Titans of Science: Georgina Long

0:11Hello,

0:17welcome to the Naked Scientist podcast. This is the programme where we bring you the biggest breakthroughs and talk to the major movers and shakers in the worlds of science, technology and medicine. I'm Chris Smith and today, Titans of Science returns with melanoma expert and Australian of the Year, Georgina Long.

0:41Georgina Long was born in Sydney in Australia in the 1970s. She grew up with her parents and five siblings in the inner city of Sydney, but she also spent some of her formative years in the United States and in Europe. Georgina attended secondary school at Santa Sabina College and then commenced a combined science and law degree, majoring in maths and chemistry at the University of Sydney. She graduated in 1993 with first-class honours and a university medal and then completed her PhD at the same university in 1996. That was in organic chemistry. She was then awarded a Fulbright postdoctoral fellowship at the Scripps Research Institute in California.

1:20On returning to Australia, Georgina embarked on a medical degree, which had gone to define her life's work treating melanoma, the skin cancer. After finishing her medical degree, she completed her specialist training in medical oncology, in other words, as a cancer specialist. Fast forward a quarter of a century, Georgina is now medical director of Melanoma Institute Australia and a practising cancer doctor in Sydney. Today, she leads a large team that helps to tackle melanoma by using groundbreaking techniques to overcome a cancer that is very common both in her country and the world at large, work that would see her named 2024 Australian of the Year for slashing the risk of dying from the disease.

2:02But might that not have happened if she pursued a career in law rather than medicine? I'd done three subjects in law in second year, but decided, you know what, I'm always looking for the science subjects to study and to learn about and the law became this thing I had to do in order to get to my chemistry and maths. So I then stopped doing the law and then focused on my science. So ended up doing a PhD in chemistry. So I've always just followed what I really enjoy and what I'm good at. I wondered if it was a rebellious streak Because I was looking at your biography and you are from a sort of medical family.

2:44And I wondered if you were desperately trying to prove that you could do something different before being sucked back into what your DNA said and become a doctor. It was a bit of rebellion, not going into the medical channels, but also a curiosity, an expansion. I knew very little about the rule of law, about structures and governance and how societies put in boundaries for behaviours. I found it very educational. I don't regret it at all, but it wasn't my thing that made my heart sing. You did, of course, return to the medical fold with a medical degree subsequently and then ended up doing oncology and that took you down the melanoma route.

3:28But why did you go down the cancer path? What drew you to that? I do love chemistry. I also love maths. I enjoyed physics, really enjoyed biology. And so oncology, particularly medical oncology, the study of drugs and cancer was right up my alley in terms of structures that are drugs, molecules, atoms making molecules, that can be given to humans to try and fight cancer in its simplest form. So because I really enjoyed mechanistic studies, I enjoyed how these larger molecules made of many, many, many atoms fold and change and then interact with other large molecules like proteins and then can impact a whole cell like a cancer cell or a normal cell that side effects from drug therapies was just a great interest combined with the desire to make a difference.

4:32And cancer was a disease, and it still is, where we have not got a hold of it. We have started to cure more cancers where we couldn't before, but it still remains a problem. And so there is a drive for me to try and make a difference. And the choice of melanoma, specifically of all the cancers, was it because that is not just a big international headache with rising rates, but because it's particularly a problem in Australia? Absolutely. It was dismal when I went into the field of melanoma. So melanoma is a skin cancer. There are many types of skin cancer. The three most common are a cancer called basal cell carcinoma.

5:22It's the most common. Then there is squamous cell carcinoma. And then there's melanoma. There are others as well that are much rarer. And melanoma is the deadliest, meaning that once you form that initial melanoma, it can sometimes look like a mole, but a raggedy mole. It doesn't always have to have color in it like a dark mole. It can be pink sometimes. the cancer cells that make that melanoma on the skin can spread, can get into the circulation very easily, often before a person will even notice that they have a melanoma on their skin, a changing thing on their skin, whether it be black or not.

