Daleen: Please tell us more about your work and research that brought you to South Africa to lecture on integrative medicine and treatment options for cancer management.
Prof Burke: It goes back a long way. I conducted my first experiments on cancer research as a post-doctoral scientist in Dallas back in 1973. The boss of the lab put me on as one of his team to investigate why certain chemicals cause cancer, and that’s all linked to the same mechanisms that detoxify pharmaceutical drugs.
Daleen: So, you’re talking about chemicals such as cigarette smoke and petro-chemicals?
Prof Burke: Yes, very much so. The chemicals that you get in the diesel particle fumes and the smoke and, yes, the main reason why cigarettes cause lung cancer.
Daleen: Why would a particular chemical switch on a cancer gene?
Prof Burke: That’s for the microbiologists, we were entirely concerned with PAHs (polycyclic aromatic hydrocarbons). They are actually in their initial state pretty harmless.
The body turns them into something noxious, it makes little chemical changes to their structure, very specific changes, and it’s the derivative made by the body itself that causes the cancer and that’s what we were looking at and we were trying to identify which particular enzymes (it’s all enzymatic processes) were responsible. There are enzymes in the body that cause this to happen. How do they do it? What were the changes in their structure? That really was the hot area in cancer research in those days. Nowadays, because of new technology and new knowledge, it’s more about the molecular biology, the aberrant genes which cause cancer, so we were more concerned as to why they become carcinogenic.
Polycyclic aromatic hydrocarbons (PAHs) are a group of more than 100 different chemicals that are released from burning coal, oil, gasoline, trash, tobacco, wood, or other organic substances such as charcoal-broiled meat.
Daleen: And what did you discover?
Prof Burke: What we discovered was the role of the particular family of enzymes called the cytochromes P450, or nowadays we would call them the CYP.
Daleen: The CYP1B1? It is a protein enzyme?
Prof Burke: Yes, well, all enzymes are proteins; enzymes are functional proteins. This is so interesting: There are more than 8 000 of them across all forms of life, from the smallest to us. You can consider yourself fortunate when you get in right at the start in a field – they were only discovered in 1964 by a couple of Japanese scientists and they gave them the name. I started my PhD on them in England and there was thought to be only one, and it was a conundrum because enzymes are very specific.
The old idea about enzymes was one enzyme, one substrate, one particular chemical that it would work on and no other. Then it rapidly became obvious that many, many pharmaceutical drugs (pharmaceutical medicine compounds) are worked on by this enzyme. And so there were only two possible consequences – either there were lots of them (which we now know to be the case), and each of them is quite specific, or it was what we would call an incredibly bendy enzyme (it could modify its configuration). And that’s where I started and during the time of my formative years as a scientist gradually they discovered more and more of these enzymes and now there are thousands of them!
Daleen: So you are talking about the molecular structure of the CYP1B1 enzyme being flexible enough to fi t into different molecules and cause cancer?
Prof Burke: That would have been one of the original CYP enzymes that were known, and that was the concept: Was it able to handle lots of different types of structured pharmaceuticals because its active site acts a bit like a docking site (the docking site, say, for rockets on the space station). Now it has been found that it’s not so much that, but the fact that there are a lot of different CYP enzymes; there are about 35 of them in humans and there’s about 8 000 more of them out there. It’s often the case that at the start of a scientific area you think one thing and you work it to death and then you find out it was really something else. Knowledge is incremental.
Daleen: I suppose it is all part of the process. You have to start somewhere. The work that you were doing, did that have anything to do with the development of chemotherapy drugs and to try and make them more effective?
Prof Burke: Not really, as such. The work that we were doing related to what kind of chemical structural modification happened in these compounds, like benzoate-pyrene to turn them into nasties, into chemicals which cause cancer. That was really more about establishing the kind of structural changes that the CYP (cytochrome P450) enzymes could do, and that knowledge was then used later on by lots of people.
Us, we looked at one specific aspect – to further understand how the CYP enzymes transformed carcinogens. Now your question (funnily enough) was about chemotherapy agents and they are a class that’s still the most clinically used type of anti-cancer drugs; they happen to be a class that is not metabolised by these enzymes that I was passionate about. Everything I think is known about the mechanism of action of chemotherapy has no connection to anything I’ve ever looked at – be it cancer or anything else. The problem with the chemotherapy drugs is that they don’t have the right sort of specificity; we can go into that but it gets complicated.
Daleen: I would love to! Because when you’re looking at the specificity of the chemotherapy drug, the basic knowledge that we have is that they target your healthy cells and the cancer cells. So, I think this is where the CYP1B1 research comes in?
