The origins of childhood cancer | 91TV
Transcript
- So thank you, first of all, David, for the very generous introduction. Thank you guys for coming.
- It's really wonderful to see you here. I would like to start by thanking the Royal Society for
- giving me this privilege to deliver the lecture. I'm so grateful to you guys for coming here,
- and also to the people online for taking the time to listen to this lecture. Amongst
- the online audience are my children, Emily, Henry and Wilfred, who will no doubt tell me
- off for my terrible dad jokes. What I would like to do this evening is to take you on a
- journey into my research, which focuses on one question, where does childhood cancer come from?
- What I might do first is expand a little bit on myself and introduce myself more. So this is my
- life on a slide. Apparently, this thing is... Oh it works. So this is a picture of our hall,
- the dining hall at the Wellcome Sanger Institute, which is situated in a village called Hinxton,
- just south of Cambridge. That's where my lab is based. I'm a professor here in Cambridge,
- also, and a fellow of Corpus Christi College, and I continue
- to work as a paediatric oncologist in the NHS. This picture here is quite wonderful. It was drawn
- by Shathar Mahmood, who was a medical student in Cambridge, and she was a visiting student
- to our lab. I think what it quite beautifully encapsulates is sort of what we do, this interface
- of genomic research with a double helix on the one end, human development and cancer,
- and she very generously brushed over my white hair. So I'll talk you through childhood cancer,
- give you some background. I will then go on and talk about the origins of childhood cancer,
- our approach to discovering them, and then talk about the future, and what that might look like
- with the sort of findings that we make. In the UK, 1800 children are diagnosed with cancer each year,
- and 80 per cent of these children are cured. So one could look at this and say, this is really
- a truly wonderful achievement. The way that we have achieved this is primarily by optimising
- chemotherapy, by being able to give more, and also look after children really well to protect
- them from the side effects that this causes. This here is a picture of Sidney Farber. He is
- the grandfather of modern oncology. He is the man who came up with this idea of using chemotherapy
- to treat cancer, not only childhood cancer, but all of cancer. This is the beginning, as it were,
- in the 1950s in Boston. He was a pathologist, which is quite remarkable. I think it would be
- unthinkable in this day and age that a pathologist would consider treating children. We are so siloed
- now that I don't think that would be conceivable. What he had figured out, he was interested in
- acute lymphoblastic leukaemia, leukaemia of childhood, and he figured out through trial and
- error that the cancer cells depend on a particular vitamin called folate. Then he worked with
- chemists to design drugs that inhibit folate, and that was the beginning of modern chemotherapy,
- and what was once a universally fatal disease, the most common type of leukaemia, B-cell acute
- lymphoblastic leukaemia, can now be cured in more than 95 per cent of
- children. That's an extraordinary achievement. So one could look at this and be sort of not
- happy, but maybe content, and say, that's not bad, but I would suggest I look at this differently,
- and I would suggest that most of my paediatric oncology colleagues will feel very similar,
- that actually 20 per cent of children are not cured. Then, more importantly,
- the children who survived do go on and suffer from late effects. What we mean by late effects,
- they are the side effects from the chemotherapy, mostly, that we give. It can be sort of reasonably
- manageable things like, let's say, some mild hearing loss on the one end of the spectrum,
- and at the other end of the spectrum it could be secondary cancer. So quite dramatic really. The
- way forward is not entirely clear. So it could be more chemotherapy, and this is really what we've
- done since that initial moment of Sidney Farber. What we have done is, we have done successive
- trials very well internationally, trialling out different chemotherapy regimens, adding things,
- taking things away, giving more chemotherapy, less chemotherapy, swapping things around,
- and those successive trials they have probably optimised what we can achieve in chemotherapy.
- I think this is this has plateaued, it has maxed out, and although probably we can make a little
- bit of gain here or there, I would suggest that most of us would agree that chemotherapy,
- more chemotherapy or a different chemotherapy, will not close that gap of 20 per cent. Could
- there be novel treatments? So we live in a very exciting era where we understand cancers
- biologically really well, and we've got clever drugs that can go and inhibit this or that in a
- cancer cell without killing it, so nonchemotherapy targeted agents. They can be very powerful,
- but unfortunately, they're only powerful in very few cases. So yes, it'll sort of
- chip away at the 20 per cent a little bit, but probably not fundamentally. Then, another line
- of investigation is about immunotherapy, this idea that we can somehow either modify or unleash the
- immune system so that it causes cancer. There are some fantastic people here in the audience
- today who are pioneering that kind of treatment, and that may be a source of novel treatments.
- What I would like to talk about today is this idea of prevention, and we need to go into this
- a little bit more detail. I'll try to connect it to this idea of understanding the origin. So what
- I'm showing you here is a picture of a malignant melanoma, so skin cancer of the cells in our
- skin that make our skin brown. We understand an awful lot about malignant melanoma. Quite
- often they arise from moles, and we establish that relatively early just by observation,
- and that means we have all learned that, when we have a mole, although we can't prevent the mole
- from being there - it's already there - we can look after our mole. We look at it regularly,
- and the moment it changes, we go to the GP, and then the GP will think about melanoma and try to
- identify it very early, diagnose it early, and thus minimise treatment and optimise outlook.
- We know even more about moles. We know that they are caused by UV light exposure, particularly
- during childhood, so we are all quite militant with our children and smother them in sunscreen.