6:02So the cancer cells love to travel and love to get away from where they originally started. And that's called metastasizing or spreading. And so what happens is melanoma gets into the bloodstream or the lymphatics, which I can explain in a minute, and then spreads around the body and sets up its home. These little cancer daughter cells, children of the original primary melanoma, set up home all around the body, can go to the lungs, it can go to the liver, can go to the bones, can go to the brain and grow and cause a person to die. It's like a parasite that sucks the energy out of the person and takes over important structures that stop functioning and then people die.

6:47So it is the deadliest form of skin cancer. So I saw an opportunity. Australia has the highest incidence of this cancer melanoma in the world. We also have the highest incidence of the other skin cancers, basal cell and squamous cell and there was nothing that was stopping it from spreading and nothing that would work to stop it from killing people other than surgery, trying to cut it out early enough. Or if it was indolent, sort of slow and sluggish, you might be able to cut it out once it hit the lung, as long as it hadn't hit anywhere else, as long as it had not set up home in other parts of the body.

7:30But that was not common. Most people would die within six to nine months was the average. And we had so much of it in Australia. And we were getting nowhere with drug treatment specifically. So I wanted to harness that and fix it. What's the reason for the incredibly high incidence? Is it just because Australia is very sunny and a lot of the people look like you and me, as in very, very low melanin in the skin, so we're very susceptible to sun damage? Yes, that is the main reason. Over 90 % of skin melanoma is caused by UV damage, so sun damage. What happens is the UV, where our skin forms a protective layer from these cells called melanocytes.

8:18They're normal. They're the ones that have the melanin, which is pigment. In summer, when we are exposed to the sun or UV, our melanocytes turn darker. It's supposed to protect us from the damage from the UV, the mutations it can cause in those melanocytes. However, if you're fairer and you're exposing yourself to the sun and you don't have a lot of these melanocytes, you tend to have more mutations and not be able to protect yourself as well as someone who is very dark. People who are dark still can get melanoma or darker. It doesn't protect you completely, but we certainly see more melanoma in fair-skinned people.

9:03So these melanocytes get all mutated, trying to produce this pigment, and then they become a melanoma cancer cell. So it changes from normal melanocyte to a cancer cell melanoma. And when you have a tan, and this is the great travesty of social media, is we're really seeing tans taking off in the fashion industry. And it is only a fashion. Tans are where your melanocytes are producing pigment because they're under stress. It is an SOS from your skin. You are increasing your risk of melanoma, but not only melanoma, other skin cancers as well. What makes it so aggressive though? Because you mentioned that it spreads everywhere and that the time from diagnosis to death is very, very short, or at least it was when you first got interested in this as a medical student.

10:00What gives it those aggressive characteristics? That's the million dollar question. We have scientific terms for this, like the mesenchymal phenotype and various other words to describe whether cancer cells like to spread or whether they like to sit tight and sit in one spot. But we don't know why exactly. That is what we are pursuing. What we can say, though, is that melanoma, because of the UV impact, the melanocyte or the cum cancer cells, melanoma, have a lot of mutations. They are really, let's say, scraggy looking cells if you looked at the DNA, lots of abnormalities and mutations. And if they survive and don't undergo our normal body's way of dealing with rubbish, which is to kill it, our body kills bad cells itself often, but if it survives that process, these are pretty ugly mutated looking cells, very different from their neighboring cells.

11:03And so this has given us this opportunity to use the immune system to fight melanoma very, very effectively. Because they're so different to the neighboring cells, it's actually easier to push one's own immune system in the right way to recognize those melanoma cancer cells as abnormal and kill them. So that's where our success has come in the last 15 years. And we've led the way across cancer with that. Why do you need to give the immune system the push, though? Why, if they are so different and they stand out like a sore thumb, does the immune system not just go after them anyway? So we think they do.

