HEALTH MATTERS | Your DNA matters, from conception to old age | HAMISH SCOTT
Well. Good evening everybody, thanks. For coming along this evening I'm Alistair vert and the executive dean of the faculty of Health and Medical Sciences I'd, like to start by acknowledging the Ghana people the original custodians, of the Adelaide, Plains and the land on which the university's. Premises, fit North Terrace wait the, Burton and Roseworthy. Are built. So. It gives me great pleasure to welcome you to the first of the IDI. Lectures this year we've rebranded. Them, as health matters, and. As, I say thank you for joining us I'm delighted to introduce professor Hamish, Scott this evening as, many of you know image heads, the department. Of genetics and molecular pathology. At, the cancer the center of cancer. Biology which. Is an alliance, between sa. Pathology and the University of South Australia. He, did his PhD in Adelaide, and his first postdoc, at Adelaide, Women's, and Children's Hospital. Followed. By five years at the University of Geneva Medical School. He's. Led many international. Collaborations, to identify, genes causing a number, of diseases. From. Severe, birth, defects, to familial, cancers. He's. Been central to introducing. A new genetic testing, take the technologies, to South, Australia to, personalize, patient, treatments, so, to discuss, you, DNA matters, from conception, to old age delighted. To introduce Hamish. Alright, thanks very much for that if I sound a bit kooky it's because of a bit, of a cold, I did. Have matters. In the title before you actually changed, it to. Health matters, because. Your DNA does, matter from conception, to old age and. I have given it a more scientific, total if you like which is about human, genetics and genomics DNA, testing, in both research and healthcare and so, I'll try and give you a flavor of where we're at in standard, care and also in research, at, the moment. Of. Course your DNA actually matters well, before conception. If, you're choosing a potential partner to breed with it might matter and it's. Not going to be unusual, in the future probably that you have your genome, readily. Accessible and it might be part of your, dating. Profile, to everyone. At laughed he, laughed at that has, a secret. And. No. One else does. Okay. So. You. Start with some acknowledgments. A lot of funding bodies to, basically. The whole body of work I'm going to present to you today a lot, of people particularly associated, with some of the work I present on fetal DNA in fetal autopsies. Alisha burns Sarah King Smith, pear arts and Chris Barnett as a lead clinician a, lot. Of work getting a lot of what we've done into routine diagnostics, particularly. Canon Kisan and Janice Fletcher, and. A whole bunch of people involved in the Katz and work that we've been doing and. A brown Chris harm over the years which. Diandra Devender Hiwassee, there's too many people to mention. So. I thought. I'd actually start, with a thought for you and, I may we'll finish this, with. This thought as well in. Australia, we've been lobbying hard since, I can actually remember and that's almost 30 years now for. An increase in research budgets, largely to no avail except. Under the doubling of the NHMRC, budget, under Howard, so. In the health arena with, approximately, 1.6, of research expenditure. Australia generates 3%, of world publications, and our citation. Rates meaning the quality of our work is, actually higher than many, other countries as well and, you. Can actually get this calm this, comment, from politicians, saying well if you're only generating, 3%, of the data and why bother at all all. Right so, three, percent of it 3 percent of patents, 3 percent of papers why don't we just leave it to everyone else leave it to America, for example leave, it to China and.
My, Main response to that because if you want to actually benefit, from the research that we do socially, economically. As. Soon as possible or immediately, and from. The research being done elsewhere you actually have to be part of generating, it and I, hope I show you some examples, of that so. We're. Going to be talking about DNA in our genome and there's. Some subtleties in what I've written in the text on here and what I wrote in the abstract, almost, every cell on the human bodies contains, two copies of a human genome, and your gametes have only one copy and your red blood cells have none so. Human genome is actually roughly, 3.2. Billion data points okay, so in, every cell you've got roughly 6.4. Billion data points got, four different chemicals, in it and these. Chemicals, called nucleotides, make up a very long molecule, called DNA. So. Each cell has two copies of 23. Long DNA molecules, which are actually called chromosomes and on, those chromosomes, is roughly 20,000. Genes that encode proteins. Which, make the physical building blocks and machines of a human, so. Of, those, 20,000. Genes that's roughly only 2% of a genome and we, know what some of that 2%, does and a lot of the rest of it is actually still a black box so there's a lot about our genome that we still don't understand, and, there's a lot of it which is actually repetitive, and. We really have no idea how that works and why it's there. So. It actually seems like a relatively simple equation. And in fact we don't have that many more genes than a small nematode, a small, worm with only 800. Or so cells so. How are there many so many different cell types and with different functions. What. Have presented you is a very static and binary vision of what a genome is with 6.4, billion data points in a cell it's, not like that at all it's, not linear it's, three-dimensional. And complex. And, to try and give you some idea of that I recommend. You go to this animation site, for this guy called drew Berry who used to work with at the Walt fertilizer Hall he, does some amazing animations. And some of them have actually received, prizes such as the British Academy Awards, for film, making so. This is an animation of DNA so here you see a DNA double helix many, of you would have heard of a DNA double helix so. This is it in its linear form and each little dot there you can see as a nucleotide, but. You see it's moving so. It's not static, more. Than that it, actually wraps itself around proteins, these are called histones and each of these proteins, have little tails hanging, out. And those little tails. Actually. If you like environmental, senses and they can be reprogrammed. Depending. On what you're doing depending, on what you're eating what you're drinking how much exercise, you're having they're modified, by things like methyl, groups which are found in the fall like folate, you might take before you're pregnant or folate, in green vegetables, so yes you should be eating your green vegetables. So. You see the DNA isn't linear it's folding, up into these complex, structures and the way that it folds up can, actually alter how, it expresses, itself so health is 20,000. Genes and the genome ever expressed, how, they're expressed is RNA, and how they're expressed is protein. So. You see these structures are going to get more and more complex, as the DNA is actually compacted. Into a form which many of us are familiar with called, chromosomes, which you've just seen there and. Every. Cell, has. To divide so this is actually photography.
