In Conversation

Over fifteen years ago Dr Julia Horsfield was working on a way to disrupt the defensive coat of HIV, the AIDS virus. Her approach is only now bearing fruit. She describes how much patience, commitment and even passion are needed to make science work. She has long been outspoken about the need for proper funding for research in New Zealand where she lives.

Transcript

This transcript was typed from a recording of the program. The ABC cannot guarantee its complete accuracy because of the possibility of mishearing and occasional difficulty in identifying speakers.

Robyn Williams: Good evening, Robyn Williams with In Conversation, this time coming from a very chilly Dunedin on the South Island of New Zealand. And that's the centre of some really top rate scientific research, interesting in a town of just about 20,000 folk not too far from the South Pole. Well, closer to it than most places. Fascinating to see how great scientific centres grow and flourish. Princeton in New Jersey that reminds you of The Sopranos, the Universities of Arizona, both of them down in the red desert, Cambridge in England in the icy fens and the University of Otago, as I said, one stop before Antarctica.

Julia Horsfield is based there; she's a pathologist and has a recurring association with fish, as you'll hear. Julia you're not actually from here are you, where did you grow up?

Julia Horsfield: So I grew up just north of Wellington in a place called Partanui, a kind of a lifestyle block situation, and my folks grew herbs and I had a pony and it was all very idyllic.

Robyn Williams: Herbs I see, reminds me of the 60s - New Age?

Julia Horsfield: Yes, if you like basil and oregano it's more like salad ingredients than any other I guess.

Robyn Williams: Nothing to do with medicines or pathology?

Julia Horsfield: No, not at all but it was my Dad who convinced me that I should be a scientist so, 'you must do science', he said, so I did.

Robyn Williams: Did he have a background directly in science at all?

Julia Horsfield: He was a marine engineer to start with and had a sort of strong maths and engineering background and he is a very inventive guy actually. If you go up to central Otago you see some salmon farms there and hydro canals and my Dad designed and partially built those rafts that you see there today and started that company. So he's a very innovative guy.

Robyn Williams: Without being distracted from you of course, what did he decide to do about all the sludge, all those terrible noxious substances that come out of fish farms and turn people off?

Julia Horsfield: Well what actually happened was that the native trout and salmon tended to eat all the waste and when Dad was setting up these farms there was a bit of an outcry from the Fish and Game Council, oh you know, the waste will poison the rivers. But it turned out the waste increased the fish stocks so much that the fishing up there is really good now and there's plenty of good fish to catch in those rivers. The rate of current movement through those canals is up to 2 cumiecs which is cubic metres per second so it's pretty fast so it carries away stuff pretty quickly. So there's not much sludge around I don't think.

Robyn Williams: Well I mention it not simply because it's always been a problem that people bring up when they mention aquaculture but it just so happens a couple of weeks ago on the Science Show I did an interview in northern Queensland to talk about ways in which algae, certain ones they are using as sort of biofuels, love fish sludge -- the more noxious and ghastly the better -- they just gobble is up, and out of it comes the kind of fuel that is very useful but doesn't require land, so there's no competition between the land use and so on. So there are ways developing for the use of stuff out of fish farms and I was just fascinated to hear your example as well. What is your father doing now?

Julia Horsfield: So right now he's part-owner of a cinema and I believe he's working on a book, so yes, watch this space.

Robyn Williams: Do you imagine that you'd have gone into science if your father had not convinced you it was a good idea?

Julia Horsfield: I don't think I would have, actually. I don't think I quite went the way he wanted me to though so I'm very much in favour of basic science, discovery for discovery's sake, in a way, and I think my father would have wanted me to have a more of an applied mind, to do something with my science and make a buck, essentially.

Robyn Williams: Be more directed. Now I think plenty of people have shown that there's evidence that most of the best applications come from basic science rather than the kind of applied stuff directly.

Julia Horsfield: Yes, well that's what I really believe and there's plenty of examples of that. But I only have to look back on say my own PhD experience to see evidence of that. I started my PhD at the University of Otago in 1992, working on a pioneering method to disrupt the replication of the HIV virus and, 15 years later, finally there's a drug testing system in place to see if we can find drugs to interfere with that process. And it's a delight to come back to Otago University and see they are so close to being a marketable and useful tool in medicine but it took 15 years to get there and it was really from basic scientific discoveries that this is what emerged.

Robyn Williams: Tell me what the problem is, HIV is so incredibly cunning, it's always one or two jumps ahead -- how did you think that you might be able to pre-empt it somehow and vanquish the creature?