- So this is quite a beautiful sort of arc where we've learned, we have such a deep understanding
- of this disease, that we can seriously talk about prevention. We can't prevent all cases. People
- still get malignant melanomas, but hopefully going forward, the next generation of adults,
- who are now children, whose skin we look after very carefully, will not. There are many more
- such examples in adult oncology and adult cancer medicine, but not in children. Think about breast
- cancer prevention, prostate cancer, bowel cancer. What all of this requires, this idea of prevention
- fundamentally requires, an understanding of the origins of cancer. If we don't understand where
- it comes from, then this whole idea of even theoretically considering might we be able
- to prevent it, is of course, not reasonable. So how about the origins of cancer? Before I
- talk about it, I need to take you on a little detour. This is a bicycle pathway that runs
- along the rail tracks heading south from Cambridge towards the Sanger Institute. This is the genetic
- code of the BRCA2 gene, and really what I want to talk to you about is the genome and human cancer.
- Our genetic code is 3 billion letters long. It has four letters A, C, G and T, and this genetic
- code is within every cell of our body, which is quite remarkable if you just sort of consider
- how Mother Nature managed to package 3 billion letters into something that can be inside a cell.
- What the key thing about our genetic code is, in relation to what I'm going to talk about,
- is our ability to read it, and when we read DNA, we call that sequencing. I'm showing you here on
- the right-hand side, Frederick Sanger, who was a Cambridge man, who was awarded his second
- Nobel Prize for the invention of a sequence of the ability to read DNA. With that technology,
- we have been able to read the human genome. The first time this was done, it was called the
- Human Genome Project. It took 13 years. It cost $2.7 billion and involved thousands and thousands
- and thousands of people to read the genome once over. I just find it incredible and so beautiful
- that we can now do that experiment. So this finished in 2003, and 22 years later we can do
- the Human Genome Project in one day. What happened is that the machine that was used to do the Human
- Genome Project, the Sanger sequences, there were these big fridge-like things that could deliver
- about 100 or 150 letters per day. You can do the math. You need an awful lot of those machines to
- get through 3 billion letters. What humans have invented, and this is, again, another Cambridge
- invention, is to miniaturise that fridge into something that can fit on a chip, in a little
- submicroscopic well, and that enables us to put millions of sequences onto a little chip, and
- thus we can read an entire genome, and that's the critical invention behind my research and behind
- the transformation of our understanding of cancer. So the next thing, then, that I need to explain is
- the relationship between our genetic code and cancer. Our genetic code is 3 billion letters
- long, and mostly, we don't actually understand what it does. It probably is junk. Most of it
- probably doesn't do anything. It just has to be there for physical reasons. Some of it does
- sort of vague regulatory things that we're only learning about now, but then there are genes,
- and about 1 per cent of our genome encodes genes. Genes are the machines of our cells. There are
- about 20,000 of them, and you can think of them as literally little machines, cars, diggers,
- conveyer belts, fridges and so forth. What happens with our genes, or with our genetic code,
- just because we live and we're exposed to chemicals that cause mutations that cause
- changes, we acquire mutations. So mutations are changes in the sequence of the DNA, and they
- can affect these machines in various places. So this might be a little chip on the window
- caused by UV light, but then we also accumulate mutations because our cells divide. So one cell
- turns into two, turns into four, and each time a cell divides that 3 billion letter code needs
- to be copied and pasted. It's an extraordinarily effective machinery, and almost no errors occur,
- but about one error per cell division does occur. So cell division from ageing are the
- other source of mutation, and here you can see a mutation causing a little dent. This stuff doesn't
- matter because we can still drive a car with a chip in the window and a dent in the door,
- but then every now and then, a mutation comes along and does something dramatic, and what I'm
- showing you here, apparently, is a Lamborghini V12 engine put into this beautiful Triumph Stag.
- So cancer is caused by mutations, and the causes of mutations are therefore the causes of cancer,
- and that's a fundamental tenet of cancer biology, something that we sort of knew is probably true,
- but until we were able to sequence cancers through those fancy machines, which started
- in the early 2010s, wasn't really proven. It's now unambiguously clear that this is the most
- fundamental biological property of human cancer, and everything else around it is also important,
- but without this, this is the sort of the very essence, and the beauty of our age is that we can
- actually now say what cancer is. Whereas 20 years ago we probably didn't have a clue. Now moving on
- from here to childhood cancer. So what this means then is, if mutations are the cause of cancer, it
- explains an awful lot about the difference between adult cancer and human cancer. So childhood cancer
- arises during human development between that period when the fertilised egg is formed and
- the baby is born. Adult cancer forms during life after birth as we as we live and grow old.
- So childhood cancer is this abnormal development that leads to cancer, and the mutations in
- childhood cancer come from that very, very rare error of cell divisions, of copying and pasting
- DNA. Adult cancer, by contrast, is caused by all the mutations that we're exposed to by living,
- by exposure to mutagens, and just through ageing. That, then, explains the fundamental
- difference between childhood cancer and adult cancer. Childhood cancer, for that very reason,
- is thankfully, very, very, very, very rare, and the tissues that get affected are the sort of
- tissues that rapidly grow, the organs and the fleshy tissues inside our bodies. By contrast,
- adult cancer is very, very, very common. and in fact, there are so many mutations around,
- and we acquire so many mutations in our body, that we really need to ask the question,
- why is it not more common? It affects the inner and outer surfaces, so if you think about lungs,
- if you think about bowels, and so forth. Now this, then, poses a problem. If you
- want to study adult cancer, our approach is a relatively straightforward one, because we are
- in front of us, we can study each other, but if we want to understand childhood cancer, really,
- we need to understand human development, and that is a major challenge that we face.
