Instant Genius - Is the cure for cancer hiding in human breast milk? – Professor Catharina Svanborg

Episode Date: May 8, 2019

Two decades ago a group of Swedish researchers chanced upon an intriguing compound with tumour-killing properties hidden within human breast milk. Dubbed HAMLET, short for Human α-lactalbumin, the substance has so far come through in vitro and animal trials with flying colours. With human trials currently underway, could HAMLET be the drug to finally give us the upper hand in the war against cancer? Hosted on Acast. See acast.com/privacy for more information. Learn more about your ad choices. Visit podcastchoices.com/adchoices

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experts name audio, alongside French acoustic specialist focal, combine handcrafted tradition with cutting-edge innovation and high-end materials, delivering digital precision with analog warmth, so you can experience exceptional sound at home. Music just as the artist intended. Visit name, Audio.com to learn more. Initially, a wonderful graduate student who was doing the work came to me late in the evening and said, oh, something funny is happening. I don't know what I'm seeing in the microscope. And we both looked and the cells were truly looking unexpectedly weird.

So, you know, what do you do as a scientist to say, all right, let's repeat it. Let's see if we get the same thing tomorrow. So it was repeated a couple of times. And then it just dawned on us that we had managed to actually kill tumor cells in this test tube in addition to its effect on bacteria. And that started a new line of work in our lab. You're listening to the Science Focus podcast from the BBC Science Focus magazine team. With the UK's best-selling science and technology monthly,

available in print and in several digital formats throughout the world. Find out more at sciencefocus.com or look out for us in your app store. Hello and welcome to the Science Focus podcast. I'm Sarah Rigby, online assistant at BBC Science Focus magazine. Back in 1971, US President Richard Nixon declared a war on cancer, pledging to pump $100 million into research and proclaiming that the time had come when the same kind of concentrated effort that split the atom and took man to the moon should be turned towards conquering this dread disease. billions of research dollars later and the war is still raging but thanks to advances in treatments such as chemotherapy and radiotherapy the tide is slowly turning according to a report carried out by McMillan cancer support

in 2016 patients were twice as likely to survive for 10 years following a cancer diagnosis as they were at the start of the 1970s but will the big breakthrough ever come one area of research showing great promise began two decades ago when a group of Swedish researchers chanced upon an intriguing compound with tumour-killing properties hidden within human breast milk. Dubbed Hamlet, short for human alpha-lactalbumin, the substance has so far come through in vitro and animal trials with flying colours.

With human trials currently underway, could Hamlet be the drug to finally give us the upper hand in the war against cancer? Here's Jason Goodyear, commissioning editor at BBC Science Focus magazine, talking to the project's leader, Professor Katharina Svanborg. So I understand you've been doing this research for about two decades now. So it's been going for quite a long time. And it's quite a new idea to me, though, even though you've been doing it for that long. But I'm just interested, how did you initially get started with this research?

Hamlet is a classical example of a serendipitous observation that leads to something completely novel. We've always been interested in in fiction biology and we're looking for antibiotics or natural. antibacterial molecules in different body fluids, including human milk. And then we threw in some lung cancer cells, for technical reasons, into the test tube, and ended up finding that the tumor cells died. And of course, we had to repeat it a few times before we could believe our eyes. But since then, we have focused on this project and try to find out as much as possible about, you know, the molecule, the mechanism, and also, of course, the therapeutic value.

serendipity observation. Yes, that must have been quite surprising then when you've noticed this effect on the, I mean, what was your response to that? The response, I mean, initially a wonderful graduate student who was doing the work came to me late in the evening and said, oh, something funny is happening. I don't know what I'm seeing in the microscope, and we both looked and the sales were truly looking, unexpectedly weird. So, you know, what do you do?

as a scientist to say, all right, let's repeat it. Let's see if we get the same thing tomorrow. So it was repeated a couple of times. And then it just dawned on us that we had managed to actually kill tumor cells in this test tube in addition to its effect on bacteria. And that started a new line of work in our lab. We were lucky enough to, I was on a committee in Stockholm a couple of days later. And a colleague who was a leading person in the area of cell death, was there and we discussed it. So he helped us a lot to set up, you know, the sort of the first-line techniques to look at cell death. And then we were off.

All right. So it was just like raw human milk that you were using? No, it wasn't actually. There is a tradition to use human milk as a source for all sorts of molecules, obviously. It's a wonderful mixture of benevolent molecular protection for babies. And we as immunologist were using it, we were using different fractions of it because either you have antibodies in it or you have small molecules or you have sugars or you have lipids. And, you know, depending on which fraction you're looking at, you can get very different results. And it turned out that one of the milk fractions was doing it. But not milk, not whole milk as it comes out of the breast. It has to be treated a little bit to bring out this hamlet molecule. Right. So, yeah, so obviously this comes from breast milk. And so just so to sort of bring us up to speed. So what's so special about breast milk? You know, what's in it sort of nutrients? And I understand it helps to protect nursing babies from certain infections, etc. All of that. And I mean, in addition to, of course, we would support anyone working on this in, you know, in the world to promote breastfeeding.

but our purpose and our mission was to actually identify molecules that can then be purified and used for the benefit of different groups of people, not just the baby, but the people who have different types of diseases that need to be treated. So novel antibiotics, novel anti-cancer agents, as it turns out. And I work from that point on with regards to the molecule was, of course, to purify it. And that was also, that was an adventure in its own right, because we kept purifying these different components in milk and losing the activity for six months until somebody realized, oh, but maybe it's stuck on our column, you know, lab columns that you use to purify things on. And lo and behold, when we looked at what was on the column, all of the activity was there. and we had a purified protein.

