Confidence is key

Monday, I went to the “How to present your best self” workshop led by Karen Fleming (John Hopkins) and Linda Columbus (UVA). The main message of the session was Confidence is key to success! And in general, Women don’t own their own confidence. During the session, they showed us multiple pieces of data from surveys from college freshman to mba scholars to show us what we already know. As women, we understatement our abilities when asked and we contribute our success to others or luck. This lack of confidence can lead to less promotions, less salaries, and overall less success. While gender stereotypes can play a role in killing our confidence, the only way to break through these stereotypes is to be strong, confidence women! First step to working on one’s confidence is identity your confidence killers. Some confidence killers are failure, fixed mindset, and the most aggressive at least for me, Imposter syndrome. Imposter syndrome is one thing many of us feel in science at times. The feeling that you are a fake or aren’t smart enough is one that haunts many graduates students, especially early on, and it really hurts your confidence. So to build confidence it’s important to surround yourself with confidence creators aka people who support your endeavors especially when you have failures. For me, my graduate advisor has been a major confidence creator for me during the rocky road that is graduate school. Mindset is also key to confidence. So always remember:

1)Set high goals but aim for good enough, not perfection.
2)Believe in yourself!
3)Remove negative people from your life
4)Failure is temporary! Setbacks are part of reaching success!
5)Don’t be scared to ask for help
6)Take risks. If you don’t even shoot, you will never score!

This BPS meeting was filled with great science but the workshops and career development session were a real highlight for me! Working on our personal growth is critical to becoming successful scientists in the future and I’m grateful that BPS is providing these opportunities! See you next year, fellow BPS goers.


Using Biophysics to Understand Heart Disease

February is American Heart Month. Heart disease is the leading cause of death for men and women in the United States, causing 1 in 4 deaths each year. We spoke with Biophysical Society members Daniel Beard, University of Michigan, and Andrew McCulloch, University of California, San Diego, about each of their labs’ research related to heart disease.

MIP_Dan_Beard_0Daniel Beard
University of Michigan

What is the connection between your research and heart disease? Why is your research important to those concerned about heart disease?

A major focus of our research is on the link between cardiac function and myocardial metabolism. In physical exercise, as the rate of work done by the heart increases compared to rest, the rate of cardiac ATP hydrolysis increases commensurately. By building computer models to represent kinetic control of oxidative (mitochondrial) ATP synthesis, we have been able to build a robust framework for simulating ATP supply/demand matching in vivo [1, 2]. Once we had a working understanding of physiological regulation of ATP synthesis in the heart, we used that working knowledge as a starting place to explore how the physiological system becomes dysfunction in heart disease. In particular, it has long been recognized that in heart failure—a condition in which the mechanical pumping ability of the heart is compromised—concentrations of adenosine triphosphate (ATP), its hydrolysis products, and related metabolites are depleted compared to normal. Neither the causes nor the consequences of these changes are well understood. We think that one consequence of impaired energy metabolism is that it directly contributes to impaired mechanical function. Our current research is squarely focused on determining these causes and consequences of mechano-energetic dysfunction, and on finding new ways to repair/restore myocardial metabolism to improve mechanical function in heart failure.

How did you get into this area of research?

My interest in this area goes back to work that was part of my PhD thesis, working in Jim Bassingthwaighte’s lab on simulating physiological transport of oxygen, and other solutes. I became increasingly interested in oxygen transport, and questions of how oxygen delivery is matched to oxygen demand in the myocardium. In this context I started to look in some depth at the physiological regulation of oxidative phosphorylation, not for its own sake, but because I was interested in how it contributed to governing oxygen transport. In other words, at first mitochondrial metabolism was on the periphery of what I was initially interested in. That peripheral interest gradually grew into a major research thrust.

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

Yes, we have been fortunate to be supported for this work, primarily from the National Institutes of Health National Heart Lung and Blood Institute.

Have you had any surprise findings thus far? 

