Eavesdrop on Experts, a podcast about stories of inspiration and insights. It’s where expert types obsess, confess and profess. I’m Chris Hatzis, let’s eavesdrop on experts changing the world - one lecture, one experiment, one interview at a time.
So, my name is Randy Schekman. I'm a professor of molecular and cell biology at the University of California, Berkeley and I am the editor-in-chief of an open access online journal called eLife. I'm originally from Minnesota but my family moved to California when I was 10 so I guess I qualify as a California boy even though I don't surf and I'm certainly not tanned and blond but I've done my entire academic life in California.
Would anyone ever think that a major ingredient in household bread could hold the key to cancer prevention?
The discovery that cells in yeast can produce human insulin was just one of the many 'eureka' moments that led Randy Schekman to the 2013 Nobel Prize for his work on cell membrane vesicle trafficking.
Now, if you don't know what that means, stick with us. If Randy had his way, all scientific research would be open and free to the public. Randy was recently in Melbourne to receive the 2018 Grimwade Medal and deliver the oration titled “From Pond Scum to Stockholm” at the Bio21 Molecular Science & Biotechnology Institute, University of Melbourne.
He sat down with Andi Horvath to discuss the need for open access science, the value of skepticism, and why you should hold on to that old microscope.
Professor Randy Schekman, let's talk about your Nobel Prize. You're kind of responsible, with a team of others, to opening up knowledge about the internal circulation system of a cell, on how it packages its molecules and sends it to another part of the cell or even outside the cell. Have I got that right?
Yes, that's right. So, this field of cell biology began early in the 20th Century with some pioneering scientists who developed tools, for instance the electron microscope, to be able to look inside of a cell and to see the unusual arrangement of a variety of membrane structures called organelles.
Cells in our body, most of them have things like the nucleus that house the chromosomes, mitochondria that are the energy powerhouses of the cell but there are another set of organelles including something called the endoplasmic reticulum and the Golgi apparatus and secretory granules which communicate with one another by shuttling molecules, protein molecules, lipid molecules back and forth in little membrane carriers, little capsules that are called vesicles.
When I was a graduate student, I wasn't working on this subject but I met one of the founders of this field, a brilliant cell biologist by the name of George Palade who did most of his work in New York at the Rockefeller University. He developed a tool of electron microscopy and cell fractionation to identify these membranes and to deduce how they interrelated to one another in things like nerve cells or muscle cells or in his case, particularly cells of the pancreas.
Finally, just before I was about to embark on my independent career, I heard him deliver a version of what was his Nobel Prize lecture. He won the Nobel Prize in 1974. I was struck by the complexity of this means of communication within the cell and yet at the time, in 1974, one knew nothing about how this process worked at a molecular level. There were no genes, there were no protein molecules, there were no lipids that were known to play a role in organising, orchestrating this complex pathway.
Now I had been trained as a biochemist with another Nobel laureate by the name of Arthur Kornberg who was one of the great reductionist biochemists of the 20th century. From Kornberg I learned how to take a complex process apart piece by piece and then put it back together in the test tube to try to reconstruct how complex processes, in his case how chromosomes, were copied.
I decided for my own career to apply that logic, that approach, that molecular dissection to the process that Palade and his students had deduced on the basis of visual tools. I decided to use molecular tools so that's what we did eventually.
You tampered with the genes and then you saw how the cell packaged its things or didn't package its things.
Yes, yes, yes.
You thought right, that's responsible for how the cell packages things ready to push out or to send to another part of the cell.
Yeah, but now the key thing that was different about what we chose to do compared to what Palade and others had done was we and my lab decided to focus on a simple organism, baker's yeast.
It turns out that baker's yeast uses the same genes to do all the transactions that a cell needs to grow and divide. That had already been recognised by other people but no one had studied this particular process, this particular protein secretion process in yeast, so we chose to work on yeast.
It was a bit of a challenge, a little difficult because the techniques had not been worked out but yeast was a good choice because it's really easy to use genetics to dissect complex processes in yeast. Much more difficult to do that with human cells. Although it's now somewhat easier to do that, back in the 1970s it was virtually impossible. So, that was the trick.
It was really on the basis of what turns out to be a fairly simple and strategic decision. Choose to study a complex process that one knew operated in human cells but study it in a yeast cell where the tools were much better, much more precise in being able to understand the genes and proteins that they produce.
I have to ask the question, what is this good for? Why do we need this knowledge? Where does it fit into the scheme of things?
