose in the serum and urine of model animals and humans. While Bliss did not explicitly highlight this, my impression is that these technological advances in basic research techniques clearly provided the backdrop for the discovery of potent pancreatic extracts that contained active insulin.

2)   As noted above, good science does not emerge from a vacuum, but rather from a series of bricks built carefully one on top of the other. What this means, for some of us scientists, is that not only is it valid to work logically and methodically on the next little step or advance, but that this is a necessary thing to do to ultimately lead to big discoveries. In other words, dream big, keep the big discovery or “home-run” or ultimate goal in sight, but know that mostly science advances by baby-steps, and slow, incremental advances. In the book, Bliss himself noted that the discovery of Insulin was a question of time—if not in 1922, then within a year or two or five at the very most—because the technology was ripe.

3)   Many critics of Banting attacked him because his hypothesis that ligating the pancreas really never led anywhere (and even some of his conclusions in the early experiments were not particularly accurate), and that essentially, the real advance came from the alterations in the preparation of the extracts, ultimately leading to active insulin. The message here, in my view, is that the significance of the biological/biomedical question being addressed is often more important than the specific hypothesis.In fact, many times the hypothesis being proved wrong or irrelevant, can be just as important, as long as researchers keep their eyes open and are focused on discovery. As statistician George Box once said, “All models are wrong, but some are useful.”

4)   I do not want to detract from the great discovery by Banting and co-workers, by spending too much time on some of the points Bliss made about his having little knowledge of the literature, both at the start and even in later stages of the research. Instead, I would point out that he chose what was at the time a very challenging project where researchers with more experience than he had had not succeeded in the past. One reason for the discovery was his motivation to succeed, and such motivation is often a prime factor in scientific success.A word of caution, however. I once attended a seminar years ago by the late Judah Folkman, a pioneer in the field of angiogenesis, and he talked of 7 years of hard work by a postdoc in the lab who had made an important discovery of an angiogenic factor. Folkman said: “There is a very fine line between demonstrating tremendous dedication to a scientific goal and simply being pig-headed.” He is correct; and that fine line runs right through the issue of whether the postdoc or researcher is ultimately successful or not! If so, the researcher goes down in history as a brilliant committed scientist, if not, simply as pig-headed…

5)   While research and technologies have changed dramatically in the last 100 years, researchers have not. The same intrigues and egos and paranoias that existed in 1922 are still around today. And I expect they will be 100 years from now, too!

 

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Lost and Wanted—A review of a new LabLit novel

Posted on September 5, 2019 by Steve Caplan

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Having recently finished the novel Lost and Wanted by Nell Freudenberger, I peeked at a smattering of the many reviews written about this novel, each claiming Lost and Wantedfor its own select cause: feminism/gender equality, race issues, friendship issues, parent-child issues (multi-generational), science and society, science and belief/religion, elitism in education, social fads, and on and on. But Lost and Wantedis about all of these issues, and yet none of them. To single out a “cause” from the novel does not do it justice. It is simply a book about modern day life and the trials and tribulations of an empathic, talented and very intelligent woman navigating her way through life on earth and the cosmos at large.

Helen is a forty-something year-old highly successful professor of physics at MIT. She has made seminal discoveries in her realm of theoretical physics, is highly sought as a keynote speaker on the lecture circuit, and manages a lab of postdoctoral fellows and graduate students. As the story commences, Helen has just lost a close friend from her college days to complications from the autoimmune disease, Lupus. Helen struggles to control her guilt at the slow and steady fissures that had been erupting between her and Charlie (aka Charlotte), and the inevitable rift that began to form between them. When Charlie’s husband Terence and their strong-willed 8 year-old daughter, Simmy (aka Simona) come from their home in California to Boston, where Helen and her 7 year-old son Jack live—as well as Charlie’s parents, Freudenberger’s talents in depicting complex and compelling characters become evident. Friction between ne’er-do-well surfer-husband Terence and Charlie’s upper-middle class parents leads Terence and Simmy to move out of the in-laws’ space and rent the lower level unit in Helen and Jack’s home, allowing a unique friendship and new-found mutual appreciation between Helen and Terence to surface, as well as between Jack and Simmy.