Our first big surprise followed from my lab’s first NIH funding award, for which we proposed to investigate a conundrum in the field cardiac energy metabolism: How is ATP synthesis supply matched to changing demand levels in light of apparently constant concentrations of ADP and inorganic phosphate (Pi) in the heart? Our answer to this question is that, in fact, the ATP supply is not matched to demand while maintaining constant levels of ADP and Pi. Specifically, our model-based analysis of the in vivo data on phosphate metabolite levels in the heart predicts that changing [Pi] provides a critical feedback signal to stimulate increasing ATP synthesis with increasing rates of ATP hydrolysis. This simple idea fundamentally challenges established ideas in the field. In fact, our hypothesized role of Pi as a primary feedback signal for oxidative ATP synthesis in the heart is still at least a little bit controversial and it would be incorrect to say that it is universally accepted. Regardless, the hypothesis has survived all of our attempts to disprove it!

Beard Image

The next big surprise came when we applied our models of cardiac energy metabolism to analyze data from animal models of heart failure. We found that hallmarks of myocardial energetics in heart failure—diminished ATP and ATP hydrolysis potential—could be effectively captured by simulations in which mitochondrial function is normal. At first blush that finding seems contradictory: Since 95% of ATP in the heart is produced by mitochondria, how can diseased hearts with diminished ATP have normally functioning mitochondria? The explanation pointed to by our analysis is that reduction in cytoplasmic metabolic pools is a critical driver of energetic/metabolic dysfunction in the failing heart. Those predictions were later put to the test when, in collaboration with Igor Efimov’s lab, we were able to measure mitochondrial function in samples from failing  human hearts, revealing no significant dysfunction compared to healthy controls [3]. This is not to say that mitochondrial function is normal in the heart in heart failure, but rather that we believe dysfunction in mitochondrial energy metabolism is not necessarily intrinsic to the mitochondria themselves, but rather driven by the local environment they find themselves in.

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

Patients with heart failure wind up seeing a cardiologist, not with complaints of impaired cardiac energetics, but with health problems—shortness of breath, exercise intolerance—directly related to impaired heart pumping. Yet we think that metabolic/energetic dysfunction can contribute directly to mechanical dysfunction in heart failure. Our current research in this area is on the link between mechanics and energetics. We are using computer models that integrate metabolic and mechanical function to better understand the physiological connection between chemical and mechanical function in the heart, to determine ways in which this connection breaks down in heart disease, and identify new strategies to improve mechanical pump function by restoring the metabolic state.

  1. Wu, F., et al., Phosphate metabolite concentrations and ATP hydrolysis potential in normal and ischaemic hearts. J Physiol, 2008. 586(17): p. 4193-208.
  2. Bazil, J.N., D.A. Beard, and K.C. Vinnakota, Catalytic Coupling of Oxidative Phosphorylation, ATP Demand, and Reactive Oxygen Species Generation. Biophys J, 2016. 110(4): p. 962-71.
  3. Holzem, K.M., et al., Mitochondrial structure and function are not different between nonfailing donor and end-stage failing human hearts. FASEB J, 2016.

Andrew3Andrew McCulloch
University of California, San Diego

What is the connection between your research and heart disease?

We use in-vitro and in-vivo experiments primarily using mouse models of heart failure and arrhythmias together with multi-scale computational models to discover cellular and molecular mechanisms of electrical and mechanical dysfunction at the tissue and organ scales.

Why is your research important to those concerned about heart disease?

Our research is becoming of particular interest to cardiologists and patients with heart diseases because we have started to discover ways to apply the computational modeling tools we validated in the lab to analyze and predict therapeutic outcomes in patients, including heart failure patients with electrical dyssynchrony who are indicated for cardiac resynchronization therapy, patients with atrial fibrillation or at risk of ventricular fibrillation who can benefit from radiofrequency ablation therapy, and children and adults with congenital heart diseases who are at risk of developing heart failure or arrhythmias later in life.

How did you get into this area of research?

It started as a MS thesis project in Engineering Science when I was 19, that turned into a PhD in Physiology and Engineering and then a faculty career.

How long have you been working on it?

