Dr Joel Mackay studied organic chemistry at the University of Auckland, receiving a BSc and an MSc. In 1990 he won a Commonwealth Scholarship to study at Cambridge University, where he looked at the mechanism of the action of antibiotics at the molecular level. Having received his PhD from Cambridge in 1993, Dr Mackay worked for a year as an experimental scientist at the CSIRO Food Research Laboratory. He began his present association with the University of Sydney in 1995, initially as a postdoctoral fellow, then as a research fellow, and now as a senior lecturer in the School of Molecular and Microbial Biosciences.
Interviewed by David Salt in 2002.
Joel, you were the first person in your family to go to university. What led you into science?
I guess I have always been interested in science. When I look back to my youth I remember being curious, spending a lot of time looking around me and reading about things, and always asking questions – sometimes to my parents’ frustration. Probably that was why I so often got encyclopaedias as presents! I’ve always had an interest in understanding how things work and trying to figure out things that people don’t already know. I always wondered, ‘Can you find out new things?’
At the age of 34, you are now the head of your own laboratory and recognised as one of Australia’s leading young molecular scientists. What pathway led you to this point?
It has all seemed very natural to carry on with the path from my undergraduate degree, to research at the University of Auckland, and then a move to England and later back to Australia. I enjoyed keeping on with research all the time, and people were prepared to support me, to pay me to do it. It always seemed so natural, and I can't think of any alternative that I would have enjoyed more.
Have any mentors influenced your science career?
I think the first person that really had a serious influence on me as a scientist was a teacher in my last year at high school in Auckland. The school was a good one, and most of the teachers were good, but this guy stood out because of his passion for what he was teaching. He was an exchange teacher from England, which was unusual, but the most unusual thing was that he had a PhD.
Most science teachers have done a bachelor’s degree in science, maybe an honours degree as well, but because they then go into a school their interaction with real science, with research science at the cutting edge, is relatively limited. It’s not their fault; that’s just the way it generally is if you are a full-time teacher. This guy, though, had done the three or four years of his PhD and then had been out in industry, doing research himself. He had been at the forefront of science, doing new work and making new discoveries, and I think that was why he was able to make things more relevant and provide much more context to us than someone that had just come out from an undergraduate degree and gone into teaching. He had much more of the excitement of science in him, and he was really able to communicate that to the students.
You studied for your PhD at Cambridge University, one of the world’s finest institutions. Did you gain from being there with other researchers?
When I was at Cambridge, I didn’t think much about the research being done by any of the people ‘down the corridor’. They were just there. But I realise now what an incredible hotbed of intellectual discovery Cambridge was. Some of those guys down the hallway were in contention for Nobel Prizes; many were already world leaders in the sort of research they were doing. Not until I stepped back from being part of the place did it become clear how incredibly invigorating it was. You can see now that the people you got to meet, and the people that were always coming through your department from other places, and also the people you were working with, many are now starting to lead their own fields, in their own chosen areas. It was a great opportunity to make contacts, to meet interesting people and just to be involved in this community of such high-profile people.
How would you describe your type of science?
The work we do is very much trying to understand processes that happen in the bodies of all organisms. We want to understand them right down at the most fundamental level, at the basic molecular level, to find out how individual protein molecules and individual pieces of DNA actually interact with each other and how their interactions allow all of the functions that go on inside us to be carried out.
We focus on one particular area, DNA transcription, trying to understand how that works. You can think of that as part of the process by which different cells in different parts of your body are able to carry out different functions. Every cell in our bodies contains exactly the same sequence of DNA, and the sequence of DNA that we have – our genome – is a blueprint that describes everything about us. And one of the fundamental questions in biology is how all these different types of cells can arise when they all contain the same information. A cell in your heart and a cell in your brain both contain exactly the same DNA, but clearly they have very different functions, they look very different from each other and a lot of the chemistry that they carry out is very different. So for some time now our interest has been in understanding how this differentiation can occur.
What types of projects are you currently involved in? Maybe you could give us some examples of your lab’s work.