Of A cell dividing, and what, you'll see is that the chromosomes, have replicated and, they're now lining up along the middle of a cell, whoops. I've stopped it that's. Very annoying and. In. A minute they're, about to be pulled apart and the cell will split so this is a DNA replication, called. A mitosis. I'm. Sorry that seems to have stopped short so okay. There's a DNA replication. So. The point is that we start off as a single celled organism, where sperm, and egg are combined and we have numerous. Cell. Divisions after that which. Happen, over time. So. You can actually inherit the mutation, and so have a mutation in your, DNA, in one of those six billion data points that you got from your mom or your dad or, you, can actually get them during these so replications. As they go along or they, can be invoked by environmental, mutation, so agents. Such as benzene. Cigarette. Smoke obviously, radiation. As. We. Age we actually, automatically, accumulate. Mutations so, that's partially because of our environmental, exposure and that's partially because the system isn't completely perfect. Or it's pretty bleeding amazing, in terms of replicating, things perfectly, every time you have a cell division. And. So as we get older by the time we're about 80, there's, probably one in two of us who are suffering from cancer simply because we've accumulated, a whole bunch of mutations, and it's too much for the cell and it starts, hyper, mutating, and hyper proliferating. Mutation. What, does a mutation mean a, mutation. Can be as simple as one single, data point from those 6.4, million data points which alters, the function, of one of these proteins. It can't be more subtle than this it doesn't have to alter the function of a protein but with simplicity we're going to say that it alters the function of a protein maybe. It cuts the shape of one of these building blocks or the size of one of these building, blocks in half and.
That Can be enough to cause, a severe, defect, at birth something. Which manifests, a little bit later in life, or. Indeed, cancer. It. Can be more complex and can include a lot more of the, data points than those 6.4. Million so if, you've heard of Down's syndrome for example, Down. Syndrome children have, a a, trisomy. Of a whole chromosome, but it's actually it so, they've, got about 1%, more of the whole human genome than, most other people do. So. How do we actually end up knowing all this is a photo, of Gregor Mendel a monk, who performed. Lots of experiments. With peas back. In the 1800s. And so, you might have heard of Mendelian inheritance this, is named after him, but. Really a lot of the knowledge that we've got at the moment and the power we've got in human genetics and genomics comes, from knowledge aided, by the human genome project, so. The human genome project was markedly. Controversial, when I was proposed and. It cost roughly and three billion dollars over 15, years and this and comparative, pricing, for you I haven't, put the Joint Strike Fighter up, because no one knows how much it's going to cost yet. The. Funding actually came from NIH, was the National Institutes of Health in America, but it also came from the Department of Energy in America, so. Why would funding for a project like this come from the Department of Energy the, Department. Of Energy actually used to be called the atomic, Commission. In America, and they. Were actually after techniques, to measure how. DNA, was changed by d--ation. Because. They've noticed for example after you drop a couple of atomic bombs there's, an increased risk of cancer and they want to understand, that. So. The genome was announced, is finished by. Tony Blair in the background, and Bill Clinton, in, 2000. It. Turned, out to be a race between the public and the private this is Francis, Collins who headed the public effort he's, now head of NIH he, survived, Trump and this, is craig Venter. Who. Headed the private, effort and once made lots of money and patent everything. So. This, man here he's been recurring during. Genomic. Science he's. Very persistent it's, one way of putting it Amy stark raving mad and, incredibly, ambitious is, another.
Guess. Whose genome, he sequenced, when, he was in the private effort it was largely his own genome, he, was also responsible for, sequencing, the first domestic dog guess, whose dog that was a man. Of no small ego. So. Since that happened, at cost of three billion dollars, they estimate, that the first human, genome the, draft of a human genome sequence, cost a hundred million dollars and, since. Then particularly, since the late 2000. There's been an absolutely, massive, drop, in how much it costs to sequence, a human genome in. Fact, this has gone a lot faster, than Moore's law of computing, which is having in price and doubling of processor, time which. Actually causes some problems with the massive datasets that we generate, in genomics. Now in terms of being able to have sufficient processing. Power. Now. They keep on updating this slide. But. I've stopped bothering because it's got down to roughly, $1,000 and but. This is a bit of a lie, you might have heard of $1,000 genome what. They're saying is that's the cost of consumables. To put on a machine. They're. Not counting the cost of doing, an analysis, and so. How. Much does it cost to actually store your data and, think about it and work out what the heck it means because you've got six billion data points. But. How did we get to do that well there was a massive, boost. In miniaturization. And parallelization, so part. Of the Human Genome Project was, actually, focused. On technology. Development and, it worked very well so. We've gone from working in tubes like this to micro capillaries, like this so we've got a strips of eight two strips of 96, where. We literally have what's called massively, parallel sequencing, where. We're just throwing DNA, onto a microscope, slide and running, thousands, of reactions, or. Millions, of reactions, on one on one slide, so. This. Is a history, of some of the technology, and you can see how it's developed this, was the first groundbreaker back in 2005. Which allowed a whole human genome to be sequenced for, roughly a million dollars and. There's been a slew, of these different technologies afterwards. Now. If you remember I said the thousand dollar genome was. A lie because you didn't count the cost of the analysis, it, also doesn't count the cost of buying a machine and keeping a technology, up-to-date so there's no immortalization if, you're going to be a businessman, about it, it. Didn't stop in 2012. 2014. 2015. The Garvan Institute invested. Heavily in this massive, system called an Illumina, highsec, x10. Which. Was roughly ten million dollars and yes it could do a human genome for roughly a thousand, dollars in consumable, costs and had, the capacity to do something like 18,000. Human genomes per year and there's. Several of these machines, throughout, the world so we're probably in a position if we really wanted to to sequence massive populations. And that is occurring in some places. This. Is one of the latest machines that we bought to caught a pack buyer you don't need to see all the detail, it's, a machine which is about the.