Over 35 years.

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

Yes, we rely almost exclusively from NIH funding via the NHLBI, NIBIB and NIGMS though we have also received valuable support in the past from the NSF, NASA, DARPA, AHA and Heart Rhythm Society.


Have you had any surprise findings thus far?

Yes, we have found with and novel mouse and computational models that phosphorylation of specific serine residues on cardiac myosin regulatory light chain not only affect crossbridge dynamics, but also give rise to a feedback that affects the calcium-dependent active of the thin filament. We have also found that patient-specific models have the unexpected potential to predict and optimize the outcomes of device therapies for heart failure.

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

The power of modern multi-scale and systems biology modeling to help understand genotype-phenotype relations in animal models of heart diseases.

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

The potential for computer models to improve the early diagnosis and clinical management of heart diseases in adults and children.

Thinking back on BPS18

The last day of the Annual Meeting is over and I’m again sitting in my old lab at Stanford University, still somewhat exhausted from the intensity of the last couple of days. I will leave this meeting with many new experiences – after all, this was my first BPS Meeting, first big conference, first time presenting a poster and first time blogging!

I think the best with this conference has been all the interesting scientific discussions I have been having with people and I will bring many new things to think about with me back home. I really enjoyed the diversity at the poster sessions, both in terms of topics but especially in terms of presenters. Anything from undergraduate students to professors presented posters and walked around to discuss science with other presenters. I believe this mix was great for spurring discussion and networking over different age groups, something that might not happen very naturally otherwise.

I also learned a lot from all the platform sessions, some of it related to my own field but I also got some new insight into other research areas, something that is always valuable as new ideas tend to show up from unexpected places. All the social activities, dinners, and pub visits were of course incredibly fun and gave me the opportunity to meet both old and new friends. With all that said, I had a great time at the Biophysical Society Annual Meeting and look forward to BPS19 in Baltimore!

P.S. For those who still have some time to spend in San Francisco I would like to encourage you to explore other parts of the Bay Area. With Caltrain it is easy to visit places like San José, Palo Alto or Mountain View. And with Bart you can go to Oakland and Berkeley. Of course I would recommend to visit Stanford University in Palo Alto (but I’m a bit biased in that regard) and the Computer History Museum in Mountain View is great too!

How to use the time before your flight

BPS is over! What a wonderful meeting. If you are still in SF waiting for your flight and  looking for things to do, here’s a list of some of my favorites in the city.

The View Lounge: Seated on top of the Marriott where Doudna gave her keynote address, The View is a bar and lounge on the 39th floor with 360˚ views of the city. Guests seat themselves, and many just stand, so don’t worry about not finding a seat. Free to go up. 4p-1:30a.

Coit Tower: If you’ve walked around the wharf or northern SF, you’ve probably seen this white tower on top of a hill. It offers 360˚ views of the city, but from the northeastern side of the city where there are less skyscrapers in the way. Lillie Hitchcock Coit was an advocate for civic beautification, and after her death in 1929, her estate paid for the tower. $8 to go to the top. 10a-5p.

California Academy of Sciences: Located on the Western side of SF, this natural history museum has an aquarium, a planetarium, and a climate-controlled indoor rainforest. The building itself is famous for its living roof, which is covered in a lightweight soil and a carpet of grass. The rainforest was by far the most unique experience offered here. The dome-shaped structure is 3 stories tall, and just covered in living organisms. $35. 9:30a-5p.

Golden Gate Park: Surrounding the California Academy of Sciences is the expansive Golden Gate Park, one of the most visited urban parks in the US. The park consists of miles and miles of trails, more than one thousand acres, botanical gardens, a fine art museum, outdoor music venues, and several lakes, meadows, groves, and statues. Free. 24h.

The Exploratorium: Located on pier 15 on the NorthEastern side of SF, this kid-friendly hands-on science museum is loaded with interactive activities and exhibits.  $30 for adults, $20 for children. 10a-5p, (Adults only 6p-10p).

Wherever you’re going, have a safe trip. Hope to see you in Baltimore!