- So this is where the detour ends. I'm taking you back to Cambridge. This is the Eagle Pub,
- which is owned by Corpus Christi College, where I'm a fellow, and apparently this is the pub
- where Crick and others announced the discovery of the Double Helix. So if you're ever in Cambridge,
- go there and have a pint. I'll move on to talking about our approach. So the issue
- that we have is human development is a black box, which we can't readily study. Naturally,
- we cannot do experiments on developing humans. We could try to do this in animal models. So let's
- say we were interested how a childhood kidney cancer develops. We could try to model this in
- mice. The issue is this. When we model something, we need to know that we got the right thing. So
- yes, we can make a tumour in the kidney of a mouse that looks like a like a childhood kidney tumour,
- and it may be that, but we are not interested in the end result. We are interested in the
- developmental phase, but because we don't know what the correct sequence of events is that leads
- from fertilised egg to the kidney cancer, we don't know whether what we are modelling is the right
- thing, which is why the modelling approach is not quite right. So we can generate childhood tumours
- in mice left, right and centre - that's not the issue - but we don't actually ever know whether
- we've done it through the correct sequence, because we don't know what the blueprint is.
- So how else can we study human development? One simple approach is comparing cancer cells with
- normal cells, and all one does is take a cancer cell and compare it to relevant normal cells.
- That used to be quite boring because of technical issues. We couldn't just generate good enough data
- to do this, but in around 2016, '17, something came along which is called the Human Cell Atlas,
- this effort to systematically characterise all cells using a technology called single-cell mRNA
- sequencing. What that does, it's an incredibly powerful tool to give us, at the resolution of
- a single cell, a readout of what a cell is and what it does. So RNA is the message of the DNA,
- so when we use our DNA, when we read it, or when a cell reads it, it produces these molecules called
- RNA to tell the cell what machines to make, and the collection of those RNAs, thus, tells us what
- a cell does and what it is. This technology came along. It was used to define normal cells, and we
- saw an opportunity therein to look at cancer cells and set up this experiment. Let me do single-cell
- RNA sequencing of normal cells and compare it to cancer cells, and compare it to relevant normal
- cells, and in this case human foetal cells. Now, it was an incredibly powerful approach,
- which we have applied to a variety of tumour types, starting with the childhood kidney cancer,
- Wilms tumour. We looked at all sorts of different things. I should highlight that everything that I
- show you is an incredible team effort, but I just need to embarrass certain individuals. So this is
- work that's been led by Matthew Young, who's really the mathematical brain behind this
- particular line of inquiry. What the issue is, so we say that a cancer cell looks like
- this normal cell, but that doesn't mean that the cancer cell has arisen from that normal
- cell. So if I'm interested in the question of origin, it isn't actually, definitively,
- helpful because it might be - I mean, just to say something quite absurd now - that a blue
- cell actually is a normal cell from which this blue cancer cell arose and it just underwent a
- colour change. The fact that there is a blue cell that looks a little bit like the blue cancer cell
- doesn't mean that it is a cell of origin. It's quite a pedantic sort of point to make,
- but it's an incredibly important point to make, as I would suggest that the literature sort of
- has gone a little bit - the interpretation of such data has become a little bit generous,
- and we sort of maintain quite a strict view that we cannot infer the origin of cancer cells just
- by saying something looks like something else. So how else could we do this? This goes back to
- mutations and what we can do with them. So when I was a PhD student, or towards the end of it,
- my supervisor, Mike Stratton, had this wonderful idea, why don't we use mutations as barcodes of
- development? The idea is this. If you were to start with a single cell up here - that doesn't
- really matter - if you look at cell number one, the white cell, it turns into two cells,
- turns into four cells. Remember, I suggested that with each cell division, a cell acquires about one
- mutation. That means that as these cells divide and evolve, they acquire a postcode of mutations,
- a barcode, a developmental barcode that, if I'm able to read it, I can then reconstruct where the
- cells come from. The mutations here are depicted with letters A, B, C, D, and F, and so forth.
- So if I were to read the bottom row of cells, you could quite easily infer that there was a red
- lineage and a blue lineage, and each of those gave rise to two cells. This is the sort of fundamental
- approach that I had the privilege to develop as a PhD student, and then we looked for ways of how we
- might be able to apply this to our questions about cancer. This is now going into data,
- and I hope I'll make a reasonable job of explaining that. Apologies if it's either
- too detailed or too superficial. So we start with Wilms tumour, which is a childhood kidney tumour,
- and this is the first time that we did this sort of experiment in childhood cancer. This
- is a picture of Max Wilms. He was a surgeon and a pathologist and a sort of developmental biologist,
- which apparently one could all be in the late 19th century in Germany, and here I'm showing
- you a picture of a Wilms tumour. The reason why we went for Wilms tumour in the first instance,
- is because it is a tumour where we not only get the tumour, but also the surrounding normal
- kidney. and that then enables us to study the very tissue from which the tumour has originated.
