 My name is Professor Frank Bloomfield and I'm director of the Liggins Institute and it's my real pleasure to welcome you to this evening's inaugural lecture of Professor Mark Brickers. Before we get underway, just a few housekeeping announcements. Could you please all turn your phones to silent form or turn them off? Bathrooms if you should need them are outside across the foyer or down the corridor and should there be an emergency the red lights will flash and science will go off and we should all meet outside in the quad please. So the annual inaugural lecture series is an opportunity for the university to showcase its new professors and this is of course the highest rank of the university and an honour well worth celebrating. And this evening of course we're here for the inaugural lecture of Professor Mark Brickers, an accidental journey into developmental programming. So Professor Brickers has elected to deliver his lecture in his academic for Gaelia this evening meaning that I had to wear mine also. And this mode of apparel dates back to the late 11th early 12th century when all of the academics of course were members of scholastic orders. In those days the copes were completely closed so that they couldn't show off the finary of their clothes and could maintain their modesty. But in the time of Henry VIII that as academic robes became more formalised that fell by the wayside and robes became open precisely so that people could show off their finary and we'll see that from Professor Brickers this evening. So the robes of the University of Auckland are based largely on those of the universities of Cambridge and Oxford and the introduction of specific colours for specific degrees is actually quite a late invention only in the last couple of hundred years. So Professor Brickers' career actually is in science started when he took on the role of a research assistant in the research centre for developmental medicine and biology. The precursor of the Liggins Institute really which was in the department of pediatrics under the supervision of Professor Bernhardt Breyer. Mark worked for Bernhardt for three years before going on his OE to Germany and then returning back to do a masters and then a PhD under the supervision of Bernhardt and Sir Peter Gluckman. I'd really like to welcome Professor Bernhardt Breyer back to the Liggins Institute. It's great to have you here this evening Bernhardt. So Mark's PhD was awarded the best doctoral thesis of the University of Auckland. Perhaps not surprising when the first publication from his PhD was published in the American Journal of Physiology and resulted in a paradigm shift in the field of the developmental origins of adult disease. It's been cited almost a thousand times. It was the most cited paper of the decade in the American Journal of Physiology and it reported the effects of the postnatal amplification of a prenatal phenotype with postnatal diet and I think it's fair to say that the images of Mark Vickers fat and lazy rats has been flashed up on conference screens around the world, not always by Mark. Subsequent to his PhD he continued his research at the University of Auckland and undertook research into interventions to try and reverse these adverse effects of the individual environment and this resulted in the award of the Hamilton Prize which is a very prestigious award from the Royal Society for a really seminal paper by an early career researcher. So in his career to date Professor Mark Vickers has published over 130 peer reviewed articles and 16 book chapters presented his work widely in international conferences and has numerous international collaborations. And his work of course fits perfectly with the work at the Liggins Institute into how the alterations in early life environment can lead to increased risk for development of metabolic and cardiovascular disease later in life. So Professor Vickers is going to tell us today about how his research has provided invaluable empirical evidence to support the developmental origins of health and disease paradigm. And although that was initially treated skeptically by many, not Mark's research of course, but the hypothesis in general, I think the contribution that is made has meant that it has now become firmly established as an important mechanism. So Mark, we're looking forward to hearing about your unexpected journey into the field of developmental programming. Thank you very much Frank for that wonderful introduction and I feel quite privileged now to have my career mapped out like that in such a short time. So I've been around for a long time as many of you may guess, I've stuck to a good thing, I've had a good formula and I've been very well mentored and supervised over my career so I never actually saw the need to actually leave what is now the Liggins Institute. And hopefully I'm around for a while to go yet as well. So if you look back at my university entrance, this is the proof that I used to have here back in the old days. If you look at where I started back in school, I wasn't heading towards a sort of a science background where I've ended up now. So I was doing the arts type subjects, English economics, geography, history and so forth. So I sort of fell into this by accident. So a lot of you who know me will know how I got into this role through Bernard Brahe, who I basically owe my whole career to basically. So thank you again Bernard for being here today because by luck I landed on your desk and I haven't left basically. I think this is why I was single for so long. So basically, hey, oh come on, come on. Stress made it all fall out. Doing a PhD. So I started off with my BSc in geography because I did geography because it was a subject I liked. I was one of those suckers at the time who fell into a subject I liked so I carried it through the university. But there aren't many options available with geography so I had a bit of a brick wall. So I was there, I was actually unemployed for a period of time. And then I fell into a government work scheme whereby they placed people and I was managed to get a position with Bernard Brahe. And then I worked as a technical assistant at the Department of Pediatrics for a while for three years. And also through Bernard Brahe, he found me a contact in Germany through Dr Bernard Bloom who I'll talk about in a minute. So I went over to Germany and worked as a technical assistant at the Children's Hospital in Germany. So I spent about two, three years in Tubergin which is just outside of Stuttgart. And then I spent about a year at the Institute for Physiology just outside of Munich. So I had a great time overseas. And then I'd got the bug about research so I decided to come back and follow my research interests. So I came