Where do the Candidates Stand on Science?

White-House-SD-Qs-Banner.jpg2016. An Election year in the United States. It’s nearly impossible to turn on the television, pull up news on the computer, or scan your social media accounts without seeing some sort of political news. Often the coverage is about the horse race aspect of the election— polling numbers, for example—or the candidates’ whereabouts on the campaign trail.  Occasionally the coverage is policy based.  Rarely, though does this include a candidate’s views on scientific issues.

Earlier this month ScienceDebate.org released 20 science questions to which it would like the Presidential candidates to respond.  The Biophysical Society assisted in the creation and vetting of the questions and endorsed the final list.  Along with other leading science organizations, the Society would very much like to hear where Clinton, Trump, and the third party candidates stand on these important questions that touch on vaccines, climate change, jobs, and research.  The questions received attention from the press, but the candidates have yet to respond.  We hope that they will in the coming weeks.  We also hope to see some of these questions posed in the national debates.

Here are the questions.

ScienceDebate.org was originally started in late 2007 to garner support for science issues to be included in Presidential debates prior to the 2008 election. Candidates Obama and McCain did go on record with responses to the questions then; here’s hoping Clinton and Trump let us know where they stand!

Biophysical Society Summer Research Program: The Time of Your Life

li_alexMy name is Alex Li. I am a rising third-year undergraduate student at UNC-Chapel Hill, majoring in B.S. Chemistry with a focus in biochemistry. I first found my love of chemistry in high school after taking AP Chemistry and now I wish to specialize my interests in organic chemistry after taking a two-semester sequence of it with Michael Crimmins. I have always loved science since I was a kid – it led me to questioning “why” and “how” to every scientific phenomenon, as if I am the detective trying to fit every piece of a jigsaw puzzle. In my free time, I like to play the piano (classical), listen to new music (rap), and try new outdoor adventures (skydiving). I plan to pursue a dual-DDS/DMD and PhD in dentistry and organic chemistry in the future, as I am interested in career options such as clinics, industry, and academia.

I first heard about the Biophysical Society Summer Research Program from Howard Fried, who strongly suggested that I should apply to this program, because he wanted me to get exposed to the field of biophysics. I chose this program because it lasted for so long and I wanted to get the most out of learning and research this summer.

I worked this summer under Kevin Weeks, under whom I researched about different conformations of the RNA genome within satellite tobacco mosaic virus (STMV). This work is related to biophysics in that the research can be applied to visualize RNA structure and dynamics in vivo with high-throughput analytical methods (i.e. x-ray crystallography and cryo-electron microscopy). By understanding the biomechanics of the STMV viral life cycle (i.e. entry, disassembly, replication), we can obtain the knowledge to develop antiviral drugs that are effective against more complex viruses (i.e. adenovirus, rhinovirus, poliovirus) that have the same structure as STMV’s. It was a rewarding and challenging summer in Kevin’s lab, especially working entirely independently and discovering literature sources to plan out my experiments.

What I liked so much about BPS Summer Course was that it is different from what other REUs [Research Experiences for Undergraduates] provide to motivated science students during the summer. It is a combination of everything: lectures/recitations, career panel workshops, seminars, lab tours, and fun social events! The lectures provided a brief overview, but intensive insight, into different fields of biophysics from UNC faculties; we also had fantastic TAs who helped us understand biophysics since it was confusing a lot of the time. There were workshops that gave helpful advice and learning tools for graduate school or MD/PhD admission process, GRE testing, abstract and personal statement writing, and much more. Different faculties from universities across the United States gave seminars about their biophysics research, which were very engaging and interactive. We also got to tour different lab facilities across UNC’s campus (which I never knew about!) to see some of the coolest science equipment, such as atomic force microscope. Some of the best memories I have made this summer was during the Emerald Isle beach trip – a social event that should be continued for future classes!

Overall, I am beyond elated to say that this summer program was a blast – both educationally and socially. I am glad I applied and I strongly recommend others to do so in the future. I will dearly miss all of the friends I have made this summer and like to thank all of the BPS Summer Course coordinators that helped made this summer possible.