This is a well-developed and clever, intellectual novel, describing realistic and interesting people, among them two key scientists: Helen, and long-time friend, colleague and collaborator, Neil—a fellow physicist working with the LIGO (Laser Interferometer Gravitational-Wave Observatory)team that was founded to detect gravitational waves and essentially test Einstein’s predictions that violent cosmic explosions can cause ripples in the fabric of space-time. Indeed, 3 of the founders of the LIGO program were awarded the 2015 Nobel Prize in physics for this very discovery. Author Nell Freudenberger, who to the best of my understanding does not possess a graduate degree in physics or astronomy, has done a masterful job in reviving the excitement and basics of the discoveries made during this period to the readers of Lost and Wanted. More than that, however, she has managed to clash with the science by enlisting belief and the supernatural, through mysterious texts that Helen receives from Charlie’s stolen phone after her death.

Lost and Wanted, however, is so much more than a LabLit novel. The relationships between children and their parents are artfully described—not only Jack and Simmy with Helen and Terence, but also the relationships between the adults and their parents. The novel is delightfully embedded with wit and  humor: for example, when Helen returns home from a scientific meeting in Switzerland to find her babysitting parents each sprawled out on the floor—her father to unclog the kitchen pipes (due to the artichoke leaves her mother insists are necessary for a proper nutritious lunch), and her mother in a yoga position—she is reminded of a conversation with her sister in which they discussed the possibility that “mom retired too early.”

Lost and Wanted is perhaps an exceptional novel because, like the LIGO inferometers and the massive LIGO collaborations, the novel manages to integrate so many moving parts—all of them balancing each other without distracting. Ultimately, the sum is greater than any of the many individual (and significant) themes dealt with in the writing, making the novel an entertaining but also illuminating experience—one that makes many (gravitational) ripples.

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The Renaissance and Preformation

Posted on June 7, 2019 by Steve Caplan

This is a tale of woes, and oh, what a tale. And it all begins with some introspection as to whether we, as human beings, are “preformed.” If we venture back a mere 350 years or so, to the time of Italian biomedical scientist and microscopist, Marcello Malpighi, we can find the origins of a rather intriguing (if not somewhat childish) scientific theory known as ‘Preformation.’

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The concept of Preformation

According to Preformation theory, adult organisms are the result of growth of preformed (body) parts contained either within the sperm or egg. With the advances in microscopic resolution, however, Preformation was largely abandoned in the 18th century, and scientific inquiry ultimately provided the more accurate concept of fertilization and embryonic growth that is predominant today.

Certain recent experiences, however, have led me to question whether the concept of Preformation may actually have some merit—if not regarding the growth of embryos, at least with regard to the morality and behavior of human beings. Allow me to explain:

The Renaissance in 21st century technology, including computers, cell phones and communications, has had an enormous impact on society as a whole. But here I would like to focus on a personal story, one that relates to the massive globalization effects that computers and the internet have wrought—for better, or for worse.

First the good! In a remarkable coincidence that would be fit for the cliché that ‘truth is stranger than fiction,’ I came across a photo of a woman who went to elementary school with me from 1st grade through 6th grade, and who I last saw about 41 years ago. Yes, 41 years, and still easily recognizable. And despite the fact that we almost never talked to one another during those school years, when I contacted her (98% certain that it was the same person), over the last 3 years we have become great friends, had a wonderful visit together last summer at my home in Omaha and are planning a second visit together at her family residence in Toronto. Truly a Renaissance!

However, as I have learned, sometimes the expression ‘let sleeping dogs lie’ should be adhered to. In this story, the anti-hero is someone who we will call G.H. When I served in the Israeli army back in 1983, one evening while in basic training I was dismayed to find that my duffel bag had been cut open and my winter jacket was missing. As I stood freezing and shivering in formation, I couldn’t help but notice that the soldier lined up directly in front of me, one G.H., happened to have the name “STEVE” emblazoned on the back of his green parka in huge, bold black marker. With my handwriting of course. A “giveaway?” It didn’t seem to bother G.H., to whom stealing appeared to be second nature. And all of this has been chronicled by yours truly in Chapter 30 of my second novel, “Welcome Home, Sir.”

