This podcast was produced for The Kavli Prize by Scientific American Custom Media, a division separate from the journal’s editorial board.
Megan Hall: How does the stomach tell the brain that it is full? How do cells grow and divide in our body?
James Rothman realized that the fundamental biology behind these processes is essentially the same. In 2010, he shared the Kavli Prize in Neuroscience with Richard Scheller and Thomas Südhof for their work on how nerve cells communicate with each other at the microscopic level. Three years later he received the Nobel Prize.
Scientific American Custom Media, in conjunction with The Kavli Prize, spoke with James to learn more about his discoveries and the future of this work.
Hall: James Rothman was pleasantly surprised when he received the Kavli Prize in Neuroscience.
James Rothman: I had always considered myself a biochemist first and a cell biologist second. And I never really considered myself a neuroscientist.
Hall: He applied to a high school neuroscience program…
Rothman: It all made perfect sense, except that I wasn’t allowed in.
Hall: But James isn’t the kind of person to worry about labels. In fact, he has explored a range of scientific disciplines. As a student at Yale, he studied physics, perhaps in part because he grew up in the 1950s.
Rothman: Scientists and doctors were really the most admired in the 1950s. And it was mainly the physicists. Einstein, Oppenheimer, people like that.
Hall: But his father was concerned about his career prospects, so he convinced James to try a biology course.
Rothman: And I just fell in love.
Hall: So he dropped out of physics and decided to go to Harvard Medical School to learn more about biology.
Rothman: In the end, I never finished medical school.
Hall: But while he was there, he stumbled upon his life’s work.
Rothman: I was a first-year medical student listening to a lecture in our histology and cell biology course.
Hall: The professor showed images captured by scientists just a few decades earlier. They showed for the first time how complex the cell is.
Rothman: The cell isn’t just like a stupid little liquid inside. It’s a highly organized place. It’s more of a city than anything else.
Hall: This city within a cell has departments that share information, factories that build proteins, and even machines that move those proteins inside a cell and release them outside the cell.
Rothman: And if the proteins go to the wrong places, the cell’s organization is lost and it can no longer survive.
Hall: James was fascinated. He wondered, how does all this complexity work? How does a protein formed in a cell travel to the right place?
Rothman: And there has to be some kind of other machine, I call it a van, to take the cargo, the working parts, from where they start in the factory, through a warehouse in the distribution system, to the final destination. .
Hall: At the time, cell biologist George Palade suspected that small sacs filled with fluid called “vesicles” had something to do with it.
Rothman: A vesicle is a small ball, like a small balloon. It’s not bigger than five hundred or a thousand atoms of hydrogen, the smallest atom. And the cell has tens of thousands of these little vesicles at any given time.
Hall: And they are everywhere…
Rothman: These small vesicles are found everywhere in nature. They can be found on every nerve ending, they can be found throughout your digestive tract where they store insulin for example, in your gastrointestinal tract, especially in the pancreas. And so they are found throughout the body.
George Palade, who later received the Nobel Prize, thought these vesicles were the vans to move proteins around the body. But he couldn’t prove it.
He couldn’t figure out how many different kinds of vans or vesicles there were. And he couldn’t really track them in the cell from where they start to where they go.
Hall: And most importantly, he couldn’t explain the mechanisms that allow vesicles to pick up proteins and deliver them to the right destination.
Hall: Was it your job to sort out all those details?
Rothman: Yes, I made it my job.
Hall: But how? James started with the premise of biochemistry: that everything that happens in a cell is really just a chemical reaction. And if you can isolate that chemical reaction, you can understand how it works.
Rothman: And the way to do that is first and always to reproduce the process, no matter how complicated, outside the living cell.
Hall: So he decided the best way to study how transport vesicles work was to break open the cells and recreate vesicles in a test tube.
Rothman: And the three-dimensional organization was so breathtaking. Every part of the cell was in the same place in every cell. I come over and say, well, I’m going to disrupt that organization.
Hall: Biochemists had used this approach to understand everything from how proteins are made to how energy is stored in the cell.
Rothman: And the only thing that wasn’t there yet is whether we can reproduce, outside a cell, exactly the processes that determine the three-dimensional organization of the cell itself?