-Alexander Y. Z. Li, 2016 Biophysical Society Summer Research Program Fellow

Epithelial Folding: How Planar Cell Polarity Regulates 3D Organogenesis

BPJ_111_3.c1.inddIt is a nice season to enjoy the river by canoeing or kayaking. But do you know that mammalian eggs also drift over a deep channel? This channel, or epithelial folds, is in a tubular organ named the oviduct, or Fallopian tube in humans, connecting the ovary and the uterus.

Viewing the cover image, you too can experience going through the oviduct from the point of view of an egg. The epithelium of the oviduct in the image was obtained by a mathematical simulation. The epithelial folds are straight and align longitudinally along the ovarian-uterine axis in mice and other species of animals. Previously, we reported that a Planar Cell Polarity (PCP) factor Celsr1 regulates fold patterning in mice. But the mechanisms connecting PCP with the well-patterned alignment of the epithelial folds are still unknown.

Here, we analyzed the mechanical regulation of the epithelial fold patterning by mathematical modeling where the epithelium was defined as an elastic sheet. We found that PCP could mechanically regulate the three-dimensional morphogenesis via the polarized cell array. Furthermore, our model scheme is also useful for analyzing mechanical effects on epithelial morphology generally. Our simulation could recapitulate the morphology of various types of epithelial folds, some of which can be found in other organs in vivo.

A sophisticated three-dimensional morphology is important for the organ’s function, but we are still far from a comprehensive understanding of the mechanism to build it.  The oviduct is not only where we come from, but is also a good place to start our scientific journey.

-Dongbo Shi, Hiroshi Koyama, Toshihiko Fujimori

On the BPS Code of Conduct, Anti-Harassment Policy

Sharona Gordon, Professor, University of Washington and Editor-in-Chief, Journal of General Physiology shares her views on sexual harassment in science and the code of conduct and anti-harassment policy the Biophysical Society instituted in 2015.

In my view, a successful society must protect the interests of the most vulnerable among its population. In our global society that means the poor, the sick, the disenfranchised, and any others who do not enjoy the privilege those of us in the upper echelons take for granted. In a professional society such as the Biophysical Society (BPS), the most vulnerable among us are trainees. Students and postdoctoral scholars depend entirely upon the support of more established scientists for access to mentoring, experimental resources, introduction to a broad network of other scientists, and letters of recommendation required for career advancement. For the vast majority of us, this power we hold over trainees is the power to protect. However, for some among us, this power is used to intimidate and exploit.

Sexual harassment has been in the news in the last few years due to some particularly horrifying and long-lasting patterns that came to light. The behavior of exoplanet astronomer Goeff Marcy at UC Berkeley seems so surreal that it is human nature to dismiss it as an exception that must surely be exceedingly rare. To illustrate this, a colleague I ran into at a seminar, who happens to be a department chair, asked me whether I thought anything like the Marcy incident could happen at our institution, the University of Washington. As if to underscore my answer that I was sure it was happening even as we sat there and discussed science, months later a UW colleague named Michael Katze was revealed to have led a decades-long sexual circus in his lab. If institutions can be blind to such egregious cases spanning years, what hope is there for getting institutions’ attention for acute, more mundane incidences of harassment?

Is sexual harassment at BPS-sponsored events a problem? Yes because it happens and yes because it undermines the free exchange of scientific ideas our meetings and events are meant to promote. Although I have not seen data examining the collective experiences of our members, I have personally experienced sexual harassment at the annual meeting. I have avoided events at which a past harasser was likely to be present. In addition, I have observed sexual harassment at the meeting and intervened in sexual harassment at the meeting. Even if my direct experience of harassment at BPS sponsored-events were unique, our members come from a world in which harassment based on gender, race, ethnicity, sexual identity, religion, and other factors is commonplace. Policies governing harassment are even more important at professional society events, where scientists of all ranks mix more freely and the protections of the academy may seem distant. In short, sexual harassment happens at BPS-sponsored events, as it does at events sponsored by all professional societies, and the reduced contributions from those affected by harassment diminish the value of the meetings for all.