Well, that wasn't what drove me. At first, I've always been fundamentally driven by wanting to know how cells work, how they grow and divide.
Well you kept really good Nobel Prize company.
But I think most scientists, in fact most Nobel laureates are driven by the same passion to try to understand and not necessarily - their first thought isn't always how can I apply this knowledge. But I've learned over the years, and my conviction remains, that when you make a discovery of fundamental importance there will be people with a practical bent out there who will figure out a way to use it.
Fortunately, in my case it happened very early on. When we discovered that yeast cells have the same process that allows them to secrete proteins for their own purposes that human cells have, the biotechnology industry was growing up in the San Francisco Bay area and I became involved as a consultant for one brand new company that decided to harness yeast for the production of important clinically relevant human proteins.
One of them that they succeeded at early on with my advice was engineering the production of human insulin. So, if you take the gene for human insulin and you engineer it into a yeast cell you can trick the yeast cell into manufacturing lots of human insulin that it secretes into the growth medium outside of the cell. So, you can grow now thousand-gallon fermenter vats of yeast cells that are producing human insulin in huge quantities. That was, of course, much more practical than the techniques of using pig pancreas to isolate it.
Around the same time it became possible to manufacture the human Hepatitis B virus immune vaccine in the yeast cell at a time when it was very difficult to do it any other way. So, now anyone who's ever been vaccinated against Hepatitis B has little particles that are manufactured in yeast cells that they've been injected with. That's now 100 per cent of the world supply. It turns out that Hepatitis B infection if unchecked leads almost inevitably to liver cancer. By simply immunising with these particles made in yeast you could in principle reduce the incidence of liver cancer tenfold.
A little knowledge has gone a long way. Or actually it's a lot of knowledge because you spent a lot of years studying this particular area inside a cell and how it packages into little sacks and takes it over there and makes molecules and things like that.
Take us back to the young Californian chap, the one you describe as not the surfer dude.
Yeah, well I'm short in stature and I'm not particularly athletic, but I had an interest in science when I was just a kid and it developed when I was about 11 or 12 years old.
I remember at my what was then called junior high school in seventh grade, I toured their science fair where the older kids had developed projects and they had displays. Somehow this resonated with me in a way that nothing else in my course work ever did. I felt that this was exciting, you got to do your own project, you got to make a display, you got to show it to other people, compete for prizes.
This excited me and around the same time I had a toy microscope that I got for my birthday. I remember collecting a jar of pond scum from a dry riverbed near my home and I put a drop of this pond scum on the glass slide and even through this toy I was amazed at the forms of life that you could see. For me it was a revelation.
So, I shared that excitement with my parents at the dinner table and I remember my father was somehow sceptical that this toy could be so revealing. I was a little offended at his remarks so I decided to save my earnings. I used to babysit and mow lawns and deliver newspapers. I decided to save my earnings and to try to build up a fund of about $100 to buy a real microscope. I saved my money in an envelope in my bedroom but I could never quite get to the $100 that I needed because my mother kept borrowing the money.
One Saturday I was so offended, I was mowing a neighbour's lawn and I bicycled to the police station and I told the duty officer that I was running away from home because my mother was stealing my money and I couldn't get my microscope. They called my father in and he spoke with the captain of the police station and he came out looking rather severe but I learned a valuable lesson that afternoon because we drove right from the police station to a pawn shop in a nearby city and I bought my great pride and joy throughout high school, my Bausch and Lomb student professional microscope. That was what I used for all of my science projects all the way through the rest of high school.
Then of course, I went away to college and they had better microscopes so it got put away. But fortunately, my parents saved that microscope. They threw everything else of mine away but somehow, they knew I'd want it later on so when I had my own family in Northern California, they mailed it up to me. It sat unused in a utility closet because regrettably neither of my children ever displayed any interest in science but then on that day in October 2013 when I learned that I'd won the Nobel Prize, several days later I got an email as all laureates do, asking for some artefact from my past that was a reflection of my development in science. So, I dusted the microscope off and sent it to Stockholm and there it sits now on display in the Nobel Museum.
Now you're still an active researcher. What are you working on now?
Well we no longer work on yeast. We've moved into animal cells, human cells. We continue to study how vesicles move things around but in the most recent years we've started to study how cells, human cells take vesicles that they make inside of the cell and they ship them outside of the cells intact.
Our body, in the blood and all the bodily fluids that we have, there are little carriers moving around, little vesicles that carry protein molecules but they also carry small bits of nucleic acid, small pieces of what's called RNA.