back to Auckland and once again through support from Bernard and Peter Gluckman I managed to get into a Masters of Science and Medical Science which I did in reproductive biology and then I passed on to, I went on to do a PhD in pediatrics. So all under the guidance and mentorship of Bernard Brahe. So here's a picture up here of Bernard in the old days. And I think that's Peter Gluckman. So these jumpers wouldn't have gone amiss from the midwinter party we had this year at the Liggins. So that's where I started off. That's my first lab desk there, Research Centre for Developmental Medicine and Biology. And I went to work for Dr Bernard Bloom who was very well noted in the Growth Form in IGF1 area. And also Professor Michael Rankey who many of you may know as well in the Growth Form in Biology area. So I was very lucky to get a position at the Hospital in Germany. We know with Germany not speaking a word of German so I just fell into this position. Luckily everything in the lab there was in English so it all worked out quite well. And after German tubing in here I moved on to the lab of Dr Helge Selvine and I did some sort of large animal stuff looking at the role of BST and so forth in cows. And where I worked there also happened to be the home of the oldest brewery in the world. So it actually fell into almost a perfect work environment there. And I was also only a couple of train stops away from the Munich Oktoberfest. So that was great. But at some point that fund had to stop. So what I did here is I spent a lot of time setting up radio menu assays and so forth that I'd learnt how to do back in Bernard's lab. So I came back to Auckland, got serious and did my other degrees. But while I was in the lab over in Germany I did pick up the bug for doing research and I did manage to get a co-authorship on a couple of papers. We looked at old methods like FPRC looking at nephrodex in Germany's kids. But when I started in Bernard's lab I was actually completely lab naive. I'd never been in the lab before I made a few mistakes so I don't even think Bernard knows about. A classic one was doing free fatty acid assays the old way with it yet to shake the tubes manually. And I used the wrong kind of tubes and came back after lunch and they'd all melted all over the lab bench. Quickly kind of hide those away. But what I did learn back then was attention to detail. If somebody told you a protocol that says shake for five minutes, you shook for five minutes. You didn't try and take a shortcut and do three or three and a half. Of course I learnt the hard way that things don't work if you don't follow detail. And that's an aspect of my career that I followed through to all my animal studies and so forth to make sure they were designed to the nth degree. So I did my MS thesis with Bernard Briar along with a couple of andrologists Curtis Gravance and Patrick Casey. And we looked at the effect of growth of 1.9gf1 on sperm characteristics. So primarily the effect of growth of 1.9gf1 on sperm motility, sperm morphology and so forth as well. And obviously that was a highly successful project so we managed to get five papers out of my master's project. So I knew I was actually working in the research environment which was going to nurture me through my PhD studies. So that was a great introduction to postgraduate study. So then I fell into this area of developmental programming. So about the time I finished my master's work there was a lot of burgeoning interest in this whole idea of fetal origins of adult disease or foad as it was called at the time. And the definition of that, most of you in the audience will know, a stimulus or insult operating at a critical or sensitive period of development that results in a long standing effect on the structural function of the organism. So I moved away from the sort of andrology, the sperm work and wanted to get into this whole idea of what happened in the early life environment dictated largely what happened in later life. And David Barker, who sort of popularised this work, I was fortunate enough to meet David quite a few times during my career. And he knew what we were doing back here in Auckland and he always had some constructive advice on, oh you should be looking at this and you should be looking at that. So I was very fortunate to meet the person who actually popularised the science on a number of occasions. And this is one of the prime examples of the work that David Barker did in the early days, showing the link between birth weight and impaired glucose tolerance. So as birth weight goes down, impaired glucose tolerance goes up. Back in these days there was a heavy emphasis on birth weight, but birth weight is just a proxy for a programming phenomenon. And we also know there's a kick in the tail here. So we know at the other end of this birth weight spectrum there's also problems in terms of macrosomia and large babies as well. So a programming of the years, initially it was met with some scepticism. People didn't believe how important the early life environment was and they couldn't believe it's such. An early life environment dictated such a large degree of later disease. But obviously as we know, programming has become a major area of science internationally. It's been popularised in the press such as here and it's even grown enough now to have its own journal that a lot of us contribute to. So in terms of critical windows opportunity, so I want to talk about my journey into setting up these models to provide empirical data to support the programming work and also how then we went into doing intervention strategies. So now we have our genotype and we've got our environment feeding into a period whereby in early life where we're developmentally malleable, we're plastic. So we're very, very susceptible to the cues we're picking up for the external environment. And the combination of these feeds into our adult phenotype. In this graph you've seen many, many times and I think it's been redrawn a lot of times as well. But it simply shows how important this early life period is in terms of plasticity and how this is the optimal time to intervene if you're going to. We all hear about these treatments for diabetes and obesity in later life and they're largely ineffective. So I concentrated most of my career on this period here where I had the greatest chance of intervening with some effect. So the earlier their intervention, the bigger the effect on later risk reduction. So what does determine a health potential? We know that what we eat and how active we are feeds into disease risk. But we also know what happens now in the early life period provides the first hit, the primary hit, then we have the sort of one-two sort of second hit hypothesis. So