For both the Marcy and Katze cases, the financial benefit to the institutions of looking the other way may have been a factor in the longevity of the harassment. Professional societies, in contrast, are not direct beneficiaries of the millions of dollars in grant money brought in by established faculty. Membership dues paid by one person make little difference to the financial health of the professional society, so that societies may be in a unique position to address harassment without the conflict-of-interest that arises from the economic value of a given faculty member. I believe that professional societies thus have an obligation to proactively educate their members about harassment and ensure it is not tolerated among their ranks.

When the Marcy case was first reported in the popular press, I wondered whether my professional society, BPS, had an anti-harassment policy in place. What I found was that BPS was among the majority of professional societies in its lack of policies governing professional behavior and prohibiting sexual harassment. As a member of BPS for more than 20 years, a former member of Council, Co-Chair of the Program Committee, and past member of the CPOW, Nominations Committee, and Thematic Meetings Committee, I felt it was my responsibility to help BPS correct this deficit. I wrote a letter to the BPS leadership explaining the need for an anti-harassment policy and pointing to the bylaws and anti-harassment policy of the American Astronomical Society as a model for its anti-discrimination language and its policy governing its meetings and events.

My confidence that my BPS colleagues would take up my charge was satisfied rapidly. I wrote my letter in October, 2015 and a policy was in place in time for the 60th Annual Meeting in February, 2016. The BPS Code of Conduct and Anti-Harassment Policy covers the definition of harassment, outlines an investigative process, specifies disciplinary actions, and an appeals process. I am proud of BPS for taking this step forward in protecting the interests of trainees and others vulnerable to harassment and intimidation. I am proud to be a member of a Society that strives to create a safe, welcoming environment for the exchange of scientific ideas. I would also encourage all members to participate actively in BPS because, as a collection of individual members, each of us can make a difference.

Connect with the author on Twitter @ProfSharona.

Biophysics on World Hepatitis Day 2016

July 28 is World Hepatitis Day. Viral hepatitis is inflammation of the liver caused by a virus. There are five different hepatitis viruses, hepatitis A, B, C, D and E. Hepatitis C affects approximately 250 million people worldwide. We spoke with Jiawen Li, University of Texas at Austin, Institute of Cellular and Molecular Biology, about her research related to hepatitis C, for which there is currently no vaccination.  

What is the connection between your research and hepatitis C?

Here in the Johnson lab we use transient-state kinetic approaches to characterize viral polymerases, specifically to measure nucleotide specificity, polymerase fidelity and dynamics. More importantly, we apply these methods to understand the mechanisms of action of nucleoside analogs and non-nucleoside inhibitors that are developed to target viral polymerases. For example, to combat HIV, reverse transcriptase is primarily targeted for anti-AIDS therapy. As the RNA-dependent RNA polymerase for Hepatitis C virus, NS5B is considered an important target for effective antivirals as well. Thus the focus of our research is to develop assays to determine kinetic parameters governing RNA dependent RNA replication by NS5B and establish the mechanisms of action and efficiency of various clinically relevant anti-HCV drugs.

Why is your research important to those concerned about hepatitis C?

Hepatitis C affects approximately 250 million people worldwide and chronic infection can lead to hepatitis, liver cirrhosis, and cancer. There is no vaccine available, but combination therapies with direct-acting antivirals including nucleoside analogs and non-nucleoside inhibitors targeting NS5B have been recently advanced and have dramatically improved the potency of HCV treatment. Surprisingly, besides the identification of binding site on NS5B, very little is known about the inhibition mechanisms of drugs that are currently on the market. Two pharmaceutical companies, Gilead Science and Alios Biopharma, have generously provided us with some of their inhibitors to study. Our primary goal is to analyze a handful of these inhibitors in depth to establish their mechanisms of inhibition and to set evaluation guidelines for the effectiveness of each class of inhibitor. Ultimately, we want to apply our methods to each FDA-approved inhibitor for HCV treatment to aid information for the development of even better therapeutics.