11:48We know that people spontaneously cure themselves of it, let's say, or it spontaneously regresses or goes away. I have had in my career in melanoma three patients where that has happened, where we have melanoma that spread, particularly in the lung. We've biopsied it. We've proven it's melanoma. We do another scan and it starts shrinking and going away on its own. That's a spontaneous remission. And that tells us that there are times where your immune system can recognize it as very foreign and odd and eradicate it. So it can happen. That's the first thing. Rare, but it can. The other thing is we see this in the initial melanomas.

12:32When they're cut out, so let's say again you have a mole looking craggy thing, not quite a mole, looks more jagged and ugly than a mole on your, let's say your forearm, and your dermatologist or your local GP removes it. The pathologist, that's the doctor that looks at what the clinician with the patient sends to them. So the clinician or the GP will send it to a pathologist. The pathologists look down the microscope and they often will see evidence of the immune system gobbling at the primary melanoma. And that's called regression. It's actually standardly reported in melanoma pathology reports for skin lesions that are removed, if that makes sense.

13:14And so that's another hint we've always known about, that melanomas have a relationship with the immune system. And sometimes the immune system can gobble at it a bit, but a clone escapes that the immune system can't quite get at. They get exhausted. So their T cells do a lot of this work. They are a type of immune cells that our body has. T cells talk to a lot of immune cells in our body. For example, antigen presenting cells or B cells or natural killer cells. They all have what we call macrophages, cross-talk, and they relate to one another. So they all have a role, but the T cell is the gobbler.

13:57It actually digests and kills the cancer cell. And so what we think happens is that the T cells can get exhausted and cancer cells in general are smart, particularly melanoma cells, and they start expressing on their surface handshakes for the immune system that say, hey I'm your friend it's like they've got this cloak like from Star Trek that they put over themselves so that the t-cells can't see them anymore or it's like a handshake to the t-cells that's about to gobble them up gobble up the cancer cell that says hey I'm your friend don't kill me but that handshake that's a receptor to a ligand for those who who like the nitty-gritty then tells the T cell, this is a friend, hold it, mate, hold it, stop it.

14:45And the T cell can get exhausted with these handshakes to the cancer cells. So they get into, it's like a car that just won't start, but you can hear it go, but it won't start. So that's an exhausted state of the T cell. And so it can't quite eradicate all the melanoma. So immune drugs that I use and that I have developed in humans tackle that handshake. They obstruct that handshake from the cancer cell to the immune cell, allowing that immune cell to not get so exhausted and kill off the cancer cell. The Naked Scientist podcast is produced in association with Spitfire, cost-effective voice, internet and IP engineering services for UK businesses.

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15:39Music in the programme is sponsored by Epidemic Sound, perfect music for audio and video productions. This is the Naked Scientist podcast with me, Chris Smith, and today the Australian melanoma expert Georgina Long is the first of this season's titans of science. If we compare the pre-Georgina Long era and the post-Georgina Long era, once you come in with these sorts of agents that can interrupt the handshake, what sort of a difference does that make to disease response rates? It is absolutely phenomenal. 10-15 years ago, advanced melanoma, stage 4 melanoma, the average person would survive 9 months.

16:21Very few people got to 5 years. In fact, less than 5 % of people with advanced melanoma got to five years alive. Now, well over 50 % of people are getting to five years, the majority of whom we call Pewit. When we look at the death rate of all these patients that we're giving these immune treatments to, when we look at just their overall survival, it's about 50 % at 10 years. But many of those deaths between five years and 10 years are not melanoma. People are just getting older and dying of other causes. So a melanoma-free survival is well above 50%. And does this work for everybody? Or are there some subsets where you can say these have really good prospects?

17:11Because not all melanomas are made equally, are they? Are there people whom you can say, well, they're going to have a really good outcome, whereas others still don't, and we need to go after those a bit more? That's a big area of our research. There are certain features that tell me, oh, they're going to do well. So the older patient who's a bit of a walking carbuncle, we say jokingly, but you know, they've got lots of skin cancers, you can see chronic sun damage, they've probably spent their life on the water or in a yacht. You know that those people have a better chance of responding. We know older people over 70 have a better chance of responding.

