Center Stage: Lisa Manning & Mechanics in Morphogenesis

M. LISA MANNING

A half dozen or so years ago, Carl Woese and Nigel Goldenfeld characterized biology as the new condensed matter physics.  More recently, Eugene Koonin advised “biology has to become the new condensed matter physics”. It’s an area of scientific research that is indeed ramping up, and not a moment too soon, after decades of puffery about a so-called selfish gene.  But what exactly is meant by “the new condensed matter physics”?  I decided to contact Syracuse University physicist Lisa Manning to help sort it all out in a conversation that follows.

Lisa Manning is on a meteoric rise as a young scientist.  She’s a distinguished educator, leader of her own research group, talented speaker, as well as a Simons Foundation investigator on two fronts—the glass problem and the mathematical modeling of living systems.

She’s also got a furious schedule to go with all that.  Over the last couple of weeks I’ve been lucky to catch Manning for comment in her office in between bits of microwaved lunch, briefly while on the road, and post-quality-time with her husband and two children  before boarding a plane for the West Coast.

We first communicated during a break in the proceedings of a Princeton symposium she co-organized in February having to do with the new condensed matter physics, titled: “Mechanics in Morphogenesis,” which organizers of the event thoughtfully streamed to the public over the Internet!  One of the Princeton speakers described the meeting as “revisit[ing] D’Arcy Thompson with the power of 21st century developmental biology.”

“What took them so long? It’s been 100 years since D’Arcy Thompson’s On Growth and Formembryo geometry investigator Stuart Pivar remarked after viewing the Princeton presentations, otherwise completely  delighted to see “Mechanics in Morphogenesis” take center stage.

Following Princeton, Manning flew to Los Angeles for the annual American Physical Society meeting where she gave the 2018 Maria Goeppert Mayer Award Talk: “Surface Tension Is Weird in Confluent Biological Tissues” and accepted the APS 2018 Maria Goeppert Mayer Award.

This week Manning is guest lecturer in Manhattan at a Simons Foundation public gathering.  The talk, “A Body Made of Glass,” takes place in the foundation’s “state-of-the-art” auditorium following high tea.

Glass (silica, SiO2) is an amorphous material—mechanically solid but microscopically disordered. And as it turns out, roughly 90% of all solid matter around us is amorphous material.  Furthermore, because of mechanical interactions between cells, the tissues of our body behave like glass and influence pattern formation.  Figuring out how it all works is the focus of the Simons glass collaboration.

Manning’s Simons lecture on March 7 essentially kicks off the 2nd annual meeting of the Simons glass collaboration—a three-day pow-wow at the foundation’s Flatiron headquarters.

The Simons glass group—its director is University of Chicago physicist Sidney Nagel—notes the following strategy for tackling the glass problem:

“The collaboration has developed a numerical scheme that takes advantage of the flexibility offered by computer simulations for sampling configuration space to bypass and overtake experimental dynamics.  We are now in a position to study glass configurations that would have taken thousands or more years to prepare in standard experiments.  These systems will allow us to gain unprecedented insight into the structure and dynamics of amorphous materials.”

At Lisa Manning’s university home base in Upstate New York, she serves as both leader of the Manning research lab and as a professor of physics (departmental teaching awards 2014, 2013).  The Manning Group’s research focus is the modeling and computer simulation of mechanical properties of biological tissues and non-biological materials—working in collaboration with experimentalists in various parts of the world.

Manning’s professional distinction comes as little surprise since she’s been thinking about scientific problems most of her life.  Her roots are in an engineering family in Kentucky, and she was an international science prize-winner as early as high school.

However, Manning does recognizes that women continue to be underrepresented in physics, and so two years ago she co-organized a conference at Syracuse University in support of undergraduate women in physics.  It was sponsored by the American Physical Society, National Science Foundation and the Department of Energy.