- Now, conventionally, the way we think about Wilms tumour is as follows. That there is
- somehow an embryology during human development, we get the fertilised egg, it develops, develops,
- develops and develops, and then there is this group of cells that makes the kidney,
- and then it grows. Then a single cell acquires mutations, and that single cell then turns into
- a Wilms tumour, into a cancer. So there is a single seed in the developing cell that gives
- rise to the cancer. That would be the conventional model of how we think Wilms tumour comes about.
- We did a pilot experiment in one patient in Cambridge, and what we did is we got a blood
- sample, which I'll explain in a moment why, and we went to theatre, retrieved the kidney,
- took it to the pathologist and asked, 'Can we have some tumour samples, please? Then, from
- the other end of the kidney, give us some normal sample, please,' and then we just sequenced them
- on those fancy machines that I showed you earlier. Now I'm trying to show you some raw data, to sort
- of give you an idea of the stuff that we look at. What I'm showing you here is the genetic code of
- this child's blood. So we go into any position in the genome, we sequence all the positions
- in the genome, and then we get reads, and reads are strings of letters about 150 letters long,
- and each of those black lines is a read. The first thing to notice is that we don't just sequence a
- genome once these days, we sequence it several times over, to give us confidence in what letter
- there is. In black is the human reference genome sequence, so the sequence that we would find in
- all humans, and now we can read the genetic code of this child's blood, which is Aa, C and T in
- every position. So it's entirely normal. We then look in the tumour, and we found a mutation in the
- C See position, a C to an A. Now, this is the very essence of cancer sequencing. So these are the
- mutations that have turned the normal cell into a cancer, so everything so far is entirely expected.
- What we then expected to find when we sequenced the normal tissue is this, that the normal tissue
- would also just look normal, because it's normal tissue, it shouldn't contain cancer mutations.
- This would be perfectly consistent with this sort of idea of a seed, that then gave rise to the
- kidney tumour. but what we found instead is this. We found cancer mutations in the normal tissue,
- and the starting point of this was a single such mutation. At that time, I still had only
- just started, so I didn't have my own office yet, and behind me said this PhD student called Tim
- Coorens, who's sitting over there in the audience. I showed him this mutation and said, 'Tim, can you
- go and find some more?' and so he did. What we found - and I'll try to articulate this - is we
- found several mutations - not hundreds, several - that were shared between the tumour and the
- normal kidney tissue, that were absent from blood. So a cancer mutation would be one that is present
- in the cancer and the blood, as in just in the cancer but nowhere else, but this was different.
- This was a trace, a root of the tumour within the normal tissue. It was not the case that all the
- tumour mutations were in the normal kidney. Only a few, only a handful. What's also very important is
- that the kidney tissue looked entirely normal. When we make these findings, the first concern
- that we have is because we look at 3 billion positions in the genome, we just come across
- freak data every now and then. So we then spend probably half a year trying to convince ourselves
- that this is not rubbish, and the way to do that is to do a bunch of analyses, but really to look
- at many more children, which I will explain in a moment. The overall model that arose from this
- is as follows. That rather than being derived from a single cell, there was a root, a cancer
- root within the developing kidney, and the cancer is only one of many cancers that has formed. It's
- born from this root. The cancer is not derived from a single seed that turned into cancer. There
- was green field with lots and lots of weed roots underneath, from which this tumour had arisen.
- So we looked at many more cases later - and there's just something that I would like to
- mention which is so wonderful about our community - it's this ability to collaborate widely. So in
- Cambridge we see about four to five children with Wilms tumour per year. We need quite a lot of
- cases. That's one problem. The other thing is it can't just be any tissue. It needs to be processed
- in a certain way. It needs to be fresh, it needs to be frozen, and not only do we want tumour,
- we also want normal tissues. So these things are difficult to deliver by any one unit,
- and in paediatric oncology we're really quite amazing at clubbing together. In the UK we
- have a study called the UK UMBRELLA study, which was set up by Kathy Pritchard-Jones,
- and is now led by Tanzina Chowdhury, who is also in the audience. What we have done through that,
- or what this study has done, is systematic sampling of tumours around the country in all
- 21 paediatric oncology units over a decade and a half. So we had all the samples that we needed.
- What we found is we found these cancer roots in normal kidney tissue of about 50 per cent of
- children. Now, what causes these? This then goes back to let's look at the mutations in genes,
- and what we found was a very, very peculiar kind of mutation. It's not the mutation that
- changes the letters of the genetic code, but what it does is it hides the letters through
- a mechanism called hypermethylation, and the particular gene is called the H19 gene. All it is,
- it's a brake on the kind of signals that make a cell grow, and if you take away the signal,
- the brake that prevents the cell from growing, of course, they explode. So this is one example I
- wanted to give to you. I'll come back to it again later on when we talk about the future. So let's
- talk about another topic. So this was our first paper and I can't even remember when we published
- it. Five, six, seven years ago, something like that. I'll give you the most recent example of
- our inquiry, which is in cancer predisposition. So perhaps you may not have known this,
- but about 10 per cent of children who have cancer have a predisposition. So they have a mutation.