One of the things we focused on very early is how specific protein molecules can attach themselves to DNA and to other protein molecules, how these large complexes of proteins can be built up surrounding pieces of DNA, and how they can then control how certain genes are switched on and switched off. You can understand processes like that at all sorts of different levels; we are trying to understand at a very fundamental level how these individual molecules can interact with each other – how strong these interactions are, and how specific, and also, when these interactions take place, what effects they have on which genes are expressed and which are not.
One thing we have been interested in is the development of blood cells, because that is one of the best understood developmental processes within mammals. So we have focused a lot of our work on how specific proteins that are involved in blood cell development interact with each other and with DNA to control the development of blood cells.
That work then has led us on to looking at how some of these specific types of proteins are suitable for the processes that they carry out, such as for binding to DNA, or for interacting with other proteins. We know proteins all have different, very specific shapes that allow them to carry out their functions, so we have tried to understand why these specific structural motifs – these specific shapes – are suitable.
Some of these shapes seem to be very, very robust and able to tolerate lots of mutations (changes in their amino acid sequence). And so we have realised that these different structures may be actually very useful as a kind of designer drug system. That is, you can take a specific protein shape – a molecular scaffold, if you like – and introduce changes onto its surface so that the scaffold is then able to interact with a target such as some sort of protein or other molecule that has gone haywire and is giving rise to a disease condition, for example. Indeed, a lot of cancers are based around one or more proteins doing something they are not supposed to be doing, or doing far too much of whatever they normally do. So if we can make specific designer molecules to target those recalcitrant proteins, we might have a good chance of blocking their bad effects and the diseases they are causing.
How do you figure out the shape of a protein, of a molecule? They are too small for you to take a picture of them by microscope, aren’t they?
That’s right. They are about 10 times smaller than the scale that the most sophisticated microscopes – electron microscopes – can look at. There are basically two experimental methods that can be used to determine the shapes of proteins by ‘looking’ at them indirectly. One method is X-ray crystallography: essentially, X-rays are fired at a sample of your protein, which is in a crystalline form, and the way those X-rays are scattered can tell you the shape of the protein.
We have used another method, nuclear magnetic resonance spectroscopy (NMR) – for which Kurt Wütrich was awarded the Nobel Prize in Chemistry this year, in 2002 – because it has been the most suitable for the proteins we’ve been looking at. In a way it is more complex to understand, but it works by taking advantage of the fact that a protein molecule may contain thousands of hydrogen atoms. If we irradiate the protein with radiofrequency radiation – basically radio waves – the individual hydrogen atoms will respond and absorb some radiation. And then we are effectively able to measure that absorption.
The key feature is that we are able not only to measure the absorption of radiation by an individual hydrogen atom, but also to see correlations, or connections, between pairs of hydrogen atoms that are close to each other in the structure of the protein. Now, imagine that a protein has thousands or hundreds of thousands of hydrogen atoms all over its surface and all over its inside as well, and that you can create a map that tells you the distances between each pair of those atoms. Essentially, that allows you to describe the shape or the structure of the protein. And that’s the method that we use by choice.
It sounds like working out the sizes of jigsaw puzzle pieces, and how they might fit together.
That is an extremely good analogy. It’s a cross between a jigsaw puzzle and a logic puzzle. You have a whole wealth of information in front of you, and you have to sift through that information and make connections between, in this case, pairs of hydrogen atoms or a larger series of hydrogen atoms. You have to try and find an answer to the problem of identifying which hydrogen atoms are which, and which ones are interacting with which others, and you have to find a solution that is entirely self-consistent.
You start off by saying, ‘Let’s suppose for a moment that this hydrogen atom is such-and-such. If that’s the case, that leads me to conclude that this one must be something else, and this one must be something else again.’ And you are led through this series of deductions, until either you find an inconsistency and you have to go back because one of your assumptions wasn’t correct, or you come to an entirely self-consistent solution in terms of the identities of these hydrogen atoms and the connections between them. So it is very much like a jigsaw puzzle.
Do nuclear magnetic resonance and X-ray crystallography produce actual pictures showing the molecules?