How did you get into this area of research?

With a bachelor’s degree in Biochemistry, I was accepted into the Biochemistry graduate program at UT Austin in 2011. During my rotation in the Kenneth Johnson lab, I was fascinated by transient-state kinetic methods such as combining rapid quench-flow and stopped-flow techniques to accurately measure and analyze nucleotide incorporation by HIV RT. Of course I immediately joined the lab and I was very enthusiastic to work on other viral polymerases. The hepatitis C viral RNA-dependent RNA polymerase, NS5B, is known to catalyze de novo RNA synthesis, which means RNA replication is divided into two distinct mechanistic phases: initiation and elongation. Previous studies in our lab along with other groups in the field have made tremendous efforts to develop assays for efficient NS5B replication, but were always hindered by the slow and inefficient initiation phase. Therefore, although the crystal structure of NS5B was solved a decade ago, kinetic characterization of enzyme mechanism, specificity and fidelity are limited, and little is known about the mechanistic basis for inhibition. Finally in 2012, Zhinan Jin, who graduated from our lab and worked for Roche at the time, succeeded in developing conditions for formation of highly active HCV elongation complex. I then continued the work he has accomplished and further optimized the kinetic assays for NS5B inhibition analysis.

How long have you been working on it?

It has been four years since I started working on HCV NS5B in 2012 as a second year graduate student here at UT Austin. I know several lab members had tried to establish conditions for efficient NS5B replication over a decade ago. I am glad this project is brought back to life again!

Do you receive public funding for this work? If so, from what agency?

Yes, we received funding from the Welch Foundation and the National Institutes of Health.

Have you had any surprise findings thus far?

Yes, we have had several surprise findings along the way. Firstly, we now have successfully developed robust kinetic assays to monitor RNA replication by NS5B from initiation to elongation. To our surprise, once the elongation complex is formed, it is extremely stable with half-life of more than a week, which makes the crystal structure of NS5B ternary complex highly promising to obtain in the near future.

Secondly, we have been able to establish modes of action for four classes of non-nucleoside inhibitors. One class of NNIs, the thumb site II inhibitors (NNI2) were shown to be most interesting. NNI2 do not significantly block HCV initiation or elongation; rather they act as allosteric inhibitors to block NS5B transition from initiation to elongation, which is thought to occur with a significant change in enzyme structure. To further examine this allosteric inhibition, we collaborated with Dr. Patrick Wintrode from the University of Maryland and his postdoc Daniel Degrede who mapped the effect of NNI2 inhibitors on the conformational dynamics of NS5B using hydrogen-deuterium exchange kinetics. HDX shows that NNI2 rigidifies an allosteric network extending up to 40 Å from the inhibitor binding site to enzyme active site, providing the rational for blocking NS5B transition at the molecular dynamics level.

NNI2-NS5B HDX (Jiawen Li)

Peptic fragments resulted in significant decrease in HDX upon NNI2 (magenta sticks) binding are shown in dark blue. Rigidification of a large network of enzyme dynamics was observed starting from inhibitor binding site throughout the protein, especially surrounding the enzyme active site, suggesting a long range allosteric effect from inhibitor binding on NS5B conformational change.

Meanwhile, we also explored the mechanisms of NS5B inhibition by nucleotide analogs. We found that both pyrophosphate and NTP mediated excision of incorporated nucleoside analogs were relatively fast reactions, suggesting the important role of pyrophosphorolysis in evaluating the effectiveness of chain-terminating inhibitors. In fact, wild-type NS5B polymerase catalyzes the nucleotide-dependent excision reaction faster than mutants of HIV reverse transcriptase that have evolved to overcome inhibition of nucleoside analogs. This is a significant problem for design of nucleoside analogs to treat HCV infections. We are in the process of publishing this work soon.

