Molecular Mechanics & Asthma

May has been designated Asthma Awareness Month by NHLBI and the Asthma and Allergy Foundation of America. The World Health Organization estimates that 235 million people worldwide suffer from asthma. The Biophysical Society is taking this opportunity to highlight how advances in basic research contribute to our understanding of this disease. BPS member Anne-Marie Lauzon of the Meakins-Christie Laboratories of the Research Institute of the McGill University Health Center studies the role of specific proteins in determining the contractile properties of smooth muscle, in particular as they pertain to the problem of airway hyperresponsiveness in asthma.

Figure Lauzon-Asthma

What is the connection between your research and asthma?

Asthma is an inflammatory disease characterized by airway hyperresponsiveness, an exaggerated bronchoconstrictive response to various stimuli. Because airway smooth muscle (ASM) is the final effector of bronchoconstriction, it is commonly believed to be hypercontractile in asthma. This paradigm is supported by animal models but has never been demonstrated in human airways. We measure the biophysical properties of asthmatic and control human ASM to determine whether or not it is hypercontractile in asthma. We study the ASM bundle mechanics as well as their molecular mechanics in order to elucidate what is abnormal with asthmatic ASM. Molecular mechanics measurements allow us to investigate the mechanisms of ASM contraction and also provide us with additional tools to measure the mechanics of ASM in airways too small to be dissected and studied at the bundle level.

Why is your research important to those concerned about asthma?

Even though asthma was first described in the 1860s there is still no cure. Current medications alleviate and control the symptoms but there is still no therapy, no doubt because of our lack of understanding of the exact causes and mechanisms responsible for asthma.  Millions of Americans suffer from asthma and environmental factors worsen those numbers every year.  In addition to the poor life quality of asthmatic subjects, in some cases asthma can be fatal.

To date, most research on asthma has focused on the inflammatory aspect. Few laboratories address the ASM mechanics in asthma and even fewer address it directly in human samples. Along with my collaborators at the Meakins-Christie Laboratories of the Research Institute of the McGill University Health Center, we address the effect of inflammation on ASM mechanics from the whole human subject to the intracellular molecular motor level. This multi-scale approach allows us to verify at given scale levels theories developed at other levels.

How did you get into this area of research and how long have you been working on it?

As an undergraduate student doing a double major in Physics and Physiology at McGill University, I got very interested in the rheology of air and blood flow. Montreal counts several world renowned laboratories that perform pulmonary research so I had the chance of getting involved quite early on in pulmonary mechanics studies. Then, I pursued at McGill University a Ph.D. addressing the time course of bronchoconstriction, followed by a post-doctoral training at the University of California, San Diego, where I studied the distribution of pulmonary ventilation in weightlessness. A second post-doctoral training at the University of Vermont allowed me to specialize in the molecular mechanics of contractile proteins.  In July 1998, I was recruited back to the Meakins-Christie Laboratories to start my research on the mechanics of human ASM in asthma.

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

My research is currently funded by the Canadian Institute of Health Research, the Réseau en Santé Respiratoire du Québec, and the Natural Science and Engineering Research Council of Canada (funding for the basic aspect of smooth muscle contraction). I was also recently part of a multi-PI research group funded by the National Institutes of Health (NIH).

Have you had any surprise findings thus far?

The biggest surprise that we have had so far in this research is that even though asthmatic ASM is commonly believed to be hypercontractile, it is not at all easy to demonstrate its altered mechanical properties. We started our investigations with the trachealis muscle because of its ease of dissection and we found that it behaves exactly the same in asthmatics and in controls. Because we previously showed in rat models of asthma that inflammatory cells can enhance ASM mechanics, and because more inflammatory cells are found in the peripheral airways than in the trachea, we concluded that the trachealis muscle was probably not representative of peripheral ASM mechanics. This later fact was verified in a horse model of asthma, the horse with heaves, in which we showed a perfectly normal trachealis in horses with hypercontractile peripheral ASM. Repeating these studies with human peripheral airways is however not a simple task, but it is the main endeavor of my current post-doctoral fellows Gijs Ijpma and Oleg Matusovsky and research assistants Nedjma Zitouni and Linda Kachmar.

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

Our thorough characterization of the mechanical properties of asthmatic ASM will delineate the relative importance of other mechanisms also potentially responsible for airway hyperresponsiveness and asthma. Such other mechanisms include alterations in airway-parenchyma inter-dependence, neural control, surfactant properties, etc.