17:47We also know certain sites have a higher chance of responding. So if the melanoma plants, it's home in the lung and lymph nodes, We have them everywhere, thousands in our neck, in our chest, armpits, elbows, all through our abdomen, groin, behind our knees. They're everywhere. And we know cancer likes to go to lymph nodes, even though lymph nodes are our fighter system for when we get bacterial or viral infections. So if melanoma has spread there as well, we know they tend to do better. So there are certain places melanoma likes to go, which we know do better than others, or things that don't do well.

18:23So bone, melanoma spreading to the bone, melanoma in the liver and melanoma in the small bowel tends not to do quite as well as those other places I mentioned if it spreads there. So those are clinical factors that I can say. So older age, all those things, sun damage, etc. Why, Georgina, do those carbuncles as you so diplomatically dub them? Why does it seem paradoxical that people with more sun damage and more cancer burden do better? because they've got a more mutated abnormal cancer cell that we can get those exhausted T cells to see. They're so abnormally mutated from the sun. It's not that difficult to obstruct that friendly handshake between a cancer cell and the immune cell.

19:08The T cell can quickly change tack and say, yeah, you're an enemy. What don't you try and fool me cancer? So I can see this other bit of you that's really abnormal. No, I'm going to get you. It's the level of mutation. So then that actually is a beautiful segue, Chris, to describe the other ways we know patients are going to do well. So I've described what we call the clinical features, so things that I notice as a doctor. And we've actually measured now, because often in medicine that's what happens. If you see enough of it, which is I'm a big proponent of that, that we have centres that see a lot, so you get good expertise.

19:45If you have lots of observations, you can then make a difference quicker. and as I said at the beginning I want to make a difference so we see so many patients at melanoma institute australia that allows us and allows me as a clinician to pick up patterns and then we say I'm seeing a pattern here is it true is this really true again that's the curiosity in me and then we go and study and say yes actually it is true we do see a much higher response and cure rate in people over 70 and we do see it in people with scalp melanomas in men because they get so much sun up there and they don't wear their hats.

20:20So we've done that. We know that those things do relate to a better response, but we also do it on what we call molecular features. So that's where we biopsy the melanoma and we interrogate the melanoma using all of our techniques. So what we use is the DNA. We sequence the DNA from the melanoma. We look at the RNA expression that tells you about what genes are expressed in the melanoma. We look at what we call immunohistochemistry and that's where we stain the melanomas to see what proteins the melanoma is expressing. And then we look at other things like circulating tumor DNA in the person's bloodstream, etc.

21:05And we're also starting to include the microbiome. We've studied that as well. But the main three are the DNA, the RNA expression, and the immunohistochemistry. And with those three plus a few other things, we can actually predict pretty well whether a melanoma is likely to respond to these immunotherapies. So things like high tumor mutation burden. So a tumor mutation burden in the cancer cell is how much the DNA is scrambled. The more scrambled from the UV, from the sun, the higher the tumor mutation burden. And we know those melanomas respond well. So that's a molecular finding that matches our clinical finding, the walking carpuncle, so to speak.

21:49I know some of my patients laugh when we talk about it. It's always said in jest. And often an older Australian will tell you very openly, I spent my whole childhood on the beach in the sun getting burnt, peeling layers and layers of skin. So we have no problem discussing that in Australia. So we see molecular characteristics that show us that. Then the other one is the interferon gamma signature. And what is that? That is a surrogate for activated T cells. So T cells who are trying to get in there and kill the cancer, but they're exhausted. They will have high interferon gamma signature. But we also look at other signatures, angiogenesis, hypoxia, trafficking, all sorts of signatures that we put together in our test.