Julia Horsfield: Well this research comes primarily from Professor Lauren Tate's interest in how messengers that encode proteins are actually translated into the proteins that are necessary for viral replication. So in the HIV virus the messages are compressed so that two proteins can be made from the same message, whereas usually genes encode one message which gets translated on to one protein. So HIV has messages that overlap, so you get two proteins from the one message and the production of these depends on a shift in the reading frame of the message, so that you get these two proteins that are produced. And it's a hallmark of viruses such as HIV that are retroviruses, the premise was if we could interfere with the frequency with which the two proteins are produced from the one message then we could prevent HIV from replicating properly and producing the right ratio of proteins.

The premise hadn't even been tested when I started in the lab and so really that was the first thing to do. Now it's actually been proved that you can alter the frame shift efficiency to produce different amounts of proteins and that completely disrupts viral replication.

Robyn Williams: At what stage though does it disrupt it when it's not yet done its damage? In other words can you use it to stop the thing taking off in the body?

Julia Horsfield: What it does is it stops it making the right number of coat proteins per replicated particle in the virus. So if you think of a virus as a little teapot and the coat proteins are like a tea cosy that goes around the teapot, if you disrupt the ratio then you might have a lot of teapots about the place but no tea cosies to go around them, or not enough tea cosies. And it's only the ones with the tea cosies that can get out of the cell and replicate. The way the virus is set up so that it makes exactly the right number of proteins that would make a tea cosy for one and every teapot that makes the virus.

Robyn Williams: So 15 years later someone has actually helped crack the story that you tried to set out to tell? Before we talk about the rest of your life, when is there going to be a drug or some sort of therapy the stems from this work?

Julia Horsfield: So right now there is, as I understand it, there's a viable platform on now which these drugs can be tested because it's not really possible to predict what certain drugs might do. You need a large high through port format to test different compounds as they come along to see if it's going to affect the ratio of the proteins. And to do that you need a really viable system and it's taken 15 years to set up that system. Maybe it will take another 5 years or more before effective drugs are found but the reason I wanted to talk about this is that it just illustrates how long it can take from an original idea to develop into something that is saleable at the bench or be turned into a drug that will help people. And so when we think about targeted research we shouldn't be thinking in terms of 3 years or even 5 years, we should be thinking in terms of 20 years or maybe even 50 years before we get revolutionary outcomes.

Robyn Williams: Even though during the war, the Second World War of course with penicillin it took them about three but they were concentrating pretty hard. After your PhD then what happened?

Julia Horsfield: I've always had a long standing interest in developmental biology and I chose to do a post doctoral fellowship in the lab of Rob Saint and Helen Richardson who were working at the University of Adelaide at the time in drosophila genetics in the cell cycle. What I really got interested in there is how the cell cycle is co-ordinated with the animal development such that cell division in developmental processes need to be controlled together so you can get a whole animal from a single cell during embryonic development.

Robyn Williams: Getting that story out has been one of the world's great challenges hasn't it? How one blob that's pretty much the same manages to divide and produce slightly different blobs with the same DNA in each cell. Some decide to become brain cells, some decide to become stomach cells, I was going to say blood but of course blood cells, red blood cells don't have DNA in the middle, they dispense with it. So where did that take you?

Julia Horsfield: I'm really still interested in the actual concept, in fact it drives my research even today and Rob and Helen's lab are really interested in how cell cycle regulators -- that is factors that control cell division -- per se can be integrated with developmental signals that tell the cells what to be. So when an embryo develops there are certain developmental signals that a switched on at certain times and they tell an embryo where to put the head, where to put the arms and the legs, and it turns out that these development signals have to speak to cell cycle regulators to tell a cell to either keep dividing, we don't need you to be anything yet, or stop dividing it's time you were a fingernail or something. Now I'm actually working on kind of a reverse pathway where cell cycle regulators themselves are feeding back to development signals saying well I have divided, I'm waiting for information to tell me what to do next. But I believe I think that cell cycle regulators have frequent duel functions and telling cells whether to divide and also informing developmental processes. This is something that has been emerging in recent years I think.

Robyn Williams: Well let me just ask you the question, I have a picture, just imagine an organ, the heart, there might be from what you say a kind of mission control where the instructions come out. Now I was told by Dennis Noble, who is one of the great heart researchers in Oxford, that this is absolutely not the case, that you do not have heart cells being governed from a kind of centre bit...and so it's almost mind boggling frankly when you think of the trillions of cells have all got to be developed at roughly when they are supposed to be, you know as you grow up you get juvenile cells and then there are massive signals going out to mature and become sexually adult in all sorts of ways. And all this co-ordination is going on and yet there is no in each organ mission controls -- so how does it work?

Julia Horsfield: That's a very good question and I think a lot of energies are going in to finding out how these sorts of things work. Some of the things you are describing can be applied to regeneration research and things like tadpoles or even fish -- you can chop off fins and they'll grow a completely normal fin back, or a limb back. And what people are trying to understand is how the positioning information of a cell instructs it what to be.