In the course of the 3 months of basic training, G.H. proved to be a terrible person—the type who would lie and cheat his own grandmother. Indeed, in the final forced stretcher march—an activity which often highlighted the character of the people in the platoon, G.H., stumbled at the back, complaining that he had had enough and couldn’t go on. Along with another soldier, I was assigned to help support/carry/drag G.H. across the finish line, which was still 20 km away. It was no easy task, since G.H. was uncooperative, and cursed and resisted us the whole time—until he lost his temper and tried to take a swing at me with his rifle. He was subsequently court martialed and sent off to military prison, never to heard of again. Almost.

Which brings me to philosophize as to whether an 18 year-old can change—or whether he is predestined/preformed to a degree that his life trajectory has already been predetermined by that age. Or perhaps even much earlier.

Given my favorable experiences in unearthing persons from my past, it suddenly occurred to me that perhaps I might find traces of G.H. online. Perhaps he had turned his life around after the army, become a professor of history, or CEO of a start-up company? Gone to law school and become a supreme court judge? Become mayor of a city? A teacher at school? Anything productive?

A quick Google search turned up a single article in the Israeli newspaper Haaretz, about a man named G.H. (an uncommon name, by the way) who was exactly my age, and had just rammed the truck he drove into a bus stop full of people and killed two of them, and was awaiting trial for murder (or to see if he was deemed fit for trial). Why? Apparently, he maintained that the police and government had killed his children—who were alive. And in the end, with all the sadness at the futile loss of life in this story, does anything really surprise me? The truth is no—it does not. And unfortunately, perhaps Malpighi and his 17th century scientific colleagues had a point about Preformation—although perhaps the notion would have been more accurate at the conceptual/metaphoric level rather than scientifically.

As for me? I think I will now take a hiatus from my digging into the past—while it can bring intense pleasure, and while knowledge is power, it can sometimes be better not to know…

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Life lessons learned–from others’ mistakes…

Posted on April 27, 2019 by Steve Caplan

I did not enjoy my service in the Israeli military between 1983-1986; in fact, I hated it. But I do know that it taught me many lessons, and I have long thought that my experiences in the army have helped me both in life and in science. The following is an example of one such instance. Many years ago, in 1984 to be precise, I stood in the Negev desert on a cold, dusty army base at attention for an inspection.

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Yours truly, circa 1984.

I was an artillery soldier, not yet having gone through command training to become a non-commissioned officer, and the inspection was to be carried out by the general who was the commander of the entire Artillery Corps. All of the soldiers were tense—to date we had only had inspections from higher officers from our own unit—such as the unit commander. So there was a great deal of fear that the general might punish us for doing a poor job, by revoking leave privileges, etc.

We had been cleaning our weapons, checking our equipment and readiness all night. Morning had finally arrived, and we were standing by our artillery pieces, in full battle gear, at attention. The general strode up and stopped 2 soldiers over from me and asked: “How many bullets in each clip?” The soldier replied, “Thirty-five.” One of the things about Hebrew, the language in which this all took place, is that every word has a masculine and feminine form, including numbers. And since the plural noun “bullets” is masculine, the masculine form for 35 should have been used. But wasn’t. The general quickly corrected the soldier, and stated the masculine form of the number. He then moved on to the next soldier, who promptly made the very same mistake, and was subsequently corrected. The general then turned to me, and of course, I answered “35” using the correct masculine form. Hearing my Hebrew accent, the general asked me where I was from, and how long I’d been in Israel. I told him that I was from Canada and had been in Israel less than a year. He said to me, in a loud voice meant for everyone in the vicinity to hear: “You’ve been here less than a year, and already your Hebrew is better than these soldiers who have been here all their lives.” When I tried to point out that I had the benefit of hearing him correct the two soldiers, he stopped me and said: “That is the point—you learn from others’ mistakes, without making your own.”