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

Getting a better understanding of asthma will take us one step closer to potentially curing it, but at a minimum, of finding better relief medications.

Do you have a cool image you want to share with the blog post related to this research?

See the figure at the beginning of this post. Airway tree section from a control (A) and an asthmatic (B) subjects in which the actin is stained with TRIT-C phalloidin thus, showing primarily the airway smooth muscle. Airway cross-section of a control horse (C) and a horse with heaves (D), a disease very similar to human asthma. (E) A dissected smooth muscle strip hooked up in an organ bath for mechanics measurements.

A New Mechanism for Initial Activation of T-Cell Receptors

BPJ_108_10.c1.inddQ. How did you compose this image?

The image corresponds to a snapshot from a long molecular dynamics simulation of the cytoplasmic CD3 epsilon chain embedded in a liquid-ordered, liquid-disordered membrane domain mimic. Pre-rendering was done using the VMD visualization package (http://www.ks.uiuc.edu/Research/vmd/) and posteriorly rasterized using the Blender rendering software (https://www.blender.org).

Q. How does this image reflect your scientific research?

The main drive of our research is to understand the molecular details of the immunological response. To be more precise, we aim to understand the molecular mechanism by which the T-cell receptor (TCR) engagement triggers the response in the cell. It is generally accepted that the cascade is amplified by the phosphorylation of tyrosine residues localized in the cytoplasmic domains of the receptor. Here, we used a coarse-grained model (using the widely used MARTINI model) to understand the molecular mechanism by which these tyrosines are activated. We use the CD3 epsilon chain as a model system. In the resting state (not activated), the protein is localized close to the liquid-disorder membrane domain. Moreover, the tyrosines are deeply hidden in the hydrophobic regions of the membrane. The equilibrium, however, can be modulated by the presence of a facilitator molecule (e.g., ganlgioside), driving the configuration into the liquid-ordered domain and exposing the cytoplasmic domain and tyrosines to the surface. This study highlights the critical role of the membrane and its composition during the TCR activation.

We hypothesize that the basic ideas are translatable to other ITAM bearing receptors (BCR, Fc Receptors) and to Receptor Tyrosine Kinases that have unstructured cytoplasmic tails with tyrosine phosphorylation sites.  For example, Stuart McLaughlin proposed electrostatic interactions control the accessibility of the EGFR tail (J. Gen Physiology 2005; Biophysical J. 2009).

 Q. Can you please provide a few real-world examples of your research?

Membrane domains play key roles in a variety of cellular processes. One example is in host-pathogen interactions. It has been shown that several viruses, including HIV, require the presence of rich cholesterol domains in order for internalization to proceed. Other pathogens like Vibrio cholera make use of gangliosides-rich domains in order to internalize their toxins.

The involvement of membrane domains has been cited in many different aspects of the immune system.  There has been long- standing debate regarding their roles in immunoreceptor activation, which are challenging to validate experimentally.

 Q. How does your research apply to those who are not working in your specific field?

This collaborative project was first conceived by brainstorming sessions of our modeling team from the Center for Nonlinear Studies (Los Alamos National Laboratory) with cell biologists and signaling experts at the New Mexico Spatio Temporal Modeling Center (STMC; at the University of New Mexico). As you may expect, researches from different fields (immunologists, engineers, physicists, chemists, biologists) were providing inputs and clarifying doubts during our extensive meetings. The experimentalists are now trying to validate (or invalidate) the predictions of the model. This back-and-forth process will be useful for refining the models. So, in summary, it takes an interdisciplinary group to tackle these kinds of big problems.

 Q. Do you have a website where our readers can view your recent research?

For more details of our work, people can refer to:

http://cnls.lanl.gov/External/

http://stmc.health.unm.edu

https://newmexicoconsortium.org/

– Cesar A. López, Anurag Sethi, Byron Goldstein, Bridget S. Wilson, S. Gnanakaran

BPS’s Stance on the America Competes Reauthorization Bill

On May 20, the US House of Representatives is scheduled to consider the America Competes Reauthorization Act of 2015.  the bill, introduced by Science, Space, and Technology Committee Chairman Lamar Smith (R-TX) on April 15, would   reauthorize the National Science Foundation (NSF), the Department of Energy (DOE) Office of Science, and National Institutes of Standards and Technology (NIST), and Office of Science and Technology Policy for FY 2016 and 2017. The full Science, Space, and Technology Committee approved the bill on a party line vote on Wednesday, April 22.