Size Of a big fridge/freezer. Eight. Hundred thousand dollars its. Technology, is actually better than some of the other machines but it's consumables. For sequencing, a whole genome cost. $30,000. All. Right so it's better quality, genome, you get out of it but it's more expensive and, the Machine is still costly. One. Company, has become the predominant, provider. Of most DNA sequencing. Technologies, across the world and. We have one of these in Adelaide we have a couple of these we have one of the we, have one of these, what. We desperately need, is one, of these. So. These came out roughly. 18 months ago so. If you've got a lazy 1.4. Million dollars hanging. Around come and see me with your checkbook afterwards. Because. This is what we need to stay competitive in South Australia at the moment and there's, only a couple of these in Australia. So. We're. Going to be sending DNA, into massive centres in, the future, well who knows I told you this all came about because of miniaturization, and that miniaturization, and continues. So this was the release of a couple of machines in 2014. 2015. This, one was the size of a lunch box and as. With many of these technologies that they're actually superseded. Before, they get to commercialization, and, they, don't make a huge impact on the market and so the amount of venture capital, being sunk into this technology is amazing, and. This, is the latest technology. From one company called Oxford nanopore, so. In, the future you might be sequencing your genome at home, ok. It's. Not beyond the realms of probability, and the, small personal, device that you have whether it be an iPhone as depicted, here or, some other device might be actually doing your DNA data analysis, for you. So. Who cares we, can sequence human genomes. Well. We started out pretty well we, did a few, celebrity. Genomes because afterwards. Sequence craig Venter and his dog we. Wanted to know what made Ozzie Osborne tick we. Did destined to -, we. Did a few other celebrities.
But. Really that's. Not my cup of tea I prefer sequencing. Serious. Medical. Problems, because this is where the power is in the immediate oh you, may have read recently that, the twin, astronauts, had had their genome sequence, the. Way some of this gets, distorted, in the press is also amazing these, twins, were actually said in the media to have 7% of their genome different, once. The twin had spent a year in space and came back this, actually shows the correction, that NASA issued saying, no no no if they're actually they're still twins, okay, the DNA is still identical, it, was seven percent of those twenty thousand genes are expressed a, bit differently so it's quite a different story but. Going into space that does alter environments. It does alter the way your genome is expressed. So. There are all of these large-scale. Genome. Projects, going, on with massive amounts of sequencing, so. There's a massive amounts, of sequencing, going on in cancer, to try and understand, why. Cancer, occurs and how you might be able to treat it. Genomics. England started. Sequencing roughly, a hundred thousand, people, to. Try and work out rare diseases and also try and follow populations. Longitudinally. To develop addressing. Health. Theta craig. Venter he's still around he's still doing lots of things he's got an institute, named after him of course the Venter Institute. He's, got a company as well and their, sequencing, really old people trying, to work out why people can live, long and healthy so. There's lots of different things you can do this technology. But. In terms of politicians, David, Cameron was one of the first people to recognize, the power of this and. That's probably, very likely. Because. In, 2003. He. Had a child was affected, with a rare genetic disorder. Called. Otto Harris syndrome, and, his child died at six years of age so. If you want to make a change in this type of field just have a politician. Who's, affected, and. Has something to actually gain from these technologies or. Hasn't been has an understanding, of what might be gained by these technologies, so. What, were we doing here we had some of these machines actually, before we had these machines, we. Started to think about what we could do so. We know that personalized, genomics, is going to be on the rise it's relevant, to trying to work out why people might be intellectually, disabled, what. Inherited, diseases they have for. Pharmacogenomics carrier. Screening prenatal. Testing familial, cancer and, oncology. And. Of course the best thing that you can do in medicine, is, actually work out, how you should be treating someone so, if you've got a diagnostic. Test is positive and you, know you should be treating someone that is the most effective, and normally the most economical, way of doing. Medicine and so, genomic, testing has a massive possibility. In this area. So. This is the way that genetic testing used, to be done for largely for children, a child. Would present to a genetic clinic, and the, commission would look, at the child and look at some of his laboratory features. And maybe if the child was slightly dysmorphic having a slightly abnormal face, would, try and work out what gene he thought and was responsible the disease. While. Their acumen, by their experience, and, then they'd order a gene test for roughly two thousand, dollars, and. It might come back negative come back positive sometimes, it might come back negative and so, then they've gone and ordered gene to became, if, it was negative gene, 3 and this, is what was called a diagnostic, Odyssey, and many.
Patients Went, through and their families, went through these diagnostic, Odysseys, and you, can imagine that at roughly two thousand dollars a gene. Started. Out more expensive, than that but say roughly two thousand dollars a gene the, Turner untimed you actually had a diagnosis. And so you know what you're meant to be treating, your patient, for was, actually massively, long, extremely. Costly and what. Those patients, and their family should be doing is. Very difficult. So. The. Ability to sequence all genes, of the human genome or a whole human genome at once has basically transformed. Genetic. Diagnosis, so you can sequence all genes at once and then analyze, it and see what's wrong with the child easy. You say. Well. It's like finding a needle in a haystack so, if you actually look at the person next year. Unless. They're from a totally, different ethnic, group or from. The greater apes. You'll probably have roughly four million different sequence variants between you and that person which. One is the one which causes, what you want to call the physical. Or phenotypic difference between you or maybe some other phenotype, what causes that person about Republican. God. Knows. Or. What causes them to be musical these are the types of phenotypes, so actually working that out is very difficult. And there's. Clearly a level, where. We can go to an a diagnostic, lab and then, when it turns into research, because we reach the end of our knowledge, at that time. So. We, actually started using, whole genome sequencing, and this was one of the first families in South Australia that we did and. The. Parents, of this small child who has a disease called diamond Blackfin anemia set, up a foundation and, they raised over 4 million dollars to research the causes, and they, spent, $20,000. Of that. Accessing. Whole genome sequencing, very early, in. When, whole genome sequencing, was available so I was still at $20,000. He, was actually diagnosed, at 8 weeks of age he had, a transfusion, dependent, disease so. He was transfused. Over. 100 times by the time it was, 7. Years old I think. And. He's also an increased risk of developing cancers. Including, MDS, and AML. So. This was sent to Illumina. We shouldn't have said that the big big, American, company, to try and work out was wrong with him and his. Sequence, was sent back because, they couldn't find out what was wrong. They're. Searching, for the needle in the haystack didn't, actually work out what was wrong we. Actually did work out what was wrong with him based on the data which was generated, elsewhere, ok, so we worked out that that small child, there had basically.
