A perfect experiment and the poop factor

In the midst of the pandemic, it was time for me to plant my tomatoes. Being unwilling to visit local nurseries for obvious reasons, I did the next best thing and ordered 12 tomato plants online. The drawback was that the selection was limited, and the only plants available then were cherry tomato plants. Not a terrible thing.

Last year, I planted 7 plants adjacent to one area of the backup of my home. I drew conclusions that although there were some nice tomatoes, the yield was low because: 1) they were much too crowded (I should have planted 3-4 instead of 7),  and 2) because tress and shrubs limited the direct sunlight hours–and everyone knows that tomatoes love sunlight. So this year, I made a new plan. I built 2 boxes on each end of the garden, that like the area I planed last year, generally face south. But in addition, the boxes were away from the house and expected to garner a lot more sunlight. I decided to do a controlled experiment, and plant 4 in last year’s location, and 4 each in the new boxes.

All 4 locations received the same new topsoil with nutrients (all purchased online), and I planted the very same-sized cherry tomato plants in the 3 locations, convinced that the 2 new locations would produce dramatically enhanced yields. And like almost every scientific hypothesis in my lab, the results yielded some minor and major surprises!

  1. By the house– a decent yield (this was my “control”)

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2. Southwest new tomato location– the best yield, with lush multi-branched tall plants, full of fruit!

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3.  Southeast new tomato location–Surprise! the poorest yield! Something in that location caused the plants to grow slowly and the yield is minimal!

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Now for the real surprise! Every experiment in the lab has one of these! And the responsible party is none other than our Ginger:

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We noticed that in another area of the garden, a tomato plant began to grow, outpacing and overcoming its neighboring hydrangeas and gladiolas. But unlike my cherry tomatoes, the leaves were larger and different in shape. And as the fruit began to grow, it was easy to see that these tomatoes were not cherry, but the same strain of “tomatoes on the vine” that we prefer to purchase from the supermarket. Add to the story that Ginger loves eating the ends of tomatoes when we are making salad, and the picture starts to unfold…

Poop plant…

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Conclusion: Even the best planned and simplest experiments oft go awry–that is the fun of science. And never discount the poop factor.

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In the shadow of the great narcissist

Having written my last post titled “Preliminary lessons from a global pandemic” on March 8, before my self-imposed sequestration at home for the past 6 weeks, I find it too depressing to write a sequel on additional lessons. Much has been said about the complete failure of leadership in the US, and unfortunately, most of it is true. In fact, it’s often far worse than one could sensibly imagine, making the US one of the most pitiful countries according to Irish journalist Fintan O’Toole.  No country has been spared this suffering, the loss of lives and the the illness, but one might have expected that a purportedly first-world country with resources, leading scientists in many fields, and lots of time to prepare, might have done more. But then, most countries are not led by the great narcissist…

Instead of lamenting over the situation here, which I do all too frequently, perhaps I will explain how one active research scientist (me) has been trying to stay focused throughout this pandemic. And I should mention that I have another two weeks at home (at least) ahead of me.

Speaking with many colleagues, I know there is a wide variation in how researchers feel about their productivity and this once-in-a-lifetime (hopefully) pandemic stuck at home. It’s also very different if one is a student or postdoc, as opposed to someone like me, a principal investigator, who seldom (never?) carries out any actual lab work anymore, and is rooted to a computer terminal in any case.

First, I went home about 6 weeks ago in a rather unique sweet & sour situation; on the one hand, a terrible pandemic striking and sadness all around. On the other hand, I had just received unofficial notification of the funding by NIH of a new grant, one that takes me out of my natural realm of endocytic trafficking to study centrosomes and cilia. This has been a long process. I began working on cilia 6-7 years ago, on and off, and published a collaborative paper. About 5 years ago I began a collaboration with a colleague at another institute to study centrosomes, and we also published a paper. At some point, about 3 years ago, I realized that I had enough interest and data and ideas to start putting together a proposal for the National Institutes of Health. And now, a couple more papers later, 4 arduous grant submissions later, and finally, a funded grant for the next 4 years on this project (to complement our ongoing endocytic research). So the happiness and relief at having this grant funded helped buoy my spirits in these tough times.

However, from a purely personal standpoint, the self-imposed isolation has not really been a hardship to me. Unlike those in New York City in small apartments, or people in Milan or Madrid, Omaha is a very widely-spread city with a modest population of under 1 million. I live in a comfortable house on a little lake with a walking path, have a treadmill on the lower level facing the lake, and a covered deck for breakfast lunch and dinner outside facing the lake (on nice enough days). My wife is a research scientist who works with me, so we have a lot to talk about scientifically (if not personally!). We have groceries delivered and except for going out every day for walks with the dog, little direct contact with the outside world. An introvert’s dream…

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Each morning I would wake up, have coffee and breakfast, do some weight training and stretching, spend an hour on the treadmill, either answering emails or watching films on my laptop, shower, have a cup of tea and a snack and settle down to work. Work consisted of a lot of administrative issues to deal with, many papers to review for several journals (how people are able to submit these days is a mystery to me! Good for them!), reading, strategizing over research plans for each of the students and postdocs, and attending various meeting by zoom. After lunch, usually at 2 pm, my wife and I would meet our lab people (usually 1/day) for 60-90 minutes for updates, plans, strategizing, practice talks etc. We’d have a lab video meeting once a week where someone would present, and a journal club once a week with someone (including me!) presenting a paper in our field.

