Dr Rohan Baker received a PhD in 1988 from the John Curtin School of Medical Research at the Australian National University. It was here that he discovered and analysed a gene sequence for human ubiquitin. Ubiquitin is a small protein that serves as a universal signal for the degradation of other proteins to which it is attached. He has continued to research the ubiquitin pathway since then.
During 1988-91 he was a postdoctoral fellow in the Department of Biology at Massachusetts Institute of Technology in the USA, where he investigated how cells select proteins for degradation and go about attaching ubiquitin to them.
In 1991 Baker returned to the John Curtin School as a Research Fellow in the Molecular Genetics Group. He is now Head of the Ubiquitin Laboratory, where research centres on the role of ubiquitin in the destruction of other proteins (proteolysis) in the cell and how defects in the ubiquitin system affect the cell.
Interviewed by Mr David Salt in 2002.
Contents
Growing towards molecular biology
Rohan, was it something in your early life that steered you toward science?
Probably it was my family life. My father is a research scientist and he always encouraged us to be inquisitive, asking us questions about the environment and our surroundings, and getting us to think about what was going on in our lives and in the world. I guess that awakened an interest in asking questions.
What pathway in your education led you to become a molecular biologist?
Well, although I was born in Townsville, North Queensland, and lived there till I was 11, we then moved down to Sydney and I did high school there. I went on to undergraduate studies at the University of New South Wales, intending to become an organic chemist like my father. But at university I took some biology and, ultimately, biochemistry subjects to fill in my subject load, and became very interested in biochemistry as a combination of organic chemistry and biology – defining how molecules interact inside a cell, the physical properties of organic molecules and how they function in different life processes.
In my last year of undergraduate studies the subject of molecular biology was just being introduced at the University of New South Wales, and that sparked my interest so much that I carried on to do honours in molecular biology. So you see, during my undergraduate degree I gradually changed my interests from organic chemistry to biochemistry and then to molecular biology.
Yes, except for a postdoctoral fellowship of three and a half years at the Massachusetts Institute of Technology after I finished my PhD. I've been back at the John Curtin School for 10 or 11 years since my postdoc.
What is molecular biology anyway?
You now lead a laboratory in molecular biology at the John Curtin School. What is the connection between molecular biology and medical research?
Molecular biology enables us to study how molecules interact – the biology of molecules. Interactions within the cell and then within an organism underpin our normal health, and defects in those interactions can underlie many disease conditions. So understanding how molecules interact and their biology is very important to understanding what has gone wrong in many disease states.
Most people connect molecular biology with genetics. Are they the same thing, or is one a subset of the other?
I guess genetics is a more classic discipline which follows the hereditary nature of genes – of phenotypes, of how things behave. Molecular biology is connected with genetics in the sense that it is partly a study of DNA, the molecule that makes up your genes: a piece of DNA is inherited through any sort of genetic offspring. There is certainly a connection between molecular biology and genetics, but they are different disciplines. In a way, molecular biology these days is more of a technique that underpins a lot of modern research. We can use it to study many different disciplines, be they genetics or biochemistry or physiology.
An innocuous-looking signal protein called ubiquitin
Most of your scientific career has been devoted to studying the protein ubiquitin. What is it, and why is it so important?
Ubiquitin is a fairly innocuous-looking protein. It's very small, as proteins go, containing 76 amino acids – an amino acid being the basic building block of a protein. It doesn't seem to have any enzyme activity of its own, but it is very important because the cell uses it as a mechanism to mark or signal other proteins for destruction in the cell. The cell takes this little ubiquitin molecule and attaches several moieties of it (several units of ubiquitin) to a protein; that targets the protein for degradation at a large proteolytic complex inside the cell, called the proteasome. That is a collection of proteases that specifically bind to the ubiquitin component and then destroy the protein to which ubiquitin is attached. So it is not an enzyme in itself, but it serves as a universal signal for degradation of proteins.
I stumbled into it early in my PhD, when I was working in a laboratory at the John Curtin School with Philip Board to study glutathione transferase proteins. They are proteins in a cell that detoxify carcinogens we might take in from our diet or from insults like tobacco smoke. I actually obtained a gene for ubiquitin as a false positive in the first lot of screens I was doing. At the time, nobody had isolated a human ubiquitin gene, or the DNA that codes for ubiquitin in humans – there was only one paper reporting a sequence from yeast – so it was a very new area. A bit of biochemical study on ubiquitin had shown that it was involved in protein degradation, but it wasn't yet realised how fundamental this process was in controlling the activity of many proteins in the cell.