A Deletion not, of one nucleotide, but, a hundred and eighty-four thousand. Nucleotides on, a chromosome, which, in companied a gene which, had previously been shown to cause that disease diamond Blackfin anemia. So. We're sure that that's what caused the, disease. And that child that. Was a seven year diagnostic, Odyssey for the child with. Massive expense. You. May have seen this in the Sunday paper recently. This. Is again one of the first patients we actually sent to the same company where we got the data back to try and work out what was wrong with that child I'm. Sorry with the two previous pregnancies, that this couple had had which didn't go to term. So. There. Was nothing known that was wrong with these children. Which, had ended up being terminated, and we had to go well into this area. And, work out what, that needle in the haystack was, in effect we generated, an animal, model of the, disease which. Had killed the, two babies of this family, so. We. Actually became quite, expert, in analyzing. This data and, in, fact generating, this data and, there. Was an alliance forming, in Australia, and we've. Tried to form an allowance, and South Australia as, well and. In fact we were the first in South, Australia sa, pathology, to, receive accreditation which, is what you need to do these tests, clinically, for. What's called whole exome sequencing where, as we look at those 20,000. Genes at a time which. Is quite something, because lots of people in Australia wanted, to be first to do that and. We're. Part of. Collaborations. Not just in South Australia but nationally, and internationally, we're. Trying to work out what's wrong with children, because we have 20,000. Human genes and there's, so far been roughly 5,000, human diseases caused by mutations, in genes described. But. There's 20,000, genes there might be a lot more than that. Okay. So I've said that germline mutations. Matter from conception, to old-age let's have a bit of a look at what's happening in conception. So. I've, told you that as you age you, accumulate, somatic, mutation, and this ends up causing cancer when, you're born, it's. Frequently, your germline mutations. Which might be responsible for whatever medical problems you have and in fact a huge, proportion of admissions, to Children's. Hospital are, caused by rare genetic disease, and so. These obviously, have in the environment, which that child is in basically, today's world a very, negative selective, pressure and effect a huge proportion, of pediatric, deaths under five years of age of due to monogenic, disease, okay. So as, you can older your somatic, mutations, become. Become. Accumulate. And again. You. Can either have somatic, mutation, germline mutation sir which might protect you from cancer or they might predispose you, to cancer and we'll come on that in a bit. So. I'm gonna have a quick look what, happens here okay, in utero, from, 13 weeks of age to 28, days after, birth so. This is called perinatal, death and, the. Underlying cause, of death of fetuses. In South. Australia or in worldwide, is actually, unknown in roughly. 50% of cases which means you don't know what the chance of that happening for children. For. Couples, is again it, mates assisted, reproductive. Technology, is not possible, if you don't know what's what's. Happening and, there's. Guilt self-blame, anxiety. And depression in these families, who are unable to have children or. Have repeated pregnancy, lost no, I have no idea how, people do some of these health economic, analyses, Price Waterhouse and Coopers soon to plot numbers out of somewhere. Andrew. I didn't say where. And this, was an estimation, that they made a couple of years ago about, the economic, loss that stillbirth, causes, in Australia, which is quite incredible. So. We've actually been sequencing. Still births I'm. Sorry, performing either whole exome sequencing, or whole genome sequencing, and undiagnosed, cases, of perinatal.
Death To try and identify. Genes. Or, the mutations. Which might be responsible for this if they are but. Then we have to take it beyond the standard knowledge and we need to actually prove causality. Of. Selected, candidates, using, by informatics, and both laboratory work as well. So. If we find something we'll have an answer for the families, we. Have to tell them how. To avoid. Having. An additional still births or children who might be affected by severe genetic disease and they, can use assisted. Reproductive, technologies. The. Identification of new disease genes actually is, quite stunning in terms of what it does in terms of biology as well but that's taking it a little bit out of the personal. But. You know working out what a gene actually does so, we understand, some of the function of human human. Biology is pretty important, as well. So. This is 40. Families, that we've sequenced and. We. Sequence the mum the dad and the, stillborn child, and, what, you can see is. That in roughly 30 percent of cases we've. Solved, what's wrong with. Those children, and so why. Why. This family is having still this or unborn, children, in. Another 30 percent we think we know why we're not quite sure. In. Another small proportion, we have multiple candidates, so we think it might be this model, it might be that that we're not quite sure so. We need to go in and do lots of functional, analyses, to work out why. There's. An awful, lot of new, knowledge in, here as well as helping the families. Roughly. 30 percent of the genes that we're pulling out here, one, unknowns because in the phenotypes, that were observing in the fetus so. What does this mean for developmental. Biology, basic developmental, biology, is absolutely, massive and there's. A huge proportion, of these as well where. We actually have to go in and do functional, studies so, it's going above and beyond a basic level of knowledge which would be possible, in a diagnostic, lab. So. Already. We've had four families, using pre-implantation. Genetic. Diagnosis. And three healthy babies I think it's just three they've gone up here again it Alicia no okay so that we know of and this, is the family which was on the Thanh the front of the Sunday Mail a few. Weeks ago and, many. Of these families are actually reaching, or. Even might call for the, woman the end of their biological, period. So it's pretty important, to try and solve these as soon as possible so they can have a family. We're. Actually continuing, to work on cases which we haven't solved, and we're actually about to take this whole study national, and we'll, be sequencing, 250. Cases per year for. Two for the next two years at least that's, what we know we're going to be able to do and. Our success, rate of solving, these is close to 60% at, the moment which is absolutely massive. And we're still working on those unsold 40%, and as I said the least 30%, of that is new knowledge that's amazing. So. If you actually take children. Who survived that perinatal, birth. The. Perinatal, period and actually present, with a child with the syndrome at a hospital. How. Should you diagnose, them now should. You do this gene test by gene test should you lots, of repetitive. Pathology. Tests or should you do one of these whole exome, or whole genome sequencing, so. This is a study which came out of the Murdoch. Children's Institute or, the Royal Children's, Hospital in Melbourne where. They took 101, children, who presented in the clinic at birth so you'll, see that if they put them through all of their standard, routine, analysis, they end up with 11 percent rate, of diagnosis. When. They use these new genomic technologies, they're getting roughly the same rate of diagnosis. We're getting 60%. You. Look at how much it costs to reach those diagnoses. 27,000. Dollars without using this genetic technology, only 6000, dollars if they, did use these genetic technologies. So. 5, times more patients, diagnosed. Cost. Per patients reduced 75%. And it, actually changes. What you do with those patients it changes, the treatment, now the change for the treatment isn't always fabulous, it.