What is particularly interesting about the work from the perspective of other researchers?

Our detailed mechanistic studies have provided a fundamental understanding of RNA-dependent RNA replication by HCV NS5B and established the mechanisms of action of different anti-HCV drugs. We hope our experimental and analytical methods will benefit other researchers for studying HCV polymerase or similar viral polymerases and eventually assist screening and design of more effective inhibitors to combat HCV and other viral diseases.

What is particularly interesting about the work from the perspective of the public?

It is great news knowing that more and more anti-HCV drugs are being developed and approved by FDA. With the platform we built for inhibitor analysis, we would like to incorporate more inhibitors into our study and determine their biochemical role of inhibition. We think our work will help providing insights for the development of drugs that are safer and effective against broader range of HCV genotypes.

 

 

Microtubules form dynamic network with help from motors

BPJ_111_2.c1.inddThe cytoskeletal network is of vital importance in proper cellular functions. Microtubules, one of the major cytoskeletal components, interact with various associated proteins and generate hierarchical network structures spanning tens of micrometers to millimeters. The network dynamically varies during a cell cycle according to physiological roles in the cell.

To gain the integrative perspectives of network formation and its dynamics, we have extensively surveyed the pattern formation of microtubule-motor mixtures in vitro and found the bundling and sliding of microtubules are the key to pattern formation.

This cover image, acquired with a confocal microscope, shows the network spontaneously formed in the mixture of microtubules (magenta) and a member of the kinesin-5 family, Eg5 (cyan). Radial microtubule structures (asters) are formed through the clustering of plus-ends of microtubules by Eg5, and these asters form a global network spanning up to several millimeters. The sliding activity of Eg5 finally induces the contraction of the network.

The experimental system exhibited various distinct spatiotemporal patterns according to mixing ratios of motors to microtubules. A coarse-grained numerical model we developed can explain these experimentally observed dynamics and demonstrate how bundling and sliding activities of motors determined these spatiotemporal dynamics. Now, together with the model, our system will provide a beneficial platform for the investigation of dynamics and mechanical properties of cytoskeletal architecture.

– Takayuki Torisawa, Daisuke Taniguchi, Shuji Ishihara and Kazuhiro Oiwa

Impostor Syndrome: The Dilemma between Who We Are and Who We Are Perceived to Be, Part Three

Marina Ramirez-Alvarado, Mayo Clinic and a member of the Biophysical Society’s Committee for Professional Opportunities for Women and Committee for Inclusion and Diversity, and Dwight P. Wynne, California State University, Fullerton, explore the problem of imposter syndrome in this three part series. Read part one and part two.

In this series we’ve explored impostor syndrome as being a result of two different types of tensions: (1) individually-defined experience vs. community-defined competence and (2) personal vs. community identity. Generally, individuals with impostor syndrome are encouraged to work through their issues on the personal level. However, in communities such as ours, in which a large number of people have these issues, it is also worth investigating potential changes that we can make at the community level.

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To address the tension between experience and confidence, the most important thing we can recommend is to institute programs that stress the collective experience of failure in science. Many of us who make it this far in science are unaccustomed to failure: we assume that our failure is proof of our incompetence. We don’t know how to deal with it, and we don’t understand (or remember) that everyone else is dealing with it too. Academia is a leveled field where all of us go from being the top students to being” just one of them.” When all we see from other scientists are their successes, it’s incredibly easy to believe that we’re the only ones failing, and from there it’s a short trip to impostor syndrome (“My colleagues are so successful while I regularly have failures”).

There are a number of ways this recommendation could be implemented. For younger scientists, this could be instituted as part of a mentorship program or even a one-unit graduate course (ideally taken during the semester before qualifying exams). For older professionals, this could be instituted as a rotating workshop that could accompany scientific conferences or annual meetings of scientific societies. We have also found that even just instituting a safe space for people to talk about their scientific frustrations, allowing them to recognize that they’re not the only ones feeling this way, can positively affect how people calibrate their abilities relative to their peers.