The intent of the original America Competes bill was to bolster the U.S.’s position in the world and increase its investment in science and technology, including basic research and STEM education.  The bill was based on a National Academy of Sciences report, Rising Above the Gathering Storm, which received bipartisan support in Congress when it was released in 2007.  A follow up report, Rising Above the Gathering Storm, Revisited, was published in 2010 and expressed concern that the U.S .was not acting quickly or strongly enough to maintain its position as a global leader in science and technology.

While the reauthorization bill currently under consideration would provide small increases for some research, it includes several provisions that the Biophysical Society finds troubling. Specifically, the bill funds NSF by directorate rather than as a whole, allowing Congress to direct funding to areas of science that it finds most worthy. In the case if this reauthorization bill, it significantly cuts funding for social and behavioral science and geophysical science research at the NSF.  The bill also requires NSF to explain how each individual grant funded by the agency is in the national interest.  At the Department of Energy, funding is to the Office of Energy Efficiency and Renewable Energy (EERE) would be cut significantly.

The Biophysical Society sent letters to Chairman Smith and Ranking Member Eddie Bernice Johnson (D-TX), as well leaders of the House, opposing the bill as written.  The Coalition for National Science Funding and the Energy Sciences Coalition, both coalitions of which the Society is a member, also released statements opposing the bill.

The individuals Congress really needs to hear from though, are its constituent scientists.  Please take this opportunity to let your Congressman/woman know you oppose this legislation.  You can do so here.

Biophysicists Finding Balance

May 10 is Mother’s Day in the US. In honor of the occasion, we spoke with Biophysical Society members Pernilla Wittung-Stafshede, Umeå University, and Taviare Hawkins, University of Wisconsin, La Crosse, about what it is like to be a biophysicist and a parent, and how the two roles impact each other.

Pernilla Wittung-Stafshede

Pernilla mother's day

How many children do you have? What are their ages?

I have two girls. Selma is 13 years old and Hilda is 9 years old.

At what stage of your career did you have children?

My first daughter was born in 2001 in New Orleans just when my tenure application at Tulane was submitted. I got my tenure, but because I had a baby at home I never worried about the outcome. My second daughter was born in Houston when I was tenured at Rice during Hurricane Rita in 2005. I started to think about kids already as a postdoc, but things did not turn out as we planned. Thinking back, it was good to have the kids later when my independent research group was up and running.

Has your career been influenced or changed by your role as a parent? How?

Definitely. I have always worked a lot and I love what I do. However, having children made me become more efficient and it has also given me a perspective on what is most important in life. Before the kids, science dominated my life; it still does but not to the same extreme.

What has been the most challenging aspect of being a biophysicist and a parent?

Time management. You want to work a lot and you want to spend a lot of time with your kids. It is a dilemma. It is easy to feel guilty that you do not do enough towards both work and kids. Also, I missed a lot of conferences when my kids were little. It was simply too complicated to go away for a long time. I still find it hard to go to conferences as it is a lot of logistics to organize – but I know it is important for one’s career and it is always very inspiring.

Have there been any benefits to being both a mother and a scientist?

Yes, absolutely. As a scientist I work very freely and I can do a lot from home. That means I can take time for the kids when needed, when they are sick, need a ride, or have doctor’s appointments for example. Also, because I had my kids in the States at the time when there was really no maternity leave, I worked around this by taking sabbatical to avoid teaching; instead I was home with the baby while at the same time I worked from my house. For me this was great because I would not have wanted to take off for 1 year (the common maternity leave in Sweden). It does not work if you are a group leader.

Would you encourage your children to be scientists?

I will encourage them to study at higher levels and I will definitely support them to go abroad for university studies in order to experience other systems and see the world. I have a feeling I have talked so much about science, performed experiments at home and organized their birthday parties in the lab, so they will pursue other careers.  I have already noted that my oldest daughter is very talented towards art and writing, although the little one is analytical like me.

How would your children describe your work?

I guess they would say their mother has a job that involves eating a lot of chocolate while trying to save the world. They have both been with me to work so they know my group, and my colleagues, and thus have an idea of where I spend my days. I suspect they would complain that my job involves too much reading and sitting in front of the computer, which is what they see at home.