- They're born with a mutation in their body that predisposes their body to have cancer. A bit like,
- you may remember the story with Angelina Jolie and her predisposition to breast cancer. Now, knowing
- that a child has a predisposition can save lives, but only in very specific predispositions, where
- that has been established through long standing clinical studies. Mostly, however, knowing that a
- child has a cancer predisposition is not helpful, because we do not know which child will develop
- cancer. That's a fundamental problem that we have, because on the one hand, one could say,
- 'Well, all we need to do is, let's screen all the babies in the country for cancer predisposition,
- mutations at birth,' and then we're going to screen those children who have a predisposition
- very early on - a bit like, imagine you have a mole and you look at your mole every day,
- something like that - but that doesn't work, because we don't know who will develop cancer,
- and the majority will not in most predispositions. So the root that I talked about earlier to be in
- the kidney, in these children, they are born with it in every single cell. Every single cell is a
- little bit like a mole. Although it looks normal, it is one step closer to cancer than a normal cell
- would be. So the way we went on about this problem is to look at neurofibromatosis type 1, NF1.
- It's a complex neurodevelopmental disorder. It's actually reasonably common, one of the most common
- congenital disorders in man. Individuals are at risk of developing cancer. We don't understand who
- will get cancer, and therefore we don't routinely scan children to look for tumours. These children
- get many different types of cancers, but they particularly get cancers of the brain and the
- nerve tumours, and the gene they have faulty is the NF1 gene. The NF1 gene is another of those
- brakes. Thankfully, Mother Nature was clever enough to give us two copies of each gene,
- so even though these children are born with one faulty copy, the other brake still works,
- and one brake is good enough to keep the car under control. If you lose that second brake, we think
- that that is when cancer develops. Or does it? So we ask the question, how often do we see a
- mutation in a second copy of NF1? The way we did that is to do a post-mortem study in children who
- died from incurable brain tumours. I just want to pause a little moment here and think about that
- sentence. I mean, I'm always deeply humbled by this, and I find it quite unbelievable,
- but we just sort of need to recognise that these are parents whose children have just died,
- who then somehow find the generosity to say, 'Look, why don't you do a post-mortem,
- and why don't you take some research tissues?' because we need the brain tissue,
- because that is where the NF1 cancers arise. So what we then did, or rather what Toli did,
- who's also sitting in the audience - it must be everyone's worst nightmare - so he had to cut
- out with a microscope, with a laser, all these little tissues from all the different organs,
- so that we can sequence purified genomes of purified cells, and that was an incredible effort.
- In order to get 1000 such cuts, he probably would have had to cut 2000, and this is many, many,
- many weeks of work staring down the microscope. We sequenced 1000 genomes from these tissues. I
- also want you to reflect on that number briefly. So remember I said it took 13 years and £2.7
- billion to sequence a genome once over, and Toli in his experiments sequenced 1000 genomes,
- but not only once over, but 20 or 30 times. So he did the Human Genome Project 30,000 times over.
- Our expectation was, what I articulated earlier, that we know the child had a germline mutation,
- so germline mutation that they were born with, and we expected the other copy to be intact, except
- for in the testees that had formed cancer. What we found instead is this. We found that, across the
- brain and the spinal cord, we found multiple instances of the NF1 gene, the second copy,
- also having a mutation, but again, these tissues looked entirely normal under the microscope. These
- were perfectly functional neurones, because the child didn't have any neurological issues before
- they had a tumour. When we looked at how many cells were affected, this wasn't just the odd
- cells. These were large chunks of tissue where most cells in each tissue carry that mutation.
- Then, when we looked a bit further, we could find certain mutations in different parts of the body.
- That could mean in different parts of the brain, that could mean one of two things. It could either
- mean that the same mutation arose in different places along the brain, in the spine, or what
- might have happened is that there was one cell during development that then pervaded different
- regions of the brain and the spinal cord. By doing those postcode comparisons that I talked about,
- we could establish that actually within the brain what has happened, is very early on in embryology,
- during human development, that mutation, that cell with a mutation in the NF1 gene with a second
- mutation, went out and grew into different parts of the brain. So these are early deep
- developmental mutations. So to articulate the finding, what we found here is that the second
- copy of the NF1 gene is frequently mutated in normal looking non-cancer tissues. Our follow
- up experiment showed that this is a fundamental feature of NF1, and it isn't just one or two
- cells. It's essentially, hundreds and millions of cells that have lost both brakes. Yet - and
- this is so fundamental - they are not cancer. What we postulated from this is, because this
- child who died had a particularly aggressive tumour, and we could show that the mutations
- arose particularly early, might it be that the distribution and timing of these second mutations
- is what links the predisposition to developing cancer, and if so, we would have something that
- we can measure and quantify to understand the rules of cancer-formation in children with a
- predisposition, and that then would be the key to doing screening and prevention the right way.
- So let me talk about the future briefly. Coming back to the to the discovery of those roots in
- Wilms tumour, can we identify those cancer roots in children at birth? So could there
- be a future where we take the first urine of every child and do an assay to see whether the
- odd kidney cell that floats around in urine might have those cancer roots? Then we could
- pick out those children and follow them up with ultrasound scans to discover the tumours early,
- because Wilms tumour is one of those tumours where it's unambiguously clear
- that the earlier we pick it up, the better. Then, could we understand perhaps biochemically
- what maintains these cancer fields, and could we then develop drugs that do something to get
- rid of these fields? Or could we even go one step further, could we give some supplements to women
- during pregnancy to prevent the cancer from arising in the first instance? Now,
- that sounds like an entirely mad idea at first, but then I'll make reference to this here.
