Neuroscientist Medha Pathak and the “Mechanome in Action”

Medha Patak 2
MEDHA M. PATHAK

She loves Southern California’s beaches and whenever possible exploring their tide pools, coves and hiking trails.  But University of California-Irvine’s Medha Pathak is foremost a committed scientist—a biophysicist and neurobiologist at the crest of the wave of research into the mechanome, which she defines as:  “the collection of molecules in the cell or in the body that participate in generating, detecting and transducing mechanical forces relevant to biological systems.”

Pathak is currently a professor of physiology and biophysics at UCI and heads the Pathak Lab’s investigation there into “how mechanical forces modulate neural stem cell fate in development and repair.” 

Earlier this year Pathak was the recipient of the NIH director’s New Innovator Award ($1.5M) for her research:  “Building the brain:  How mechanical forces shape human neural development.”

Medha Pathak is also affiliated with UCI’s Sue and Bill Gross Stem Cell Research Center as well as the university’s Center for Complex Biological Systems

She is a native of India.  Her BS degree is in biochemistry from St. Xavier’s College in Ahmedabad and her MS in neuroscience from the National Centre for Biological Sciences in Bangalore.  Pathak’s PhD is from the University of California-Berkeley in biophysics.  Pathak was a postdoctoral fellow in neurobiology at Harvard Medical School.

I managed to catch Medha Pathak recently for a brief telephone interview on her return from Europe and in between her lab and beach investigations.  Our conversation follows.

Suzan Mazur: Were you encouraged in India as a young woman interested in science?

Medha Pathak:  Yes.  I had a lot of support from my family as well as from my teachers and professors to follow this route. With their strong backing, I never felt like I was lacking in ability or opportunities.

Suzan Mazur:  Are your parents scientists?

Medha Pathak: My father was an engineer, and my mother taught child psychology at the university level and later as a school teacher. While they were not scientists professionally, they had the highest regard for scientific research and encouraged all the kids to pursue STEM education.

Suzan Mazur: Congratulations on the recent “Mechanome in Action” symposium you chaired there at University of California-Irvine. Would you tell me what you mean by mechanome?

Medha Pathak: The mechanome is the collection of molecules in the cell or in the body that participate in generating, detecting and transducing mechanical forces relevant to biological systems.

Suzan Mazur:  Is sequencing the mechanome feasible? 

Medha Pathak: By sequencing the mechanome, I assume you mean building a “parts list” using an “omics” approach, of all the molecules involved in generating, detecting and transducing force. . . .  It is difficult to control and visualize mechanical force in biological systems. . . . That said, new technology and identification of novel cellular mechanotransducers are making this feasible.

Suzan Mazur:  Do you see neutron scattering as a useful tool in this regard?

Medha Pathak:  I haven’t actually used the neutron scattering technique so I can’t say how feasible it would be to retain the native cellular mechanical conditions, to visualize dynamic changes or to determine the magnitude of forces involved.

Suzan Mazur: I don’t hear much about Darwinian natural selection these days.  Has a deeper understanding of biology’s dynamic physical mechanisms largely replaced the old dogma?

Medha Pathak:  This is only tangentially related to my work so I wouldn’t want to go into it in an interview!

Suzan Mazur: I don’t blame you.

Would you tell me about the Pathak Lab’s research involving the mechanome?

Medha Pathak:  The Pathak Lab studies ion channels—molecular gates found in the cell membrane—that convert mechanical signals to chemical and electrical signals. We examine, from a multiscale perspective, how mechanical forces modulate neural processes—from embryonic development of the brain to neurodegenerative diseases later in life. Our focus is mainly on processes that involve neural stem cells, whose differentiation we found to be regulated by the mechanically-activated ion channel Piezo1.  We examine the role of Piezo1 in neural stem cell fate at the molecular, cellular, and organismal levels.

Mechanotransduction events occurring at a molecular level can have effects that manifest at the organ level, and we try to understand how that happens. My group is composed of cell biologists, bioengineers, microscopists, stem cell biologists, and developmental biologists who work together, bringing different technical expertise and conceptual perspectives to solve these complex problems.

Suzan Mazur: Your direct outreach to the public for research funding for your lab on neural stem cell transplant therapy is a bit unusual, isn’t it?

Medha Pethak:  With the growth of social media, researchers can now go beyond the traditional system of applying to federal agencies and private foundations for grant funding.  Researchers can interact directly with the public to generate funding and share research results and knowledge. 

We did a crowdfunding project in 2015 in partnership with an organization called Benefunder. There are a few similar platforms like Kickstarter and experiment.com.

Suzan Mazur:  How successful have you been in receiving funding?

Medha Pathak:  Through Benefunder we generated a few thousand dollars.  This seed money was helpful in kickstarting a new line of research that at the time was not yet mature enough for a federal funding application.  We now have two NIH grants, which grew out of the crowdfunded research, and are very grateful to everyone who responded to our outreach for support.

Suzan Mazur:  Are you familiar with Matthew Lang’s article on the mechanome from 2008?  It was published in the National Academy of Engineering journal Expanding Frontiers of Engineering.  He described the mechanome this way: 

“The design of biological motors can be classified by cataloging the motor’s general structural features fuel type, stepping distance, stall force, and other mechanical parameters. Detailed measurements of the motility cycles and underlying mechanisms for motility also provide information about how these mechanisms work.  Ultimately “sequencing” the mechanome will lead to the discovery of the design features of biological motors in general, enabling us to catalogue them and outline the rules that govern their behavior.”

Is that along the lines of what you’re thinking?

Medha Pathak:  The focus in mechanobiology when Lang wrote that article was largely on molecular motors, which are the molecules that burn ATP to generate mechanical force.  But, 10 years later, the field appreciates that the mechanome is much more than molecular motors.  There are also molecules that detect force and molecules that transduce force into electrical and/or chemical signals. Cataloging is certainly important.  But ultimately you have to know how a cell uses mechanical information and how it integrates that information with genetic and chemical information. And to do that you have to go beyond a “parts list” to an understanding of how the parts actually function, individually as well as in concert. 

Suzan Mazur:  If you google “mechanome,” you don’t see that many references to it.

Medha Pathak:  The term is catching on. The first Mechbio conference, organized by colleagues Padmini Rangamani, Juan Carlos del Alamo and Debanjan Mukherjee in 2016 at UC-San Diego, was called “Putting Together the Cell Mechanome:  Finding the pieces, building the puzzle.” 

When organizing the 2018 conference, the second one in the series, we—Jun Allard, Albert Siryaporn, Timothy Downing and I—wanted to go beyond putting the components together to function and decided to call the meeting:  “The Mechanome In Action.” 

Suzan Mazur:  Is there a final point you’d like to make?  Is there anything more you’d like to say about the mechanome.

Medha Pathak:  Traditionally the focus in biology has been on genetic and chemical cues.  Mechanical cues have largely been understudied because until now we haven’t had a good way of working with them. 

It isn’t easy to measure or manipulate mechanical forces in squishy cells, organs and tissues.  Moreover, we have lacked an understanding of the molecules that transduce mechanical forces in cells.

Over the last decade or so, these bottlenecks have started to clear, largely because of collaborative efforts between engineers and biologists and physicists and computational scientists and chemists.  It is an exciting time for the field of mechanobiology, and I believe we are on the brink of making several paradigm-shifting discoveries.

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