So the active component is the most abundant protein in human milk. It's called alpha-lactalbumin. And the secret of forming Hamlet is that this protein changes its structure and binds to a lipid. So it's a protein-liquid complex that kills the tumor cells. And that's the name Hamlet, human alpha-lact albumin made lethal to tumor cells. That's where it's coming from. So a lipid is a fat, right? a fat and a protein together.

Okay. So what's, I don't know if you've looked into this at all, but what do you think this compound's purpose is in the breast milk? You know, why is it there in the first place? That's a wonderful question. I mean, it's being ingested by babies five times a day or more. And we've been trying to focus on, especially on the local effects in the large intestine.

There are things that need to be removed. There are virus-infected cells. There are cells that instead of developing to become more mature, more grown-up, would be de-differentiated and start looking like cancer cells. So you could think of these molecules as scavengers almost, that remove cells that go the wrong way, essentially. There is old data on breastfeeding, being protective for childhood lymphomas and also for certain kinds of intestinal cancers.

But we have topped that up by doing studies in animals prone to colon cancer. And we can take our molecule, our hamlet molecule, and feed it to these genetically susceptible mice and prevent them from developing colon cancer in at least 60% of the cases. So it's a very, very strong effect. And I imagine that the baby, of course, doesn't have colon cancer, but there may be pre-stages that the milk might protect from developing further. So we just touched on one there, but you've ran a number of different trials,

like in, I believe, in vitro trials and animal trials, and you've had success with those. Could you tell me a bit about those, please? Yes. And in the vitro trials, the early ones were really accelerating because we borrowed from all our nice colleagues around the departments here, we borrowed different cancer cell lines. Most of them are what we call carcinoma,

so they are from tissues that develop into cancers. But we also looked at leukemia and so on. And to our great surprise, these different types of cancer cells, most of them died with a similar pattern. We call it apoptosis. It's a nice form of cell death. That's not the whole story of the mechanism, but essentially many different tumor cells died.

So we were thinking that we had the fortune of developing a molecule that is pressing some conserved button into tumor cells. And so the test tube experiments are very promising. Then, of course, one cannot set up. up 40 different cancer models in, you know, but we have looked at quite a few. One is brain tumors where the model is that you take the human tumor at surgery and you put it into an animal for it to develop. And then you treat the animal by local injection of a drug into the brain. This is a model that has been developed much recently and it's very promising. And so we saw quite

potent protective effects in the animals that had received hamlets compared to a placebo control, which was quite exciting. The second one that we did was colon cancer, as I already told you about, that is both therapeutic and prophylactic. And the third one is bladder cancer, where in the urinary blood, mice can develop quite rapidly large tumors. And if we inject our hamlet or our now second generation synthetic drug into these mice,

we can see a very potent dose-dependent therapeutic effect that we are very, very happy about, very excited about. Without getting too complicated, could you explain the mechanism, how this actually works, please? Hamlet is a bit like a bulldozer. It has multiple effects on tumor cells. And it starts at the membrane. Cancer cells have a more primitive membrane than the normal differentiated cells.

And it appears that the molecule is benefiting from this. It's inserting into the membrane and starting ion fluxes across the membrane, essentially. Then it travels through the cytoplasm and into the nuclear ion. in the nucleus, it binds to, you know, the very substance that the DNA and the proteins in the nucleus make is called chromatin, histones, molecules like that. So it's a bit like pouring cement on these cells. They just can't make new molecules and survive any longer. Right.

So will this work against any type of tumour? I mean, nothing is, you know, as a scientist, I'm used to being. very critical. And when you tell the story of Hamlet, there is, there is always a risk that it sounds a bit too good to be true. So I would never say that it works against all sorts or that it's totally specific for cancer cells and not healthy cells. It just has that sort of, it has that ability to interact with a lot of different cancer cells, whether or not that we translate into therapeutic uses in the future. You know, we will have. have to see. We take indication by indication and see how we can develop it for the best.