So while there is no centre control in a cell telling it that it's part of an arm or a leg or a fin there's something to do with the environment that the cell is in that then instructs it how to behave and how much to proliferate and then what to do once it has finished proliferating. And I think there's another whole area of research that is going into discovering how do limbs know how big to be -- so if we grow arms, legs and hands how do they know when to stop growing and be a particular size. They are all in quite good proportion and nobody really knows why that is. A great many researchers are trying to find that out. I'm not one of them but it's a very interesting area.

Robyn Williams: I don't remember seeing someone whose one arm is gigantically bigger than the other arm, somehow most of the time it seems to work, doesn't it?

Julia Horsfield: Yes, that's right so it's really fascinating. So while we often think we've discovered a lot about biology and that we know a lot of developmental processes that control it, there's a whole lot we don't know that's really, really fascinating, I think. And also in regenerative biology it's very important to understand that process so that maybe some day we can figure out ways to heal things like spinal injuries or grow back hands or limbs or bits of organs that we're missing.

Robyn Williams: And that being isolated and focused shouldn't be that difficult.

Julia Horsfield: Oh I don't know but I think you'd be on to a winner there if you could actually grow teeth.

Robyn Williams: A third generation of teeth. OK well that's where your mind was working over this broad area of how bodies work. What are you focusing on now?

Julia Horsfield: The last eight years before I started my job at Otago I spent in a Zebra fish lab with Phil and Cathy Crozier at the University of Auckland, and that lab is particularly interested in blood development and how proliferation and differentiation are balanced in blood with regard to diseases like leukaemia.

So we really wanted to understand the basis of normal proliferation versus leukaemia using the zebra fish as a model to do that. I started out there doing a genetic screening of the fish. So what this means is that it means randomly mutating genes in a fish and then looking at the blood to see if you can see changes that might reflect leukaemia or changes on the patterns of where genes are expressed; so as to inform whether you've done something to blood development. So the screen took a number of years and I found a mutation that when the mutation was homozygous in the fish these fish lacked blood and they also distinctly lacked expression of a particular gene that's necessary for blood development but only in a certain time and in a certain place.

And the same gene is involved in leukaemia --then the hunt was on to find out what was the mutation that I'd created in these fish. And what it turned out to be was a mutation in a cell cycle protein, so back to the old cell cycle and development story again. And the cell cycle protein is a protein that's involved in holding chromosomes together when cells replicate, so when a cell replicates it's like you have pairs of socks and each sock is a chromosome. When you want to separate the sock it helps if you have them all paired up in the first place, so if one person grabs one sock and one person grabs the other sock, if you have seven different coloured pairs of socks then each person will have a sock of the right colour.

Robyn Williams: I think you've heard of the blind man conundrum?

Julia Horsfield: Yes, that's right so I'm stealing that.

Robyn Williams: Yes, the a professor in Oxford posed the puzzle in fact I've broadcast it on the Science Show where these two blind men go out to buy socks and for some reason their wives, as he said it, his story, their wives insisted that they get different coloured pairs and for some reason the woman who was serving them in the shop got terribly confused and separated, well in fact had them -- not in each blind person's bag, you know, a full set each -- instead they were all mixed up. And so the puzzle was how do you make sure that these blind men are able to choose on their own, without any guidance, without there being anything different about the socks, a full set of each colours. And of course the answer is that you've got this connecting bit at the top and each blind man gets hold of either end of one pair and pulls and this pulling represents exactly what happens in cells during cell division. And of course the little bit at the top is the key thing that was being investigated. OK so that's the story as was told -- now back to your story.

Julia Horsfield: So I'm afraid to say it's the same story but it's such a nice analogy that I thought I'd steal it and the bit at the top, the socks, is actually the same protein that I'm studying in my lab now. And it turns out that this protein not only has a role in the chromosome or sock separation, it has a role in animal development and gene expression as well and recently, just a couple of years ago now, human syndromes were found to be associated with mutations and the components of these proteins or the ability to stick them onto chromosomes in the first place. These human syndromes aren't merely as a result of not being able to divide your cells properly; they seem to have specific defects that reflect specific developmental abnormalities. And the feeling is in the field that these developmental abnormalities arise as a result of mistakes made during development as a result of certain genes not being turned on or off at the right time during development.

The question now is what's chromosome glue essentially, or sock clips, what to do with animal development and how on earth can these proteins regulate these different genes during development. And so my group is using the zebra fish as a role model to try and understand what these proteins are doing because in fish we have a distinct advantage that we can see the animal develop so it starts as a single cell inside of a transparent fish, and can grow this into a fully patent animal in about 24 hours so we can see all of that in real time under the microscope which makes it a very powerful tool for studying such things.