- What I'm showing you here is not a baby with a tumour. I'm showing you a baby with spina bifida,
- which is a congenital malformation. It happens because the brain, as it develops at the bottom of
- the spinal cord, doesn't properly fuse. Now, that disease has essentially been not quite eradicated,
- but radically reduced in incidence through giving women folic acid during pregnancy,
- which was established by this incredible study, the MRC Vitamin Study. Therefore, I would suggest,
- given that childhood cancer is a developmental disease, it may not be entirely inconceivable
- that, if we understood the biochemistry of those roots just well enough, that there might
- be a supplement out there that we could give. So with that, I will just pause a few moments and
- thank a bunch of people. This is a wonderful drawing by Antonio Garcia for a cover for
- a journal, that the journal didn't like, but I love the cover. So I would like to conclude this
- lecture by expressing my gratitude to a variety of individual groups and organisations. First of all,
- I would like to thank my funders, especially those who fund the sort of wild experiments that we do,
- and in particular this would be the Wellcome Trust. But I would also like to highlight the
- charities led by families of children with cancer, such as The Little Princess Trust and Alice's Arc,
- who are willing to take risks on bold ideas much more often than traditional funding bodies.
- I owe a great deal of gratitude to you, my wonderful colleagues and collaborators at my home
- institutions across the United Kingdom and abroad. I am so very fortunate to be surrounded by such
- wonderful and supportive people. This does include my wonderful clinical colleagues, of course, who
- support not only my science, but also my clinical practice through their patients and experience.
- So then the next thing to say is, I am merely the conductor of our science. I don't do the actual
- work. The actual work, the hard labour, the clever math, the wading through tons and tons and tons of
- rubble to find a single golden nugget, that work is delivered by my team, who are individually and
- collectively quite extraordinary people, and thank you so much for turning up tonight. This
- prize is as much yours as it is mine. I would also like to thank my family, and I was told in
- no mistaken terms, I'm not allowed to say any more than that. I would like to draw this presentation
- to a close by showing you this wonderful picture here. This again was drawn by the Shathar,
- the aforementioned Cambridge student. I think this really beautifully illustrates the atmosphere,
- the reality of a children's cancer ward, which is mostly happy, and you will find
- children scooting around on drip stands. I would like to say, last but not least, really,
- I would like to thank the children, who are at the heart of my research. Thank you very much.
- Professor, thank you so much for a truly inspirational lecture.
- Thank you.
- We have time for questions. In the middle there.
- Hi. Lovely talk. I think you said you'd come back to the H19, and I didn't hear the follow up.
- Oh, we came back to it when we talked about the future of this idea of,
- you know, could we screen the urine for H19 hypermethylation to find kidney cells to get a
- signal from the kidney, and use that as a basis to then think about screening and prevention.
- If I could ask one? So that, then, sort of touches on the whole topic of epigenetics. So to what
- extent do you see epigenetic changes associated with the syndromes that you're looking at?
- So I have been, unfortunately, rather ignorant of epigenetics for quite a long time,
- mainly because we were so busy looking at DNA sequence. So I think the next five to
- ten years of what we do will be thinking about epimutations and epigenetics. Epigenetics is
- that business of hiding letters, as opposed to changing the letters. The technology also
- now is much better to do than in the past. In the past, it was a bit like RNA sequencing used to be,
- utterly boring, because the technology just wasn't good enough. So data was analogue. It
- was sort of, a bit here, a bit there, not really insightful. The same is true for methylation,
- all methylation data, but this also has changed. So the new data that we have
- available is a new sort of era, a new world that we can explore.
- Okay. Thank you. Question in the middle there.
- Thank you very much. That was a fantastic talk. Really outstanding. I have a simple
- question. Do you have any interaction with the 100,000 Genome Project?
- You mean the newborn project?
- The newborn screening.
- So I had, as some colleagues here, and so we were asked - I and others were asked - to make
- some suggestions as to predisposition genes. So I'll tell you. We need to maybe just explain a
- little bit. So the UK Government is quite bold, actually. I mean, every now and then they make
- some extraordinary decisions. So one would have been David Cameron's era to do 100,000 genomes,
- and then suddenly we did 100,000 genomes, and I didn't think we could pull it off, but the country
- did. I mean, it's absolutely gorgeous. Now the country, what we're doing at the moment, is we are
- sequencing the genomes of 100,000 newborns, and the idea is that we identify genetic changes that
- herald severe life-limiting conditions in infancy, so that we can diagnose babies before they get
- sick and thereby save their lives. They're sort of metabolic disorders, so sort of things that one
- might be looking for at the moment on the Guthrie spot, the thing that your children get done when
- they're born with a heel prick. There's a bunch of conditions like that that one could look for.
- Now, of course, now the blood is taken and the genome is sequenced, there's a great opportunity
- to look for cancer predisposition, and then think about what could we do with these children.
- There's a fascinating discussion. We sort of get two camps. You get the paediatric oncologist
- who will say, 'We have to identify all those children, and then we have to screen them and
- do this and this and this and that,' and then you get the clinical geneticists who tell us, 'Well,
- that's a great idea, but where is the evidence that you're not doing more harm than good?' This
- is the eternal debate. There is an ongoing tension forever. We've had many robust discussions,
- and could agree on a very small number of genes, and we sort of managed to slip one or two in,
- as well, that I don't think anyone.... Let me not go there. It is highly controversial. There
- must be a solution there, but it all comes to the problem of penetrance. If we don't understand the
- rules that govern penetrance, then it is utterly hopeless, and we need to understand those first.