To some extent, this life-lesson provided by a general from a far-away desert scene, has been a pillar or hallmark of my life and scientific career. Indeed, if someone else made that mistake, why not capitalize and take advantage of that?

As a graduate student I did a lot of protein work, separating them by electrophoresis, and examining them by immunoblotting. These techniques require a step where proteins are transferred by electric current from a “gel” to a piece of filter paper. One of the most common errors is hooking up the electric current—nearly every researcher has at some point done this in the reverse direction, so that all the proteins float off into the buffer instead of into the filter paper. Throughout my bench career, I have been wary and every time I connected those wires to the power supply, I was able to remind myself of the “35 bullets story” and take an extra minute to make sure the orientation was correct, so as not to make a mistake.

There are countless ways in which people can learn from others’ mistakes—in science and in life overall. Unfortunately (for others), someone else’s pain can prevent our own pain. But the trick is to recognize how others have erred and to correct that error in our own thinking and behavior. This is not always so simple.

I will end this little parable with a “joke” I once heard—certainly not a pedagogical joke, but it does illustrate this point again. A mother brings her child to kindergarten for the very first day. She says to the teacher: “Johnny is a very sensitive child—if he misbehaves or does anything wrong, please shout at the child beside him. That’ll ensure that he behaves properly.” Regardless of the cruelty of this little joke, it is incumbent upon us to “be Johnnies” and to really learn from the teacher who shouts at the neighboring child. It will certainly make our science move faster.

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How far should students go in striving for professionalism?

Posted on April 22, 2019 by Steve Caplan

What is the beginning of eternity and the end of time?

Sometimes the simplest answer is actually the right one: in this case, the letter “e.”

Having served as chair of my departmental graduate and admissions committee, professionalism is an issue I have spent a great deal of time thinking about. Without a doubt, in this Orwellian society, we are not only continually evaluated and observed, but often recorded. Our words, even misconstrued, come back to haunt us. So the question remains, how “professional” must students be?

At this point, an example is needed. In the course of my career, I have witnessed oral defense dissertations, which are seminars given students who are defending their research—certainly an anxiety-ridden event for anyone. To my amazement, occasionally I have observed a student  who has very successfully navigated such a tricky presentation lose the façade of professionalism at the “acknowledgment stage.” Thanking one’s parent briefly—I have no problem. A spouse, fine. An uncle who steered one into science, sure. A brother, a sister—perhaps that’s pushing it. When we arrive at the kindergarden and elementary school teachers, pets ranging from cats to parrots, then I think we have a problem…

This, however, is only an example of a wider issue for students (and postdocs and junior faculty) to consider: we are constantly being evaluated. There is no respite. In our professional lives and exposure to colleagues, we cannot relax—certainly not in formal situations.

While rules and regulations can stymie creativity and boldness, I think nonetheless a few guidelines are warranted to help younger researchers decide what constitutes a professional approach.

  • When in doubt, stay conservative. Personal reference—not wearing more formal attire, at least for some job interviews, may have negatively impacted past job searches.
  • Be reasonable—all things in good measure. It’s fine if you want to briefly acknowledge various people at the end of a talk. But for a 45-minute seminar, acknowledgments that extend longer than a minute or 90 seconds will be too long. They will bore the audience, and perhaps detract from the seminar. Remember the “peak effect”—people will piut emphasis on the last things you present, include over-done acknowledgments. Adding your garage mechanic, plumber, piano teacher and pet turtle will not go over well on the audience.
  • Humor is fine—but as a side dish, not as the main one. A good seminar often has a humorous slide or includes a brief joke/story/anecdote to keep the audience engaged. That’s usually an excellent strategy—except that you want the audience to appreciate you for your science, not for your stand-up abilities…

In reality, professionalism is really just common sense in one’s working environment. If you are in doubt about whether any particular behavior is sufficiently professional, just ask colleagues and mentors–but do so beforehand, rather than afterward. That is the essence of professionalism.