The interest is that the RNA pattern seems to change, for instance, during metastatic cancer. Biotech companies have become very interested in characterising these small RNAs to see how they may change by way of developing diagnostic tools which may then be applied in what are now referred to as liquid biopsies.
It may be there may come a time in the not so distant future when you go to have your annual check-up, you'll have a blood test that will test for things like cholesterol and sugar and other things but you will also be able to test the small RNAs that are in your blood and that may lead to early diagnosis of something like metastatic cancer long before there are any other pathological symptoms.
That's particularly interesting and valuable but again I'm a basic scientist, I'm interested in understanding how those RNAs get into these little vesicles and they the cell bothers to manufacture these things and ship them out. What are they doing in your blood? Are they being taken up by other tissues? Are they delivering information just as a hormone does but in this case an RNA molecule? I think this is a quite fascinating new area, one that I'm keen to pursue.
It's a publish or perish world. There's a lot of pressures on scientists and I know you've commented on this. Has research lost its way? Have publications lost their way?
I have some very strong feelings on this subject. I don't think research has lost its way. There's still compelling questions that imaginative young people want to pursue. But the field, the discipline, of academic science has changed quite dramatically in the years of my career.
It used to be that, when I was a student, the choice of journal, scientific journal that we publish in was dictated by who was interested in reading our work and what scholars were involved in evaluating our work and how they would reflect on what we'd done. But since then, I think largely through commercial influences, the nature of the decision about where one publishes and how the work is evaluated has changed, I would say in a bad way.
Some years ago, as the biomedical literature has exploded, it's become difficult for people to be able to read everything and to evaluate what's important. So, unfortunately, I would say some publishers have in a way capitalised on this by creating journals that are excessively exclusive, that cater to the vanity of scientists by accepting so few papers that everyone is desperate to join their club and they measure themselves by a number that was created four decades ago to be used by librarians to decide which journals the library should subscribe to.
It's called the journal impact factor. It's a measure of the popularity of the journal. It is not a measure of scholarship. It was never intended to be a measure of scholarship and yet it has morphed into that and people around the world in every country are obsessed with getting their papers into journals with a so-called high impact factor.
But very often, these papers that are highly cited turn out to be wrong and journal editors then cater to this by looking for research subjects and for papers that are going to generate a lot of buzz, that are going to generate a lot of citations which are used by professional editors to measure themselves. I have been very highly critical of journals in the life sciences, in particular Nature, a journal called Cell and a journal in the US called Science, that have intelligent professional editors making decisions but these people are not active scholars, they don't necessarily know what's going on in the field other than what people tell them and I'm afraid though I know they will deny this, that their decisions are often based on the potential impact of the paper.
They're looking for buzz because frankly they're in the business of selling magazines. I think this has really been a toxic influence in biomedical literature around the world and I've been trying in my own little way to try to crusade against this.
On the very day of the Nobel Prize ceremony five years ago, I published an editorial in The Guardian that took these journals on. I announced my intention to boycott these journals and then the very morning of the ceremony I arranged to have a BBC Four live debate against one of the science editors. There are more people who know me for that Guardian editorial than know anything about my science.
You created open access science and eLife.
Well I didn't create open access science. It certainly existed before me. It was pioneered by a British journal and taken to a higher level by a consortium of journals called PLOS, the Public Library of Science.
But I have embraced that view and this journal eLife started six years ago with funding from some very powerful organisations, the Howard Hughes Medical Institute, the Wellcome Trust in Britain and the Max Planck Society in Germany. It was started not simply to promote open access, though that was certainly a founding principle, but with the intention of trying to recover the decision-making process away from professional editors and more to active scholars.
Now there are a lot of journals that are run by active scholars around the world but they have lost market share, to use a commercial term, to these very successful businesses. The publisher Elsevier in Europe is the largest publisher of the scientific literature in the world. They have a huge profit margin, larger than any corporation anywhere and it's because they exploit scientists' labour in doing the review, and they charge an arm and a leg for people to read their journals and subscribe to them.
It's a big business. Elsevier and the Nature publishing group Springer Nature, very successful business enterprises. Their plan is to brand themselves. They've done so very effectively and they unfortunately have captivated a market of scientists who are looking for attention. I think this has caused a distortion because people now want to publish in these journals and that influences the kinds of things that they choose to do because they're looking to do things that are going to generate lots of citations.
I'm not sure that what I'd started with 45 years ago would be taken up now because I wasn't interested in lots of citations. I wanted to discover new things. People of course still want to do that but I'm afraid that they are unduly influenced by the choices that they will make about where to publish their work.