one of the first studies we did which I'll talk about in a minute was combining early life adversity with postnatal high-fat nutrition and that amplified the postnatal phenotype. And we at the Legans were the first group internationally to do that and that kind of approach now is used widely around the world. So we also know we have this vicious cycle of disease. You've got your fat boy ice cream sandwich and your chocolate coated potato chips here. So you've got your maternal under nutrition. I don't think we can buy these here, this is in the States. So maternal adversity, it could be under nutrition. We've done both ends of the spectrum maternal under nutrition and maternal obesity. And we have to remember that maternal obesity in itself can be a form of malnutrition as well. Leading to altered fetal neonatal nutrition feeds into this with diet, physical activity, childhood obesity. And as we go round and round we see this vicious cycle ensuing. And we need to break this cycle because as we know from reports a couple of weeks ago, New Zealand is actually now the third-fatest country in OECD behind USA and Mexico. So the programming work we does is a key element in breaking the cycle across generations of disease. And where I came in was animal models. And once again, I was very naive. I think my first experience with working with rats was with Sonia Wattle who's also here. And I think I was just let loose in Sonia's room. There was no health and safety, no legislation training, no nothing. Here's a room, there's some rats in it, go on play. That was it basically. And I think Sonia came and saw me afterwards and said, what did you do to those rats? You remember that? A long time ago now. But that was my introduction to working in animal models. So preclinical models are a key tool for the investigation of mechanisms that underlie the early life development of obesity and related metabolic disorders. So what actually can be programmed? Oh, I was meant to animate that. Sorry, the eyes came up first. So what actually can be... Looks a bit sad, is she sorry. So what actually can be programmed? Nearly every aspect of physiology that we've looked at it during my career anyway and that would collaborate is can be programmed. We've shown evidence of altered cardiovascular system, blood pressure, obesity, we've done some work on lung, stress access, puberty, polycystic ovaries, depression type disorders, inflammatory disorders, changes in insulin sensitivity, bone density, glucose control, hepatic steatosis, renal function, nephron deficit and unsurprisingly if all these things are perturbed that you get reduced lifespan. So we always have this ethos of making the most of the animals that we've used in their experiments as well and either through our group directly or through collaboration, we've looked at nearly every single aspect from central down to the gonads and through debsilboda we've done a lot of work actually in the ovary as well showing altered ovarian ageing and reproductive disorders for example. So when we first started back with Bernard on my PhD it was looking at maternal under nutrition because that was at the time that was what most people were developing. So models of maternal or fetal growth restriction. And it's very easy to mimic this experimentally. Obviously if you undernourish a mother you get short, lighter pups. You see quite significant growth restriction here which mimics quite nicely the clinical setting of IUGR. But what happens is this pup here grows into this one here. And these guys are eating the same diet. These guys have just got a programmed disorder, a thrifty phenotype. They store energy for a rainy day but that rainy day never comes. So these guys are eating the same food and what we did then through the guidance of Bernard Breyer we actually coupled that with a postnatal high fat diet to amplify the phenotype. And at that time nobody had done that before. So it did show some considerable insight from Bernard as well. That was the paper at the time. Fetal origins of hyperphasia that has been zapatite disorders over eating, obesity and hypertension and postnatal amplification by hyperchloric nutrition. As Frank said it was the most cited paper of the decade, 2001, 2011 in AJP. It's cited almost a thousand times now. And it was the first study to use a high fat diet to amplify the programmed phenotype. And this approach is actually now standard. If you look at the literature, 99% of the papers you'll see a programming model coupled with a high fat diet to amplify the phenotype. And you'll see another couple of Liggins authors here at the time, Wayne Cufffield and Paul Hoffman. So you remember that? Cytation classic isn't it? And this is just an example of some of the data that came out of that paper. If you look at systolic blood pressure, fasting, plasma, insulin left, these are our control animals for the standard diet. So this offspring of normal pregnancy, normal, normally nourished mother, blood pressure is normal. You give them a high fat diet, blood pressure goes up a bit as you'd expect. But this blue line here represents the effect of the maternal, nutritional environment on offspring blood pressure. So the so-called programming effect. I mean I don't like using the word programming a lot, but I haven't got an alternative at the moment. So you see quite a marked programming effect. So these animals become hypertensive purely on the basis of what their mother ate during pregnancy. If you give them a high fat diet, you amplify that phenotype even further. And very similar here for insulin. Maternal diet makes the offspring hyperinsulinemic, add a high fat diet into the mix and they're even worse off. And as they age, this sort of mismatch, I'll talk about in a minute, actually amplifies with age. So the greater the nutritional disparity between early life and later life, the greater the effect on phenotype. And also at this time we had access to some pretty high tech equipment at the time for looking at locomotor activity. So in these boxes using an array of infrared beams, we could actually measure locomotor activity in these animals. And nobody looked at locomotor activity as a consequence of programming before. So we put these animals in this box and looked at their activity. And we were the first to show that animals that were born under nourished mothers actually had reduced physical locomotor activity. This is voluntary locomotor activity. And concomitant with that, they had increased appetite. So they were hyperphagic and lazy basically. And if you had added a high fat diet into that mix, you amplified that phenotype. So they became very inactive and they spent a lot of time just sitting around and eating. And we also