Let’s talk about breast cancer in Marin. The Buck Institute came out with some research a couple of years ago that showed the excess in Marin breast cancers were estrogen-receptor positive. Does that mean that those cancers have to do with an increased lifetime exposure to estrogen?
We don’t know that for sure. What’s interesting about that finding is that it says the cancer is skewed toward that particular type, which, to be fair, is the most common type. So does that mean that there’s something in our water that acts as an estrogen agonist, a toxin that has estrogenic properties? Chris Benz, the Institute’s breast cancer researcher—and the one who discovered the skewed distribution of breast cancers in Marin—argues that if we really were being exposed to high quantities of an estrogen agonist there would be a lot more uterine tumors, because the uterus is certainly estrogen-sensitive. My rejoinder to that is, what if you have a toxin that has estrogenic properties that are specific to the breast and not the uterus? Then perhaps you’d see just what Chris discovered.
Is that something that the Buck Institute is pursuing?
I think it’s an incredibly important area. And I think that one of the priorities in having an institute here is for us to be of practical use. So when you have what looks like an emergency in the county, with an increase in tumors, we want to be involved. But we don’t know a lot more now than we did when we first learned of it—for example, we don’t understand why living in Marin longer doesn’t seem to correlate with a greater likelihood of developing breast cancer. But clearly breast cancer is common in Marin—my wife was diagnosed in ’99. She had seven operations. She went through hell. She had earlier discovered a tiny, tiny lump. It literally was like a BB. And all the doctors told her forget it, it can’t be. Finally, after two and a half years she said, “Look, just humor me and take it out.” And by the time they took it out they said, “Oh, it’s invasive.” It was a total disaster.
1999 was the year you came to the Buck Institute. Had she been living in Marin before that?
We had been in Marin during the ’80s, when we were both in training at UCSF. She’s a family practice physician, and she lived here from ’83-’89.
Does she think there’s some environmental cause for the high rate of breast cancer in Marin?
She thinks there’s something going on, but she doesn’t know what it is. She actually thinks one possibility is dairy ingestion. She read this book on exposure to dairy products with bovine growth hormone. She stays away from dairy now. However, we’ve got two daughters and of course we’re worried about them. Breast cancer does not run in her family. So yeah, she might have been exposed to something, we don’t know.
I see that someone here is looking at environmental factors in Parkinson’s disease.
Julie Andersen, a faculty member here, is looking at a couple of things. One, what causes Parkinson’s? If you look at a cell [goes to the whiteboard, picks up a pen and draws a cell]—this is a brain cell, and of course it’s got to have its energy, its PG&E. And the PG&E for most cells are mitochondria, they’re the powerhouses of the cell. They have specific complexes, groups of proteins. There are often about 40 proteins that work together. It turns out that, when you have Parkinson’s, one of those complexes, Complex 1, is abnormal. And if you take a normal animal and you inhibit Complex 1, you get Parkinson’s. The second thing Julie has found is that one of the things that can cause damage and may lead to Parkinson’s is too much iron exposure, especially when you’re a newborn. So I think her work is eventually going to lead to a reevaluation of how much iron should be in formula.
Wow! So that can determine what’s going to happen to you when you’re 65?
Isn’t that amazing? What Julie and her lab have found in animals is that exposure to iron at birth and shortly thereafter can determine what’s going to happen much later. This is what happened to the people who were doing drugs [from a tainted batch of synthetic heroin] in the ’80s and developed severe Parkinson’s. This was a big story at the time and it gave us new insight into what Parkinson’s is. It turned out that when this stuff was made they got a side product, MPTP [methyl-phenyl-tetrahydropyridine], which is highly toxic to your nerve cells, and it damages Complex 1 and gives you Parkinson’s. Now, some people who had a low-level exposure didn’t get Parkinson’s then, but they did when they got older.
You’ve got a symposium coming up in October called the Pharmacology of Lifespan—this is about anti-aging medicine?
We’re beginning to understand the genes that have an effect on life span. In nematode worms, you can make a few mutations and make the worms live over six times as long. It would be like a human living over 400 years. And it’s not like the worms get old and they just sit there—they have a much longer time until they get decrepit. Everything gets extended.
So it’s like they have a longer childhood, a longer adolescence and so on?
Exactly. They’re slower to grow.
So that’s not something that would necessarily be desirable for humans.
Well, some humans would love that! But you’re right, there are likely to be many ethical and moral issues that we face. If someone told you that you could live much longer, but you’d take longer to grow up, and while you’re growing you’re not going to be as competitive with other kids your age because they’re going to be bigger and stronger and faster—but when you finally do grow up, you’re going to outlive them by a lot—what would you choose? And would our government allow you to have a choice? It looks like this goes on in nature all the time. Nature is selecting for the bully who’s tough and grows up quickly but dies young. Everybody knows these kids—when they’re 12 they look like they’re 18 and they’re shaving and beating the crap out of everyone. They’re highly competitive. They typically don’t live as long as some of the later bloomers.
Are you saying that there’s a certain body chemistry that determines if you’re going to be a bully?