Sure. So how is the drug administered? So far, it's administered locally. So locally into the brain, locally into the gut, locally into the bladder. We also have done in a human study, we did skin papillomas, where we just put it locally on the lesion in the skin. This was published in the New England Journal of medicine actually. So we're quite proud of that. And so it's a substance for local application so far. And how about side effects? Have you noticed any negative side effects? Now this is the thing. Now again, nothing is black and white. But it's actually both in the human studies and in the animal studies, we have seen that the substance is taken up by the tumor. And we have not

seen adverse effects in the adjacent tissue, healthy tissue adjacent to the tumor. We've also done formal toxicity studies done by commercial companies or specialized in these type of work, and they also haven't seen any adverse effects. So so far, it looks as if it's a very nice molecule or group of molecules. So how does the treatments using Hamlet compare to other treatments that are currently used

which people we probably familiar with such as chemotherapy or radiotherapy? What we can say is that the lack of toxicity is a major difference obviously and conceptually if it's possible to remove tumour cells without destroying healthy tissue that would be a new paradigm. I can't say that we are there yet.

We need to look at more, you know, do more human trials before we can draw that conclusion. But that might be one difference. Secondly, the actual efficacy of Hamlet compared to all the cytotoxic drugs needs to be defined better in comparative clinical trials, I think, before I draw any conclusions there. Okay, so as I've just said, you originally found this molecule or molecules in human breast milk. So there might be an issue, though, with obtaining a large, consistent supply of it. But I understand you've managed to produce a man-made version. Yes, thank you. We were fortunate at the same time as we got funding to really do these clinical tribes in a professional way.

we also found that part of the molecule of the hamlet molecule, which can be synthesized, is actually responsible for the cell killing activity. And so we could synthesize that as a small, as a peptide, and then add the lipid, the fat, as you say, and make a functional complex. And this is the one that has now been produced, you know, state of the art. We call it GMP and in factories with serility and all of the things that we need to do. and now is being tested in patients with blood cancer. So it's producing essentially the same effects?

It is. And we are quite happy to see that and very excited. So is the manufacturing process difficult or expensive or anything like that? The fascinating thing for us is that we get to know all of these fantastic individuals and organizations who specialize with professionals to do this. these kinds of things. So we have we have collaborated with a multinational company that's specializing protein synthesis and they have delivered excellent material and then a group of consultants that specialize in the rules, the FDAs of the world, you know, the rules that you

have to follow and how to how to find the data and fill in the forms and so on. It's been a several year process but it's been it's been a wonderful way of getting. to know about all the competence around and to meet all these people who are helpful and, you know, who like to work with new drugs. Also a bit of idealism there. So, and as we said earlier, like you're currently undergoing a trial at the moment. So what's the time scale? When can we expect some results from that? We're actually due to finish our first, what's called a phase one-two trial at the end of June. this year and are very excited looking forward to getting the data from that. It's a double-blind

placebo-controlled trial, so we have no idea who is getting the drug and who is not. We are collecting both a lot of, of course, patient data, which is done by the hospital where the study is being done, and also laboratory data and scientific data. So all of this should be combined into an information package sometime towards the end of June, early July, I hope. And what kind of condition do the patients have that you're treating? They have bladder cancer, what's called superficial bladder cancer. And in part, we selected this indication because we have previously performed a human study, an academic human study in bladder cancer and seeing some positive effect.

So it was considered that the most realistic indication for a first phase one-two trial. We're already very happy because there is no evidence that we have pressed to release this. So this is public. There's no evidence of severe side effects, which is quite a relief for the future of the substance. And then, of course, we'll have to wait and see if the patients really benefit from this treatment. Platic cancer is in the U.S. that has very good statistics on this. Pladder cancer is the most costly form of cancer because it's a recurrent illness that requires

many years of therapy and frequent hospital visits and so on. So fingers crossed that you get the results that you're hoping for in this day. I mean, what are your plans for the future? We are already planning for what's called a dose escalation study, which is to take the opportunity of providing patients with increasing doses to see if the efficacy is higher with increasing dose. We have very good animal data suggesting that this will be the case, but it needs to be done properly with all of the controls and safety assessments. Then we are very interested in the brain tumor aspect because the animal experiments was very promising.

And we hope we have started a collaboration with a clitorial. team in the UK and we hope to proceed there to clinical trials, you know, as soon as possible. Okay, great. Yeah, that's fantastic. That's really interesting. It's definitely something as a science focus will be keeping an eye on in the future. And thanks very much for taking the time to talk to us. Thanks for your interesting questions. I really enjoyed it. Thanks very much. That was Katharina Svanborg talking about Hamlet, a compound found in human breast milk that shown promising anti-cancer properties. Thank you for listening to the Science Focus podcast. The May issue of BBC Science Focus is on sale now. In it, we marvel at the first ever photo

of a black hole and find out what we can learn from it. We look at new dementia research that's providing hope for patients and talk to a psychiatrist that's keeping patients awake all night in a radical new treatment for depression. And as always, there's much, much more inside. Thank you for listening to the Science Focus podcast from the BBC Science Focus magazine, team. With the UK's best-selling science and technology monthly, available in print and in several digital formats throughout the world. Find out more at sciencefocus.com or look out for us in your app store. This podcast is sponsored by Name, Audio and Focal. The texture and emotional depth of music can be lost through digital sources or poor signal. Name audio believes you can have digital precision

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