The 2013 Nobel Prize in Physiology or Medicine goes to James E. Rothman, Randy W. Schekman and Thomas C. Südhof for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells
Steve Mirsky: Welcome to this special Nobel Prize edition of Science Talk, the podcast of Scientific American. I’m Steve Mirsky.
Juleen Zierath: Here are the 2013 Nobel laureates in Physiology or Medicine.
Steve Mirsky: Juleen Zierath heads the section of Integrated Physiology, Department of Molecular Medicine and Surgery at Karolinska Institute and is a member of the Nobel Assembly. She announced the prize shortly after 5:30 a.m. Eastern time this morning.
Juleen Zierath: Professor James Rothman from Yale University, New Haven, Connecticut, USA; Professor Randy Schekman, University of California Berkley, USA; and Professor Thomas Südhof, Stanford University School of Medicine, Palo Alto, California, USA.
The 2013 Nobel laureates have been interested in questions related to fundamental cell physiology. One of the greatest mysteries of cell physiology was how the right substances could be delivered to the right destinations at the right time. How are molecules such as hormones, transport proteins, or neurotransmitters correctly routed to their appropriate destination, and how is this process controlled with temporal precision.
The 2013 Nobel Prize honors three scientists who have solved the mystery of how the cell organizes its transport system. Each cell of the body has a complex organization that separates specific cellular functions into compartments. This compartmentalization vastly improves the efficiency of many cellular functions and it prevents potentially dangerous molecules from roaming freely within the cell.
Molecules are transported around the cell in small bubble like vesicles. These vesicles shuttle their cargo between different compartments in the cell. The three Nobel laureates have discovered the mol-, the molecular principles that govern how this molecular cargo is delivered with precision to the right place at the right time in the cell. Location and timing are everything.
Randy Schekman studied how the cell organizes its transport system. In the 1970s he studied the genetic basis for this transport process using yeast as a cell model. Schekman identified yeast cells with defective transport machinery, vesicles, piled up in certain parts of the cell. Schekman found that the cause of this congestion was genetic and he went on to identify the genes that mediate specific steps in vesicle transports.
James Rothman also studied the nature of the cell’s transport system. In the 1980s and 1990s Rothman discovered specific proteins. These specific proteins form a complex enabling vesicles to fuse with their target membrane. In the fusion process proteins on the vesicle and target membranes bind to each other like two sides of a zipper. This ensures that the vesicle fuses at the right location and that the cargo molecules can be delivered to the correct destination.
But questions still lingered. How is the release of the cargo controlled in such a precise manner?
Thomas Südhof, he was interested in how nerve cells communicate with one another in the brain, and how signals instruct vesicles to release their cargo with precision. In the 1990s he searched for calcium sensitive proteins that control this process. He identified molecular machinery that senses calcium ions and triggers vesicle fusion. Calcium binds to this machinery and triggers the complete fusion of the vesicle with the target membrane.
Südhof’s discovery explained how temporal precision was achieved and how vesicles could rapidly release their cargo upon command. The vesicle is routed towards its membrane. Proteins on the vesicle and the membrane bind to each other like two sides of a zipper. The vesicle fuses with the membrane. Once the vesicle is in position it must wait until calcium enters the cell. Calcium binds to a molecular sensor on this complex, and that explains how temporal precision is achieved and how signaling substances can be released from the vesicle on command.
The vesicle transport system is critical for a variety of physiological processes, ranging from signaling in the brain to release of hormones, to release of immune cytokines.
Without this wonderfully precise organization the cell would lapse into chaos. Defective vesicle transport occurs in a variety of diseases including a number of neurological and immunological disorders, as well as in diabetes.
The 2013 Nobel laureates have discovered a fundamental process of cell physiology. Their discoveries have had a major impact to advance the understanding of the machinery regulating vesicle traffic, a major transport system in the cell.
Steve Mirsky: Following the Nobel Prize announcement, Göran K. Hansson, Secretary of the Nobel Assembly, took questions from the audience.
Göran K. Hansson: Had they been collaborating scientifically? Yes. I think Rothman and Schekman have been collaborating, right Juleen?
Juleen Zierath: Well they started their work all independently, and it was very interesting that the work of Schekman and yeast, and the work of Rothman and mammals, they were aware of each other’s studies. And so that led to collaborations later. And I don’t believe that they have collaborated with Südhof. So that’s a complimentary line of research.