May Be that the child. Treatment. Will stop of the child and they'll. Go into care. Until they die but because we know there's nothing they can do for them but, you know you to, have a diagnosis. And to be able to prevent this occurring, again for some of these families is incredibly, important, so. It's faster, it's, cheaper it's better. Ok. What, about later in life do we have any information later, in life what happens with people after they're presenting, a bit later, than. At birth if you're, presenting with something from the perinatal period or, straight after birth you obviously have something pretty catastrophic which. Is going wrong so, maybe these ones going to be a bit harder to look at, so. For, about the last 13, or 14 years I've, been collecting familial. Leukemias. And familial image, or malignancies. Familial. Cancer is, tragic. As I'll show you in a minute and a quick summary of my career. In. This area, would be first of all people said it didn't exist and. They said it was too rare to matter then. They said we have no idea what you can do with it and then, they said it, has no relevance to anything else so. A quick summary of the rebuttals, is it's, a lot more common than they thought it has, a lot of implications, for standard, care of classical, standards and cancer. Patients so and. In fact, studies. From that we have done have, actually made and, classification. Of patients, who are predisposed, with leukemia, into the World Health Organization. Classifications. Of leukemia. Why. Did people say that it didn't exist when wait back in 1861. If we've got new German speakers in the audience you can see there were already publications. Saying that you did have leukemia running. In families, and, the first massive, family. With. Or a couple of families actually three families, with. Familial, that came here were published back in 1999. So. We, started collecting families, which showed these predispositions. Till they came here and, we've. Got over 140 families involved, we've. Led the identification of a couple of new genes this is a list of all of the genes for these disorders which they said didn't exist. These, are the types of malignancies, which are running in the families, so. My, dysplastic syndrome, in acute myeloid leukemia we have a lot of lymphoid, diseases, as well so this is non-hodgkins, lymphoma and the Hodgkin's lymphoma, so. Roughly 25 percent of, these families, are solved, so. What. So. This is an Adelaide family. I'm. 13 or 14 cases of, acute. Myeloid leukemia teach. You how to read this this is a woman this is a man and this, means they're married, or the partner. To have children these are the children a son and a, daughter okay so. This, guy here got, acute. Myeloid leukemia, and the line through him means that he died, so. Cute male leukemias, not normally that bad it's. Not nice but. If you look through this pedigree there's only one person who's affected with acute myeloid leukemia he's, actually survived, and. We actually worked out what the mutation, in this family was through world first and. It was a mutation in the gene called geta - and if, it says t3 54m that means that this patient, carries. The mutation which, predisposes them, till they came in. So. They can get the Leukemia young some. Of them are obviously still managing, to survive and great, but. Many of them aren't. They. May have some other phenotypes, which are associated with this acute myeloid leukemia. But. One of the most tragic things with these families, is. That when. An individual, is identified. The first thing you do is you look for Miriam for bone marrow transplant, donors and you normally look amongst their relatives, and so. In this family for example this core family over here a whole, group of them were diagnosed, roughly, at the same time soon, because one of them got leukemia, and then the rest of them were tested to see if they'd be suitable as bone marrow transplant, donors and they were all found to have leukemia. So. The only survivor, in here was transplanted, aggressively. At the first signs of leukemia. But. This is the curious thing about genetics. It's not a hundred percent your fate is not absolutely sealed by your genes we've, got two individuals who carry these mutations, who should be predisposing. To leukemia, and they're, well into their 60s, and they're, well now.