Any advice for other mothers or prospective mothers pursuing science careers?

Being a scientist and a mother is a good combination but – and this extends to everyone pursuing an academic science career – you have to truly enjoy doing research as it is never easy and there will always be a lot to do.  An important aspect is to have a husband who you can share all the responsibilities with. This is common in Sweden, but not always true in America. I am married to such a guy and it definitely helps.


Taviare Hawkins

IMG_1249

How many children do you have? What are their ages?

I have one child, a daughter, age 9.

At what stage of your career did you have children? 

I had my daughter at an in-between stage in my career. I was in a faculty position, at a small private liberal arts college, and I was ABD [“all but dissertation”].

 Has your career been influenced or changed by your role as a parent? How?

Yes, after she was born I finished my dissertation and changed the focus of my research to biophysics.  I had done computational biophysics but now I work in experimental biophysics.

How has your career been influenced by your own mother?

I think the biggest way that my mother has influenced my career choice is that she has always encouraged me to pursue my interests, whatever they were. Even now as a college professor, she manages my child so I am free to work till I drop in the lab, travel to give talks, and to perform research with collaborators at other institutions.

What has been the most challenging aspect of being a biophysicist and a parent?

Explaining to my daughter why mommy needs to travel so much; to conferences, to give talks, and to do research. When she was little I didn’t think she understood where I was going but now she asks about it and even looks forward to summer travels. She asks, “Where are we going this summer?” She has buddies all over the place.

Have there been any benefits to being both a mother and a scientist?

Yes, it definitely buys you little kid cred! On the playlot, others know who I am from my kid, so from time to time they will ask me science questions.

Would you encourage your children to be scientists?

Of course- right now she says she wants to be a bioengineer.

How would your children describe your work?

I’ve heard her tell her buddies and teachers that her mom is a physicist who works on cell stuff; she’s a biophysicist. She uses a microscope and some math to look at these stringy things (microtubules) that are in cells. She wants to know more about how they work.

Any advice for other mothers or prospective mothers pursuing science careers?

Just do it! It’s never a “good time” in academia to have a kid, but it can be oh so rewarding!

Correlating Tissue Architecture with Tissue Mechanics

BPJ_108_9.c1.indd

The cover image of Biophysical Journal (Volume 108, Issue 9) shows a cross-section of spinal cord tissue; a microscopy image of fluorescently labelled cells at the top, and an an idealized contour map of the tissue’s local elastic stiffness at the bottom. Two distinct areas are visible in both images: the butterfly-shaped gray matter in the center, and the surrounding white matter. In the stiffness map, not only the difference between white and gray matter is visible, but even subtle differences in elastic stiffness within the gray matter are apparent to the naked eye. Recent work at the interface of life and physical sciences revealed that most types of cells respond not only to chemical but also to mechanical signals in their environment. Mechanical signals, on the other hand, may change during development and disease. In the spinal cord, for example, tissue stiffness changes in neurodegenerative disorders, and probably also after injury. However, we currently know little about how local mechanical tissue properties change in space and time. In our study, we used atomic force microscopy to measure the mechanical properties of the spinal cord in three dimensions at a spatial resolution that is relevant to individual neurons, and we correlated local tissue stiffness with the underlying cellular structures. We then developed a simple model that allows estimating local tissue stiffness based only on easily accessible optical microscopy images. The model we developed might enable laboratories that are not equipped with methods to measure tissue mechanics to approximate local tissue stiffness using standard optical microscopy, and to investigate mechanical signaling in a large variety of physiological and pathological events.  To read more about the influence of mechanics on neuronal development and neurological diseases, please visit: http://www.pdn.cam.ac.uk/staff/franze/index.shtml David E. Koser, Emad Moeendarbary, Janina Hanne, Stefanie Kuerten, and Kristian Franze

Earth Day: Biophysics Research on Biofuels

April 22 is Earth Day. The goal of Earth Day, established in 1970, is to draw public attention to issues affecting the environment. In honor of the event, we spoke with Biophysical Society member Gnana S. Gnanakaran of Los Alamos National Laboratory (LANL) about his research on biofuels and the role of LANL in pioneering biofuel research.

bpj96_8.c1.indd

What is the connection between your research and biofuels?