Male: Could you say something about clinical use of this research? For instance what kind of medications have been created from this.
Göran K. Hansson: I think we’ll ask our clinician, Jan-Inge Henter to comment on that.
Jan-Inge Henter: So first of all we have to realize that this is a prize on physiology, on cell physiology. But these beautiful discoveries have importance for understanding of the human body, and obviously implications for various organs such as the nervous system, diabetes, and immune disorders.
Göran K. Hansson: Could you perhaps gives us an example of – I know that it’s used in diagnostics. Is it?
Jan-Inge Henter: Well yes, so there are a set up of indications. First of all we can thank of tetanus, tetanus is a top bacteria, toxin, that affects this vesicle transper, transport. And of course it’s the death of hundreds of thousands of children each year. That’s one example.
We use also in immune disorders in children with high degree of inflammation we use the analysis of vesicle transport in the diagnostics. And based on these findings we decide treatments. So yes, they have clinical implications.
Göran K. Hansson: And there are, I think genetic disturbances, rare diseases, but there are genetic disorders in this machinery. One of them causes a severe immune defect as Dr. Henter mentioned, with hyper inflammation. Another one leads to, mainly affects the brain and leads to epilepsy and mental retardation. So there are clear medical implications.
Female: You said there are clear medical implications, but so has this discovery led to new medicines or is it just a way of understanding how the disease works? Is it still early stages? In what way?
Göran K. Hansson: It has not led to any medicines yet, but it has led to diagnostics. But as Jan-Inge has said, these discoveries are on the basic machinery; others have applied them to understanding or developing diagnostics. Please.
Göran K. Hansson: Diabetes. Juleen.
Juleen Zierath: So, yeah, the implication for diabetes that we know is insulin is produced in the pancreas and it’s released in a calcium sensitive manner. And so this machinery operates in the release of insulin into the blood stream.
The machinery also works in tissues that respond to insulin, the hormone that mediates sugar uptake. And so it’s a fundamental process in all cells, and that has really led to a greater understanding of disease pathogenesis and prospective treatments.
Göran K. Hansson: Down here.
Male: You mentioned the central nervous system. Could you give an example of a disease that is connected with these mechanisms?
Göran K. Hansson: Jan-Inge.
Jan-Inge Henter: I think actually we mentioned the tetanus, because that is related to the nervous system and affecting the muscles. So this is associated with the nervous system, yes.
Male: Anything else?
Jan-Inge Henter: Well there is a disease called botulism, which is also related to the nervous system.
Male: How does this work in _____?
Jan-Inge Henter: This is in the same way that there are bacterias that produce toxins and they destroy this vesicle transport, and that causes potentially fatal disease. We can actually use this toxin also to treat children that have spastic paralysis or dystonia in the muscles to release the tension in these muscles. So it’s used therapeutically as well.
Steve Mirsky: Juleen Zierath spoke with an unnamed interviewer about this year’s price.
Juleen Zierath: So it’s a fundamental discovery of cell physiology, and it was not entirely easy for these investigators when they started. So Schekman, for example, did yeast genetics, and Rothman was doing biochemistry in a cell, in a test tube, and Südhof was doing biochemistry and some functional studies with animal models.
Female: Could you explain a bit about the vesicle transport system for our lay audience just in easy words?
Juleen Zierath: Right. So think of a cell as sort of a factory and it needs to produce proteins, and they need to shuttle these proteins and cargo from one work station to the next so each protein can get a little bit better refined along the way.
The fundamental discovery here is how the package is, the molecules, the cargo, is shuttled from one compartment in the cell to the other, and how these molecules can be also exported from the cell. So it’s that process which we have awarded the Nobel Prize in.
Female: So what were, if you should – the key breakthroughs that make them worthy of the Nobel Prize, those two gentlemen, what was the three steps?
Juleen Zierath: The three steps. So Schekman used yeast genetics, and he was studying temperature sensitive mutant yeast, and he could morphologically with a microscope see that some of the vesicles in the mutant yeast were building up in the certain parts of the cell. And he understood that that disturbed the traffic. And he went onto identify the genes that controlled this traffic. That was a pretty bold approach, because at the time people didn’t necessarily think that studies of yeast would be of relevance for mammals.