There's Actually a lot of effort going in to, working out why people in families, like these who, carry mutations which, should make them sick oh well, why. Aren't they sick because, there might actually be therapeutic, benefit for lots of different people and working out why they are and, we've got a few clues on that is you can ask me about later if you want what. Is this to do headspace, this. Group here they. Know they're at risk and this is without having any genetic, testing, they've, all had their marrow frozen, prophylactically. To try and buy them a bit more time should they become sick they, can have that marrow put back into them to hopefully help them survive for a bit longer. And. That's. Actually this, guy here and this is his mum and. You say that's a pretty awful nuclear. Family outcome so. We actually worked out what was wrong with this family and introduced genetic testing for these and before anyone, else in the world. So. This is another Adelaide family a. Similar. Type of history except this time they. Don't just have acute myeloid leukemia running. Through the family they have thrombocytopenia, as, well and we. Noticed that they had skin, disorders, and. Arthritis, running, through the family. And. Then. We looked at other families, who have mutations, in run x-1 this gene my next one and, we found a number of families, who they, didn't just have myeloid leukemia, they had a lymphoid and leukemia, but, they also had psoriasis, or eczema skin, disorders. On this, individual, here down below was. Actually treated with a very novel drug for psoriasis, and it, totally, cleared up his psoriasis, in, fact we're now testing that, drug to see if it works on acute. Myeloid leukemia, not. Just in families, which have mutations. In one x one but, any cancer, which have mutations, in one x one which. Is actually up to 30% of, all acute, myeloid leukemias, so that's work actually in progress where. The clue is actually came from studying a, rare. Family, in fact a rare Adelaide family, so. That's, work in progress which may lead to new. To. New drugs or repurposing. Of drugs. So. If you actually have a germline mutation. Which predisposes you. To developing, a tumor the, tumor doesn't, develop in isolation, so. These are basically individuals, from these families, each, column, is an individual. And. Each line is a different gene and every time you see red it, means that the cute myeloid leukemia, which developed in those individuals. Actually. Developed. A mutation and that's why the tumor, started progressing if, you remember I said that cancer, is often accumulation. Of mutations, so. So what, well. What do you do in a family like it's how. Do you tell what's. Going to happen to them well. The obvious answer is you try and work out whether you can tell when. They're going to develop leukemia. And then. See if you can intervene, and so. This is basically showing this. Patient, here over. A number of years and, we can find a mutation which. Starts off at very low level in the blood and then progresses, goes, to higher level. As their. Disease progresses. So. This, is basically, monitoring, for pre malignancy, or molecular. Monitoring. Now you might have seen in the press, circulating. Tumor DNA, monitoring. Well. They've. Got an acute myeloid leukemia so, it is a circulating, tumor and, it is DNA, and so, it's basically the same theory, is that can we detect, when. The disease starts to progress and so, this is one of the major questions what would they do with these families, is how you conduct, surveillance on them and when, you intervene, and by, looking at these families, more systematically, we're hoping we can answer those questions. So. This is one of the latest genes that we worked out was predisposed, to acute myeloid leukemia. And, my dysplastic, syndrome, but, there's a major difference here between. Those other families if you look at the age of onset of these individuals. They're. Old. Right. So. Until the average life expectancy of. Our. Populations. Went up to this stage you wouldn't have been foreseen that this mutation even, mattered, right. Does. It matter now well, yes these people are getting leukemia, we. Think we know how to treat it better because they have that mutation. But. It's, making choices in people's lives so for example, one, of the ladies here was. Used as a marrow transplant, donor when. One of her siblings got, ill and one. Of the ladies I think it was this one here her ovaries.
Were, Used for. An ovarian transplant. With one of her daughters here alright so if you like that's passing, on the disease you know you know why which is probably less than desirable. Now. Um. That's. Talking about Myotis plastics you know an acute myeloid leukemia, what. We noticed when we looked at other tumors, which occur in this cohort is that we do have other tumors, and. In fact if you look at non-hodgkins, lymphoma and, Hodgkin's, lymphoma. They. Tend to cluster together with. Tumors, like breast cancer prostate. Cancer and, melanoma, and. When we start sequencing, these families, we start to find mutations in, genes such. As pal b2, which is a known breast. Cancer, predisposition gene. Okay, it's. Not Bracco we do have families with bracket mutations, in them as well which, is the Angelina, Jolie gene but. This is another breast cancer, predisposing. Gene so here you can see our family, who. Was ascertained, with, Hodgkin's, lymphoma, over here, okay. And, when you expand, the family tree out you can see on another side of the family they've all got breast cancer, and. A similar case down here we've got diverse types, of cancers. Occurring. So. What, does that mean that, actually, means that this tumor, streaming, which people have been performing, saying you've got breast, cancer and you're predisposed, to breast-cancer and. Well you've got colorectal cancer, and you're predisposed, to colorectal cancer, well, true is not completely, true which. Means that you won't might want to be able to monitor not. Just for, breast. Cancer but for Hodgkin's. Lymphoma in these families, and how do you do that and this. Can again alter, the treatment, of these families. So, how can actually alter the treatment, in these families. This. Is actually what's called the DNA damage repair pathway, and, there's. New drugs called PARP inhibitors, which, are working in, these, DNA. Repair pathways, for, treatment, of patients, as we speak in those clinical trials and routine, care. So. The large hope. Of, genomics. Is that. It will have massive implications for, health but. Particularly, cancer so. At the moment there's, a massive group of cancers, that we just lump them together and we give the radiotherapy and/or, chemotherapy. And they. Fall into these different groups, and. Those some. Of those groups are desirable, and some of those groups are not, desirable, so. Drug not toxic, and beneficial, you'd love to go in that group because that's curing, you, drug. Toxic, but not beneficial, that's probably a least favorite group okay. Now. Some of the newer drugs which. We're getting out for cancer, are a lot less toxic, than some of those common treatments, but how do we know who. Should be treated with which drug. And. In fact when you look at cancers. Every. Year in Australia, there's. 52,000, diagnoses, of. Less. Common, cancers. And I actually calls 25,000. Deaths, so. These, are all the big cancers, acute myeloid leukemia breast. Cancer, prostate bowel, and these. Things are called less common cancers, and rare cancers. So, here's research, dollars being spent total. Cancer burden of disease and the number of deaths and. You see across in this rare corner, there's, very little money being spent on less common and rare cancers, which. Actually all of my families, fall into is less common in rare cancers. The. Burden, of cancer death and. The cancer burden is actually very high okay. And. There's probably over a hundred and eighty plus cancers. As defined, by various. Traditional. Pathology, techniques, within. These groups. So. The solution, for these types of things we, think is. Molecular screening, and therapeutics. And so this is a clinical trial which is happening it's. Called most for MOS. T and. A number of clinical studies which are going on so if you take these rare tumors, and new.