Some of Lisa Manning’s honors include:  American Physical Society’s Maria Goeppert Mayer Award (2018, for “her use of computational and analytical tools to develop microscopic understanding of flow in disordered materials, from metallic glasses to biological tissues”); International Union of Pure and Applied Physics Young Investigator Prize (2016, Statistical Physics); Simons Investigator MMLS (2016); Physics Department Teaching Award (2014, 2013, Syracuse University); Department Chair’s Service Award (2007, Physics, University of California, Santa Barbara); Physics Circus Outreach Award, Department of Physics (2004-2006, University of California, Santa Barbara) (partial list).

Lisa Manning received her BS degree in physics—summa cum laude—and her BA degree in mathematics from the University of Virginia.  Her MA and PhD (2008) are in physics from the University of California, Santa Barbara.  She was a postdoctoral fellow at Princeton University.

Our conversation follows.

Suzan Mazur:  Are you from a science family?  I would guess that you’re not related to Peyton and Eli.

Lisa Manning:  I wish.  Maybe I’d get better football tickets.  I grew up in Kentucky, outside of Cincinnati, Ohio. My family was, indeed, very interested in science.

Both my parents are engineers.  My mom is a civil engineer.  She got her degree in civil engineering when it was rare for a woman to do so.  She stopped working for a while when her kids were young, but both she and my dad always made it clear that they really value scientific inquiry.  As a kid, I’d ask lots of questions and my parents were always eager to help me figure it all out.  Athough I do think they wanted me to become an engineer, not a physicist.

Suzan Mazur: Studying physics at school you also found yourself in a place where women were underrepresented?

Lisa Manning: I went to Notre Dame Academy, an all-girls high school in Covington, Kentucky.  I actually had a great physics teacher there—Sister Mary Ethel Parrott.  I entered projects in a bunch of science fairs during those years and won an international competition in the engineering category. I bought a car with some of the prize-winnings, since my family didn’t have a lot of money.  That allowed me to go away to college—to the University of Virginia—and to be able to drive home from school.

So I did get a lot of support in high school.  It was when I got to college and to graduate school that I began to recognize that there were a lot fewer women in my classes and a dearth of role models and people to talk to.

Suzan Mazur:  You began your research career in the physics of glasses then moved on into morphogenesis.  What is the tie-in?

Lisa Manning: I was interested in how physical forces generate patterns in embryos because the cells inside embryos are quite often disordered, although not all the time.  It seemed there wasn’t a lot of theory or framework for thinking about global mechanics.  I did my PhD on how a disordered material responds if you push on it.  It seemed no one had answered that question for disordered material that makes up embryos.  I thought the subject was interesting.  Because if you want to know how signaling changes an embryo into an adult, then you have to understand how material responds when physical forces are applied.

Suzan Mazur: One of the presenters at the recent Princeton University conference “Mechanics in Morphogenesis” you co-organized characterized the meeting as “revisit[ing] D’Arcy Thompson with the power of 21st century developmental biology.” Thompson was, of course, fascinated by physical forces.  Eugene Koonin has told me “biology has to become the new condensed matter physics.”  Others have said physics is actually moving toward biology. Is soft matter physics the new condensed matter physics  Eugene Koonin is referring to?  What is your perspective on all this?

Lisa Manning:  There are several exciting frontiers for condensed matter physics.  Exactly as you said, soft matter and its applications in biophysics is one of them, but not the only one.  Metamaterials is another.

I view soft matter physics as the study of things that occur at a scale where objects are soft.  That’s typically on the scale of microns, which is the same scale as cells.  Also, the focus is typically on systems where quantum mechanics does not play an important role.  Fluctuations are introduced by things like changes in temperature rather than quantum fluctuations.  That makes soft matter physics a great toolkit for approaching biology. Because it’s at the right scale and it considers fluctuations that are not quantum mechanical but could be induced by cells moving or, say, ruffling their membranes, etc.

Also, in the work that we do in the Manning Group here at Syracuse and in other groups like ours, there’s an exciting interplay where physics provides new information about how to understand biology.  Models we’re studying just to mimic biology actually introduce totally new physics.

I’m part of the Simons glass collaboration.  Some of the models we developed initially to think about morphogenesis we’re now using to probe deep fundamental mysteries of the glass transition in ways we did not think of before.

