Bogdan Dragnea: Physical Virology & Harnessing Viruses

 

Bogdan Dragnea
BOGDAN DRAGNEA

Something in the way they move—viruses, that is—fascinates Indiana University physical chemist Bogdan DragneaDragnea calls it “cooperativity.” Luis Villarreal calls it “gangen.” But it’s clear from recent Zika and Ebola epidemics that understanding the path of a virus continues to be frontier science.

Dragnea, whose roots are in a small town in Romania near the Ukraine border, has been investigating the structural properties of viruses, and in recent years “[p]hysical principles in the self-assembly of immature HIV-1 particles“.  He is now at work  harnessing the powerful path, the motion of viruses—although he does not consider viruses live organisms. 

The Dragnea Group is experimenting with using viruses as a scaffold to make nanoscopic light for laser-guided surgery—among other lab projects sponsored “through the years” by DOE, NSF, NIH, the US Army Research Office and Human Frontier Science Program.  

Aside from nanophotonics and the physical principles that “govern” morphogenesis, research interests include bio-inspired materials and the thermodynamics of small systems.

Bogdan Dragnea’s latest scientific papers appear in the Royal Society of Chemistry journal Soft Matter (self-assembly of convex particles on spherocylindrical template); Springer (in vitro assembly of virus shells around nanoparticles) and ACS Nano (virus coat protein assembly around metal nanorods). 

He is Provost Professor in chemistry at Indiana University (but says he has “no administrative function”).  In naming Dragnea Provost Professor,  the university expressed the following

“Dragnea is a leading researcher in physical virology whose work has helped place IU Bloomington at the forefront of the field. Part of the physical chemistry group in the Department of Chemistry, he conducts research on the assembly, disassembly and intracellular tracking of viruses in living cells.

He was among the first researchers to recognize that protein self-assembly used in nature to create virus particles could be exploited to create nanoparticle “cages” with well-defined structures and novel physical properties. He more recently developed a new research direction seeking to understand the assembly of immature HIV-1 particles; the research explores early events of HIV-1 budding and assembly, with the long-term goal of developing ways to inhibit growth of the virus.”

Bogdan Dragnea is also a professor of physics at IU.  Outside of his research lab and teaching, he enjoys hiking Indiana’s trails, sculpting wood and building timber frames.

Dragnea told me he gets back to Romania a couple of times a year to see his parents.  While in Romania, he visits key scientific institutes there and is a member of the Horia Hulubei Physics Foundation in Bucharest.  He reports that interesting research is taking place in Romania. 

His PhD is from University of Paris-Sud and his undergraduate diploma from University of Bucharest—both in physics.  Postdoctoral research, with Stephen Leone, was in near-field optics at JILA (Joint Institute for Laboratory Astrophysics). 

I spoke recently by phone with Bogdan Dragnea at his lab in Bloomington.

Suzan Mazur: Are you related to the Romanian politician with the same last name who’s been in the news?

Bogdan Dragnea:  No, I’m not.  My family name, Dragnea, is relatively widespread in Romania.

Suzan Mazur: Where are you from in Romania?

Bogdan Dragnea:  From a town of about 20,000 people in the northeast bordering Ukraine.

Suzan Mazur: Do you come from a science family?

Bogdan Dragnea: My dad is a veterinarian and my mom has a college degree in biology.  She taught elementary school.

Suzan Mazur:  Do you get back to Romania from time to time?

Bogdan Dragnea:  Yes, once or twice a year.  My parents live there.

Suzan Mazur: Is important scientific research being done in Romania these days?

Bogdan Dragnea:  Yes.  The resources, of course, are different from what we have in the US, but science in Romania has come a long way in terms of organizing itself and establishing focus areas. Each time I visit I spend some time talking to people at research institutes. 

Being part of the European community is a big factor in promoting science there.  But science is not as popular as when I was growing up in Romania.  There are now more lucrative professions, I guess, for young people.

Suzan Mazur: Your research has significant US government support—DOE, NIH, NSF, Army Research Office.  What is the Army’s interest in your work?