Sequence, Them with a limited, panel you, can find what we call actionable, mutations in. Greater, than 20% of these patients so instead of offering them just standard, chemotherapy and radiation therapy, they. Can go on to very specific, therapies, and, if you don't find an actual, mutation you can put them on to an immunotherapy which, people might have heard about, which, is a much more recent and very effective, therapy, here's. That group that we talked about PARP inhibitors, for DNA, repair because, this is becoming a lot more common than we thought so. There, was a report issued in January this year. With. By Greg Hunt the federal Minister for health in. Association. With the rare cancers, Australia, and the. Recommendations. Were that we should be able to have local clinical, trials, to. Test and confirm local, clinical trial design, we. Should have subsidized, access, and we should have collaboration. To infrastructure, so. They want to have a network, where, patients. With cancers, can, be fed into the appropriate clinical trials. This. Actually became government, policy, for one party. That. Party didn't do very well I'm afraid. So. If any money follows, through who knows. But. If you actually look at cancer more broadly and this is data from David, Thomas at the Garvan, Institute if. You take over 300, cancers, at presentation. And you sequence them. You. Can find actionable, variants, in at least 46. Percent of them one saw what that means is that you can find a new. Or a different way of treatment and compared to standard treatment in. Almost 50% of them and if. You. Can access the appropriate clinical, trial, here. Most for, example, you, can get a significant, proportion of those patients onto, a new less toxic, therapy, which. Will hopefully lend, chemo or radio, which. Will hopefully if. Not cure them at least make them survive with a greater, with. A greater quality of life hopefully for longer period of time. So. This. Is the progress of that molecular screening, study. To date, so. Here's. South Australia, okay, we, don't have funding to do this. Here's. The Kingman Cancer, Center and the Chris O'Brien life house in New South Wales, who. The lead contributors, to this study so. You ended up with a rare cancer ask, you the question, where, would you want to be would. You want to be in Sydney or. You'd want to be here I don't, think the answer is pretty obvious which is why you want your governments, and your researchers, to be invested, in this type of problem, so. We are part of a national network here. With. Roth and, the son of cancer biology and sa pathology, trying. To get this up and going for. South Australian, patients, as well but we're funding dependent, we're hoping that money's going to come from the feds but we also need contributions, from the state government so. Which. Takes us to our South Australian, genomic health alliance. So. Here's the investment, that, various countries, and, states. Have made in genomic, medicine if you like the investment, of sequencing. People sequencing, tumors and. What you can see down the East Coast is that, each state government, has put in relatively. Large amounts of money not nearly as much as England or or America. But, relatively large amounts, of money into. Trying to make genomic, medicine part, of their standard healthcare that. Red dot here in South Australia is a hopeful question, mark and there, has been substantive, federal government, funding of which we do get some of that in South Australia but it's not nearly enough. So. Our genomic alliance in South, Australia is basically to help develop, better value health care through genomics, we. Want to be visible we want to make sure that genomics services in South Australia are state-of-the-art.
We. Want to make sure that we're keeping research, activities, and innovation. Right. Up -. Right. Up to the cutting edge to make better healthcare for patients. So. This was helped a few years ago by. A, large infrastructure, grant from the Australian, Cancer. Research Foundation where we opened a genome facility, we, had additional money from the, state government and some other bodies, including University. Of Adelaide and. This. Is set up an ecosystem, but this ecosystem still, needs more support. Where. We have basic, research, and translational, research where. We're diagnosing, patients whether, they be with genetic disease, predisposition. Cancer, or cancer. And. We can end up with a clinical diagnosis. That can background to a clinical, trial or can end up going back to basic research because, of discovery, of a basic, biological. Mechanism, so, this is the ecosystem, that we've tried to set up and support, for, the benefit of South Australians. It. Has a flow-on effect. So. Since, that genome facility, was opened these. Are the number of grants, that that, genome facility, with. Our expertise. Has actually been consulted. On. To. Try and attract additional grant funding from the feds, or. From. Other other, organizational. Bodies and, you can see it's been pretty significant. Bringing that expertise, into South Australia, has, brought extra, research dollars into South Australian, extra expertise. Into South Australia, so we believe, instead. Of saying that someone else is going to do it it, can all be done in Melbourne. It, could all be done in Sydney, can all be done in China it can be done cheaper and better these. Are the types of benefits that you get from doing it here and. Actually if you look at the number of samples, which have been run through that, genome facility, there, is a number of research samples, which have been run and. These are the number of diagnostic samples, which have been run and you see that we're clearly converging. The. Latest technologies, from being research only to, being diagnostic. As well. So. For. Me this all seems bleeding, the obvious we, should be sequencing everyone, when they're born, see. What's wrong with them what they're going to get if. You get a cancer, we should be sequencing it and see how we can treat so why aren't we. There's, a lot of ethical concerns, because. What. You have in your germline also, affects other people in your family, amongst. Other things do you have the right to know what the future of your child is going to be based. On what they have in their genetics the. Economics, is horribly frustrating, for me who. Pays for the testing, a very simple question. Now. For some of these rare genetic diseases, if you actually come back as having a positive test, there, are treatments, available not, for very many of them but if there is a treatment available, that treatment might cost hundreds, of thousands, of dollars a year so, who's going to actually pay for them and. Then you have this catch cry throughout medicine, called. Evidence-based, medicine. And. What they want to know is does it alter clinical, treatment. Does. It save lives, does. It save money. But. By the time you actually accumulate. All that evidence, it may be too late for you your loved ones and. Your family, and then. We have the question of Education is, that, people don't know it's available they, don't know how they can benefit, it. Can benefit from and the medical profession, is not totally aware of all of these things as well. So. I'll leave you with that final thought again my. Main message is that embedding. Research, with. Standard. Healthcare is vital if you, want to have access to, the, best standards, of health care possible. Then. Tell. Your politicians, so you think we need extra funding. Get. Ready for your grandkids to. Be playing in their bedroom with. A thumb prick they're not doing them their diabetes anymore. They're. Actually sequencing, their genomes and posting on tinder. And. I'll. Leave it there and be very happy to take any questions thank, you. Thanks. Hamish fabulous, lecture, this, is open for questions. Maybe. I'll start by you. You, mentioned. Early on about some of the limitations. Around interpretation. Of the data and that talks to the kind of bottleneck about, bioinformatics. With. Artificial, intelligence machine learning are we quickly going to that this, is a situation. That will be on the iPhone and so on I. Wouldn't. Say quickly but yes eventually. I'm. Actually trying to prepare a, document at the moment which is outlining, to. See. Medicos. He, might be referring, in. Australia, South Australia about, any genetic, testing. Why. This should remain in the private in the public system why, this data should remain in the public system because if it goes into the private goes into a database, they.