Research highlights: Morphogenesis

I would like to describe two excellent talks given at BPS 2018, both on tissue morphogenesis, that were not printed in the BPS 2018 abstracts publication. It would be a shame if they didn’t get the exposure they deserve. (Disclaimer: this summary and any possible inaccuracies are entirely my own.)

1) Sevan Hopyan gave a talk entitled “Volumetric Morphogenesis in the Mouse Embryo” in the Mechanobiology subgroup on Saturday. The Hopyan lab studies how cell rearrangements remodel epithelia, and the talk focused specifically on the mandibular arch in the developing mouse. In a short, four-hour period, this arch morphs from a small, bud-like protrusion to a larger bulbous protrusion with a narrow neck. 

How does this simultaneous expansion of the distal region and narrowing of the neck region occur? They thought at first that directed dilation of cells explained it entirely. It turns out, however, that changes in physical properties and cell division are insufficient to explain the tissue’s shape. In the mandibular arch, mesenchymal cells are actually so dense that they appear similar to an epithelial sheet. The researchers asked whether mesenchymal cells crawl forward or simply exchange neighbors (intercalate) to remodel the tissue.

The researchers found that a particular type of neighbor-exchange occurs (termed T1) and that this exchange could help drive the morphogenesis of the arch. They modeled these cells in analogy to bubbles in a foam and asked what kinds of energy changes might correspond with the neighbor-exchanges they observe, following prior work by Lisa Manning’s group. Particularly interesting was the shape fluctuations observed in the cells, which may help bump cells over the energy barrier that prevents them from exchanging neighbors.

They then went on to explore molecular mechanisms underlying this process, making use of in vivo tension sensors designed by Carsten Grashoff to probe the forces experienced by the adhesion protein, vinculin. The importance of Ca+ signaling through mechanosensitive ion channels was also highlighted in their results.

2) The second talk I would like to highlight was given by Ron Vale at the Cytoskeleton Symposium on Tuesday, entitled “How the intestine got its stripes.” Ron very graciously stepped in for a speaker who was, unfortunately, not able to make it. He started by asking the broad question: What governs the patterning of cells? The answer, he promised, would in fact involve the cytoskeleton.

To answer this question, Kara McKinley (postdoc in the Vale lab) used in vitro intestinal organoids. She made two initial observations: First, during mitosis, the dividing cell first rounds up and thereby moves closer to the apical surface (the one near the inside of the gut). Second, cell divisions appeared to generate an alternating protein expression pattern because the two daughter cells would move away from each other rather than remaining neighbors.

They found that mitotic rounding toward the apical surface was dependent on the actin cytoskeleton but not microtubules. This result, they believe, is consistent with how epithelial cells anchor themselves to the apical surface via adherens junctions, adhesions that connect primarily to the actin cytoskeleton.

To determine how daughter cells separate, they paid particular attention to the shape of the cytokinetic furrow. What they saw was that dividing cells only furrow from the basal surface, such that during cytokinesis, an outline of the two cells would appear similar to a cartoon heart shape (but without the pointy part). This basal gap allows a neighbor cell to insert itself between the two daughters.

Because the neighbor cell that is inserting into the gap must migrate over one of the daughter cells, the researchers asked whether the height difference between the mitotic cell and its neighbors could regulate this interspersion. In a collaboration with Loic Royer, they modeled cells as Brownian spheres and found that the height difference between mitotic cells and neighbor cells could plausibly determine whether daughter cells dispersed or remained in isolated groups.

This finding appeared to be confirmed by biological experiments and observations. For example, Wnt signaling that promotes a shorter, more cuboidal morphology also results in clonal patches rather interspersed patterns. Fetal organoids are also cuboidal and rarely exhibit neighbor insertions. The results from the Vale lab therefore shed light on the importance of physical parameters in determining tissue patterning.

What made this BPS annual meeting unique?