- Hello. Again, a really good lecture. It was really interesting. I have a particular
- interest in microbiology, and I've read about how certain tumours and stuff can have their own
- sort of microbiomes, and there are a lot of interactions between that. I was wondering
- if you had any experience seeing that in research, or anything like that.
- So not in my research, and I'm probably not particularly qualified to answer that question.
- What I found interesting in reading the literature, or in scanning headlines,
- a wonderful chap called Ludmil Alexandrov, from San Diego, who I was a PhD student with many,
- many years ago at Sanger, recently published a paper showing that
- a certain bacterium that colonises our colon causes a lot of mutations, and that might
- explain this new wave of young-onset bowel cancer. So that's quite fascinating, but I
- guess that's not what you're talking about. You're talking about the interactions of cancer cells and
- bacteria. I really don't understand that field. That's one thing to say, and the other thing is,
- I have turned into quite a radical purist. I used to be a bit more open minded, but because everyone
- is getting away from cancer cells at the moment, and talking about the things around the cancer,
- I've just decided I'm stubbornly going to say, 'We need to understand the cancer cell,
- and everything doesn't matter.' That's the very wrong perspective on this, so please don't
- quote me on it, and I wouldn't copy that view, but I have become quite radical. It's all about the
- cancer cell, it's all about the mutations, and I'm going to ignore everything else.
- Thank you.
- But it's wrong, my view, just to be clear.
- Question over there.
- Hi. Thank you. Great talk. So I was just wondering about the Wilms tumour. As I understood,
- the model was that, within the healthy kidney, a bunch of cells will acquire these mutations,
- and one of those cells with a mutation will then go on to become a tumour. So I was just wondering,
- within the spectrum of these mutations, there are different mutations and different cells
- of kidneys, is there like a pattern, like do they occur within certain regulatory regions,
- or like near a certain gene, or it's just entirely random? Like, is there any pattern with these?
- Thank you for that question. It's a beautiful question. The only mutation that we could
- identify that did something, was that not mutation, the epimutation, that hiding of
- the gene H19. All the other mutations that we saw were little dents in the door, or maybe a chip in
- the window, but nothing functional that would have fundamentally changed the function of the gene.
- Can I ask?
- Of course, yes.
- About this hypermethylation mutation, was it inherited from the parents,
- or is it something that the baby acquired during development?
- Again, it's a superb question. The idea is that, at birth, the pattern of methylation,
- so the hiding and revealing of genes, all of that is wiped out at fertilisation,
- and then is reacquired as the human develops. So your question is really excellent. So this is not
- something that was inherited from the parent. This is something that arose, genuinely arose,
- during development. Now, there is one exception to it, which is so rare and so unusual that we
- won't talk about it, but essentially, you cannot inherit methylation changes. Now, that then also
- means it happened during development, so it could either be intrinsic to the embryo, or it could
- have something to do with the interface between the embryo and the placenta, and thus with the
- outer world. So that's quite an interesting sort of connection. Wilms tumour is also one of very
- few cancers, or childhood cancers, that has good epidemiological variation, one is tempted to begin
- to think maybe it's got something to do with that. Now, the other thing that I would like to say is,
- I am sure that many, many, many of us will have these fields of hypermethylation in our
- normal kidneys, and the tumours are just the tip of the iceberg. So a much more - well,
- not a much more - but a fundamental question would be to just systematically try to understand how
- many humans are born with these fields of hypermethylation within the kidney.
- You talked about how, in your field, the whole of molecular
- biology has been revolutionised by next-generation sequencing,
- and just totally changed everything. Where do you see the next technical threshold
- or challenge? What is limiting what you can achieve at the moment at the technical level?
- Thank you for that question, David. I mean, I sort of have to say AI now, but I don't... Okay.
- I'm going to say AI, data volume, that sort of thing. It probably is the issue. We generate vast
- amounts of data. We need, I think, to generate much, much more data, and then there's going to
- become a point where we're not going to be able to handle it in a reasonable way, and maybe this
- is the point at which AI is going to deliver. I think we all think about AI all the time. I'm sure
- it's going to deliver something, but I'm sort of - what's the right word? - I'm trying to resist it,
- but I can't really. So we're doing AI as well, but I'm trying to resist it. I still have a
- sort of fundamental conservative view of, I would like to see the mutation and then think about it,
- but again, it's a very old-fashioned view and maybe it's time for me to retire, I don't know.
- Another question.
- Hi. Thank you so much. It was a brilliant talk and my jaw did drop several times. So my question
- for you is, my understanding is that - or my assumption is - that this work was conducted
- within the UK. Are you familiar with or do you know about any other studies that have
- been conducted around the world on these kinds of topics? I'm particularly interested in those maybe
- in India or Africa, just in terms of whether they found similar stuff to what you've outlined today.
- Thank you so much for the question. So this particular work that we've done,
- we have replicated recently in a different paper where we wanted to look at other stuff
- in a much larger cohort, this time drawn from the UK, from the Netherlands and from Germany,
- but going outside Europe, we haven't done that. Now, the beautiful thing about the UMBRELLA study
- is that it actually is an international study. So we are speaking to our colleagues in Brazil,
- we are speaking to our colleagues elsewhere to see might there be scope for collaborative
- research. That goes back to how wonderfully collaborative the paediatric oncology unit
- is. Just think about this for a moment, that in a hospital in Egypt or in Brazil, tissues are
- sampled and stored, and children are treated in the same way as in a hospital in London.
- Good. Any more questions? Yes, a question there.
- I have a question. So you've spoken about...