 

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How *NOT* to deliver a seminar

Posted on March 8, 2019 by Steve Caplan

It seems that people are apt to try and recreate or relive their greatest successes, and it turns out that I am not immune to this behavior. Some years ago, a combination of exasperation and disbelief coupled with an attempt to educate others led me to publish a satirical piece called “How NOT to get a lab job.” 

In those years I was besieged with a multitude of poorly conceived and written emails from scientists wishing to join my lab as a postdoctoral fellow. I had emails addressed to “Dear Madam/Sir,” as though the writer had never bothered to assess with whom he/she would like to work. Other requests were sent to my email, but addressed to other scientists. Others still urged me to hire their spouse, or told me they like my project on –and here they cut and pasted the entire synopsis of my work from my website, different color font and different style/size text and all! In my analysis of these emails, I tried to illustrate to the reader how such emails were perceived from the standpoint of the employer—the person running the lab.

Remarkably, the satirical piece that I published on Lablit.com received a lot of attention, and I was swamped with comments from many scientists who appreciated my attempt at humor—and from several who did not. And now, years later, I still struggle at trying to surpass this achievement. And finally, I had an idea…

Every scientist spends countless hours listening to seminars—but not all seminars are created equal. There are good talks, and there are talks that need significant improvement. And while I try to remain positive and polite with my critiques, it seems that I open my mouth more than most—and thus, a colleague asked me: “You seem to have a pretty good idea about how seminars should be delivered—how about putting your money where your mouth is and giving a lecture to our trainees on the art of delivering a seminar?”

I had now effectively painted myself into a corner, and it was time to “put up or shut up.” And I guess that I just don’t have it in my DNA to shut up. And thus, my little seminar, “How *NOT* to Deliver a Seminar,” was born…

Lesson #1:

The key, I surmised, was to lead by example. So, after being introduced, I stood up, walked over to the front of the lecture hall, buried myself behind the podium so I was virtually invisible and unable to make eye contact with a single person in the audience, and began to mumble quietly so that anyone farther away than my belly-button would not comprehend a word. I then flashed on my “title slide.”

Slide01

There is nothing like yellow-on-white background so as to be poorly visible to the audience—and when there are spelling mistakes, inconsistent spacing between words, and no affiliation listed for the seminar speaker (and so on)—well, perhaps it is better if it is not easily visible to the audience….

Lesson #2:

Connecting with an audience is very important, as is delivering good content that is well organized. But that is not enough. So I moved to my second slide.

Slide02

As it turns out, a great way to lose an audience is to pack a slide full of words/sentences/paragraphs, with no respite for the weary. Drone on and on. The typical scientist in the audience will likely not even get to the third written line before abandoning hope of reading whatever is written, and start to tune out.

 

Lesson #3:

The Model. Every scientist appreciates a “model”—a simplified explanation of the best-guess for how something actually works. Models can be expanded upon, modified, altered, or even switched around completely, depending upon new incoming data that supports, negates, or allows modification of the model.

Slide03

But when the model looks more like circuitry for the wiring of a hard drive or nuclear transformer, and the lecturer does not focus in on a more select arm of such a tangled and complex pathway, this is another great opportunity to elicit snores and provoke latent narcoleptics into acute ones.

Lesson #4

Scientific terminology is cumbersome. Perhaps because scientists want to show off their ability to rattle off big names, or perhaps because the big names help formulate the accurate descriptions that scientists desire.

Slide04

In any case, lecturers often use a variety of acronyms to make their talks easier—easier for the lecturer and harder for the audience! When introduced once and usually rapidly, a typical person in the audience will have a difficult time remembering that dSTORM stands for direct Optical Stochastic Optical Reconstruction Microscopy, or that BBSome is derived from Bardet-Biedl Syndrome.

So to help put things in perspective, and not only show what NOT to do, I formulated an abbreviated series of recommendations for the presentation of a seminar–in other words, WHAT TO DO:

Why bother? Is it worth my time?