Robyn Williams: And of course these parts of life are pretty much the same whether a cucumber, a human being, a fish or whatever, presumably what you learn in the fish could be understandable for people.

Julia Horsfield: That's right. Invertebrate development in all animals a lot of the same processes are reused over and over through evolution to instruct fish how to develop. The same as flies, with mice and people but because the next best model being mammals we can't really observe them developing in real time because they are developing in utero, so it's really helpful to use fish and amphibians because you can see them developing outside the mother and you can use a number of different tools to visualise their process and see what goes wrong. For example if you disrupt chromosomal glue and see what sort of malformations happen and why they are happening. So what we are trying to find out is what genes are going wrong are not being regulated properly when this chromosomal glue molecule is missing aside from this normal processing cell division.

Robyn Williams: And of course that's basic science but who knows where it might lead. What does your father now think of the work you are doing?

Julia Horsfield: I still have frequent arguments with him.

Robyn Williams: He understands the fish but he doesn't understand necessarily the rest.

Julia Horsfield: Yes, I think when I started out in science I knew a lot less and I think humans in general knew a lot less than we do now. I think it's staggering the ground that we've covered in the last 20 years and I'm absolutely thrilled to be part of that process but I fear that we needed to keep talking about it and passing on those ideas to our mums and dads so they still understand what we're doing.

Robyn Williams: As well as young people. Now you do a tiny bit of science communication and it's a struggle because some of the concepts that you describe -- what is a gene, what is cell division, you use the words homozygous just now which I didn't bother to catch you up on because the story was quite plain but those sorts of things are hard to get across, especially to young people who get restless. How have you found the response to be amongst young people say here in New Zealand?

Julia Horsfield: Generally people really do want to know what we are doing as a scientist. I think the onus is on us, the scientists to find effective ways of communicating our science to people and I'd like to think that we can learn to do it in a more direct and more accessible fashion than we do now. And it's a learning process, like you said, it's very, very difficult to find the right words to describe something but I believe that young people really are interested so earlier on in the year I ran a course for hands on science which is a sort of summer course for high school students that come to Otago University and the learn about science. It's a wonderful experience on both sides because these kids are smart, they're keen, they're excited and it's a joy honestly to be teaching them and it's challenging because half the words that you'd use in a normal sentence to a colleague, these kids couldn't possibly understand. But you had to remember that these kids are smart, you can't talk down to them and you can't dumb it down but you have to figure out how to communicate it effectively.

So, so far the feedback we've hand from hands on science, myself and other people is extremely positive and there were huge waiting lists to come to the course. I think it's something that Otago does pretty well on the whole but I'd like to see us do more of it and I'd like to see us cast a wider net and really engage with the public. Because I think everything is understandable, it's just whether we can explain it adequately really.

Robyn Williams: A final question, and that's really something that was brought up by one of your colleagues here at the University of Otago and that is the way young people are so involved with IT so you don't actually talk about ideas you Google them and you see billion of bits and somehow not only is your knowledge base fragmented but the practice in taking about these things is also somehow stymied -- are you finding that a problem from what you say or not?

Julia Horsfield: I actually really don't know, I suspect you might be right, people are generally well informed out there but the information is presented to them in a quite fragmented fashion so it's whether it can be absorbed to understand a certain platform or point of view or not.

Robyn Williams: The test is whether they can articulate it themselves. From what you say the young people were pretty forward.

Julia Horsfield: Yes, I think today that people studying too bring a lot more to the classes than I remember doing when I was a student. I remember just turning up and being told to do things or else, and sitting tests and never complaining about the grade I got or anything. But if people don't think you've done something right as a tutor or teacher they'll tell you these days so it's a lot more forward from the student's point of view. Whether we can engage in a dialogue when students, our students, or the wider community on the basis of what we know now I really don't have a feeling for just yet, but hopefully we'll find out ways to effectively engage people in the process.

Robyn Williams: And she's doing just that in Dunedin at the University of Otago. Dr Julia Horsfield, Senior Lecturer in Pathology there. And if you want to look up that blind men with their socks conundrum you can actually find it on line in the Science Show website in a program dated 15th March this year with Professor Kim Naismith. Next week at this time I shall be in Conversation with Dr Chris West, Director of the Zoo in Adelaide and coming up in Catalyst in two minutes from now you can join Jonica Newby in Cambridge with mathematician Daniel Lightwing who has Asperger's syndrome and Professor Simon Baron-Cohen who says Asperger's is an excessive expression of maleness. That's ABC1 at 8 o'clock - I'm Robyn Williams.

Guests

Dr Julia Horsfield
Department of Pathology
University of Otago
http://www.otago.ac.nz/phonebook/dep-path.html

Presenter

Robyn Williams

Producer

Nicky Phillips