In a sense. I’m saying that in general the organisms that grow up the quickest die the youngest. The reason I say “bully” is that, if you’ve got two organisms and one of them is twice as big as the other one, it’s going to win. On the other hand, in our society, if we have an agreement we’re not going to kill each other and allow these [slow-growing] kids to grow up, you could potentially have a kid who would live much longer.
Speaking of ethical controversies, the Buck Institute was born in controversy.
[rolls his eyes] Don’t I know it.
Do you still get complaints from people who believe the Buck Trust money should have been spent in other ways?
Just the other day a colleague of mine sent me something that was in the Marin IJ. It was a local citizen saying the Buck Institute is a giant boondoggle. I think everybody’s entitled to his or her opinion, and I do think there are two fundamental ways to think about giving money for the good of people’s health. One way is to give it as food and blankets and drugs today. If we were dealing with a situation where we needed more penicillin, that would be the way to go. Give them more penicillin. But we’re in a situation where we don’t have treatments for end-stage prostate cancer, Parkinson’s, Alzheimer’s or most of the diseases of aging. So in that case, it’s only a very short-term solution to give more drugs. We don’t have any drugs that do much. So I think the only way to make a fundamental change is to go back to basic research. Yes, it’s slow, we don’t have all the answers overnight, but in the long run it will give us the answers we want. And these diseases don’t just affect older people. People are getting breast cancer in their 30s. Michael J. Fox had Parkinson’s when he was very young. We had a friend who had a disease that’s very much like Alzheimer’s—Pick’s Disease—when she was 29. She died in her early 30s. As we work on aging we’re going to get treatments for cancer, for degenerative diseases, I think all sorts of good things are ultimately going to come from this.
Any complaints from the animal rights people?
I’ve talked at length with Elliot Katz from IDA, In Defense of Animals. I consider him a friend, he’s a good guy, and he and my wife are quite close. She’s very much an animal rights person. And one of the things we’ve tried to do here is to absolutely minimize the use of animals. Of course you’re not going to give a drug to your daughter without putting it in an animal first. But to the extent that we can, we use the computer, we use cells in culture, we use everything other than animals for as much as we can. And we don’t use any animals other than rodents and things like fruit flies and worms. We don’t use rabbits, dogs, cats—nothing. So I think and hope that the initial concerns have been put to rest.
Tell me about your work with what you call the Jekyll-Hyde gene, that can either suppress or promote the growth of cancer cells.
This is a central concept that we discovered 12 years ago. Up until then [it was thought] there were only two kinds of cancer genes—tumor supporters, or oncogenes, and tumor suppressor genes. What we found is there’s a Jekyll and Hyde gene that can go either way, depending on its environment. And these things feature in a lot of things—how your nervous system develops, whether you’re going to get cancer or not, whether it’s going to metastasize or not, and now we know it features in whether you’re going to get Alzheimer’s or not.
And there’s a protein that determines if the gene acts as Jekyll or Hyde.
Netrin-1 is the protein for one Jekyll-Hyde gene, but there are probably many more such genes. Netrin-1 tells the cell whether to switch off the cell suicide program and allow it to become cancerous, or whether to allow the cell suicide program to occur, in which case you ramp down the likelihood of getting cancer. It’s a molecule that floats around and helps decide whether or not you are going to have a tumor.
Is this something that everybody’s body creates?
Yes. You make more or less of it, but everybody makes it.
And what accounts for whether we make more or less?
We don’t know yet. The mice we used had been artificially created to make high levels of this, and they developed colon tumors. Whether a person makes more or less of it depends on the individual’s chemistry and their family history, their molecular genetics. It’s an area that’s very under-explored because we haven’t known until recently that it’s likely to be important in tumor development. One of the next things we need to know is, let’s say you have high levels of netrin-1 and I have low levels—does that mean you’re more likely to get cancer than I am? We don’t know yet.
If it turns out that that is the case, then I assume the kind of therapies that might be possible would be something that would turn off the protein?
Right, or block its interaction with its receptor.
And what is its role in Alzheimer’s?
It’s the same general idea, but cancer and Alzheimer’s are working in reverse. Too much cell survival gives you cancer. Too much cell death gives you Alzheimer’s or another degenerative disease. So this says that neurodegenerative diseases and cancers can be two sides of the same coin. We just had a group here last week from the Netherlands, Korea and the University of Texas, and they had a program studying DNA repair. There are many people who have problems repairing their DNA, so they get mutations in the DNA—and then, one of two completely different things happen: If the cells are able to commit suicide because they recognize that they’re damaged, you lose the cells, you don’t get a lot of extra cancer, but, guess what? You age more rapidly and you get neurodegeneration. On the other hand, if the cells aren’t able to recognize damage and kill themselves, then they survive and you get cancer. So very similar problems lead to two completely different outcomes, depending only on your body’s response. It’s almost as if you’re damned if you do and damned if you don’t. If you let them survive—cancer. If you don’t let them survive—aging and degeneration. So what it really tells you is, take good care of your DNA. When you go out in the sun, get that block on, just like your mom always told you. Patients who have poor repair of their DNA get the same damage we all do, but the difference is, most of us fix our DNA. These people don’t fix their DNA.
