This podcast was produced for the Kavli Awards by Scientific American Custom Media, a division separate from the magazine’s editorial board.
Megan Hall: How does the stomach tell the brain that it is full? How do cells in our body grow and divide?
James Rothman realized that the basic biology behind these processes is basically the same. In 2010, he shared the Kavli Prize in Neuroscience with Scherrer and Thomas Sudhoff for work that detailed how neurons communicate with each other at the microscopic level. Three years later he was awarded the Nobel Prize.
Scientific American Custom Media, in partnership with the Kavli Prize, interviewed James to learn about his findings and the future of this research.
hole: James Rothman was pleasantly surprised when he won the Kavli Neuroscience Prize.
James Rothman: I always thought of myself as a biochemist first and a cell biologist second. And I never thought of myself as a neuroscientist.
hole: He applied to a neuroscience program in graduate school…
Rothman: Everything made a lot of sense, except I wasn’t admitted.
hole: But James isn’t the kind of person who cares about labels. In fact, he has studied various scientific fields. As an undergraduate at Yale University, he studied physics, perhaps in part because he grew up in the 1950s.
Rothman: Scientists and doctors were the most admired in the 1950s. And it was especially a physicist. Einstein, Oppenheimer, those people.
hole: However, his father was concerned about James’ career options and persuaded him to try a biology course.
Rothman: And I just fell in love.
hole: So he decided to drop physics and go to Harvard Medical School to learn more about biology.
Rothman: In the end, I never graduated from medical school.
hole: But while there, he stumbled upon his life’s work.
Rothman: I was a first year medical student listening to lectures on histology and cell biology courses.
hole: The professor was showing images taken by scientists just a few decades ago. They showed for the first time how complex cells can be.
Rothman: A cell is not just a little liquid inside. A very organized place. It’s more like a city than anything else.
hole: This intracellular city has departments to share information, factories to build proteins, and even machines to move those proteins around and release them out of the cell.
Rothman: And if the protein goes to the wrong place, the tissue of the cell is lost and can no longer survive.
hole: James was fascinated. He wondered how this complexity works. How do proteins formed in cells move to their proper locations?
Rothman: And then we need some sort of separate machine that carries the cargo and working parts from the origin of the factory, through the warehouses of the distribution system, to the final destination. I call it a delivery truck. .
hole: At the time, cell biologist George Parrard speculated that small fluid-filled sacs called “vesicles” were involved.
Rothman: Vesicles are tiny balls that look like tiny little balloons. It is no larger than 500 or 1,000 hydrogen atoms, the smallest atoms. And there are tens of thousands of these tiny vesicles in the cell at once.
hole: And they are everywhere…
Rothman: These tiny little vesicles are found everywhere in nature. They are present in every nerve ending and throughout the gastrointestinal tract, for example in the insulin-storing gastrointestinal tract, particularly the pancreas. And they are found all over the body.
The future Nobel Prize winner George Parrard saw these vesicles as transport trucks for moving proteins around the body. But he couldn’t prove it.
He had no idea how many different delivery trucks and vesicles there were. And he couldn’t really follow them in the cell from where they went to where they were either.
hole: And most importantly, he failed to explain the mechanism that enables vesicles to pick up proteins and deliver them to their proper destinations.
hole: So your job was to figure out all these details?
Rothman: Yes, I made it work.
hole: But how? James began by drawing out the basic premise of biochemistry that everything going on inside the cell is basically just a chemical reaction. And if we can isolate that chemistry, we can understand how it works.
Rothman: And the means to do so is to first and always reproduce the process outside of a living cell, no matter how complex.
hole: So he decided that the best way to study how transport vesicles worked was to destroy the cells and recreate them in vitro.
Rothman: And the three-dimensional composition was breathtaking. Each part of the cell was in the same place in each cell. I came over and said, “I’m going to disrupt that organization.”
hole: Biochemists have used this approach to understand all kinds of things, from how proteins are made to how energy is stored in cells.
Rothman: And the only thing that hasn’t existed yet is whether the very processes that determine the three-dimensional organization of the cell itself can be reproduced outside the cell.