That’s the assumption I made as a 25-year-old young scientist, and you know what, I might have been wrong.
Hall: It turns out he was right. After years of trial and error as a Stanford postdoc, he was able to mimic the entire process of a vesicle transporting a protein to a specific spot in a cell.
Rothman: We can take those vesicles and add them back to a cell extract. And they would deliver their cargo to exactly the right place as if they were in the living cell.
Hall: After recreating these vesicles and then studying how they transport proteins, James quickly discovered that the process is similar to how packages are delivered.
Rothman: Each package has a barcode, such as a tracking number. The truck has to go and he has to unload the deliveries with the correct order number.
Hall: But instead of sequence numbers, vesicles are stamped with what’s called a v-snare protein. These vesicles reach their destination by floating around and looking for their match, called a t-snare. When the two snares meet, they lock in place or fuse together.
Rothman: Those snare proteins are found in plants, in yeast, in humans. There are nuances that allow the snare proteins to function in different species and at different places and times in the organism. But the basic physical principle is general.
Hall: The principle is so general that James accidentally solved a neuroscience question while trying to understand how these snare proteins work.
Rothman: My postdoc, knew how to measure these snare proteins, didn’t know what they were made of. And so we didn’t know where to get the most out of it.
Hall: So they started examining different tissue samples, looking for the best place to find high concentrations of snare proteins.
Rothman: And that turned out to be the brain.
Hall: They used samples from a cow’s brain to isolate and purify these snare proteins.
Rothman: And when we identified it, it turned out that there were already known proteins.
Hall: Neuroscientists had already looked at the same type of samples to understand how neurons in the brain connect and communicate through the tiny gaps between them called synapses.
Rothman: We weren’t trying to do that intentionally, we wanted to solve a more general problem.
Hall: But it turns out that their general question – about vesicles and how they transport proteins – also answered a more specific question – how vesicles do the same thing to share information between synapses in the brain. It all came down to these snare proteins.
Rothman: And once we saw that they were the same as a subset of those in the synapse, we can locate them and say, that’s how the synaptic vesicle works. It is part of a general principle.
Hall: James had inadvertently solved an important question about how the brain works. So important, in fact, that he received the Kavli Prize.
Not bad for someone who couldn’t get into Harvard’s neuroscience department. James says, it was all supposed to be like this.
Rothman: It was only because I was lucky enough to be rejected by neuroscience that I was able to essentially accidentally solve a problem in neuroscience when I was actually trying to solve a broader problem in cell biology, isn’t that funny?
Hall: James says his research time was about understanding a cell’s machinery, but scientists are beginning to understand more about mysterious substances that are also in the mix.
Rothman: There are biological materials where these machines come together in a way that forms a material that behaves like a continuous solid, or liquid, or like a rubbery elastic. It’s actually very strange.
Hall: He says understanding these foreign substances could change our approach to medicine and deepen our understanding of how the body functions.
Rothman: We’re going to see state changes of what parts of the cell and what we don’t understand today, and we’re going to learn how to manipulate them and they’ll turn into disease.
Hall: What is his advice to young scientists trying to unravel these mysteries?
Rothman: Oh, that’s easy. Never take advice from an old scientist.
Hall: He says researchers today face different challenges than he does, including less freedom and funding to take big risks and work on a problem over a long period of time.
But if he could offer some general advice, he’d say the US should increase its funding for basic research so that dedicated scientists like him are more likely to stumble upon important discoveries intentionally or accidentally.
Hall: Professor James Rothman is the chair of the Department of Cell Biology at Yale Medical School, a biochemist and a cell biologist.
In 2010, he shared the Kavli Prize in Neuroscience with Richard H. Scheller and Thomas C. Südhof.
The Kavli Prize honors scientists for breakthroughs in astrophysics, nanoscience and neuroscience – transforming our understanding of the big, the small and the complex.
The Kavli Prize is a collaboration between the Norwegian Academy of Science and Letters, the Norwegian Ministry of Education and Research and the US-based Kavli Foundation.
This work is produced by Scientific American Custom Media and made possible through the support of The Kavli Prize.