Might Issue a single clinical report but all the rest of that data is lost. So. How do we get to a state. Where you might have artificial, intelligence helping. Us you, have to have very large-scale. Databases. Which we're going to require cloud infrastructure, and detailed. Data. Which. Won't come. Solely. From private, it needs public investment, in it so, you can imagine that you, should have your genome sequence at birth and this should become of your one. Of your health records, and, I actually do have my genome on my iPad if anyone wants to look at it. My. IPad with you with me you, can look it up on tinder though. And. It's perfect, so if you want to reproduce please, see me I. Think. We'll pass on. Yes. Please. Well, that's, the million dollar Ithaca, question. So. I know, ethicists. Who would like to be controversial, and saying why wouldn't you. Yeah. Why wouldn't you wipe out one, of these diseases if she could I. Can. Tell you that CRISPR has already entered the clinic and the. Child I put up there with diamond Blackfin anemia. He. Could probably be treated with CRISPR technology at, the moment but there'd be risks associated, with it, but. Though we would not go in and touch his German, so you wouldn't affect, his. His. Future, at the moment I'm, his future offspring Vanina, you might have children, so. That's a massive ethical, question, which has yet to be answered. You. Know that in some genetic, communities, there's. A. It's. Very interesting so the deaf community for example you know there's resistance to have cochlear implants. Because. They think there is special culture, and that well, they, are and they. Don't want to lose that culture. There's. Non-invasive. Prenatal diagnosis. Available, for a lot of genetic diseases at the moment but it's come to the fore for, Down. Syndrome and so. If you like the elimination. Of Down syndrome has actually become a public health goal of. Lots of countries, and it's done, pretty well in some countries, I know it was national Down syndrome day the other day and, if you see that car karaoke, with the Down syndrome kids. Look. It up. You. Know should, we be eliminating, these things or. Should. We just be living with them I'm not sure I think it's very personal, question. So. I prefer to leave it to people rather than make it but. They're touching, the germline. I'd. Be very very cautious. Yes. Many. Of those are doing what I call recreational genomics. And. That's fun there's, a whole bunch of websites out there that they, generate different types of genetic data okay so it, might not be as complete as having a whole genome so, it might only access a certain number of bits of the genome but, there are websites out, there which you can upload them and see, you're related to so if you're an Ashkenazi, Jew you'll be related to Sergey Brin.
Yeah. You, might discover long-lost, cousins. You. Can essay you can work out how athletic you meant to be and probably be disappointed because you're not or. So. There are these recreational, genomics, sites out there I I. Think it's fun if you want to have the money and you want to spend it on that go for it. You. Know ancestry.com, is, an absolute classic and you see the ads on telly I think. It's fun I think it's a great educational tool. 23andme. Got into a lot of problems when they tried to sell it and provide, medical information basically. Because the FDA in America wasn't convinced, by the. Veracity. Of their, medical advice because they didn't have decent oversight, of it and, I think that's the problem. Because. Most. Genetic tests particularly when it comes to germline are, given, with a significant, amount of genetic. Counseling, explain, to you exactly what this means for you and your family, and, if. You don't have that counseling. Doctor. Google's not bad but it's, not perfect either so you know it's it's it's, dangerous. Education, is and massive part of this so. I quite like recreational. Genomics, but I'm frightened, of it at the same time you. Know I walked into my GPS. Office. After. I had my. Genome sequence, and said you know hit my genome sequence in his interest level was a big fat yeah. Hopefully. That'll change because. There. Are some things in my genome which maybe. They're not quite perfect. Shocking. As it may seem. You've. Just lost, that previous offer. We've. Been CRISPR correct ma'am that's okay. I'm. Gonna ask you to restate, that question, in a different way I didn't quite understand, in English it. You're. Identifying, new genes that are related to particular disorders. Continuously. It's definitely not at the moment. So. Will it be I, don't, think so not until the biology, behind some of those genes is a bit more sorted out. You. The, funny thing is that amongst some of the known genes which are popping up in that perinatal, death cohort, for example there's some old favorites, like in, Juwanna days mika poly saccharide isis type 1 but, there's also probably. A significant, number of. Cancer. Predisposition genes. So, where, yeah. The fetuses, are being. You. Know being. Miscarried, so. Driver. Of targets, I think, there's some systematic, efforts out there will this help maybe. But, the. The problem so. One of the major problems with personalized, medicine we whether it be for a germline or somatic is. Often you're talking about N equals one, right. And I, mean I didn't present but there's one case here where we found a defect, in a in. A vitamin. Transporter, and you gave that we get the chopped vitamins, and. It. Was massive, and clinical, improvement its N equals one and. Many of these cases are N equals one until you can prove the relevance of the biological, pathway, to, something significantly, border, I don't think there's much interest from Pharma, so. Even. That one case where we've. Probably shown. That. A Genentech, drug for. Psoriasis, is relevant, to acute myeloid leukemia. Where. It just did people, with R and x1 mutations, are interested genetics, not that interested, I, don't. Really understand, but. Okay. I think we'll need to draw, it to a close so Hamish. Thank you very much for. Demystifying. Genomics. For a general, audience I. Think, you've given us a great oversight. Of the opportunities. But. Also some of the challenges of modern-day sequencing. There. Is just a couple of minutes left if people, want to queue up who have a lazy, 1.4. Million, or your new sequencer, but. Thank, you and thank you all for coming there just worth one parting. Token. Of appreciation. One. Of which may have some epigenetic. Effects. Thank. You once again. And. We. Look forward to seeing it for future, future. Health, matters lectures. Thank you.
2018-03-25 12:41