Professor Randy, what misconceptions do people have about the world of science, scientific research or even your work?
Well I think the largest misconception is a) what scientists do and I think even more importantly, what the scientific method is.
People who want to exploit some particular political position will often misrepresent the science and will exaggerate the science and will argue against things like evolution because after all, it's not proved and scientists can't explain everything.
Well, regrettably, because of terminology it's called the theory of evolution but it's not less solid than the theory of gravity. No one seems to challenge the theory of gravity but why is it that they challenge the theory of evolution? That's as solid a foundation for biology as exists. No one could pursue a career in biology without appreciating evolution as the foundation of life on earth.
There is that misconception that takes its form and politicians arguing against the overwhelming evidence for climate change and of course as you know, in the US and even in Australia these questions are raised by politicians who have their own particular purpose in mind but who exploit a general lack of understanding of what the scientific method is.
In order to be successful in science you want to challenge prevailing views. You don't want to reinforce - you don't earn your reputation by simply reinforcing what someone else has done. You want to challenge it. You want to challenge it in new and creative ways. Theories are tested. The principle of scientific research, and of science itself, is to use falsifiability as a way of testing a prevailing theory. This is how evolution has advanced in more than a century. This is how our understanding of climate change has advanced. It's by attacking theories. It's not by using some phoney reason to prop something up.
People have a basic misconception about what science is. Okay, that's fine. I don't expect everyone to be a fully trained scientist. It is our responsibility as educators to constantly renew this understanding, to explain to people what science is and what it isn't and hope that people will listen that will have an open mind to that. That's the problem. People need to have an open mind to what is and what is not science.
The scientific method has had a profound influence on the development of civilization over centuries now. People had false beliefs in things that couldn't be explained until science developed in a way of testing things and advancing things. I think we can look forward to the centuries ahead if we survive, to being able to explain things that are now currently impossible to understand. The scientific method to me is the most important invention of civilization in the last three or four centuries.
A palaeontologist once said to me when I was interviewing him about why he studies dinosaur bones and why it's important and he said because it dispels superstitions.
Sure, sure. Well you can say that about any field of science but right now the public acceptance of science is perilous.
Politicians have found a way to exploit the misunderstanding of the scientific method to their own purposes. Scientists feel powerless to do anything about this. In the US it's particularly bad. I was at a meeting recently where a very prominent biologist said he felt that in the current climate we should just lay low. We shouldn't go out and defend ourselves any more than we already do because science has a way of taking care of itself. Well I respectfully disagreed with him.
I'll give you an example. In the US there's a very important organisation called the National Academy of Sciences where people who achieve a certain level of accomplishment in their career are elected. It's very competitive so it has 2500 or so of the most prominent scientists in the US and around the world.
That organisation in my mind should stand up for science. After all, it's a private organisation, not a public organisation. It was started by Abraham Lincoln to advise the government on the application of science to technological development. It's done that admirably over 150 years and now is the time it seems to me, that that organisation needs to stand up, to speak out in defence of science.
Yet, the leadership has taken, I'm afraid, a very timid role in this to protect the organisation, to protect its relationship with government. They've taken a step back and allowed other people to try to speak out but I think it's a missed opportunity.
Professor Randy, I'd like to turn our attention to young scientists. I know you've had lots of graduate students throughout your career but what's your advice to young biologists out there now?
Well I think for a university student for instance here at the University of Melbourne, the most important thing they can do, and some of the professors may not appreciate my advice, but the most important thing they can do if they're really interested in science is not spend their time in the classroom. It's to get into a research laboratory.
That is really the only way that you can experience what science is all about because it turns out a research career is not for everybody. You have to learn to deal with the daily frustrations of failure. You have to be willing to repeat something over and over and over again until you get it right, until you learn something one way or the other. This is not for everybody but until you have that experience of the pleasure of discovering something new, even if it's a tiny little new thing, until you have that pleasure you can't possibly know what science really is.
You can learn lots of facts in classes, you can do well on tests, you could excel and get high marks but that is not what science is. Anyone who has an inkling that they may have an interest, that's what they should do and I have had that opportunity and I've provided that opportunity to now generations of undergraduates at UC, Berkeley.
All right, you young scientists, back to the laboratory. The public sometimes have a perception that scientists have a ‘eureka’ moment. Do they?
Well if you're fortunate you do have some in your career and I had one in particular that I'll never forget.
Several years after I started my research at Berkeley, I had a fantastic new graduate student and the two of us embarked on a search for the genes that are organising the process of protein secretion. We did this by looking for mutants, mutations in those genes that cripple the process.