Cellulose, an assembly of glucose polymers, is a vital renewable energy resource originating from plants. A major barrier for biofuel production is the efficient extraction of cellulose fibers from biomass and their degradation to glucose. We conduct theoretical studies on biomass in order to obtain a molecular level understanding of the resistant properties of the cell wall components. Our studies probe these properties using computational techniques at varying levels of resolution comprising quantum chemical calculations, all atom and coarse-grained molecular dynamics simulations, polymer and statistical mechanical models, and agent based and mechanistic kinetic models. Our multiscale approach towards the molecular level understanding of biomass architecture and breakdown has offered significant new strategies to improve biomass conversion.

Why is your research important to the public?

Renewable liquid biofuel for transportation promises to replace some of our non-renewable fossil fuel and reduce greenhouse gas emissions. This is evident from the rising popularity of ethanol as a biofuel, particularly in blends with gasoline and diesel. To be competitive, the production cost of ethanol needs to be reduced, including the cost of raw materials as well as their conversion to fuel. Many key issues in lowering the cost are related to the cellulose-to-ethanol conversion technologies, which are hampered by uncertainties in the physical properties of the feedstock. The conversion of cellulosic biomass, such as agricultural waste products and energy crops, into ethanol involves the extraction and pretreatment of biomass components (cellulose, hemicellulose and lignin) and the enzymatic breakdown of crystalline cellulose fibers into monomer glucose by combined action of many enzymes.  Then, a conventional fermentation process is utilized to obtain ethanol.

Over the course of evolution, plant cell walls developed great strength in their architecture and molecular design in order to deal with environmental stresses and pathogens. With biofuels, we are looking for a way to break down these strong plant cell walls so that we can access the cellulose. As biophysicists, we are probing the biomass, including the unusually high thermal and mechanical stability of cellulose, to identify the weakest links that can be targeted during the conversion process. Also, optimal synergistic action of various enzymes known as cellulases is critical for efficient digestion of cellulose. It is an interesting and challenging biophysical problem, because heterogeneous catalysis occurs on crystalline cellulose surfaces where numerous factors play a role in overall hydrolysis. We have developed spatial models of cellulose degradation that can capture effects including chemical crowding and surface heterogeneity that have been shown to cause a reduction in hydrolysis rates.

How did you get into this area of research?

It was nearly eight years ago when two senior scientists at the Los Alamos National Laboratory (LANL), Cliff Unkefer and Paul Langan, introduced me to biofuels. Back then, I was working on protein dynamics and folding/misfolding problems. We decided to try using computational biophysics to gain a better understanding of carbohydrates and aromatic polymers associated with biomass. A local LANL grant headed by Paul Langan, currently the director of the Spallation Neutron Source at Oak Ridge National Laboratory, provided the initial funding to probe the different forms of cellulose crystalline structures. Several X-ray and neutron structures from Paul Langan’s team were instrumental in many of the computational problems that we handled.  Initially, we learned a great deal about the structural aspects of oligomers of glucose.  An effective collaboration with a USDA Scientist, Al French, helped us to fast-track almost two decades worth of structural knowledge on carbohydrates.  Also, the Center for Nonlinear Studies (CNLS) has supported several postdocs who worked on many of the biofuel projects.

How long have you been working on it?

Initial efforts that began in late 2007 focused primarily on cellulose. Subsequently, we also expanded our research portfolio to cover lignin and the enzymatic degradation of cellulose. Recently, we also started to look at biophysical problems linked to photosynthesis in algae. Making fuel from algae has now gained renewed interest, as it has the potential to produce valuable byproducts in addition to fuels. Algal fuels, unlike lignocellulosic ethanol, can also be used as fuels for aviation and don’t directly compete with food demands. We are fortunate to be working with Richard Sayre, a renowned crop researcher and molecular biologist. A few years back, he moved with his large research team to LANL in order to work on algal problems.

Have you had any surprise findings thus far?

We’ve had several surprises over the years. The first one relates to the nature of cellulose. In textbooks, the remarkable stability of cellulose fiber is often explained in terms of inter- and intra-chain hydrogen bonds. However, this didn’t quite explain why we needed to heat the cellulose fiber to almost 500K to even separate the sheets. By using a statistical mechanical, two-dimensional lattice model, we were able to show that multiple, alternative hydrogen bond patterns can exist within the crystalline layer, and that this “plasticity” of the hydrogen bond network greatly contributes to the stability of the layers over a wide range of temperatures. This was published in the Biophysical Journal in 2009 (image above). It was followed by a replica exchange molecular dynamics study that showed – in contrast to what was typically observed in non-interacting polymers – that cellulose oligomers become more rigid as the degree of polymerization increases.