Bogdan Dragnea: To be honest, one never knows.  You send a proposal and the Army Research Office advises whether it likes it or not.  It is interested in fundamental problems or fundamental questions that may lead to unexpected consequences. 

So, if it’s new enough, I think that’s the criteria—at least the program that funds me—if the research is new and interesting, it will fund the research.  If there is something really interesting that comes up in the research that we cannot predict, then it is going to take the project to a different level.

Suzan Mazur:  Is the Army currently funding you?

Bogdan Dragnea: It is funding me at present for things that I want to do.   I think it’s because the research that we are doing here seems creative. 

Suzan Mazur:  Can you say what you’re working on for the Army?

Bogdan Dragnea:  I can say I work on principles of organizing soft condensed matter using radiation fields, using light basically.  The project that is funded concerns the ability of changing the organization of colloidal particles by using light, lasers.  The phenomenon of self-organization, bioinspired phenomena.

Suzan Mazur: Your PhD is in physics but you are Provost Professor in chemistry and you’re studying viruses.  You’re  a physical chemist?

Bogdan Dragnea:  Professionally I think of myself as a physical chemist.  I found that depending on where I am active, people are going to consider me one thing or another.  My background, as you said, my degrees are in physics, but when I came to the US I was advised that the kind of physics we like to do here is chemistry.  So, it depends more on the local perception than on my own perception. 

I think of myself as a physicist but I am interested in chemical problems and biological problems.  It’s where the edge is.

Suzan Mazur:  You are Provost Professor in chemistry.  Is this administrative?

Bogdan Dragnea:  The Provost (was called Chancellor a few years ago) elected to give me this title but I am not a provost.  I have no administrative function.

Suzan Mazur:  I understand that you have an expertise in optics and have been studying virus morphology with state-of the-art microscopy.  What are some of the tools you’re using and what are you seeing now that couldn’t be seen without such tools?

Bogdan Dragnea:  We use atomic force microscopes to probe how viruses deform on contact. When viruses infect they have to first bind to the cell membrane. At that point there is a tug of war between the cell and the virus.  We have a mechanical deformation problem. 

Atomic force microscopes can image very, very small objects—objects such as viruses, a few  tens of nanometers across.  By tapping a virus with a nanoscopic probe—this is a physically sharp silicon pyramid that we bring in close contact to the virus—it allows us to actually detect its morphology and changes in response to pressure.

Suzan Mazur:  You can see this tug of war going on.

Bogdan Dragnea:  Yes.

Suzan Mazur: Are you using the transmission electron microscope also?

Bogdan Dragnea:  Yes.  For us that’s more of a routine technique we use to check the quality of virus particles and substrates.

Suzan Mazur:  What is your perspective on the importance of neutron science, using neutrons to probe materials, including living cells to study structure, motion and function. The Spallation Neutron Source at Oak Ridge National Lab in Tennessee is being expanded. China Spallation Neutron Source is under construction in Dongguan. And there are several neutron science facilities currently operating in Europe with a dozen countries involved in the research.  The European Spallation Source at Lund University in Sweden (46% complete) is being touted as the most sophisticated facility for neutron science.

Bogdan DragneaNeutron scattering has been used very early on in the study of viruses. This is how we learned where the genome was located with respect to the protein shell, when no crystallographic (X-ray) data was available. As brighter sources are coming on line new progress is expected in understanding the protein-nucleic acid interaction in fully formed virus assemblies.

Suzan Mazur: Do you consider viruses live organisms since viruses can recognize their targets, attach, and infect their hosts—most viruses using a tail spike and needle [see following Parent lab image]—and as you’ve noted, they can “drive large-scale phenomena across the entire biosphere”?

tail spike and needle

Bogdan Dragnea:  No, I don’t.  I will stick with the definition that requires for a living organism to reproduce and produce mechanical work in a thermodynamic cycle. If it could do that, then I would say it’s alive.  But the virus cannot do mechanical work as part of a cyclic transformation.  That is because they do not have a metabolism.  A virus can do mechanical work, but  not as part of a cycle, that is, returning to an initial state after extracting energy from environment.  It doesn’t do it in a cycle like we do it. 