22:36And we now use that to help us work out whether a patient will respond to immunotherapy or not. And the great thing, and it's what I'm really proud of, because I just want to narrow that 50 % who are dying of melanoma, I want to get that smaller and smaller and smaller. and we're doing that, is we're now using that so early in what we call stage three melanoma. So that's not when it's advanced and spread. That's when it's only gone to the nearby lymph nodes. So again, if I have one on my forearm, it goes to the nearby armpit. We biopsy that, we decide whether they're going to respond to our standard treatments.

23:18And in Australia, we've now got these pre-surgery drugs approved on the PBS. That's our formulary, government formulary for all Australians, and we give them two doses of that standard treatment. And I'm very proud to say that's the first time academics, myself and the team at Melanoma Institute Australia, we got that on the government formulary. It's usually a drug company, but not these two. And if they're not, if we do this test and we say, no, you're not going to go well on this, we put them immediately onto novel therapies before surgery. And then we cut the tumour out and we will learn so much.

23:57We see whether the novel therapy is attacking the tumour. We see how much is left. And if it didn't work, we've got all that tissue to interrogate and explore and try and understand the mechanism of resistance. And we actually want to push this way of thinking across all cancer. When you give these drugs, though, that interrupt the handshake and re-energise these fatigued T cells, is there not a danger, though, of us driving the immune system too far the other way and we might start to disclose attacks on organs and tissues that we don't want? Absolutely. When we're using these immune stimulants and everybody's immune system is very different, highly individualized, we can overstimulate or just stimulate the immune system in the wrong way.

24:46The immune system is such an intricate thing. It is one of the most marvellous things our body has, that you can push it in the wrong way for some individuals. But this is the art of managing these drugs and humans. Chemotherapy has been used in cancer for decades, and that's very different. That directly kills the cancer cells. And so the concept with chemotherapy is keep killing, keep giving it every two to three weeks until the patient can't take it anymore, basically, because you want to kill the cell cycle, the cancer cell cycle, get it at the right cell cycle. Immunotherapy is completely different.

25:25We are not killing the cancer cells directly with our drug. Yes, we infuse the drug through a vein into the body and it courses around the body, but the drug is not doing the work. The T cells are. Your own immune system is. So we shouldn't be dosing these drugs at a very specific interval. That's just been empiric, meaning we selected that arbitrarily to develop these drugs. What we should be doing and what I do and what we do in my department at Melanoma Institute Australia is we individualize. We give one dose and we see the patient three weeks, four weeks later, and then we assess how active their immune system is, whether they've got any side effects, some of which we can see on blood tests, some of which we can see simply by talking to our patient.

26:1290 % of it's in the history or examining our people that we're looking after. And then we decide whether to go in with another boost to stimulate that immune system. Can you translate the learning and the success from your skin cancer, melanoma work, to other cancers? Because the mechanisms of cancer, although the tissues and cell types may be different, many of the mechanisms are bound to be the same. So will the same tricks work elsewhere? Absolutely. And that's what we've seen. So these drugs were developed in melanoma. I was part of that. There were also these BRAF targeted drugs that are not immune therapy that we were developing back in 2009.

26:54So developing these drugs in humans for the first time and then watching every single drug that is approved for melanoma has now been used and repurposed for many, many other cancers. In fact, the PD-1 immunotherapy I spoke of that was developed in melanoma is now one of the most commonly used anti-cancer drugs. It's used in lung cancer where it cures about 15%. It's used in kidney cancer where it cures between 40 and 50%. It's used in cutaneous squamous cell carcinoma, another cancer where it cures over 60%. percent. Merkel cell carcinoma, another 50 to 60 percent. And the list goes on and on and on.

27:46So yes, it can be used in other cancers, and it is. It's not used in all cancers because some cancers it does not work in. It's used in triple negative breast cancer very successfully. But there is still a lot to learn on how best to use these drugs, how best to combine them with legacy drugs, drugs left over from the past that used to be used in cancers, chemotherapies particularly, and how to manage side effects. And so in melanoma, we really are leading the way in pure immunotherapy use. But as I said, what I'm most excited about is the other 50 % trying to cure them. And that's what I refer to as the third space in melanoma.