I was very lucky that the research environment I was in, with Phil Board and the Human Genetics Department, encouraged me to go off on this little tangent. Discovering the ubiquitin sequence was rather serendipitous in the first place, but it has kept me interested for the last 17 years.
What does the name 'ubiquitin' mean?
I guess the names that scientists give things must seem funny sometimes, but essentially this is called 'ubiquitin' because of its ubiquitous distribution and conservation. It's in every organism except the very simple bacteria. It is in the simple eukaryotes such as yeast, right through to ourselves, in every cell in our body. And it is the most strongly conserved protein known, the one that has changed the least during evolution. That is because it has this very fundamental role in destroying – very selectively – proteins in the cell.
Crucial roles for the ubiquitin pathway
We would all have heard that an important part of the way a cell works is by making lots of proteins. Is the destroying of the proteins as important?
It is absolutely critical. In a closed system such a cell, you can't keep synthesising new molecules without destroying the old ones. (Eventually the cell might build up and explode!) You need more synthesis than degradation because as a cell is dividing it needs to generate new material for the daughter cells it makes.
The ubiquitin pathway involves picking out, and specifically destroying, one protein from perhaps 1000 or 2000. Some of the proteins it destroys are molecules that are essential for regulating cell growth, division and development. It is critical that those proteins are produced at the right time and active, but it is just as critical that they are destroyed when the cell no longer requires them to be active. Just as the absence of a certain enzyme could be detrimental to cell growth, the overabundance or overactivity of a molecule could be detrimental to cell function, so it is critical to have a balance between synthesis and degradation. My view, perhaps biased, is that even these days the degradation aspect is a little bit overlooked. But I think it is being realised more and more how important the selective destruction of proteins is to the cell.
Might a knowledge of ubiquitin's role in this lead to any applications?
Oh definitely. In my lab my main interest is in the area of cancer research. Many of the proteins that ubiquitin is involved in destroying are ones that we might call oncogenes. They are proteins that would cause cancer if they were present at too high a level in the cell, so it is critical for the ubiquitin pathway to remove them from the cell, to stop them functioning.
One example from my research is that one of the enzymes we work on can snip ubiquitin back off a protein (one that we haven't identified yet). If we overproduce that enzyme in a cell, it can actually cause cancer; it will cause tumours in mice. So our model is that this enzyme, by snipping ubiquitin off the protein, is preventing degradation or destruction of the protein and keeping it at too high a level in the cell. And the protein goes on to promote unregulated cell growth, which is cancer.
So I'm interested in two aspects. One is the fundamental mechanisms of how ubiquitin is attached and removed from proteins, and how that regulates degradation of proteins. The other is research into cancer and other diseases where you have defects in cell growth or cell division because proteins are not destroyed before they promote too much cell growth.
Opportunities for innovative, integrative science
Is the John Curtin School of Medical Research a good place for a researcher in your field to be?
Definitely. When I first came to talk to people at the John about doing a PhD I was encouraged by the breadth of expertise and of the research questions that were being asked there. That may not have been so important 15 or 17 years ago, but now it is becoming very important that we integrate as many aspects of biological research as we can to address a question. I think the days are gone when you could just focus on your favourite technique, your favourite protein, and ignore other aspects of cell physiology. You have to integrate as many different approaches and techniques as possible, and the knowledge and expertise of other people.
The John Curtin School is an ideal place, I believe. It covers quite a broad range of research fields and its breadth means there is always someone whose door you can go and knock on to ask a few questions about something that's out of your own area. There's a lot of expertise in there that you can rely on. And there's a freedom to explore and investigate, which often leads to extremely important findings.
Where does Australia stand, then, in the field of molecular biology?
Australia is definitely out there at the forefront. I think we can hold our heads high in that respect. We've had many of the early pioneers in molecular biology, including researchers from ANU, and we stand very well in the world scene in modern molecular biology, molecular genetic research.
This field is becoming very expensive, especially to do the large-scale projects such as genome sequencing. Probably Australia can't cope financially with those. But we have contributed to the Human Genome Project – mainly through Grant Sutherland, in Adelaide – and we can certainly benefit by getting onto the more functional questions that arise from it. Now that we have the blueprint, we have to go in and find out how it all fits together and makes an organism function. Australia has always been very good at asking the right questions, the clever questions, and getting answers.
The exciting challenge of moving back into the whole cell
Your research is largely done in test tubes, outside the cell. How does this relate back to what is actually happening inside the cell?