Ultimately yes, and you do get to see what the shape of that protein molecule is like. As to the sort of information that arises initially from NMR spectra, the NMR images that we obtain are initially not direct images but a list of connections between pairs of the hydrogen atoms contained within the protein. So if your protein has a thousand hydrogen atoms in it, analysing NMR data will allow you to extract a whole list of distances between pairs of them. You will be able to say, for example, that hydrogen atom A in the protein is about five Ångstroms – 0.5 nanometres, which is 0.5 times 10-9 metres – away from hydrogen atom B, and hydrogen atom X is five or six or seven Ångstroms from hydrogen atom Y.
You can feed a list of hundreds or thousands of those individual pieces of information into a computer program, together with the amino acid sequence of the protein. (Remember, a protein is a linear polymer containing a whole series of amino acids.) And if you tell your computer program, ‘This is the amino acid sequence, and hydrogen atom A is next to hydrogen atom B, and X is next to Y,’ and so on, the computer program will use that information to fold up the protein chain – to take this linear chain and contort it into a three-dimensional shape that satisfies all of the individual pieces of information that you have provided. Hydrogen atom X ends up being five Ångstroms from hydrogen atom Y, and so on. And what comes out of that is your picture of the protein molecule.
And these pictures are the basis on which you will create designer drugs?
That’s right. Probably 80 or 90 per cent of the drugs that are available now have been discovered by random screening events, where a particular target is simply screened against a library of thousands or tens of thousands of different potential drugs – and, simply, the ones that have an effect are chosen. In that sense it is not a rational design system but a random system. There is nothing wrong with that. It has produced almost all of the drugs that we use at the moment.
But the alternative, rational approach, involves knowing in exquisite molecular detail the shapes of the proteins that are your targets. This is because, if you know the shape of your target, you can alter the shape of the scaffold that you want to use as your drug so that it fits in to a specific cavity or a specific groove on the surface of your target. And one way to do that efficiently is to know the molecular structures of both the target and the drug that you want to make, and see how they fit together.
Where do you think this work might go over the next 10 years?
There are two branches to what we are interested in. On the more applied branch – working towards discovering designer drugs – a clinically useful product is probably still more than 10 years off. I would hope, though, that by the end of 10 years we would have a very good understanding of these specific protein structures and how we can manipulate them to make them interact with specific targets.
Meanwhile, we want to get in place a whole wealth of information for a complete picture of how these structures are able to be changed, how they are able to tolerate change and how they are able to be modified to interact with specified partners. I think that will put us in a very good position to attack specific targets of clinical interest, and I hope that over a 10-year time frame we will be able to start actually targeting specific clinical problems.
Could you give us some examples of some clinical problems – diseases, cancers – that this might be solving?
Cancer is certainly a very good candidate, because a lot of different types of cancer, particularly blood-cell cancers like leukaemias and lymphomas, are often caused by one or more proteins being ‘over-expressed’ – made in much larger quantities than they are supposed to be. The effect of this over-expression is normally to stop cells from differentiating into the specific types of cells they are supposed to be, such as red or white blood cells. They are held in an immature stage where they just keep dividing and dividing, and basically this uncontrolled division is what cancer is. Because these cancers are so often caused by one or more specific proteins, which in many cases have been identified, we have good targets to aim at. For example, it is known that a specific protein called BRCA1 is very strongly implicated in causing breast cancer. So there you have a molecular target which you can potentially design your designer protein drug to inhibit.
You have chosen to work here. How does Australia rate in molecular biochemistry?
I think Australia does well. Some research fields, obviously, involve enormous capital outlays which to some extent will inhibit Australia in competing, but in an area like molecular biology or structural biology, which I’m involved in, Australia is certainly in a position to make a substantial, significant contribution. We have a set-up at the University of Sydney which is as good as many of the other institutes that I have visited around the world. We’ve gained access to a whole host of different experimental techniques that are essential if we are to figure out what the structures of individual proteins are like and how those proteins work.
I see no reason in principle why I can’t make a contribution here as large as those of many people from other places in the world. In this day and age it is so easy to collaborate with people overseas – I have a number of collaborations with people in the United States and in New Zealand, for example – that there is really nothing to stop you from becoming involved in high-profile work that is being carried out on the other side of the planet. So I don’t see Australia’s geographical position as a great hindrance these days.
