The Kavli Prize Presents: Understanding the Machinery of the Cell [Sponsored]

by The Insights

This podcast was produced for the Kavli Prize by Scientific American Custom Media, a separate division of the magazine’s editorial board.

Megan Room: How does the stomach tell the brain that it is full? How do the 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 Richard Scheller and Thomas Südhof for their work detailing how nerve cells communicate with each other at the microscopic level. Three years later, he received the Nobel Prize.

Scientific American Custom Media, in partnership with The Kavli Prize, spoke with James to learn more about his findings and the future of this work.

Entrance: 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.

Entrance: He applied to a neuroscience program in graduate school…

Rotman: It all just made a lot of sense, except for the fact that I wasn’t admitted.

Entrance: But James isn’t the kind of person to worry about labels. In fact, he explored a range of scientific disciplines. As an undergraduate at Yale, he studied physics, perhaps in part because he was growing up in the 1950s.

Rotman: Scientists and doctors were really the most admired in the 1950s. And it was physicists in particular. Einstein, Oppenheimer, people like that.

Entrance: But his father was worried about his career options, so he convinced James to try a biology course.

Rotman: And I just fell in love.

Entrance: So he dropped out of physics and decided to go to Harvard Medical School to learn more about biology.

Rotman: In the end, I never finished my medical studies.

Entrance: But, while he was there, he stumbled upon his life’s work.

Rotman: I was a first year medical student listening to a lecture in our histology and cell biology class.

Entrance: The professor was showing images that had been captured by scientists decades earlier. They showed, for the first time, how complex the cell is.

Rotman: The cell is not right, like a little dumb liquid inside. It’s a very organized place. It’s more of a city than anything else.

Entrance: This city inside a cell has departments that share information, factories that make proteins, and even machines to move those proteins inside a cell and release them outside the cell. .

Rotman: And if the proteins go to the wrong places, the organization of the cell is lost and it can no longer survive.

Entrance: James was fascinated. He wondered, how does all this complexity work? How does a protein formed in a cell move to the right place?

Rotman: And there has to be a different kind of machinery, I’ll call it a delivery truck, to transport the cargo, the work pieces, from where they start at the factory, through a warehouse into the distribution system, to the final destination.

Entrance: At the time, cell biologist George Palade guessed that little fluid-filled sacs called “vesicles” had something to do with it.

Rotman: A vesicle is a small ball, like a very small balloon. It’s no bigger than five hundred or a thousand hydrogen atoms, the smallest atom. And the cell has tens of thousands of these little vesicles at any one time.

Entrance: And they are everywhere…

Rotman: These tiny little vesicles are found everywhere in nature. They are found at every nerve ending, they are found throughout your digestive tract where they store, for example, insulin, in your gastrointestinal tract, in particular, they are found in the pancreas. And so, they are found throughout the body.
George Palade, who later received the Nobel Prize, believed that these vesicles were the delivery trucks for moving proteins around the body. But he couldn’t prove it.
He couldn’t figure out how many different types of delivery trucks or vesicles there were. And he couldn’t quite follow them in the cell from their starting point to their destination.

Entrance: Most importantly, he couldn’t explain the mechanisms that allow vesicles to pick up proteins and deliver them to the right destination.

Entrance: So, was your job to figure out all those details?

Rotman: Yes, I made it my job.

Entrance: But how? James started by building on a basic premise of biochemistry – that everything that happens inside a cell is basically just a chemical reaction. And if you can isolate this chemical reaction, you can understand how it works.

Rotman: And the way to achieve this is first and always to reproduce the process, however complicated, outside the living cell.

Entrance: So he decided that the best way to study how transport vesicles work was to break apart cells and recreate vesicles in a test tube.

Rotman: And the three-dimensional organization was so breathtaking. Every part of the cell was in the same place in every cell. I come and say, well, I’m going to disrupt this organization.

Entrance: Biochemists had used this approach to understand everything from how proteins are made to how energy is stored in the cell.

Rotman: And the one thing that wasn’t there yet, could we replicate outside of a cell the very 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 may have been wrong.

Entrance: Turns out he was right. After years of trial and error as a postdoc at Stanford, he was able to recreate the entire process of a vesicle carrying a protein to a specific location in a cell.

Rotman: We could take these vesicles and add them to a cell extract. And they were delivering their cargo to exactly the right place as if they were in the living cell.

Entrance: After recreating these vesicles and then studying how they transport proteins, James quickly discovered that the process is similar to how packages are delivered.

Rotman: Each package has a barcode, like a tracking number. The truck has to leave and it has to unload the deliveries with the correct tracking number.

Entrance: But instead of tracking numbers, the vesicles are stamped with what’s called a v-snare protein. These vesicles reach their destination by floating around and searching for their match, called a t-snare. When the two traps meet, they lock into place or merge.

Rotman: These trap proteins are found in plants, in yeast, in humans. There are nuances that allow trap proteins to function in different species and at different places and times in the body. But the basic physical principle is general.

Entrance: The principle is so general that James accidentally solved a neuroscience question while trying to figure out how these trap proteins work.

Rotman: My post-doc, knew how to measure these trap proteins, didn’t know what they were made of. And so, we didn’t know where to get the most out of it.

Entrance: So they started looking at different tissue samples, looking for the best place to find high concentrations of trap proteins.

Rotman: And it turned out to be the brain.

Entrance: They used cow brain samples to isolate and purify these trap proteins.

Rotman: And when we identified it, it turned out that there were already known proteins.

Entrance: Neuroscientists had previously examined the same type of samples to understand how neurons in the brain connect and communicate through the small spaces between them, called synapses.

Rotman: We weren’t trying to do this intentionally, we wanted to solve a more general problem.

Entrance: 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 trap proteins.

Rotman: And once we saw that they were identical to a subset of those in the synapse, we can identify them and say, well, that’s how the synaptic vesicle works. This is part of a general principle.

Entrance: James had unwittingly answered an important question about how the brain works. So important that it was awarded the Kavli Prize.
Not bad for someone who couldn’t get into Harvard’s neuroscience department. James says it was all meant to be.

Rotman: It’s only because I was lucky enough to be rejected by neuroscience, that I was able, essentially, by accident, to solve a problem in neuroscience, along the way, when I was actually trying to solve a larger problem in cell biology, isn’t that a funny thing?

Entrance: James says his days of research were all about understanding the machinery of a cell, but scientists are beginning to learn more about the mysterious substances that are also in the mix.

Rotman: There are biological materials in which these machines come together to form a material that behaves like a continuous solid, or a liquid, or like a rubbery elastic. It’s actually very strange.

Entrance: He says understanding these strange substances could transform our approach to medicine and deepen our understanding of how the body works.

Rotman: We will see changes in the state of certain parts of the cell that we do not yet understand today, and we will learn to manipulate them and they will be altered in disease.

Entrance: What is his advice to young scientists trying to unravel these mysteries?

Rotman: It’s easy. Never take the advice of an old scientist.

Entrance: He says researchers today face different challenges than he did, including less freedom and funding to take big risks and work on a question for a long time.

But if he could offer general advice, he would say that the United States should increase its funding for basic research, so that dedicated scientists like him are more likely to intentionally or accidentally stumble upon important discoveries.

Entrance: Professor James Rothman is chair of the Department of Cell Biology at Yale Medical School, biochemist and 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 their breakthroughs in astrophysics, nanoscience and neuroscience – transforming 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 American Kavli Foundation.

This work was produced by Scientific American Custom Media and made possible with support from the Kavli Prize.

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