That's a good question. I think a lot of research is very reductionist. Certainly biochemistry and molecular biology are guilty of that. You are purifying one or two components and then studying those in a test tube to see how they might interact, what consequence mutating or changing a single amino acid building-block in a protein might have for its function in a test tube. The important thing now is to put all that knowledge back together and look at the function of enzymes within the whole cell. This new, more holistic approach is the so-called functional genomics or functional proteomics.
In my research we're moving back into the whole cell, into cell biology. There are great techniques now for studying the location and movement of proteins within a living cell. We're studying how the enzyme that we know can cause cancer in mice actually moves, at certain times during cell growth, from the cytoplasm of the cell – the region outside the nucleus – into the nucleus and then out again. We're trying to understand what mechanisms regulate those movements, and where the enzyme's important function in the cell is. Is it most critical that it's in the nucleus at a certain time to function there, to prevent unregulated cell growth, or is it functioning out in the cytoplasm of the cell and just popping into the nucleus to be out of the way?
We have to understand how enzymes operate within the whole soup of a cell, which is composed of many thousands of different proteins and different mechanisms for moving proteins around. We can find out a lot of important things in a test tube, at the reductionist level, but we have to be able to then put that back into the context of the whole cell, the whole system, and understand how an enzyme or protein or DNA molecule works in that context. That's the critical area that biology is moving into.
The cell sounds like an incredibly complex place.
It certainly is. I'd love to be a 'fly on the wall', sitting inside a cell and just watching what's going on. To some extent we can already do that in living cells under the microscope, by attaching fluorescent labels to certain proteins and watching them move in the cell. We are gaining wonderful insights into protein localisation and translocation, movement around within a cell.
There are fantastic techniques available to address these questions and there's an incredible amount still to discover. Although we don't know yet know how all the blueprint information we have goes together, we can at least make a very good guess at what the various component parts of a cell would be. Now we have to go in and ask the questions. How do all those components interact in different cell types – muscle, liver, kidney? How are all those components produced at the right time? How do they function together and interact to give us the ultimate outcome of a living cell and then a living organism? This is a wonderfully exciting and challenging time to be a molecular biologist or geneticist.
You said you have been studying ubiquitin for 17 years. Some people would say that's a long time to be studying one molecule, one protein. What drives you?
Well, it's always changing. Even though I've been working on the one protein itself and the pathway it is involved in, every new discovery – whether by us or by other people working in the field – highlights more complexities in the system.
The original aspect of my ubiquitin research, for instance, was my PhD work on structure: how the DNA that codes for ubiquitin is arranged in humans, how it is expressed as the cell turns those genes on to make ubiquitin protein, and under which conditions. Then my postdoctoral fellowship work moved to the functional aspects: how the cell selects proteins for degradation and goes about attaching ubiquitin to them. And ultimately I got interested in enzymes that can actually cleave the ubiquitin back off proteins. They could not reverse degradation but they could reverse the signal attachment in the ubiquitin and thus perhaps prevent proteins getting degraded.
My research has always been on the ubiquitin pathway, because it is such an important, fundamental pathway. But the focus changes as new research aspects emerge, and that's what inspires me and keeps me involved.
Should pure research like this be commercialised?
It's a very important goal to have; I'm certainly interested in it and I have several patents coming from my research. I'm just not sure that it should be the focus of our research. To me, the more important focus is to understand fundamental mechanisms in cell biology so we can really understand how a cell works in the normal situation. Then we have a great base from which to study diseases, working out what's gone wrong between the normal state and the disease state, which we can then try to address. We must know about the normal state of not only our pathway but every other pathway in the cell, because if we manipulate a certain pathway in disease, we don't want a detrimental effect on other pathways. So it's important that we have a very thorough, basic knowledge of cell function.
We should certainly commercialise any aspect of our research that we can, but not as a primary research goal. Rather, it is the accumulation of knowledge that will help us down the road.
What traits need to be in a scientist's kitbag?
What skills are necessary for a scientist to make it these days?
Many skills, I guess. You need to be fairly dedicated to the work, especially when you are driving your own research program. You need the ability to focus your efforts on a problem. And these days there's more and more information to be aware of, so you must be able to seek and find information, by the internet or from other sources.
Most of all, you need the ability to put together lots of different pieces of information into a coherent story, a nice set of questions to follow in a coherent research program – and that requires diligence and dedication.
You said that discovering the ubiquitin sequence was quite unexpected. Is it an important aspect of science to be able to follow a clue, a chance discovery, to see where it might take you?