- Hold on just for a minute and then we'll bring the microphone.
- So that's going to be a tough question, because [?Garra 0:50:23.6] used to be my student.
- So you've spoken about the sort of secondary predisposition after treating children with chemo,
- and obviously, that's much more of a controlled environment that you can
- study better. Can you talk a little bit more about that kind of distribution of
- children that will develop a secondary cancer versus not,
- and how well that's been studied, and can you predict that a little bit better?
- Thank you. So the world of - I mean, maybe your question - I'm going to paraphrase it, and then
- maybe tell me whether it's sort of addressing what your what you ask. It's about the damage
- that chemotherapy does to children's bodies. That question was quite difficult to study until
- recently, because just technologically it's very difficult to call mutations in normal tissues,
- but that's now become feasible. We've put out some work quite a few years ago now, that sort of began
- to paint a picture of limitational onslaught by chemotherapy in children, and we've now got tech
- available that enables us to do this at large scale and more systematically. I think there's
- a really interesting science of trying to connect late effects from chemotherapy with mutations,
- not just cancer, but also non-cancer diseases. Again, if we can find a signal, we have something
- that we can measure, and if we've got something measurable, we can perhaps do something about it,
- but it all comes down to this very fundamental, basic issue of we need to understand the
- underlying biology and find a signal of it, to be able to do something about it. J
- Just to follow on, are there certain treatments that predispose people to
- developing secondary cancers more relative to others? Is it about the amount of chemo?
- So that's a question...
- Just to repeat the question for the people online.
- So Garra's wondering whether some chemotherapies
- are more likely to cause second cancers than others. Is that...?
- Yes.
- Was that the question? Yes, it was.
- Well, yes, and also, is it the amount of treatment that children get?
- Okay. I wish you hadn't asked that question. This whole field of second secondary cancers in
- children is I think, essentially, mythology, because when we made statements about agent
- X causes second cancers, there's one particular drug called etoposide. When a child gets leukaemia
- after having - it's getting quite technical now, I apologise - when a child gets leukaemia
- after having etoposide, everyone says it's etoposide-related. When you go back to where
- this notion comes from, it comes from medieval ages when we had a complete non-understanding
- of anything. People just sort of - there were a bunch of drugs, they picked one drug,
- and then built a portfolio of research on it that seems to corroborate it. If we think about
- the drugs that cause mutations, actually etoposide doesn't. So I'm sure that with our ability to now
- understand the mutational effects of chemotherapy, we will get to a place where we understand that,
- as you say, some agents are more likely to cause it. Maybe it's got something with dose. Then,
- if you've got agents that are just as good, but don't cause mutations, we could swap things out.
- I have one other question, if I may?
- Of course.
- So you differentiated adult cancers from childhood cancers. Adult cancers being,
- let's say, often environmentally-induced, and childhood cancers being developmental. Is it
- not true that even for children, and even before birth - I mean, there are environmental stresses
- that the embryo and the developing child could be exposed to that could be triggers
- of cancer. So is is this a really hard-line differentiation of adult and childhood cancers?
- So to the best of my knowledge, to the best of our knowledge, it is. So that that question of
- trying to associate childhood cancer with either lifestyle habits of parents, or exposure in
- the environment, which has been looked at multiple times in different environments,
- hasn't yielded a signal. I think the strongest piece of evidence that this is not the case,
- is the fact that if you look at what childhood cancers children get around the world,
- and the incidence of childhood cancer, it is roughly the same everywhere. The spectrum of
- diseases that we see sort of comes along in the same proportions. There are just one or
- two exceptions, and Wilms tumour is one of them. So there might be an epidemiological dimension,
- or it may have something to do with the sort of ancestral gene pool of those countries.
- Okay.
- Thank you.
- Thank you so much. So at this point,
- it's my privilege to present, and we're asked to move over to this part of the stage, to
- present the Royal Society Francis Crick Medal and Lecture is awarded to Professor Sam Behjati
- for fundamental discoveries into the developmental roots of childhood cancer.
Join us for the Francis Crick Prize Lecture delivered by Professor Sam Behjati.
The Francis Crick Medal and Lecture 2025 is awarded to Professor Sam Behjati for fundamental discoveries into the developmental roots of childhood cancer.
Cancer is a leading cause of death in children in the UK. It is thought to arise before birth during human development. However, the precise origin of most types of childhood cancer is unknown. Advances in our ability to read DNA and process vast genetic data sets have enabled investigations into the origins of childhood cancer. This includes retrospective lineage tracing approaches that build on using naturally occurring errors in DNA (mutations) as barcodes of human development. In this lecture Sam will present some of the insights retrospective lineage tracing has delivered which may pave the way for early detection and prevention of childhood cancer.
Sam is a Group Leader at the Wellcome Sanger Institute, Clinical Professor of Paediatric Oncology in Cambridge and an Honorary Consultant Paediatric Oncologist. Originally from Germany, he studied medicine at Oxford and trained as a paediatric oncologist in London and Cambridge. He underwent doctoral research training at the Wellcome Sanger Institute, studying the genetic basis of bone and soft tissue cancers. Thereafter he developed a research programme into the origins of cancer, using genomic tools including DNA sequencing and single cell transcriptomics. His research is disease agnostic and occasionally takes him to problems other than cancer, yet his main research focus are childhood cancers. Sam retains a clinical practice in paediatric oncology.
About the Royal Society
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