show that this phenotype was actually present as early as day 35. And that's about two weeks after weaning. So at a very young age before the presence of obesity, these animals, both females here and males here, were showing reduced physical activity levels. So we'd programmed this thrift phenotype, this reduced locomotor activity. And we thought this was really exciting at the time. So we actually, for the first time, submitted this to Science. And I don't know if you remember some of the communications around this burden. I mean, I was a bit pissed off at the time, but that's life. And I've learnt to get used to it now, 20 years on. But if you see the editor's feedback, you will see that the sets of comments are positive and recommend publication after minor revision. Unfortunately, we do not. That's the sort of the start of a sort of sentence of death. The guy did not believe in programming. He said it's hard to reconcile the effects of the early life environment on later life outcomes. They even made us go away and do another study. And we actually went away and did that. And they still come back. And if you look at the nature of some of the comments from the reviewers, stunningly important paper, widespread influence and endocrinology. So we couldn't get into science, despite a lot of to-ing and fro-ing with the editor. So ended up being an AJP, I think it was again. Ended up on the front page of the New Zealand Herald, born lazy, blaming other type of things. So I've got a lot of widespread press. But what's annoying is it's been cited about 300 and something times now, but it's also been cited a lot in science and nature from people who have done similar experiments a bit later on. So we may have just come along at the wrong time to get that in, because we also had a skeptic in the editor that we had at the time. A bit frustrating. So if you want to encapsulate all the work we did on maternal under nutrition, a few years' work you can encapsulate here. A lot of this work was derived from some of the initial work that Sonya had done in the under nutrition model in the rat as well. So one thing that's actually quite comforting is over the 20 years or so I've been doing rats, and I've even changed the strain of rats across. The phenotype is consistent as ever. I can predict what the blood pressure will be in the environment I've put these animals. So it shows the stability of these animals over time. If you look at this range of outcomes here, offspring of control, pregnancies here, offspring of mothers that were under-nourished, you can see for every aspect of what we looked at here, there's a marked perturbation in their program phenotype. And each one of these is actually worsened in the presence of a high-fat diet. High blood pressure, hyperinsanemic, leptin-resistant, fat, hyperphagic, increased C-peptide, lazy, and they've even got reduced rectal temperatures as well. And together with some work that Bernard instigated along with Michael Davidson and Jason Landon, we even looked at some measures outside of our typical phenotype measures and we looked at some learning. And we also showed that offspring of under-nourished mothers had quite significant learning deficits. So in addition to all the basic phenotype we looked at in terms of adiposity and diabetes and leptin-resistance-related matters, we also showed that they had learning deficits, which is very similar to what is seen in some clinical scenarios as well around STA and so forth. And this is what I was talking about, nutritional mismatch, the double hit. I showed you before about this double hit in the utero environment and the post-anal environment creating this double hit. And this is a book that Peter Gluckman and Mark Ensign put out a few years ago now called Mismatch. But this is an example that's used quite widely and that's plasma leptin. So once again you've got offspring of controlled animal pregnancies here, under-nourished pregnancies here, these guys are eating the same diet, but you see there's an increase in leptin as a result of programming. But if you put these animals that were born to an under-nourished mother on a high-fat diet, you see this massive increment in the amplification of circulating leptin levels. So the greater the nutritional mismatch, the greater the effect on later phenotype. And this is what's typically seen of things such as nutrition transitions and rural-urban migrations where people are moving into the cities where they're getting access to western-style diets. They may have been born in an area relatively impoverished, but they've actually then moved into a region where there's pinafore supply of western-style diets and that's when you get this explosion of diabetes and obesity. But then the field change. We started putting grants into HRC and so forth and under nutrition wasn't an issue that didn't like the models of under nutrition in the rodent and a more oppressing problem at the time was that of the increasing rates of maternal obesity. So we went away and similar to the under nutrition models, we went away and developed some models of maternal obesity using quite moderate high-fat diets throughout pregnancy and lactation. Once again, offspring of a controlled pregnancy, offspring of a mother that was fed a high-fat diet through pregnancy and lactation. Once again, eating the same child diet, this guy has developed a marked, profound phenotype related to hyperphasia and obesity, leptin resistance and so forth and the results are quite similar for both genders. So it was quite easy to set up another animal model looking at maternal high-fat feeding on offspring phenotype. If you want to look at some of their more broad phenotypic outcomes, look at body fat as assessed by DEXA scan, offspring of controlled pregnancies, offspring of obese pregnancies, see a marked increase in body fat. Remember these guys are eating the same diet postnatally and you can see if you look at their body weight growth curves, there's a marked divergence in body weight in those offspring who are born to high-fat fed mothers and not unsurprisingly they've got high leptin levels and high insulin levels as well. And we've started looking at some of the mechanistic basis, looking at taste receptors. So we even found programming effects and this was also reported for the first time of some work we did with Stephanie Segovia and Claire Reynolds, looking at the gut taste receptors. So even the gut taste receptor expression is different in offspring that are born to obese mothers and that's going to influence glucose sensing and so forth as well. And when we give these guys a food choice protocol, so in the cage we give them free access to whatever food they want to make, whatever diet they