Viruses are part of the fabric of life for sure.  They are extremely important for evolution, from very local to very global phenomena, but they are not organisms.

Suzan Mazur:  There was an NSF-sponsored meeting in May in Alexandria, Virginia on synthetic cell development and one of the presenters, Richard Murray, an engineer at Caltech, said that as an engineer he doesn’t consider replication necessary for making a synthetic cell. Is it a matter of opinion or is there a scientific right or wrong on this, factual basis?   By the way, Eugene Koonin sees viruses as active organisms.

Bogdan Dragnea:  When you write an article or a paper and want to make a point you have to define your fundamental concepts.  The definition for life in Philip Anderson’s paper stuck with me, which is, that you have to have replication and you have to have at least one cycle that produces mechanical work.  The organism has to go from an initial state, produce some work and come back to the same initial state—by regaining its energy somehow from somewhere.

Suzan Mazur:  Phil Anderson, the Princeton professor?  I spoke with him at the 2013 Princeton Origins of Life conference.  

Bogdan Dragnea:  Yes, the Nobel laureate.  That’s the definition for life I think makes sense.   According to that definition [Anderson’s definition], viruses are sort of borderline citizens of the biosphere.  They’re not quite alive. 

But I know that viruses tend to be very complicated, so complicated sometimes that they closely resemble bacteria.  Scientists have had a hard time distinguishing large viruses from bacteria.  If viruses have their own metabolism or rudiments of a metabolism, then the line is blurry.  It’s okay to be blurry.  Why do we have to have a sharp line between life and non-life?

Suzan Mazur:  What self-organization principles governing morphogenesis of viruses have you identified in your research?

Bogdan DragneaIn my lab here at Indiana University we look at viruses as systems of molecules that have very strong cooperative properties. The molecules tend to have evolved in such a way that the effect they have is larger than the sum of the parts.  We are tracking and establishing how those cooperative interactions can be used either by the virus to perform its functions or by us in our attempt in the lab to modify the virus to perform functions the virus has not evolved itself.

Suzan Mazur:  You’ve said viruses can drive large-scale phenomena across the entire biosphere.  Would you give an example?

Bogdan Dragnea:  Every form of life is going to have a virus.  You have viruses that prey on bacteria, viruses that prey on plants, on mammals.  The phages, the ones that prey on bacteria, are especially important because bacteria are important. 

phages image

A large amount of carbon is fixed by bacteria in ocean water and the number of bacteria fixing that carbon is regulated by phages.  They are the dark matter of the biological universe. Viruses make a difference in the balance of carbon in oceans. 

Viruses also make a difference in how large organisms, like humans, function.  There are roughly three or four pounds of bacteria in the human gut.  Bacteria allow us to digest our food.  Those bacteria are kept in a certain equilibrium by phages.  So there’s a whole universe—

Suzan Mazur:  Eugene Koonin has said animals, plants and fungi all live within the context of the microbiome, within the network of microbes and viruses.

Bogdan Dragnea:  Yes.

Suzan Mazur:  Would you say a bit more about virus shells—I assume you mean capsids—possibly being “useful in facilitating accelerated photon emission from a quantum coherent collective state, at room temperature”?

Bogdan Dragnea: Think about photosynthesis, how sunlight is collected by the photosynthetic machinery of a leaf and transformed into sugar.  You take CO2, you take photons and water and oxygen and transform them into one of the molecules of life. 

At the heart of this is an antenna that captures the light.  There’s a chemical antenna inside every leaf, a nice little ring of chlorophyll. Chlorophyll molecules are pigments. These pigments are making the leaf green.  They absorb the photon in such a way that they take its energy and then allow for very fast transport of this energy to where the reaction actually happens.  They channel that energy to the tiny chemical reactor, which can harvest the energy and put it to work—to take CO2 and make sugar out of it, glucose.

So I’m thinking. . .  At the heart of this there is an antenna formed of molecules, of chlorophylls and  these chlorophylls work together.  The inverse of an antenna would be a light source.  You take an ordered group of molecules and you make them act in a concerted fashion in order to emit light not to absorb light.  That’s what we are trying to do using a virus.  To make a strong nanoscopic, very tiny source of light for use in facilitating, for instance, laser-guided surgery. 