I hope you have all enjoyed your week in San Francisco. BPS is the last of five conferences that I signed myself into over the last three months, because I’m looking for places in Australia and thus reconnecting with the locals across three conferences. The other four meetings were all regional, with a very different atmosphere. It’s thus worth highlighting some of the unique things about meetings of this scale, especially if it was your first:

  1. At BPS, it’s better to email a few people ahead of time and set up a time/place to talk. A lot of top notch research across fields are presented here. So everyone’s running around across more than a hectare’s with of space, and catching up with other people and other research. In this environment, I’ve done a majority of my intentional meetups by e-mailing someone either before or during. In contrast with many conferences of ~10^2 people, you can consistently spot your colleagues and ask on the spot.
  2. You probably should consider bringing your poster on an extra day in the excess slots. The two hours slot for posters is a very competitive environment, given the 800 other posters as well as workshops+exhibitors. If someone is interested in your work but wasn’t there, it’s a decent idea to offer another time when you can invite them to see it.
  3. BPS has a very large concentration of editors and industry reps. For those who are even remotely contemplating non-academic futures, there’s a lot of people who were in your shoes now standing at the booth. Valuable advice is hiding in plain sight, hailing from across the entire industry.
  4. Writing a follow-up message is more critical at BPS relative to other conferences. One email to say thanks will help both you and your distant colleague remember each other. Especially for me as a really visual person, I don’t really have the ability to remember the name of whom I’ve met for twenty minutes after a year, although I can spot their face. Plus, you’ll be meeting plenty of internationals whom you won’t see normally, but may call on.

The above advice might come a little late, but never worry: there’s next year in Baltimore, and many other international-scale conferences to practice your skills. See you around.

Kv1.3 steals the show at BPS18

Kv1.3 was a hot topic at this meeting, and I saw some great posters and talks on Monday suggesting that this channel is a potential target for the treatment of autoimmune and inflammatory diseases. Here’s a rundown of the different approaches I being used by researchers at BPS18 and some of the purported health implications of specific Kv1.3 pharmacology.

A group of scientists working together across industry (TetraGenetics, Inc., Crystal Bioscience, and argenx) and academia (Cornell and UC Davis) are developing monoclonal antibodies against Kv1.3 in chickens and llamas, and they appear to have one candidate that specifically reduces current from human Kv1.3 expressed in HEK293 cells. The mAb has an EC50 of a few nM and doesn’t act on other shaker type channels, hERG, or voltage-gated sodium channels. Unlike most ion channel antibodies, these are raised against an entire Kv1.3 subunit (purified from Tetrahymena thermofila), which is likely how they’ve managed to produce an antibody with an effect on channel function.

A graduate student in Debra Fadool’s lab at Florida State Univeristy has been modifying fluorescent nanoparticles with Margotoxin and delivering them to the olfactory bulb to inhibit Kv1.3 expressed in mitral cells. MgTx is a commonly used agent for blocking Kv1.3 for research purposes, but targeted delivery in vivo can be difficult. Interestingly, when cannulated into the mouse olfactory bulb, MgTx-nanoparticles appear to help maintain normal bodyweight in rodents – perhaps highlighting a connection of Kv1.3 function and the regulation of metabolism.

Heike Wulff from UC Davis gave a talk and showed that Kv1.3 expression in microglia is upregulated after ischemic stroke, suggesting an inflammatory response to this stimulus in the brain. Interestingly, her well-characterized Kv1.3 inhibitor (PAP-1) minimizes this inflammatory response after insult and improves performance on rodent neurological function assays.

And lastly, although he didn’t specifically mention Kv1.3 as a current target, Damien Bells from Iontas, Inc. gave us a glimpse into their most recent KnotBody™ technology, which they think is the future of ion channel pharmacology. The idea is to combine tissue specific antibodies with ion channel specific knottin motifs to create highly effective blockers of ion channels that work in vivo. These structures are exciting because they harness the power nature’s own mechanisms for modulating channel function, but the modular structure of KnotBodies allows for extensive optimization on the channel and tissue level.

If you’re interested in mechanisms underlying inflammation and autoimmune disease, you may want to keep your eye on these scientists and their work with Kv1.3!