Suzan Mazur:  I have a couple of questions about the Simons glass collaboration coming up.  I’d like to first ask you about something Jack Szostak told me about making a protocellSzostak said the self-organization aspect is really not understood, “how you get molecules to work together and act like a cell.”  Thoughts about that?

Lisa Manning:  From my limited understanding of protocells, that makes sense.  My focus is more on understanding the first multicellular structures.  I’m a scale up from that question.  But at that level the same exact analysis applies.

As you know, single cells have been around for billions of years, almost as long as the Earth has been in existence, while multicellularity is a very late evolutionary phenomenon.  Happening roughly 600 million years ago.  The question is:  What is the self-organization that allows cells to group to form functional structures?

Suzan Mazur:  At the Princeton conference the point was made that there was a problem with 2D modeling attempting to predict morphogenetic flow because cells are 3D balloons not 2D.  Your lab focuses on modeling and computer simulation of the mechanical properties of biological tissues and disordered non-biological materials like granular materials and glass.  How closely do you work with experimentalists?

Lisa Manning:  Extremely closely.  All of our work in biology essentially has an experimental collaborator.  I work very closely with Josef Käs at Leipzig University who studies cancer, especially breast and cervical cancer.  He has direct mechanical measurements of tumors from human patients.  I also work closely with Jeff Amack’s lab across the street at SUNY Upstate Medical University.  Jeff uses zebrafish as a model to understand organ formation.

We’ve developed three-dimensional models, for example, for tissues in our group specifically because of that question: What is the difference between two-dimensional and three-dimensional models?

Suzan Mazur:  But you need to work with experimentalists.  You can’t just do it through computer simulation.  Right?

Lisa Manning:  I would have a nuanced answer to that.  I’d say that I always work with an experimentalist because cells are already complicated enough.  If you’re going to make a simple model for a cell, if you’re not working closely with an experimentalist, then your model is almost certainly wrong.

On the other hand, working closely with developmental biologists there’s a lot to learn from a null model, a model that doesn’t actually have too many assumptions.  Because then you discover what is universal about groups of cells.  We’ve found that you can do computer simulations and use those to help drive hypotheses of biology.

Suzan Mazur: Antonio Lima-de-Faria once said in a book called Evolution without Selection

Lisa Manning:  I know this book.

Suzan Mazur: Lima-de-Faria said we need to understand minerals before we can understand biology and he saw four routes from minerals to living organisms:  solid crystalline, liquid crystalline, quasi-crystalline and amorphous.  He also said that minerals and other pure chemicals have no genes, yet they display the constancy of pattern and the ability to change pattern by forming a large number of forms.  Do you have any thoughts about this?

Lisa Manning: From my perspective, it’s certainly true and there’s a lot of growing interest—one of the most exciting fields is the behavior of self-replicating materials.  As you say, you don’t need genes or genomes to get self-replication.  When you’re thinking about the ingredients of life and the pieces that you need, there’s an exciting interplay of structural order.  As you mentioned, crystalline, quasi-crystalline, liquid crystalline and amorphous are different ways of categorizing structural order in a system.

So when you have objects that can self-replicate, it turns out that there’s an interesting question of what structures facilitate self-replication.  Some exciting work is being done on this, for example, by Michael Brenner.  He’s one of the people at Harvard researching how structure limits the ability for self-replicating objects without going into the details of genetics.

Suzan Mazur: You’ve been looking at the glass problem in your collaborative research funded by the Simons Foundation. Why is Simons interested in your work?

Lisa Manning:  That’s a good question.  You could ask him.  I’m funded both through the glass collaboration and as a mathematical modeler for living systems.

Suzan Mazur:  That’s wonderful.

Lisa Manning:  Let me focus on the glass collaboration because that’s what you asked about.  There’s a really deep, deep fundamental question. Phil Anderson once said that the glass problem is possibly the most important unsolved problem in condensed matter physics.

Suzan MazurI spoke with Phil Anderson at the 2013 Princeton meeting on origins of life.  He was concerned at the time about origins and energetics, thermodynamics.