  • Every opportunity is a chance to improve, practice oral presentation skills, learn to better field questions.
  • Never underestimate the significance of impressing other researchers and faculty, networking, and being able to solicit strong letters of recommendation from faculty other than one’s direct mentor.
  • Being able to explain your work to a broad audience means that you may benefit from great ideas from someone outside your field, and also might potentially lead to beneficial collaborations.

In summary: Preparing a well-conceived post-doctoral seminar is key to obtaining a job

Professionalism

What constitutes a professional seminar?

  • The seminar is practiced (the more the better) and timed to the appropriate length
  • The slides are effective: clear, simple, and with good-sized words/text, images and graphs. Avoid overly crowded and complicated slides.
  • The slides should be very carefully vetted for proper spelling and grammar.
  • It is good practice for every slide to have a clear, concise informative title that summarizes the point of the slide.
  • Speak loudly and clearly. Use a microphone if you have a soft voice. It is YOUR responsibility to make conditions so that the audience can hear and follow you.
  • Don’t hide behind the podium. Talk to the audience whenever possible (rather than look at the slide), make eye contact and continually look at different parts of the audience/room.

Content (for a ~40 minute talk)

Introduction/Background (10-12 min.)

*This section should start broadly and slowly work toward the specific question(s) asked.

*If given in a diverse forum, it should be presented so that those outside the field and not familiar with the details can still follow.

*Do not include an abundance of extraneous information; everything you include should tie in and make sense when you bring up the specific question(s) asked.

The HYPOTHESIS (Objective/Goals) of your study should be understandable by the audience once the Introduction has been completed.

Hypothesis (Objective/Goals)

*The key to a good seminar is appreciation of the rationale. The logic of how the seminar is put together (the “flow”) and whether the questions and experimental design make sense and address the most important questions is crucial.

*A well-articulated (and simple) Hypothesis or Objective is essential—basically outlining your research mission in a nutshell—and in many cases a simple schematic model can be very helpful to get the message across.

Results/Data

*Ask a specific question before each data set. Sometimes a separate slide with a simple question really helps people follow.

*Use this type of format: 1) “We asked the following question….”   2) “To answer this question, we used the following approach…”   3) “From this data we can conclude the following…”

*Informative titles for each data slide help the audience follow.

*Make an effort to have good transitions from slide to slide: Example: “Now that we have shown that the sky is blue, we next asked whether the ground is also blue…”

*Beware of presenting overly technical information, or information that doesn’t fit well into the overall rationale.

*Remember the “Peak Effect” and that often “more is less.”

Conclusions/Summary

*While it is important to summarize as you move along through the results, at the very end of the seminar an overall conclusion slide should summarize the most important points learned.

*This information should essentially be simple, concise “take home information” that someone who slept through the entire talk could write down and still have learned something.

*Don’t rehash every point made, but give a general summary of the most significant things learned.

*If possible, a schematic diagram helps most people better conceptualize pathways and cascades, and gives much-needed perspective.

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Reinventing the Wheel

Posted on December 31, 2018 by Steve Caplan
CRISPR /Cas9 gene-editing: staying on top of technology is a full-time job for researchers

New Year’s Eve has always been more of a time for reflection for me, rather than a time for partying. Perhaps this stems from growing up in a Canadian climate where late December and early January (or more accurately, October through April) and the accompanying bone-chilling cold and darkness were more likely to entice me to curl up in a fetal position than chug champagne.

Just as chess champion Garry Kasparov maintained that “Life Imitates Chess,” I would venture to modify that and say that “Life Imitates Science!” Wait! Does that even make sense?! Of course not—life is science, while, pardon the treachery fellow chess players, but it is—sorry—after all, only a game. However, there is something to be said about the parallels between life and the career of a scientist. And it all begins with New Year’s Eve reflections. 

Speaking both from experience of years gone-by and based on much anecdotal inference, it seems that young people have a tendency to feel immortal. After all, for a healthy young person, age 70, 80, 90 is eons away, and the end of life is practically inconceivable. And of course, statistics bear out these ideas, clearly demonstrating that in general, young people are more reckless drivers and greater risk takers than those who are older.