The national recognition of our work became evident recently when one of the DOE bioenergy centers, Great Lakes Bioenergy Center (GLBRC), approached our team for help with theoretical calculations involving their core technology, liquid ammonia pretreatment. One of my former postdocs, Giovanni Bellesia, was instrumental in directing fundamental research work in biofuels at LANL. Shishir Chundawat, a former postdoc of Bruce Dale and currently on the faculty at the Rutgers University, played a pivotal role in establishing a collaborative research effort involving LANL and the GLBRC. Our theoretical studies targeted the pretreatment of liquid ammonia to catalyze the structural crossover from natural crystalline cellulose to another crystalline cellulose allomorph named cellulose III(I).  Experiments have shown an enhancement in enzymatic hydrolysis rates by up to five fold for cellulose III compared to natural crystalline cellulose. We looked at this enhancement from multiple angles to understand and further improve it; simple coarse-grained models of cellulose, detailed all-atom comparative studies on different cellulose allomorphs, quantum mechanical calculations, and mechanistic and rule-based kinetic models. The resulting theoretical studies captured in a series of more than 7 papers over 5 years provided clues on improving this chemical pretreatment that may help lower the cost of producing biofuels from plants.  We were able to characterize the mechanistic details of how liquid ammonia penetrates and disrupts the hydrogen bonding network in native cellulose to create cellulose III and the differences between native and non-native celluloses from the perspective of enzymatic digestion. Also, we suggested – counter-intuitively – that increased binding of enzymes to cellulose polymers does not always lead to faster breakdown into simple sugars. In addition to the enhancement in cellulose digestibility, ammonia-based treatments have additional advantages over other chemical treatment technologies in terms of both economic feasibility and environmental impact.

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

As stated earlier, crystalline cellulose exists in various allomorphic states, many of which don’t occur naturally.  A greater understanding of unnatural cellulose allomorphs, such as the case with cellulose III and their biodegradation, is bound to improve the efficiency of next-generation extractive ammonia based pre-treatments. We identified key structural and molecular features in cellulose III and the action of enzymes on this unnatural cellulose substrate that can be optimized.  Our investigation of substrate properties, especially on the structural transition to non-native form of cellulose II as a way for efficient biomass conversion, makes our research efforts unique. There are various theoretical and computational efforts ongoing at many universities, National labs and DOE bioenergy centers. The majority of them focus on the native cellulose and its degradation by biological and thermochemical conversions and pyrolysis techniques. Greg Beckham at NREL has carried out ground-breaking computational work on enzymatic digestion of cellulose and continues to make great advances.  Also, Blake Simmons and Seema Singh at JBEI have made breakthroughs and have come up with concepts towards efficient biomass treatment using ionic liquids by considering the problem with both the experimental and computational techniques. At Oak Ridge National Lab, Jeremy Smith and his team have been combining large-scale computing with neutron scattering to look at plant cell walls with molecular machines such as cellulosomes, helping to overcome the problem of resistant cell walls.

Our theoretical and computational studies on cellulosic biofuels complement a larger effort on algal biofuels at LANL. LANL was a key player in the National Alliance for Advanced Biofuels and Bioproducts (NAABB), an algal biofuels research consortium consisted of 39 partner institutions. It was formed to understand the impact of algae on overall biomass and liquid transportation fuel production.  The partners of this consortium came with expertise in feedstock supply, feedstock logistics, and conversion/production pathways. The success of this consortium has led to many active programs on algal research at LANL. Recently, we started collaborations with Dick Sayre, who was the Chief Scientist of the NAABB consortium. Sayre is currently developing novel methods to increase algal performance. We are involved in his efforts that seek to genetically engineer algae to absorb light more efficiently for cost-effective algae-to-fuel production. My postdoc, Cesar Lopez, is heading the theoretical efforts that consider the non-photoquenching mechanisms involving photosynthetic antennae systems in a thylakoid membrane mimic.