This was an assumption I made as a young 25 year old scientist, and you know, I could be wrong.
hole: As it turns out, he was right. After years of trial and error as a postdoctoral fellow at Stanford University, he was able to reproduce the entire process by which vesicles transport proteins to specific locations within cells.
Rothman: These vesicles can be taken out and put back into cell extracts. And deliver your cargo to exactly the right place, as if you were in a living cell.
hole: After reproducing these vesicles and studying how they transport proteins, James soon discovered that the process resembled how cargo was delivered.
Rothman: Each package has a barcode like tracking number. The truck must leave and drop off the delivery using the correct tracking number.
hole: But instead of tracking numbers, the vesicles are imprinted with something called a v-snare protein. These vesicles, called T-snares, float around looking for a match to reach their destination. When two snares touch, they lock or merge in place.
Rothman: These snare proteins are present in plants, yeast and humans. There are subtle differences that allow snare proteins to function in different species, different places and times within the organism. However, the underlying physical principles are general.
hole: This principle is so general that James accidentally solved a question from neuroscience while trying to understand how these snare proteins work.
Rothman: My postdoctoral fellow knew how to measure these snare proteins, but didn’t know what they were made of. So I wasn’t sure where to make the most of them.
hole: So they started testing different tissue samples looking for the best places to find high concentrations of snare protein.
Rothman: And it turned out to be the brain.
hole: They used samples taken from bovine brains to isolate and purify these snare proteins.
Rothman: And when we identified it, we found that there was already a known protein.
hole: Neuroscientists were already looking at the same kinds of samples to understand how neurons in the brain connect and communicate through tiny gaps between neurons called synapses.
Rothman: We didn’t try to do that on purpose, we wanted to solve a more general problem.
hole: But ultimately, the general question of how vesicles and vesicles transport proteins has to do with how vesicles do the same to share information between synapses in the brain. It turned out that a more specific question was also answered. It was all in these snare proteins.
Rothman: And if we find that they are the same subset within the synapse, we can pinpoint them and say, “Synaptic vesicles work that way.” It’s part of the general principle.
hole: James accidentally solved an important question about how the brain works. Most importantly, he won the Kavli Award.
Not bad for someone who didn’t get into Harvard’s neuroscience department. James says it all happened as it should.
Rothman: I was fortunate enough to be rejected by neuroscience when I was actually trying to solve a broader problem in cell biology, and I was able to solve a neuroscience problem essentially by accident along the way. Isn’t that funny?
hole: James said his days of research were about understanding how cells work, but scientists are beginning to understand the mysterious substances they contain.
Rothman: There are biological materials in which these machines combine to form materials that behave like continuous solids, liquids, or rubbery elastomers. It’s actually very strange.
hole: Understanding these strange substances could change our approach to medicine and improve our understanding of how the body works, he says.
Rothman: We will look today at the change in state of which part of the cell, which we do not yet understand. And learn how to manipulate them, they change with disease.
hole: What is his advice to young scientists trying to unravel these mysteries?
Rothman: Oh it’s easy. Never accept the advice of old scientists.
hole: He said researchers today face different challenges than he did, including less freedom and less funding to undertake long-term research at high risk.
But if I could give you general advice, the United States should spend more on basic research, so dedicated scientists like him are more likely to make important discoveries, intentionally or accidentally. he would say.
hole: Professor James Rothman is Dean of the Department of Cell Biology at Yale University School of Medicine and is a biochemist and cell biologist.
In 2010, he shared the Kavli Prize in Neuroscience with Richard H. Scherrer and Thomas C. Sudhoff.
The Kavli Prize honors scientists whose breakthroughs in astrophysics, nanoscience and neuroscience have transformed our understanding of the big, the small and the complex.
The Kavli Prize is a partnership between the Norwegian Academy of Science and Letters, the Norwegian Ministry of Education and Research and the US-based Kavli Foundation.
This research was produced by Scientific American Custom Media and made possible by the support of the Kavli Award.