want to eat, whether it's the high-fat or the chow or whatever. Offspring of obese-ogenic fed mothers always select the wrong food, the unhealthy food. Nine times out of ten they'll go for the high-fat, the obese-ogenic diet. And if you look at their weight gain over just even a 10-day period, you'll see that the offspring of obese mothers, they're selecting the wrong type of food, show a marked increment in their body weight gain over time. And that's just a picture of me having my first bear, I think, who's preference in me and sensual adiposity programming effect. So we know that maternal diet can program appetite, preference in offspring, similar effects have been shown by Mike Simons over in the UK, and there's also been, albeit limited, data from the Dutch famine cohort showing that the offspring in the Dutch famine cohort have a preference for fatty foods. So once again we can reconcile some of the animal work we've done with some clinical outcomes or epidemiological outcomes. And also when Dev Slavoda was here, we looked in the literature so there was a lot of people starting to work on high-fat, high-sugar type diets, but nobody had really looked at the effect of maternal sugar intake in isolation on maternal outcomes. So we did quite a simple study where we gave the equivalent of two cans of soda a day. So not a lot, so about 20% of the calories was derived from soda, via fructose in these mothers. And what happened, even this is one marker that came out of it, at birth in the offspring, they were already showing signs of hyperleptinemia. So this really moderate intake of fructose by the mothers during pregnancy led to this programming of leptin resistance in these animals. I can't really call it leptin resistance because we didn't call it, we didn't challenge them. But hyperleptinemia I should say. So they're already kind of hardwired to fail in early life based on what the mother had consumed during pregnancy. So maternal fructose intake resulted in increases in the BC-related hormones in offspring at birth. And this is really exciting, it got into endocrinology and a follow-up paper in plus looking at some of the mechanisms. But when the press got wind of it, it was a classic example of when not to talk to the press, especially when one of the authors was sitting in a bar in Mount Eden at the time. So this made the front page of the Herald, we've got the front page of the Herald for the second time, and the basic headline was pregnant women should not eat fruit. And that sounds funny but did a lot of damage and people were very serious about it. In some instances we had people coming in saying we were told not to eat fruit because it contains fructose. So fruit juice, apples linked to fetus harm, fructose could harm babies. And what was the other one? Why pregnant rats should avoid apples? There's some really wee headlines that came out. But it was quite serious because the whole entire message had got wrong. Fruit contains fructose, thereby fructose is bad. So we did a lot of damage control trying to educate people around what we meant by the fructose we'd used in terms of highly refined crystalline fructose, high fructose corn syrup for example. But this shows how a simple story can get completely messed up in the press. So we set up these nice models of programming. It was no doubt that programming occurred. If you manipulated the maternal environment you had an adverse outcome in the offspring. So we wanted to see if we could reverse programming. And it was a little done in this field as well. You see it from our career, a lot of the work at the leggings, we seemed to be just ahead of the game with the time in terms of our sort of innovative thinking. There was some early work done on taurine back a couple of decades ago looking in low protein model. But nobody really looked at reversing agents and most people had thought that developmental programming led to sort of a permanent change in developmental directory. So we started looking at reversal agents in our lab. So yes we can reverse programming and we've done at least an animal models as a caveat. So we've done a lot of reversal agents here. I mean over the career we've actually done quite a lot and this doesn't list all of them. So leptin growth hormone, IGF-1, choline, acipimoxinsin sensitiser, taurine, omega-3, CLA with clear anils, prevention of catch-up growth and even more recently we've done some insulin. So we've done a lot of agents that do effectively reverse some of these programming effects and I'll take you through a few sort of key examples from these. So the first thing we did was leptin. We know these animals display signs of leptin resistance in later life and we know they're hypo-leptinemic at birth. And we'd also showed some more work with Shiva, Patina, and Kanashia, one of the students in that group in Bernard back in 2001 that the link between leptin insulin was perturbed as a result of developmental programming. And if you look at these slides here of islets in the pancreas, you can see the islet from a control offspring from a control pregnancy, offspring from undernars pregnancy. It's just an example of the dysregulation, the brown staining is for leptin on the periphery of the islets. So the hypo-insul axis in these animals was perturbed and we thought, what if we replace leptin in the early life period and see if we can rescue this phenotype. At around the same time, Sebastian Beret had looked at the OB-OB mouse, which is a leptin deficient mouse model, and showed that if he replaced leptin in the early life period, he could also rescue the phenotype in that genetic model. So we did quite a simple study using a model of under nutrition in the rat. Once again you can see quite a few leptin, I mean Ligans authors up there as well. So we gave them 10 days with the leptin treatment in the neonatal period and followed them up postnatally. And as you can see, offspring born to undernourished mothers, this got fatter and heavier over time. That has showed this completely aberrant growth profile and it has kept laying down fat and so forth. But in the undernourished offspring that we gave leptin to, we completely normalised their phenotype. This is in females, it's important for a point I'll bring up later. And in this case, leptin treatment to normal offspring of normal pregnancies had no effect. And in this case, leptin treatment to normal offspring of normal pregnancies had no effect. And every aspect of their phenotype that we looked at where there was fat mass, blood pressure, insulin leptin was completely normalised in these animals. And we appeared to reset this phenotype through this early life intervention. So we completely restored their postnatal growth patterns and