15 April 2009
Why, unlike other organ transplants, are those involving a man’s testes protected from rejection by the immune system? And what causes this mysterious, privileged relationship between testicular cells and the immune response?
Seeking answers, NHMRC Senior Research Fellow Mark Hedger and his team focused on the fact that fluids bathing the cells inside the testis were able to suppress the function of lymphocytes, the white blood cells involved in the body’s immune response. They found molecules that might even have potential therapeutic value.
Here Associate Professor Hedger explains to Dr Andi Horvath that this research has important implications not just for male reproductive health but also for transplantation medicine in general.
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Voice-over: Welcome to this special National Health and Medical Research Council podcast on Ten of the Best Research Projects for 2008. Our podcasts aim to keep you in touch with major health and medical research issues and the people who shape them.
Introduction: Hi I’m Dr Andi Horvath and I’m at The Centre for Reproduction and Development at the Monash Institute of Medical Research. We’re about to meet a Chief Investigator by the name of Associate Professor Mark Hedger and he’s into tackling the challenges in male reproductive health. The immune system and the endocrine system are a complex interaction and he’s the man that sorts it out.
Interviewer: Mark congratulations to you and your research project team. Take us back in time. What did you know about male reproductive health? What was known at the time when you first started?
Assoc Prof Hedger: First of course was the observation that when men get sick — and we’re not just talking about men who become infected or develop the flu for example, but even men who have heart attacks or suffer severe stress — would show a severe decline in their reproductive potential. One of the most interesting aspects about the interaction between the immune system and the male reproductive tract was the fact that there’d been a number of studies over a number of years looking at the ability to transplant tissues from one animal to another in particular from into the testis — and the testis of course is the organ that’s responsible for sperm and hormone production — and it was found that unlike transplantations of other organs such as the kidney or the liver for example, the transplantation into the testis or even of the testis, was shown to be protected. And we called this immunological privilege and it showed that there was a very important and mysterious if you like, relationship between the cells of the testis and the testis as an organ, and the immunological system.
Interviewer: So Mark this opened up things that you didn’t know about this complex interaction between the immunology and the endocrinology of males and their reproductive health. So how did this formulate your research project from then on?
Assoc. Prof. Hedger: Well we wanted to discover why this was the case. This obviously had important implications not just for male reproductive health but also for transplantation medicine in general. Obviously if we could understand what was going on in the testis that would help us to develop novel methods, or new methods for looking or preventing graft rejection in other sites. So we particularly focused on the fact that the fluids of the testis, that’s fluids that bathe the cells inside the testis, were able to suppress lymphocyte function in vitro. Now lymphocytes of course — and we’re particularly talking about the ‘T’ Cells in this case — lymphocytes are the cells that mobilize and direct the immune system and lead to the immunological response. And we found that those fluids if put in contact with these cells in culture would cause them to stop dividing, stop producing cytokines — that is the signals that normally are important for mid cell development — and would eventually cause them to die. So our question was, ‘what was it that was in those fluids that was able to do this?’ and that’s where our research really became focused at that time.
Interviewer: Mark, introduce us to what a cytokine is and tell us about the outcomes of this research project.
Assoc Prof Hedger: Cytokines, specifically as a scientist understands them, are proteins, or growth factors which are usually proteins, which are produced by cells to allow cells to talk to one another. And for a cell that’s here to tell the cell over here that I’m about to do this and you need to do this at the same time or I’m over here and I don’t like you, you need to go away because your function is not going to work in this particular system.
Interviewer: These molecules are instrumental to the outcomes of your research, is that right?
Assoc Prof Hedger: Absolutely. All cytokines are proteins I guess, but not all signaling molecules are cytokines. So we’re also interested in other signaling molecules apart from cytokines which have cytokine-like actions such as prostaglandins for example and the steroids themselves. So these molecules are the ways in which the cells talk to one another either at short distances or very long distances, and our focus clearly was on which of those cytokines and other signaling molecules were mediating the communication between the two systems.
Interviewer: Knowing about the mediation between the immune system and the endocrine system, how has this led to the treatment of male reproductive health?
Assoc Prof Hedger: At this stage we’re not using this knowledge to develop new treatments. The molecules that we have identified, for example the bio-active lipids that were identified in the research that we’ve just done recently, which clearly inhibit ‘T’ Cell function and obviously have a very dramatic effect on immunological capacity, these molecules potentially have therapeutic value. They may be used in inhibition of ‘T’ Cells in transplantation situations but at this stage there are still a lot of issues that one needs to consider before those molecules can be taken down the therapeutic pathway. First of all these molecules are natural molecules and they have a number of roles in the body. So in order to start using them in a therapeutic context one has to know what else you’re going to be influencing by manipulating these molecules and also of course what drug development companies want to do. They want to develop molecules that aren’t actually reproductions of these molecules but are mimics or variants of these molecules that can be used to modulate specific functions that these molecules would normally have. So there’s still a lot of work to be done to look at these molecules and the structural features of these molecules.