Prof Burke: It does, ultimately. I mean you are actually talking of chalk and cheese, remember what I said: science develops. And science, tends not to develop gradually (great scientists, historians of science, have said this – not me), but rather like this (sudden growth), and what makes the change is when a really important scientist (who might not be important at that time) tweaks something and persuades everyone else it’s not like this and it’s like that.
Daleen: That’s what happened with you though, because you discovered the holy grail of cancer research!
Prof Burke: Agh! We were never that important in cancer research; there were then, and there are now, much more important people in cancer research. So, the chemotherapy drugs, paradoxically, because pretty much has been known about them for a long, long time – the reason why they go for cancer, the reason why they’re so imperfect and have all these side effects, what happens to the human body – really of all the chemicals involved in cancer they are the least involved in the things that I’m interested in, which are these CYP enzymes and what happens.
Everything, really, is known about chemotherapy drugs. I even met, as a young post-doc scientist, a couple of the now-old scientists, who had invented one of the major classes of chemotherapy. Chemotherapy works in a well-known way, doesn’t involve CYP1B1, or any of the other CYPs really, and the flaw in chemotherapy is what it targets. Basically, chemotherapy targets cells that replicate frequently.
Daleen: And they don’t know how to stop, isn’t that cancer in a nutshell?
Prof Burke: That would define very succinctly a cancer cell, but the problem with chemotherapy is that some very important normal cells, in the course of what they do for the body, have to replicate frequently. Chemotherapy drugs, because of the way they are designed, can’t distinguish the two modes of frequent replication. In essence, every drug, chemotherapy and anything else, and also natural pharmacological agents, have a molecular target. Where drugs are nice and specific, is where the target is known and the target is confined to the disease state; this is what the pharmaceutical industry uses as its design paradigm.
The industry looks for targets which were a part of the disease state, but which were confined to the disease state and don’t turn up in the healthy cells and then they can design a drug. And the chemotherapy, it turns out, what it’s targeted at are the processes that cause cells to grow and replicate – and the problem is that those targets are not confined to cancer cells. They also turn up in these very important normal cells. The chemotherapy drugs are designed primarily to act instantly at their target wherever they find it in the body. So, whatever they do to the cancer cell (which is good) unfortunately they do to the healthy cell and that is why you get the side effects. There is a saying: ‘Fast is fine but accuracy is everything’. When you think about it it’s the essence of pharmacology therapy.
If your drug doesn’t have the accuracy, that’s when you get the side effects, and because of the limitations of what was known in the days of designing and developing the chemotherapy agents, the side effects were inevitable, they weren’t meant to happen. The scientists who came up with designed chemotherapy drugs, they really thought, and you can understand this, that what they were doing was going to be helpful. The problem with chemotherapy is why, by and large, it is not successful – not in the long term. There are successes – for some types of cancers people can benefit hugely from chemotherapy, but the problems came to light later and as to why the problems occurred. . . that came to light a bit later. Of course, now we are in the era of targeted cancer drugs, have you heard this expression?
Daleen: Yes. I have.
Prof Burke: Well, that name alone gives the game away about why chemotherapy was untargeted and where the problem is with chemotherapy – the targets are not confined to the cancer cells. You know about the Human Genome Project, and what it’s borne. Thanks to this project, and what came later, the scientists know now (at last, really for the first time) what’s really going on, what’s going wrong in cancer cells. Why do they act in this terroristic, selfish way? Why do they keep on growing and disrupting the body despite the body saying, ‘no, don’t do that’? And because the scientists are now getting a grip on understanding at the molecular level which genes have mutated, which are aberrant, what are the proteins then that they are forming – because it’s the proteins that matter, the genes make us who we are, the proteins make us tick.
What are these aberrant proteins? Why are they aberrant? What’s going wrong? Right, now we know this is a protein which is aberrant, it’s malfunctioning in the cancer cell, but it’s not malfunctioning in the normal cell. Now we can design a drug, and sometimes these are antibodies (sort of proteins to fight proteins), that specifically targets the protein that is wrong in the cancer cell and wrong in a way we know and understand. For example, often these important chemicals, these proteins in cancer cells, they regulate the whole process of cell life (death, growth) and they act like traffic lights: All this information flying around needs to be regulated and these are called signal pathways signalling proteins, and these signalling proteins are like traffic lights and in the normal cell they go red and green as they should and they respond to each other.
Often what happens in the cancer cell is that they are permanently on (green), or permanently off (red), and that’s the heart of the problem, which they now know. So, they’ve designed drugs, these targeted drugs to block them, take them out of process. But there is a problem, these drugs are spectacularly effective for a few months; and then the patient develops resistance. And resistance is going to be . . . shall I stick my neck out?
Daleen: Go for it.
Prof Burke: . . . the last remaining problem for getting the anticancer drugs we need.
Daleen: Are you quite positive, are you hopeful?