physiology. And that led to quite a range of papers that came out of that. Even some stuff, Ground Wakes in the audience here I mentioned that paper later on. Even modelling some of the data. And through collaboration we had a lot in-depth work done on this through University of Cambridge and University of Southampton as well. And it shows the power of having a good animal cohort bank because together with Alwyn Firth and Jill Cornish, we actually published a paper only a couple weeks ago on this cohort which was generated back in about 2005. So we've stored samples from a precious cohort and are still milking it basically. And based on my master's work, I had this interest in growth on an IGF-1. And we know from some of the work that Sonya and Bernard had done in the early days that the growth process was also perturbed in this early life environment. So the first study we did was look at adult IGF-1 treatment. And we've also done adult growth hormone treatment. You can see the titles of the papers down here. We know like I showed you before, offspring of undernourished mothers are hypertensive, high blood pressure. But if you give them IGF-1 you can actually lead to a mark decrease in blood pressure. So we got about a 20% decrease in blood pressure. So it normalised their blood pressure as a result of IGF treatment. And growth hormone treatment in the adult showed a very similar effect. But like I was saying before, at this period of life, they're not actually that plastic. So we wanted to go back and see if we could actually look during this critical period of plasticity whether we could intervene back then with components of the growth hormone system. So together with people like Dr Claire Reynolds and Dr Clint Gray, we did a pre-winning growth hormone treatment paradigm, very similar to that one we'd done and looked at the offspring phenotype in later life. So we managed to restore all of these features as a result of this programming phenomenon, increase in fat mass. We also see a pro-inflammatory phenotype. This is Io1 beta as an example. And this is around day 150 of age in adult life. But you can see that the animals we exposed at growth hormone during that first period of life have got a completely resolved phenotype in adulthood. And a lot of the features we looked at where there was endothelial dysfunction, ventricular hypertrophy, bone marrow macrophiles information, adipose tissue insulin and all of these features with neonatal growth hormone exposure. And this work got into a couple of papers and also got an editorial feature in the journal Enecology, which is quite an accolade for the work. And I can't go through all the interventions we've done. There is a caveat to a lot of the interventions we've tried. They work extremely well in the setting of programming, but they can have adverse consequences if you test them in the setting of a normal pregnancy. So we've done that with Clare, we've done CLA conjugated linoleic acid, fish oil ben albit, and also some more recent work with Elwyn Firth and along with Justin O'Sullivan as well. So here's an example of a taurine supplementation. There was an old literature back in the 80s about giving taurine and the drinking water to offspring of low protein fed mothers, and it seemed to restore the pancreatic phenotype in those animals. And there's also some evidence that taurine can be sensitive in animals that are fed in normal, non-pregnant animals fed a high sugar diet. So we went back to our model of maternal fructose intake, and as you can see here, mums that consume fructose during pregnancy become hyperinsanemic inflammatory profile and they even show a marked score as relates to hepatic steatosis. So the liver is actually quite damaged as well due to this fructose, even though it's only a 20% load relative to calorie intake. But when we saw some taurine in their drinking water, we completely rescued all these effects. So we negated these adverse effects of taurine supplementation. So it was quite exciting data as well. And similarly with conjugated lindigaric acid, which is a compound which has found a lot of meat and dairy, which is high in a lot of the meat and dairy found in New Zealand. If you look at maternal insulin sensitivity on the left here, you can see that a high fact diet during pregnancy leads to a change in maternal insulin sensitivity. If CLA is added to the diet, we can rescue that phenotype. And also not this paternal health, but if you look at the offspring and once again we looked at the gut inflammatory profile here, you see a marked increase in TNF alpha in the gut as a result of a paternal high fact diet. But once again CLA is a supplement and the diet can restore that phenotype. But the caveat is that one size does not fit all. And the potential is that interventions in the setting of intact systems may actually lead to adverse outcomes. And we've shown that if you give toren to a normal pregnant mother, it can actually have an increase in neonatal mortality. That may be due to hypoglycemic effects, we don't know. The trouble is the old literature which is a trouble with the animal research field in itself. A lot of people don't give the intervention to a control group, so they have unbalanced study designs and that's a point we'll come to in a minute as well. So leading on from our work and given that programming can actually happen at any birth weight or across a spectrum it's a continuum, it's how best to identify those at risk of program disorders. A tailored approach, use of metabolic markers for example. And we know that for example from our leptin work, that the effects of neonatal leptin treatment are actually dependent upon prior maternal nutritional status and gender. We actually did a follow-up paper using male neonates that were treated and we showed that leptin treatment to male neonates of normal pregnancies can actually elicit an adverse metabolic phenotype. And at the time we were doing our leptin work there were a few other groups in particular who were doing some maternal offspring leptin studies and they actually thought about adding leptin to infant formula as a sort of a panacea to curb obesity and they were actually quite serious about it at the time but we know that would have been disastrous if anybody had ever taken it seriously. And another thing which is overlooked and the NOEH is coming down particularly hard on this, if you don't look at sex-specific effects and grants that are submitted to the NOEH for example, they'll ask for a reason why. I said a lot of people who set up programming models looked at the male and female, looked at the phenotypes that emerged and chose the one that best suited their needs where sometimes the lack of a phenotype versus