Interviewer: If you could sum up why you do this research in one or two sentences what would you say?
Assoc Prof Hedger: I do it because I enjoy doing it, I think the joy of discovery — one becomes a scientist for various reasons, but the main reason I think if you asked any scientist why they become a research scientist is because they like the thrill of discovery. You know you come to the laboratory every day and you want to discover new things, you want to design experiments that will test the concepts that you have — challenge the concepts that you have — and discover things that no one’s ever known before. That’s why scientists do what they do. They don’t do it for the money I can tell you right away, they do it because they enjoy it. Now on top of that of course, what we’re doing in medical research is obviously going to have long term benefits for health and that also, you know there’s the altruistic aspect of it so you can feel good about it, you’re doing something that you enjoy, but you’re also doing something that’s going to have long term benefits.
Interviewer: Mark tell us about your expertise.
Assoc Prof Hedger: Okay, my background is in endocrinology. I was a reproductive biologist interested in the role of hormones in controlling reproductive function. Back when I started that was clearly a major thrust in all kinds of research but particularly in reproductive medicine. Now reproductive medicine has moved away from hormones a little bit and the endocrine system and more into genetics and understanding at the cellular level what’s going on, but my background has always remained in the signaling and the communication between cells.
Interviewer: Mark tell us about the range of expertise in this research project.
Assoc Prof Hedger: Ah, we already had a very good team set up who had a lot of expertise in tissue culture and in manipulating cells and looking at communication between cells, measuring signals between cells. This expertise was absolutely crucial to developing the concepts but we really needed to expand our expertise a little bit because we didn’t really have the molecular, the chemical background, that was necessary and this led to collaborations with groups who had expertise in areas like Mass Spectroscopy and in protein purification and those kinds of molecular techniques were absolutely vital to being able to take our concepts and prove that what we believed was true, was true.
Interviewer: I heard on the grape vine that you were up late one night looking at a machine’s results as they were coming out at two in the morning.
Assoc Prof Hedger: Well we’ve all done that I think. All scientists do that and it’s less of an issue these days when the machines tend to give you a more rapid answer but I’m talking about the days not so long ago, when you know a lot of the results come out on a paper sheet and they’re in order and you’re looking for a response that will show — it’ll be a little shift in the counts downwards or upwards — and you’re standing by the machine and you’re watching the counts and they’re tracking along and then they start to move downwards. Now at two o’clock in the morning and you’re standing there and often these counts can take ten, fifteen minutes to come out, but it’s a real thrill that one gets when you’re watching those counts move in the right direction. So you know I think it’s a thrill that most scientists have had and it’s almost, it’s an obsession that scientists have, I mean most people wouldn’t think of standing in a darkened laboratory in the middle of the night watching counts coming off a machine, but certainly that’s something that we all — I think most scientists have experienced at one time in their life or another – and when that result is the one you want, that’s part of the reason why you do this.
Interviewer: Mark, some final reflections on being a Chief Investigator. Will you do it all again and why?
Assoc Prof Hedger: Oh of course I’d do it all again. I mean you do it because you enjoy doing this, it’s the thrill of the chase if you like. It’s the thrill of discovery — you’re not out discovering new lands — but you’re discovering new things and you’re uncovering information, ideas, knowledge that hasn’t been there before. And for all the frustrations that are involved, you know with the funding issues, with the frustration of not getting where you think you need to be getting, with all the administrative issues that one has that surround your research these days because there’s all kinds of Occupational Health and Safety regulations, animal ethics issues and just reporting to the university for example, all of those things take up your time. But there’s those moments when what you’re doing pay off you know and you’re standing in the lab at 2 o’clock in the morning watching the counts coming off the machine and there’s your result. Those moments feel very good and you go home that night and you feel really good and you know that’s why you come back and do it. And so for the next week or so perhaps it’s not quite so exciting but for that period of time at least you get that buzz and that’s why you do it.
Interviewer: I’ve been talking to Associate Professor Mark Hedger who’s an NHandMRC Senior Research Fellow at the Centre of Reproduction and Development at the Monash Institute of Medical Research. Thanks for talking to us.
Assoc Prof Hedger: Thanks Andi.
Voice-over: This podcast was brought to you by the National Health and Medical Research Council, working to build a healthy Australia. You’ll find more information about this and other health and medical research issues on our website at www.nhmrc.gov.au.