Beyond this, we believe that it is time for the community to think more deeply how it assigns competence. We hazard a guess that most people in the community believe scientific competence to be objectively defined. After all, it’s easy to count the number of publications a person has, and it’s easy to count the number of citations those publications receive. However, authorship attribution can involve complex social interactions, junior faculty generally have a harder time publishing than established faculty do, and many papers are cited due to authors’ reputation. In our view, beyond a certain baseline, scientific competence is indirectly defined through one’s social connections within the community.

Conferences and meetings, especially, are just as much about making important scientific social connections as about disseminating scientific knowledge. Implementing programs to make it easier for graduate students or underrepresented minorities or any other group to attend a meeting is a start, but simply being there and presenting some scientific research isn’t enough. What social connections are they gaining, especially those that help tie them to the community? What informal meetings, where much of the “real work” at conferences takes place, are they participating in? Do they even know that they’re supposed to be doing these things? At some level, bridging these information gaps might be work for diversity and inclusion committees of professional societies, but we also believe this is something extremely easy to institute at even the lab level.

For the tension between personal and community identity, the most important thing we can recommend is that people stress the personal journey of science when discussing their own careers. Less scientific communication should be about our research, our papers, and our grants; more scientific communication should be about why we perform that research (even when it means repeating the same experiments day after day), what drives us to write those papers (even when it means submitting them to our eighth-choice journal), and how we aspire to grow as scientists. Especially for young scientists just testing their new scientific identities, it’s easy to believe that there’s one “ideal” identity promoted by the community and that a successful scientist must project this identity, no matter how at odds it is with the rest of us. By presenting a diversity of identities, we as a community fight that preconception and allow all of us to discover our true scientific identities.

While it’s important to stress that science is a personal journey, it’s equally important to recognize and help those who are unsure of where in the scientific community they belong. In some cases, these people are strong teachers or mentors who may not have the skills or desire for cutting-edge research, stuck in an environment that prioritizes such research. These people already have fully-developed scientific identities; their problem is figuring out how (and whether) those identities fit within the larger scientific community. For these individuals, even a little bit of peer recognition may be sufficient; not necessarily in the form of an award, but simply by knowing that others value their contributions to the community.

In other cases, these people may not be fully confident in their skills or are still trying on different scientific identities. They don’t have to be early-career researchers; they could be established researchers poking their heads into new, interesting fields. In these cases it’s vital to re-frame science as a collaboration rather than a competition. Rather than dangle “incentives” for individual performance, encourage junior lab members to become involved and excited in each other’s projects. Rather than seeing a threat from researchers moving outside of their usual domains, see a potential co-author bringing a new perspective to your field. In our view, scientific collaborations provide critical opportunities for researchers to engage each other’s personal and community identities; however, few scientists intuit how to be good collaborators and even fewer learn through anything other than frustrating experiences.  Again, this is a problem that can be addressed at multiple levels: for instance, department retreats and scientific society meetings could offer encouragement and workshops about collaboration, and PIs could assign complex tasks to teams of researchers rather than allowing junior researchers to treat particular projects as their personal fiefdoms.

Finally, there are two aspects of change that must be acknowledged, no matter how the problem of impostor syndrome is attacked at the community level. First, there will always be people who leave the community because of mismatches between community and personal identities. When someone chooses to leave the community, it should not necessarily reflect poorly on that individual, his/her mentors, or the community as a whole. However, too often people leave because the community – intentionally or unintentionally – encourages them to do so. We believe that retention programs, including those that help scientists overcome impostor syndrome, should focus on promoting a more inclusive community identity, allowing more people to find ways in which their personal identity aligns with that of the community.

Second, these recommendations—and any other programs intended to help scientists overcome impostor syndrome—need to be supported by demonstration and emulation of positive social behavior. Defining acceptable community interaction through a series of rules about what not to do is a great way to breed resentment and confusion. Instead, implementing small changes in small areas where we have outsized social influence – our labs, our committees, etc. – can produce the biggest results.