a phenotype is obviously very, very informative in terms of mechanisms. And the old sort of adage that you can't use females because we try to avoid the confounds of estrus which is something I used in earlier my career is not able to be used anymore. So where possible you should always look at the effect of male versus female and sexual in programming. And here's a clear example here. If you look at the placentas from males, placentas from females, look at some of these inflammatory markers you'll see there's a very distinct inflammatory profile in the male placentas but nothing at all in the females. So those studies where they've actually discounted sex and actually merged the data, you can see why they get a lot of noise. And what about the father? A lot of work was actually put towards the father, the mother as being sort of where the blame should go. But there's increasing evidence about the role of the dad in the program disorders. A lot of this work was kicked off some work by Margaret Morris back in 2010 where they gave a chronic hi-fat diet in a mouse model, a rat model, and they showed that they could program beta cell dysfunction in the female offspring. But since then there's been dozens of papers showing transmission of these programming effects through the paternal lineage as well. And of course one of the benefits of using animal models is that we can very easily look at transgenerational effects. A lot of people use the term transgenerational when they're looking at F2 but F2 is not strictly transgenerational because F2 simply reflects an impact of the initial environmental insult to the mother. So for true transgenerational work you have to go to F3 and beyond and with the rat and mouse models you can do that quite easily. So that's one of the powers of the small animal models. And can we actually model it? Yes we can. So some of our data went to Professor Graham Wake who's here somewhere and I've got to be honest this is the only paper I've ever been a co-author on that I don't understand any of it. I'd assigned the authorship form and that was as far as it went but we at the dynamics of our leptin system our leptin reversal work we can actually model and I'm led to believe these formulas sort of lead to that conclusion at the end but so I'll have to take your word for it. So we can model the dynamic systems that result from some of our experiments as well. But our research doesn't all go to plan. I've shown you some studies that we've done over the years which have actually worked out perfectly. We've developed nice phenotypes, we've reversed. But back in the old days we did some studies a lot of studies actually which haven't even been published and Paul had done if you remember one of these ones with Troglilazone which was one of the instant sensitisers on the market at the time it was taken by thousands upon thousands of people around the world as an instant sensitiser. One of the side effects of growth hormone treatment is a diabetes genetic effect so that the animals that got the growth hormone treatment show an increase in plasma instant concentrations so we thought we'll give the growth hormone plus this instant sensitiser. It was on the market at the time FDA approved and it worked extremely well at normalising their instant sensitivity. But when we opened up these animals it was all liver. All you could see was liver. 4 or 5 times the size they should be and this was a drug that was on the market at the time and about the time we actually finished our animal study there was about 63 liver failure-related deaths in the US and in 2004 about the time we did some of this work Pfizer set aside about a US a billion dollars to cover the lawsuits. So we were testing a drug that for any we believed to be approved but it had quite disastrous effects in these animals so we don't know how it actually got through to that stage and given to so many people because the effects on the animals in terms of herpatic enlargement was the biggest I've ever seen in my career. And things have changed since I started as well. So back in 2000, Bernard I don't know if you remember that all those days that Stefan and I were in that little room with our little Breville kitchen whiz making diets 10 to 15 kilos a day absolutely no health and safety regulations at the time. But now switch forward 2017 you can go online all your diet 25 kilos press a button but our new problem is now that Cyquus is no. So it may be easier to go back it might be easier to go back to the stage here but it's very very easy to get commercially available research diets now and the good thing is about these diets they're open source so you know over a 10 year period they're not going to change. You can you can get batch to batch consistency and that makes a big difference when you're planning long term studies. And another big thing that's happened over the last few years is these so-called arrive guidelines because there have been hundreds upon hundreds of papers that have shown beneficial effects of intervention agents and animal models but a lot of them have done poorly they've been done using unbalanced study designs you can't look at the papers and get much detail about how they've actually undertaken the work. So a lot of journals now are actually signing up for these arrive guidelines whereby they want animal studies to be designed very much more like clinical studies so balanced experimental designs use of both sexes, controlled well for example and I think that's going to really improve the quality and relevance of animal models to the clinical setting because there is that barrier of translation so where to from here so I said we've done all these animal models we've proven that we can reverse programming so we need to take the next step in terms of either education or interventions in the clinic so the one thing that's sort of is funny in my career is back here which I think you can't see the date this is 1997 when I first got my Wally scholarship to start my PhD and that's what the hospital kind of looked like back then I don't know was it the Wallace block I can't remember what it was nothing has changed I was giving a talk back here on the importance of early life nutrition and I give talks now on the importance of early life nutrition maybe I'm just really really bad at it but people come up to me after talk especially when you go to GP conference they go that makes so much sense I've never heard of Doha before so they're on board once they hear about it but we haven't maybe communicated this idea well enough over the years so it comes down to this effective translation of research knowledge I've started here I've done quite a bit of work at this end now but we haven't managed to