Most of all, I have had time–for the first time in a long time–to really read the literature in and out of my field (with no guilt because I am avoiding some other obligation). In addition, I finally have had an opportunity to browse websites from scientific and biotech companies so I could see what new tools are available and that are worthy of incorporation into our research. My wife has even spent time figuring out which companies charge the least for shipping, and removed orders from those that charge too much. We have had companies begin the generation of new antibodies, ordered clones of cDNAs, designed our own siRNAs from a different (and less expensive) company, designed our own DNA insets to be synthesized and so on. When we eventually get back to doing experiments, hopefully we will be well positioned to make advances in multiple areas.

I know my experience at home has not been typical, and from the perspective of the lab we need to generate data before we can do much more strategizing and planning, but if one ignores–or rather sets aside–the misery evident in every newscast, and the disgust in watching those who would sacrifice our elders and less healthy members of the population so they can shop or dine or attend sports games–if one is able to set that aside, then so far I can’t complain too much about the past 6 weeks. I have, however, learned an important lesson: when happier and safer times come, I will not be shy in staying home more often so that I can really get things done.

 

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Preliminary lessons from a global pandemic

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The Centers for Disease Control and Prevention (CDC) map of COVID-19 infections as of March 8, 2020

1)         All humans on this planet are one species, with a genetically identical composition. The Coronavirus doesn’t distinguish between any of the so-called “races” on our planet, and because the genetic make-up of people with different levels of skin pigmentation is essentially the same, and the cells of every human being are controlled by the same proteins, the infectious virus is able to penetrate and replicate using the host cell proteins of every person on the planet. We are all susceptible, and viruses show no discrimination.

2)         We share remarkably similar DNA with the animal world, further highlighting the accuracies of Darwin’s observations, if there were ever any doubt.The origin of the Coronavirus is thought to be from pangolins, and the fact that the virus finds the host proteins and replication machinery of these mammals sufficiently similar to human cells highlights just how close we are to the animal kingdom.

3)         Cuts in funding to science, research and pandemic resources are a drop in the proverbial bucket compared to the massive loss of money across the globe during such a pandemic. Unfortunately, it appears as though we are only at the very beginning of this pandemic, at least in Europe and North America, and already the Coronavirus pandemic is having an enormous impact on the global economy. Everything from production of goods, the entire travel industry, both nationally and internationally, with all of its offshoots that include airlines, hotels, restaurants, etc. have already been impacted. When more universities and schools begin closing, sporting and cultural events are shut down, potentially even the cancellation of the Olympics, the overall toll will be staggering. Yet the US government under President Trump “got rid” of the Pandemic Preparedness team. They proposed cutting funding to the Centers for Disease Control and the National Institutes of Health. They even tried to move funding for Ebola research and preparedness to this current crisis—endangering the citizens of this country and the world should a renewed Ebola outbreak occur. This type of shortsightedness is dangerous, because had the government spent an extra 10-15 billion dollars a year to prepare for pandemics, we might be more ready today to save lives, prevent suffering, and avoid a nation-wide/international recession. The money “saved” by not supporting science, research and pandemic preparation will seem like peanuts, unfortunately, by the time we are done with this Coronavirus pandemic. 

4)         Healthcare is not a luxury but essential for every citizen. In the US, the debate has raged on over the last 10-15 years over health insurance. Democrats under Obama were able to make significant roadway and help provide affordable health insurance for 25-30 million uninsured US citizens. However, despite this significant improvement, many remain uninsured in this country, and even for those who are insured, seeing a doctor when ill is often a last resort due to expensive co-payments and deductibles. Today, presidential candidate Bernie Sanders is taking things a step farther, and wants to abolish private insurance in the US in favor of a government-run single payer system that covers everyone. One can argue about the best way to provide basic health care, whether by expanding upon Obama’s system to include the remaining uninsured citizens (as democratic presidential candidate and former Vice President Joe Biden proposes), or by Sanders’ more drastic approach. However, one thing has been missing from all the ensuing discussion—it’s not just about individual health and well-being. This pandemic is reinforcing the notion that without affordable healthcare for everyone (and that obviously means around the globe), the world is at a much greater risk for every transmissible disease. It is clear that politicians and advocates of universal health coverage need to start including this as a key rationale—if for no other reason than it may finally resonate and help convince those who already have health coverage plans that unless the entire population is protected with health care, even the risk of healthy people is heightened. 

5)        The need to protect the elderly. The current pandemic also highlights how important it is to emphasize the need to care for our elderly populations. While the numbers are still very preliminary, not surprisingly mortality rates for novel COVID-19 Coronavirus suggest a steep incline for infected patients who are above 65 years of age—indeed there is an exponential mortality risk as the age bracket goes up. In part, this is because the elderly tend to have weaker immune systems and often suffer from other conditions. However, whatever the reason, just as society strives to keep our children safe, we need to redouble our efforts and keep our parents and grandparents safe. The sad news of the death toll at the nursing care facility in Washington State serves as a somber reminder. 

6)         We are all connected. In 2020, there is no such thing as being an “isolationist.”The entire globe is connected, as never before. This is both at a virtual/conceptual level, with the advent of cell phones and the internet, and at a physical/practical level, with so much international travel and movement from continent to continent. This pandemic, clearly spread by international travel and being propagated by administrative failures and a slow response to do massive testing and prevent unnecessary spread, highlights the interconnectedness of people around the world.

 

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The Coronaviral lie detector

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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”

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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

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.

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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

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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

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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

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.’

1978_miniature of sperm

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…

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.

chayal

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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