Lisa Manning:  I think what Phil Anderson means by the glass problem possibly being the most important unsolved problem in condensed matter physics is that if you have something that goes from a fluid to a solid, you have an associated broken symmetry.  There are deep reasons in physics why that is true.

With glasses you go from being a fluid to a solid without breaking an obvious symmetry and there are a lot of tools condensed matter physicists have developed to understand how phase transitions work. When things are disordered, transitions are not well understood.  Also, you may say it’s specific to granular material and glasses but actually the same phenomenon is evident in machine learning problems that are important for artificial intelligence.  It’s apparent in protein folding, which is important for biology.

In our case, what we’re thinking about is also extremely important for understanding properties of groups of cells and multicellular organisms.  Morphogenesis.  It also shows up in neuroscience, in trying to understand complex networks in the brain.

So there’s a deep, fundamental phenomenon we don’t understand that’s relevant to a lot of modern science.  We do have a strategy in the Simons collaboration about how to make a breakthrough on that problem.  So that’s why Simons is excited.

Suzan Mazur:  Regarding the glass problem—glass-formers differ from crystal-formers in their bonding.  Recently researchers at the University of Tokyo reported that when water and silica cool, atoms assemble into patterns with a series of concentric shells forming around each O or Si atom. But while the first shell to form is tetrahedral in both water and silica, the second structure in the case of silica is no longer ordered.  There’s a lack of order in supercooled silica.  Do you know the study I’m referring to?

Lisa Manning:  I saw the paper reported but have not looked closely at it.

Suzan Mazur:  You’re probably aware of Ked Stedman’s work with viruses and silica.

Lisa Manning:  Yes, and I saw your interview with him on the subject.

Suzan Mazur:  The promo for your upcoming Simons Foundation lecture titled: “A Body Made of Glass” notes “self-organization is governed not only by biochemical signaling but also by collective mechanical interactions between cells” and that “such interactions cause biological material to behave as glassy ‘living materials’ near a fluid-solid transition.”  Can you give me a sneak preview of your upcoming Simons talk about how cells “tune their stickiness” to get the job done?

Lisa Manning:  As it turns out, many living tissues are confluent, meaning their cells are touching one another with no space between them. That means cell stickiness—how many adhesive molecules cells stick onto their surfaces, how sticky they are—determines cell shape.  There’s a bonus for cells having more area and contact with their neighbors, which is all adhesion is.

With elongated cell shapes, ones that look like pancakes basically, there is lots more area and contact with neighboring cells.

It was a real surprise to us to find that the parameter that governs the shape of cells inside tissues also triggers the fluid-to-solid transition.  Meaning you can change the global properties of an entire tissue just by tuning how sticky a cell is.

Suzan Mazur:  It’s fascinating that you’re turning a corner on this with your research.  There’s been an interest in stickiness of cells going way back, maybe 50, 60 years.

Lisa Manning:  Yes.  A developmental biologist named Malcolm Steinberg in the 1960s came up with this really cool idea, which was that organization during embryogenesis was driven by the stickiness of cells.  In that case, he really was thinking about tissues behaving like fluids all the time.

We’re now realizing that a bunch of things happen in between fluid-like and solid-like behavior.  Why do we care if a tissue behaves like a solid or a fluid?  Because if a tissue behaves like a fluid, cells can migrate.

During early embryonic development, it makes a lot of sense for cells to cover large distances—to migrate to new places for gastrulation and to form new structures. Later on in development you need things to buckle.

Also, adult organisms need to be able to support weight to do things like move and walk.  You can only really do that if you’re a solid.  So the change from fluid-like behavior to solid-like behavior at other times, understanding that can be a useful guide for biologists.

During wound healing and cancer metastasis—the opposite happens, which is there is a fluid-like invasion of tissues.  Something that should be solid behaves like a fluid.

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

Lisa Manning:  I think there are two areas of importance:  How can you get a single cell to form and replicate in the first place.  A second, related problem is the origin of groups of cells working together as well as the breakdown of groups of cells working together.  This is where some of the most cutting-edge science is happening now and where condensed matter physics or soft matter physics can be easily and effectively applied.

 

 

 

 

 

 

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