Rothman took a really bold approach. He studied this process in a test tube. Now that approach was met with some skepticism because people thought that this traffic would be dependent upon the proximity of the compartments with each other. Therefore you theoretically wouldn’t be able to break up the cell because you’d need to have an intact cell.
But Rothman broke up the cells and studied this in a test tube, and he could show that even in a reconstituted system he could build up this interaction between proteins, the protein machinery, and study traffic of these vesicles in broken cells.
And Schekman, when he came on the scene, I think he recognized that calcium could be a sensor.
Female: Südhof do you mean?
Juleen Zierath: Südhof, yes. Correct. Südhof. Südhof came on the scene. He recognized that calcium could be a sensor and he was faced with a situation where all the building blocks were unknown. And so his job was to really to put functionality and understand what are the building blocks that the calcium binds to, and how does that release vesicles in a temporally controlled manner.
Female: The winner of Nobel states that the prizes should be awarded to those who have _____ the greatest benefit on mankind.
Juleen Zierath: Right. Right. Right.
Female: So in what way does this prize fulfill this criterion?
Juleen Zierath: Well that’s true for all of the prizes. And new knowledge about how we are in the world is of great benefit for mankind. This, again, is fundamental cell physiology, so the knowledge that we’re gaining from this is applicable to all cells from yeast to humans showing how ancient this is.
And what these individuals have done is they’ve uncovered this machinery, this mechanism, and that has allowed us to understand basic physiology, but it’s also allowed us to have some insight into disease progression and prospective treatments. So it’s a pretty great benefit to mankind.
Female: You said prospective treatments, and can you just give an example in one area where this could be?
Juleen Zierath: Right. So understanding the treatments better would allow you to focus on the machinery and potentially come up with drugs. For example diabetes, it’s a disease where insulin is not release from the pancreas appropriately. So this is controlled with also the calcium impulse.
So theoretically one could work in that area and develop pharmaceuticals to improve insulin release in tissues like muscle. You have an uptake of sugar into those cells. Theoretically one could work on trying to target that machinery to have a better interaction of transport proteins to take up sugar and feed the muscle with sugar glucose.
So there’s a lot of examples of where this could be used.
Female: So why was this prize awarded this year?
Juleen Zierath: Yeah. Well it’s a long journey in terms of the vetting and how we work. And this one is mature, and we felt that we had a fundamental discovery that was Nobel Prize worthy. And so this is why we’re here today to talk about these laureates.
Female: How would you explain the importance of this prize to a, say like a grade school student?
Juleen Zierath: Right. Right. Okay, so if you could imagine that you were going to go to school and you were going to take the bus, and the bus showed up but there was no sign on that bus to tell you where it was going to tell you. All the signs on the buses disappeared. So you’d get into the bus without having any idea of where it might take you.
It might take you to your school, but it might take you to your parents’ workplace. So imagine that. You’d be missorted, and that’s a little bit what this process is. Because of this process the passengers, the cargo, they get to the right place, the school, at the right time so you’re not late, and you don’t end up at the playground or at your parents’ workplace, or somewhere else where you’re not supposed to be.
So this whole process helps the cells sort proteins so the information is moved to the right place.
Female: That’s an excellent metaphor. What’s the state of knowledge in this field at this time?
Juleen Zierath: A little bit of what I said to you before. When Schekman started people were skeptical of the idea of using a yeast model. People were unsure that you’d be able to really even do these experiments.
When Rothman started it was incredibly bold. He broke up the cell, studied this in a test tube. People were skeptical. They didn’t think it could work. Even with the Südhof work the molecules were not on the table.
Female: Do you have any idea, I mean those findings that are awarded today, long time, in the 80s, 90s, what do they work on now?
Juleen Zierath: Well you know so some of the important work is even coming today. So we have some papers that have been published in the 90s and the 2000 that are really of relevance for this work.
So all of them are active scientists. All of them are completely engaged in their projects and they’re moving these questions forward today.
Female: Personally what makes you so enthusiastic about this prize?
Juleen Zierath: Oh, I just think it’s really fantastic. I mean it’s so beautiful. The organization of this traffic in this cell is just phenomenal, and the fact that cells really require this otherwise they basically can’t survive, it’s just phenomenal how cells are able to move this protein machin-, proteins from one place to the other. So I mean I just think that cell biology, the cell physiology is really beautiful.
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