My student Peter found the first such mutant in 1978 and as luck would have it, just after he found the mutant, Professor Palade, whom I mentioned earlier, visited Berkeley to give some honorific lectures.
I had the pleasure of renewing my acquaintance with him and telling him what we were doing. But more importantly, the students organised a dinner for Dr Palade that evening and Peter told him about his new results on this first mutant that we'd obtained. Palade said "well of course now you must examine these cells by cutting a thin slice of them and looking at them in the electron microscope", which of course we had planned to do but we raced ahead and did that.
Then in the summer of 1978, I'll never forget, I was in my office and Peter excitedly called me down to the microscope which was in the basement of our building. I went down and looked at the screen and here were these yeast cells that were just full. They looked like they had the measles. They were full of these little carriers. They existed in only tiny quantities in normal yeast cells but in this mutant the process had gone awry and now the cell just filled chock-a-block full of these vesicles, thousands of them where only dozens existed in normal cells.
It was because the gene that we had mutated, that Peter had mutated, was required for the last step where these vesicles touch the perimeter of the cell and merge to discharge their content. Now fast forward, long after we had cloned that gene, the gene is required in virtually all of the cells of our body. It organises, for instance, how nerve cells communicate with each other, how nerve cells communicate with muscle cells through its role in the delivery of chemical neurotransmitters that are also carried by these little packets.
That one moment in the summer of 1978 was my eureka moment and I remember the thrill of that sensation. Second only to when I saw my children born, that was my most exciting moment.
What would you like us to think about next time we see a headline about some breakthrough research or some announcement of some very important research?
Well the first thing that you should do when you see something that looks too good to be true is to be sceptical. A scientist has to go to any new claim or even exciting discovery with a great deal of scepticism. That's what I said earlier. We're in the business of falsifying, attempting to falsify existing prevailing dogmas. We're not in the business of proving something's right. We're trying to attack it.
Unfortunately, and it's understandable, newspaper articles are typically pretty vague about the details of a discovery.
I'm always asked what is the practical application of what I'm doing? I am able to give some answers but that's not really what drives me. I'm driven by trying to understand how cells work. I know I have just a general conviction as I said earlier, that it'll eventually be practical and useful. I would ask people when there's some great new breakthrough in cancer therapy to just be sceptical and if possible, if they're interested to read more deeply.
Unfortunately, newspaper articles can't dig deep enough into something and this is one of the frustrations of the commercial biomedical literature. You're a taxpayer, you pay for most of the research that is conducted in Australia and yet the scientists at Melbourne University will want to publish their paper in Nature. Scientists at institutions like the university have a licence to look at papers in Nature but you as an interested party, if you read something in the local newspaper that refers to something that's published in Nature, you don't have access to that. If you go to the Nature website and you go on and you say I want to read this article, a little sign will pop up and it will say we will charge you $30 for the privilege of reading a paper that you as a taxpayer paid for.
This is the purpose of open access. Open access is that the literature should be open for all to be able to read irrespective of their profession or location. The papers are paid for by the person who is writing them and who is publishing them and you shouldn't have to have a licence to read a paper that you paid to have the research done for.
Science for everyone, and good science for everyone.
Professor Randy Schekman, thank you for your time.
Thanks to Professor Randy Schekman, professor of molecular and cell biology at the University of California. And thanks to our reporter Dr Andi Horvath. Thanks also to the Bio21 Institute at the University of Melbourne.
Eavesdrop on Experts - stories of inspiration and insights - was made possible by the University of Melbourne. This episode was recorded on September 19, 2018.
You’ll find a full transcript on the Pursuit website.
Audio engineering by me, Chris Hatzis. Co-production - Dr Andi Horvath and Silvi Vann-Wall.
Eavesdrop on Experts is licensed under Creative Commons, Copyright 2018, the University of Melbourne.
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I’m Chris Hatzis, producer and editor. Join us again next time for another Eavesdrop on Experts.
Biologist Professor Randy Schekman received the Nobel Prize in Physiology or Medicine in 2013, along with colleagues, for his work on cell membrane vesicle trafficking - a major transport system within our cells.
A passionate advocate of the scientific method and open-access journals, Professor Schekman argues that science needs to be vocally defended now, more than ever.
Episode recorded: September 19, 2018
Interviewer: Dr Andi Horvath
Producer and editor: Chris Hatzis
Co-production: Dr Andi Horvath and Silvi Vann-Wall
Banner image: Shutterstock