In parallel, younger scientists also feel as though the scientific world is in the palm of their gloves. I don’t mean that younger scientists are reckless, but that those embarking on careers as independent researchers are very focused on the here-and-now, as they should be. And growing up scientifically in an age where technology is rapidly advancing on so many fronts, I suspect that today’s young scientists have neither the time nor inclination to think about their careers in 20 years’ time. After all, many of us fight those early years to survive in academia—the struggle for tenure. But just as in life, aging brings on thoughts of mortality, tenure and initial successin sciencealso bring about renewed reflections on one’s future career in science.

If most young researchers think the way I did, then they may take it for granted that once one derives a measure of success in running a lab, they are confident that can be readily continued in perpetuity. But is this really the case?

Far be it from wishing to dissuade young people from a career in academic science, I do however wish to convey the need for long-term, treadmill-like persistence for success and satisfaction in this field. I have harped on how, in the past, PhD students were required to master several techniques in the course of their studies, whereas today’s students have become “jacks of all trades,” who (although they may not need to completely master the techniques) must be fluent with dozens of new technologies, many of which crop up at a startling pace. Today’s students must be highly skilled at the use of technology, particularly sucking out the benefits of computer searches that include finding technical solutions to a range of problems. But what is expected of those directing the research and running their own labs?

I find that to stay competitive in this field, I have not only had to adapt technologically to an ever-changing landscape of techniques and methods, but also conceptually to continually find new niches. First, from a technological standpoint, there is no such thing as staying current—to stay current, one needs to constantly move forward an adopt new and emerging technologies. And it can be a significant challenge to introduce new technologies in a small-to-medium sized lab comprised primarily of graduate students, when the principal investigator (PI) does not actively work in the lab. 

Just to highlight a few examples of how the research technologies in biomedicine have evolved since I have been a PI, when I first started up my own lab, the technology of knocking down a specific gene in cultured cells (to study the role of the protein encoded by that gene) was only starting to become established. Today, however, the use of the newly discovered CRISPR systems to knock down, and even more significantly, to edit or tag genes in the cell, is re-revolutionizing the science that can be done. While understanding the concept of CRISPR techniques is not especially difficult, being able to sort out the design of such editing at the molecular level and successfully direct the lab to incorporate these technologies has been a considerable task. Despite the many fine papers, excellent blogs, websites and troubleshooting readily available online, these systems are so individualized to each laboratories’ needs that it required weeks of reading, schematic scribbling and planning until we were able to set up these complex systems. And while I am very satisfied that we have met the challenges of incorporating these technologies, I suspect that the next ones will be even harder to overcome. It is important to note that I used CRISPR as a representative example, but our lab has launched into a variety of new technologies, from structural biology to super-resolution microscopy and beyond, each with its own significant learning curve. 

At the same time, my lab has been laser-focused (pun intended) on understanding endocytic membrane trafficking and mechanisms of endocytic recycling; in short, how receptor are internalized from the plasma membrane and eventually returned to the plasma membrane. While I think there have been significant advances in our field by many outstanding researchers over the past couple decades, it seems that this brick-on-brick, sure-and-solid level of advance is not sufficiently attractive for low-hanging fruit funding in recent years. To me, it seems as though we researchers are being asked to reinvent the wheel—to continually find new groundbreaking discoveries, rather than ‘incrementally’ advancing knowledge in the field. Good or bad? That’s a debate for another new year…

As a result, I have spent an enormous amount of energy to try to connect my area of expertise with tangential fields. We have connected endocytic trafficking to mitochondrial biology, and more recently, to centrosome biology. The ability to divert my lab’s research focus from its almost exclusive focus on endocytic pathways to these new realms over the past several years has been almost overwhelming for me. Even mastering the literature of a tiny area of research has become a near-impossible task—so the immersion in several new and unfamiliar fields to the level that we are able to study relevant questions and publish responsible data has taken a toll on me. 

I no longer have the cocky confidence of a newly-minted PhD. I hope that I will be up to the challenge for the next 20 years or so.

And as a Nobel Laureate for literature once wrote:  “The times they are a-changing” 

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