In fact, the most high-profile drug so far to have come out of the designer drug type discovery system was discovered right here in Australia: the anti-influenza drug RelenzaÔ. That drug was discovered by Biota, a small biotechnology company based in Melbourne, who looked at a particular protein that is essential for the life cycle of the influenza virus. Because they were able to examine its shape in atomic resolution detail using X-ray crystallography, they were able to see the shape of a particular cavity on that protein’s surface and to design a specific small molecule that would fit precisely into that cavity. It then made a whole series of specific interactions that inhibited that protein, an enzyme, from carrying out its normal function. That really is one of the first from the generation of designer drugs. And it was quite nice that the work for it was based right here in Australia.
You are not only doing science, you are managing a team of researchers. What is it like to lead a laboratory?
I find that leading a laboratory is fabulous fun. There is the opportunity to be constantly involved with PhD students and postdocs, people who are young (not that I consider myself particularly old) and bright and enthusiastic. They’re not there because it’s going to make them a lot of money or because the profession brings some sort of status, but because they want to be there. They want to be doing research, to be discovering new things. And to me the excitement you get when you discover something, when one of your students discovers something, is definitely not to be missed.
You have got a deep experience and training in science. Do you find you need extra skills in order to manage people?
Certainly I was trained as a scientist, but once you start to run a lab you end up being a manager as well and that requires a completely different set of skills – skills that, obviously, I haven’t had any formal training in. But formal training probably isn’t really the answer to something like that. It’s probably something much more natural. You may be someone who has an affinity with your students and with people in your lab, someone who can gauge their moods and what needs to be done to encourage them or to keep them interested or happy. Some people will be able to do that but some people may just not be very good at it. I don’t think formal training would necessarily make much of a difference.
To some extent, probably, you will find that successful labs are run by people who enjoy being with the people there. They aren’t managing a group of people because they’ve been told to, but because they enjoy having those people there and interacting with them. I think that’s very important.
Joel, you are into long-distance running. As you are running along, are you planning your next experiment or do you leave the lab behind?
I guess it’s a combination of the two. It very much depends on what day it is. Some days, it is a great opportunity to not think about anything at all but just look at the scenery – I prefer running in the bush. Often, especially if it’s technical running, you are spending enough time trying to concentrate where your feet are going without thinking about anything else. So it’s a nice way to switch off. But in other situations it is a nice way to just mull over things, and not infrequently something will pop into your head that you wouldn’t have thought about if you had been sitting at your desk, surrounded by a load of different distractions.
What else do you do when you get away from the lab?
A lot of sport, I guess. I play quite a bit of indoor soccer, and I do a lot of rogaining, which is like a long-distance version of orienteering, out in the bush looking for specific checkpoints from a topographical map over a period of 6 or 12 or 24 hours. I quite enjoy doing that. And bushwalking and cycle touring are two of the other outdoor things that I like doing.
If a young student was considering a career in science and was keen on getting into research, what sort of course would provide the best base?
There is a variety of different ways you can go. In our Department of Biochemistry there are some people with very strong chemistry backgrounds, some with strong physics backgrounds, and others with strong biology and genetics backgrounds who have done relatively little chemistry or physics. It very much depends on the area you’re interested in, but certainly if you are trying to understand things at a molecular level, if you really want to zoom in on the fundamental processes at a very, very basic level, then courses in chemistry, physics and maths are very important.
You can almost get by as a biochemist without having done any undergraduate biochemistry. I am pretty much in that situation myself. But when you have a basis of chemistry, physics and the like it is much easier to come into something like biochemistry or biology, which is relatively descriptive, than it is to try and go the other way – to start from a biological background and become more chemical or more physical. So in some sense I would recommend a path that included chemistry and physics, but there is no question that people are very successfully doing great science in biochemistry without having backgrounds like that.
For me the great thing about science is discovering things that have never been seen before. I really try and reinforce that point to the students working in my lab, because sometimes when you’re working from day to day on a project you get caught up in the small picture, in making very small, incremental steps towards discovering something. I try and remind the students, ‘When you discover something, when you do get a result, basically you’re looking into a part of the world that no-one has ever seen before. You’re seeing something for the very, very first time. No-one in the history of the world has seen what you’ve just seen.’ It’s a very exciting thing to be looking into the face of nature, into a place where no-one has ever looked before.
© 2022 Australian Academy of Science