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

Let me focus on the achievements of NAABB consortium where LANL was a key player. In a matter of three years, NAABB managed to develop technologies that are likely to reduce the cost of algae-based biocrude from $240 (starting baseline) to $7.50 per gallon. They were able to achieve the cost reduction by two-orders of magnitude as follows (http://www.energy.gov/eere/bioenergy/downloads/national-alliance-advanced-biofuels-and-bioproducts-synopsis-naabb-final):

  • Identified new, robust, high oil yield algal strains that can reduce the cost by 85%
  • Developed a new, efficient open pond system that reduces cost by 16%
  • Demonstrated the use of an electrocoagulation harvesting technology that reduces cost by 14%
  • Notably, they created a unique hydrothermal liquefaction system that combines extraction and conversion to deliver high biocrude yield without the need for extraction solvents, resulting in an 86% cost reduction

The above were accomplished with $48.6 million public funds from the American Recovery and Reinvestment Act of 2009 and $19.1 million in private funds.

Finally, I should point out that, since its inception in 1943 in a beautiful remote area of New Mexico, LANL has been making pioneering discoveries and transformational solutions for national security challenges.   Although primarily assigned to safeguard the United States’ stockpile of nuclear weapons, it is also home to talented and creative scientists who tackle burning security issues and challenges facing the nation, including cyber security, biosecurity and energy security.  I am glad to be part of it.

Do you have a cool image you want to share with the blog post related to this research?

The image at the top of this blog post was featured as a cover of Biophysical Journal in 2009. It depicts the following: In plants, cellulose is biosynthesized by polymerization of glucose into chains (green, dark blue). As the chains are produced, they are assembled into sheets (light blue) that stack on top of each other to form nanometer-thick crystalline microfibrils (blue rods) in the cell wall (gold). The microfibrils are encrusted in other polysaccharides and lignin. Cellulose stability is maintained by networks of hydrogen bonds (yellow dashes) within the sheets. These hydrogen bonds must be broken to release glucose for the production of biofuels.

The Rich Phase-Transition Kinetics of Inter-Leaflet Coupling in Bilayers

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The image illustrates predictions of our model for inter-leaflet coupling in a phase-separated lipid bilayer. There is intense debate about the role of “lipid rafts” (nanometer-sized domains) in cell membranes, and how closely they are related to bona fide thermodynamic phases (e.g., Wilson et al., Biophys. J. April 7, 2015). In any case, phase behavior in model systems contributes an understanding of generic interactions among lipids and/or proteins, which is essential to inferring their possible cellular roles. Furthermore, understanding this behavior could allow smarter design of artificial membranes. Our work is associated with the EPSRC (Engineering and Physical Sciences Research Council) CAPiTALS Program, which is interested in technological uses of membranes grounded in an understanding of the physics governing their curvature, asymmetry, and patterning.

Because bilayers contain two leaflets, it is essential to consider how phase-separated domains register (align) across the leaflets. By incorporating hydrophobic length mismatch in a lattice model, our theory shows how apparently conflicting observations of registration and anti-registration may be reconciled: anti-registration can be kinetically favored and can occur first in the phase-separation process, but is typically metastable. In analogy to a large body of work in the colloid and metallurgy literatures, the model predicts fascinatingly complex kinetics driven by metastable states.

Rafts are implicated in such diverse processes as signal transduction, trafficking, and virus entry. Whether and how they couple across leaflets is a crucial aspect of their function; for example, such coupling could influence co-localization of signaling proteins anchored in opposite leaflets. Do proteins and lipids of longer than average hydrophobic length in one leaflet align with similar species in the other, maintaining similarity of structure across the bilayer? Or, do they align with shorter than average species, to maintain a more uniform bilayer thickness profile? Our work suggests that kinetics in model membranes could be intimately connected to these simple, very important questions.

Our theoretical model began as an idealized lattice simulation. Detailed simulation studies will explore the theory’s predictions, and guide future molecular simulations or experiments on the thermodynamics and kinetics of domain registration both in vitro and in vivo. The image was created from simulation snapshots that exemplify the unusual kinetics in which registered domains nucleate from a metastable, anti-registered background pattern. The competing arrangements follow a color scheme inspired by a popular British candy, hence the title Lipid Allsorts. The final image was composed in Inkscape. We wish to especially thank Alexander Stukowski for the excellent OVITO package, which was used to render the simulation.

Further information on our research can be found at

www.johnjosephwilliamson.com

site.physics.georgetown.edu/~pdo7

www.capitals-programme.org

www.ovito.org

–John Williamson and Peter Olmsted