Prof Burke: I am positive that it’s the last remaining problem for two reasons, then we can talk about the hope. The reasons I think it’s the last remaining problem is that I think the problem (of which targets) has been solved – the cancer scientists now know what they should be looking for and they are very clever people. Then, why resistance is a problem: One of the most important living cancer researchers, Professor Bert Vogelstein in the States, who is medically qualified but is really a molecular scientist (he leads one of the most important molecular level research groups in the US at Johns Hopkins University) and who is also a bit of a heretic, which is why I like him, wrote a learned paper recently (2013) stating his opinion on why resistance is a problem. He went so far as to say that our best efforts in anticancer drugs, no matter how targeted, will be defeated by resistance. Because the cancer cells are clever devils, and the processes are now understood that cause them to be cancer cells. What is it about a cancer cell? Our normal cells, they grow, they live and when necessary (if they need to be replaced) they die, to help the health of the body; they obey the commands of the body. The cancer cells are selfish, they grow only for themselves. They are stupid of course and eventually the host dies.
Have you ever thought how we as a species have managed to survive all this time, for millions of years? I think it’s gradually coming to light: One of the reasons is called ‘biochemical genetic redundancy’. Where we have crucial processes, we don’t just have one (and that has been discussed very recently in science), we have lots of them. If one gets accidently taken out in the process, we have another as a back-up and we have a back-up of a back-up. And that is great for our survival as a species; it’s also great for the survival of the cancer cell it turns out. There are, as you know, thousands of genes in the cell and what people like Vogelstein have worked out is that it’s relatively few, probably less than 200 of these genes, that are really crucially involved in controlling/driving the growth and death of cells that are crucial in cancer. And the cancer cell turns out to have redundancy in these crucial processes. So, when a clever, new, targeted anticancer drug takes one out, the cancer cell (clever little devil that it is) just turns on another process (it’s always there, it might have been doing something else, it switches it, we don’t fully know) and that’s the point at which the cancer cell has now become resistant. So, the oncologists switch to a new targeted anticancer drug, they’ve all got different ones. After a while the cancer cell develops resistance to that by kicking in yet another one of the processes. Vogelstein was of the opinion (in his 2013 paper) that this may actually defeat the best that we can do.
Now, I know that you are very interested in integrative therapies.
Daleen: Yes I am, and I think that just listening to you, you know, just reinforces the fact that we need to take our health back and do something about it as much we can ourselves, with complementary approaches, be it improving sleep, improving quality of life, reducing stress, optimising nutrition, drinking lots of water, reducing toxicity around us, and then hopefully putting products into the body which are extracted to optimise the deficiency in nutrients of our food.
Prof Burke: And I have the benefit, I’m very lucky, very privileged that I have seen this from both sides of the coin. Thirty years as a member of the scientific pharmacology establishment if you like, a small part of the cancer research establishment, albeit in the universities rather than the industry. But entirely seeing everything from that angle, over the years becoming more and more impressed by what was known by the pharmacology of natural compounds and then being able, after retirement to switch. I am, if you like, a game-keeper turned poacher! Some of my old scientific friends say I’ve gone to the dark side and now I’m involved entirely in health from the perspective of the natural, plant-made chemicals which we call phytochemicals.
Daleen: I just want to go back on that, so we’re talking the difference between synthetically produced compounds versus natural product extracted compounds.
Prof Burke: Yes, entirely. You know, I say we scientists are clever but ‘Professor Nature’ is actually an even cleverer scientist. But what I would like to do is finish my trail if I may. Because what I was coming to links the natural products to the cancer molecular science, this problem of resistance.
And let me use maybe a metaphor: You’re driving down the motorway, nice and fast, on your own, and then suddenly you see up ahead all the traffic has come to a halt, there’s some blockage, but you see it before you get there. You’ve got a good SatNav or navigator with a map, what would you probably do at that point? If you can, you’ll take an alternative route, you will bypass the block and take an alternative route. Think about it: That’s exactly what the cancer cell is doing when it’s developing resistance to the brand new anticancer drugs by switching to an alternative mechanism. And this is where the natural compounds come in.
Daleen: I’d like to finish off by saying that I really wish that we can get this message out to so many people, just simply for them to have another perspective on drug therapy and on promise and potential hope that we have in using natural compounds together with chemotherapy when it’s needed.
Prof Burke: Part of integrative medicine is the focus on prevention. When we talk about prevention in the cancer-related context, the science is there why you need weekly (almost daily) to do something to help you protect yourself. You need to start that at an early age, not coming along at 50 and occasionally taking a supplement. The science is there to make it very, very clear that especially with cancer you need to be working your way at protecting yourself, and even then you won’t escape the scourge.
Daleen: It’s really sad looking at the statistics and the rise in cancer, and especially in children.
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