There is a lot of imaging done now that does not use coherent emission. When you get coherence, you get more powerful, much stronger light intensities.  We are trying to use the virus as a scaffold that connects emitting molecules. 

The symmetry is very important.  That’s why I’ve been interested in how viruses obtain these symmetries, how they assemble.  How to control and harness those properties.

Suzan Mazur:  That’s fascinating.  This is your current research.

Bogdan Dragnea:  I’m writing a paper on this right now.

Suzan Mazur:  Do you think Earth’s viruses are of Earth origin and are you a member of the NASA astrovirology community?

Bogdan Dragnea:  No, I’m not a member, but I’m not surprised people are thinking about this because viruses can be very resilient entities.  I’ve read about lab viruses that can be carried up by the wind and they end up in the clouds, high up in the stratosphere.  I’ve read reports that viruses have been found in the clouds at about 30,000 feet.  It’s really cold.  The sun radiation is very strong.  The viruses are stuck in the little grains of ice that make high altitude clouds.  Then the viruses eventually come down and they’re fine and can infect a crop of tomatoes.

Suzan Mazur:  What do you think about the emphasis now on mechanobiology?  In fact, at the NFS-sponsored synthetic cell meeting I mentioned earlier, Eberhard Bodenschatz, the presenter from Max Planck said that in its development of the synthetic cell it was going to see how far self-organization would take them without introducing a genome.

Bogdan Dragnea:  It’s not surprising about this approach by Max Planck.  It gives more control.  Waiting to see what can happen.  All sorts of things can happen. 

Regarding mechanobiology, there’s a great introduction to it from 2006 by Rob Phillips and Steven Quake in Physics Today.  It has a wonderful easy to grasp picture of how at the scale of biological organelles below 100 nanometers many phenomena have characteristic energies that converge there.

Energies Converge.gif

For instance, energies related to an electron confined to a box several nanometers in size.  Thermal energy.  Mechanical energy.  And chemical energy.  Especially those bonds that are prevalent within the molecules of life.  They all converge in magnitude at that spatial scale. There is cross-talk. 

This means you have the link between mechanics and thermodynamics and the link between thermodynamics and quantum mechanics and they all mix there in the region between 10 nanometers and 100 nanometers.  It’s that area, in particular, of mechanobiology that’s going to be extremely interesting and challenging because of the mixing of these scales.

Suzan Mazur:  Is this movement in science coming from East to West or is this focus on mechanobiology due to advancements in microscopy and other tools?

Bogdan Dragnea:  It’s more of the latter.  It’s not socio-geographical.  Science is pretty much a delocalized thing now.  Someone discovers something in Beijing, it’s going to be immediately picked up somewhere else. It’s more like you said: the instrumentation became so great that we can now measure precisely the masses of hundreds of molecules working together.  This was never possible before.  We can use electron microscopes to see single atoms.  We can probe the forces of single atoms using different kinds of tools.  The change in the infrastructure is huge.

Suzan Mazur: Do you find time for activities outside science like art, sports, or mushroom hunting?

Bogdan Dragnea:  Yes.  Yes.  Sometime.  Not a whole lot.  I hike, so from time to time I spot a mushroom but I don’t go especially for mushrooms.  I do like to spend time carving wood. 

Suzan Mazur:  Making sculptures?

Bogdan Dragnea:  Yes. Sculptures.  I also like the old way of wood construction, timber frames, for instance.  I’m passionate about learning and trying my own construction skills.  To build a shelter. Or garage.  A play room.  Things like this. Around the house.

Suzan Mazur:  Is there a final point you’d like to make?

Bogdan Dragnea:  I guess the take home message would be the point of cooperativity between molecules, which the viruses are excelling at. There is a lot that biomedical engineers can learn from viruses and get inspired by the cooperativity manifested by the molecules making a virus.  We took this research in two directions, one is mechanics, the other is photonics.  Both pretty promising.  I guess you’ll see me doing the same thing in a few years.

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