Oh definitely. I think of Pasteur's famous quote about chance favouring a prepared mind. You do need some focus in research, but you have to keep your mind open to other possibilities in what you are discovering, and even go off on a tangent at times.
Career underpinnings: experience and encouragement
What would you advise a keen young student of science to do if they want to get into the field of molecular biology?
I believe you've got to get out there and knock on doors, try and get yourself into a laboratory and experience getting your hands wet, getting them dirty. I've found a big difference between doing a biochemical practical class at university and actually being out in a research lab and working. Most universities and institutes run some sort of summer scholarship or work experience program. Because my father worked in a research company I was lucky enough to get work at the bench in my summer breaks from university, and now in my own lab I take as many vacation scholars, summer scholars, as I can. It's a great opportunity for people to try the science for themselves and see if they like it – very different from learning about it at university.
Is it important for a scientist to spend time overseas as a part of training for a research career?
I'd strongly recommend it. For me, going to MIT was a great opportunity. It opened my eyes to a big research institution and how things are done elsewhere in the world. MIT was a fairly high-pressure place, with a lot of high-profile scientists, very big names in their field. Indeed, the whole Boston environment was good to experience, with Harvard and Tufts Medical School and various other schools. A lot of good people come in giving seminars, and being there is a very good way to keep up to date on cutting-edge research.
It also gives you the chance to appreciate what a good place Australia is, and I must say I was very happy to come home to Australia and continue my research here. There are certainly goods and bads about both systems, but there's no place like home.
Have you had any mentors? Have any people made a big difference to your career?
I think scientists on the whole are very good at helping each other – mentoring, if you like, giving a shoulder to lean on and being there to give advice and opinions and help when you need them.
But two people have stood out in my career development, I'd say. My father encouraged me to get into science, and to ask questions in general and think about things around me. And I have mentioned that Phil Board allowed me the opportunity to pursue my own interests in his lab, which wasn't really working on ubiquitin at all. He realised the potential of this pathway's importance in regulating cell metabolism, and gave me the freedom to investigate that.
You are a director of the Australian Society for Medical Research. What does it do, and why are you associated with it?
The Australian Society for Medical Research (ASMR) is the peak body in Australia to promote the awareness of medical research, both to the community and to government. That is a very important aspect of doing research but is often overlooked.
I think we should see it as part of our job as scientists, and also an obligation, to get out and communicate our results to the public. Often they fund our research through their tax dollars and, after all, in medical research we are working in the hope of curing or treating different diseases. But as well as communicating our progress, we need to communicate that it's not an easy path to follow – it's an incremental set of steps to find how to cure diseases. Just as important is convincing the government of the need to fund medical research in Australia to an adequate level. It's financially beneficial, anyway, because prevention is always better than cure.
I see the Australian Society for Medical Research as a very important vehicle in that lobbying and communicating, so I am one of the board of directors of the society and we are very active in promoting medical research, both to government and to the public.
What are your other interests away from the lab?
The first one would be my family. I've been married to my high school sweetheart, Chelsey, for 17 years – ever since I started my PhD. We now have two young children (Merryn and Jackson), aged five and two. It's always great to go home to them. It really lets you unwind. You can forget about the pressures of the lab or what didn't work today, and just have fun with your family. I'm also lucky to have much of my larger family in Canberra, and my Mum has been a great support to us.
I'm quite interested in music, and at work we've started a band called 'The Major Groove' – a very poor pun on the double helix structure of DNA. (The two DNA strands give you a minor and a major groove.) That's just a bit of a release, I suppose. We've started playing a few after-dinner dances on the scientific conference circuit, and it's fun to have a bunch of scientists up on stage playing to another bunch of scientists.
Also, I have a love of carpentry and I tuck myself away in the workshop and make bits of furniture and things like that.
Looking forward to more research
You've been enormously successful in your career to this point. Where do you think you might be in 10 years' time?
Well, I hope that in 10 years' time I'll still be a full-time researcher. It is getting more difficult to secure sufficient funding for all the things that I want to do, but I am quite certain that I want to go on being a research scientist. I imagine I'll still be in the ubiquitin field somewhere and driving my own research lab.
I guess there are times when you feel a bit down about it, mainly because of the uncertainties in obtaining sufficient funding – not just for yourself but for the people in your lab as well. You need funding for postdoctoral fellows and lab technicians, and it's very uncertain for them too. So yes, there are days when I think about what else I'd be doing, about packing it in. (Maybe if I wasn't in science in 10 years I'd be a music-playing carpenter!) But no, really I'm sure I will still be here.
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