effectively translate any of our intervention strategies to any clinical scenario yet mainly based on the do no harm philosophy because most of this interventions we've shown do not work in every setting so more work is required and I've also been very fortunate to work with an early life nutrition coalition which is a panel of experts across Australia and New Zealand and over the years we've actually managed to get some statement papers out we've also put together some resources which go into the bounty packs in the hospitals here so tens of thousands of women have received these little books which give guidance to optimising nutrition during the first thousand years and later in the year I think we've got an official launch in Canberra of an advert which I'll play you My generation may not be as healthy or live as long as those in the past and it's the first thousand days of life that can make all the difference Here's what parents can do Eat while I maintain a healthy weight especially during pregnancy breastfeed for as long as possible Introduce solid foods but not before four months And remember, we learn from you Visit the Early Life Nutrition Coalition on Facebook to find out more So we've got this sort of public broadcasting now which is going to be an Australian New Zealand there's two versions of the ad there's an Australian version with a slightly different accent and a New Zealand one, that was a New Zealand one so I'm very lucky to be sort of involved where I can actually look at some of the work I've done in the animal models of basic science and actually try and help and inform some of the other end of the spectrum so I'm very privileged to be involved in some of those coalition sort of talks and another thing we've done is we've actually translated some of the research technologies we've used so for example with some work we did with Dr Clint Gray who's now left the Liggins we looked at microRNA profiles in our model of under nutrition and showed quite specific microRNA signatures in the offspring of undernourished mothers which link quite nicely to the ventricular hypertrophy and the blood pressure we saw so we thought we'll do these microRNAs have utility as biomarkers and clinical samples so luckily we had access to scope samples through Leslie McGowan and we looked at microRNA profiles in maternal plasma in 20 week pregnancy samples so this is 8-12 weeks prior to actual events so these are women who went on later to have a spontaneous preterm birth at 28-32 weeks and what we've found is at 20 weeks we could pick up very very specific microRNA signatures I mean there's no overlap in that group at all so that sort of informs that those microRNAs we picked up and this related to a cluster of microRNAs the 548 family may be very early and very sensitive and very specific marker for later preterm birth and you can see some of the individual microRNAs here we saw here no presence at all in the preterms and this got a lot of press at the time but now we have to go back and validate that so that's an example of sometimes how we can translate a bench platform we're using into a clinical clinically-revelant model so that's quite exciting at the moment Rachnaud Patel in our group is looking at the 15-week samples from this cohort as well and also together with Jackie Bay and her group we're also looking at some translation of DoHED into some of the small island developing sort of states so we've done a lot of work in the Cook Islands in particular where there's no evidence for DoHED because there's a lot of work linking early life events with later outcomes but none of this work has been done in some of these developing nations at all and sometimes it's hampered by lower experimental power so we're doing some work in the Cook Islands you can see here in the adolescents you can already see at ages 13-14 75-60% respectively male and female they're either overweight or obese so this is a population where 91% of the adult population is overweight or obese you can see where adolescents are probably the key window of opportunity because they are the next set of parents so we're going into the Cook Islands and we're actually doing checks on these kids you can see blood pressure here, we're doing glucose measurements so we're actually informing and educating the adolescents about their own health profiles but we're also doing it at the same time as we're actually going back to Rarotonga hospital and linking these outcomes the BMI and so forth with the birth obstetric registries to see if there's any early life influences on their later life health so we're doing DoHED but it's in a smaller island context and of course over my career if your photo's not up here it's probably because I couldn't find it there's a lot of people I've got to think I mean obviously Bernard Breyer and Peter Gluckman for actually giving me a start if I hadn't walked into that door as an unemployed person I mean years ago I don't know where I'd be now this all worked out rather well I think in the end but also I've been very privileged the range of students Alice is my first PhD student there she is there and Alice is here today so it's great to see her but a lot of range of students, mentors and colleagues and collaborators so it's been a fantastic journey so far even though I fell into it completely by accident and also have to fund collaborators I've been around long enough that I've actually got some funding at some point and HRC MB, AMRF we've had a couple of Marsden grants Calahar a lot of funding and support through Gravada and quite a bit of work for some commercial entities such as Fonterra, Pfizer and Denone and also I've got to think the long-suffering Emma and Lila who put up with me sort of moaning on about lack of funding but they know I'm an optimist and things will always turn out in the end so thank you very much for listening thank you very much Mark for a wonderful journey through not only your career but also the contribution you've made to the field of developmental origins to health and disease really advancing our understanding of how some of these early environmental effects affect postnatal phenotypal so how potentially we may be able to remedy those and great to see that you're now that you've got a professor you're managing to spend some time in the cochleons so thank you very much again that was a terrific lecture so that brings us to the end of this evening's ceremony so thank you very much for attending wish you a very good evening and would also like to take the opportunity to invite you to our next inaugural lecture on November the 23rd at the same time a professor at Martin Cusman so thank you very much for coming Tena koto, Tena koto, Tena koto, Tatao thank you