Does this have to do with the body’s immune response?
The immune response seems to come in later, when you have a tumor and you either reject the tumor or not. A strong immune response won’t help you repair your DNA, but it will help you deal with a tumor that results from the lack of DNA repair. Dr. Kayvan Niazi here at the Institute’s Discovery Translation Unit has done some really interesting work with immune rejection of tumors.
You established that unit to fill a gap between academic and commercial research, right? What’s that about?
There’s basic research and applied research, and there’s a growing gap between where the basic researchers leave off and where the drug companies pick up. The drug companies aren’t picking up the research at an earlier stage, the way they used to. We want to take new findings that we make here and bridge that gap. So instead of going to a drug company and saying, we have a concept, we’d like to go to them and say, we have a lead compound. Maybe it’s not the final drug for the market, but it seems to have an effect and we’d like you to test this. The hope is that they would pick this up at this later stage. This whole thing came up partly when a colleague of mine became the head of neuroscience research at Merck, and I called him up and said, “We’ve got some really interesting things, why don’t we collaborate on this and develop drugs around this new kind of cell death that we discovered?” And he said, “Well, when you get a drug, give me a call.”
I understand why the drug companies, which are focused on profits, aren’t interested in basic research. But why is the basic research not going a step further at the academic level?
Basic researchers aren’t trained to work on how you get this into a human being. So, for example, they’ll define all the gene products that are going up and down during Alzheimer’s disease. Boom! You publish a paper, move on to the next study. Well, maybe one or two of those are good targets for therapeutics, we don’t know. But looking into this requires a lot of specialization that they don’t have. You might need robotics, so a robot does the screening for you. You’ve got to get big chemical libraries, and go through hundreds of thousands of compounds. It’s tedious, it’s not easy. We can do those middle steps that will ultimately get the drug companies interested. Why do we want them interested? Because we don’t have the wherewithal to do the human trials, which are going to take millions and millions of dollars. I see that as being another part of the problem.
Tell me about that.
The FDA requires a lot to approve a drug, which protects us, but it means that the average cost to develop one new drug is 1 billion dollars. We need to find a way to become much more efficient. The drug companies, because they’ve got to make money, have to focus on things like Viagra and antibiotics that can be used by everybody. But where’s the new treatment for multiple sclerosis? Let’s cure Parkinson’s, let’s cure Lou Gehrig’s disease. They can’t do it. If it’s not something very common, forget it. Even though Lou Gehrig’s disease kills one of every 700 people, that’s not enough! If you really step back and look at it, it’s a bizarre system. Imagine a car company where someone puts the first couple wheels on and rolls it out into the yard and just leaves it there. Then maybe a couple years later someone comes along and says, “Oh, yeah, let’s finish this car.” There’s no system in this country to say, “How can we optimize our ability to make new research clinically useful?” There’s no coordination between the for-profit pharmaceutical companies, the FDA and the basic researchers. And in the middle of all this, the patients are dying! They’re wondering why we haven’t cured cancer yet. Well, we have a terrible system to do that right now. And I think more and more places are coming to the same realization and starting to set up similar sorts of units.
Are there countries that have a better system?
Singapore is really pushing to do this better. Singapore has a move afoot to be “First in Man,” they want to have their drugs into people before anybody else. And they’ve put a huge investment into building this biopolis—the whole block of a city is pure research institutes. They’re trying to wed the basic research to the development in a way that hasn’t been done before. One of the things I’m trying to get done while I’m here, which I think will make us the aging research institute of the future, is molecular epidemiology. As a physician, I spent years seeing patients with neurological diseases. We are pretty good at acute illnesses. If you have pneumonia, we can probably cure you. But we are dismal failures at chronic illnesses. If you ask us what we’re going to do for your Alzheimer’s disease, what we’re going to do for your chronic renal failure, what are we going to do for your end-stage prostate cancer—all these things, we do terribly! By the time someone showed up in my clinic with symptoms of Parkinson’s disease, 80 percent of the area of the brain that’s messed up by Parkinson’s is gone [goes to the whiteboard and draws a brain, showing a region in the brain stem called the substantia nigra]. All these years, you’ve been losing it. If you just knew when it was 10 percent or 20 percent gone, you’d be in great shape.
What would you do about it if you did know?
That’s the key. We’re beginning to understand why it goes away, so you could probably put it off. And if you could put it off for 50 years—so instead of getting it at 50, you get it when you’re 100—that would change the world. The basic mechanisms for these neurodegenerative diseases appear to be specific proteins misfolding. It’s true of mad cow disease, for example, it’s true of Alzheimer’s, it’s true of Parkinson’s, it’s true of Huntington’s and it looks like it’s true of Lou Gehrig’s disease, also. You have specific proteins that normally fold the correct way and do their job, and it’s like origami—you’ve got to have multiple folds correct in order for these things to do their jobs correctly. In the future, doctors will be able to read your molecular tea leaves. They’ll take a swab from your mouth and say, “OK, you will get Parkinson’s when you’re 51, plus or minus five years, but we can put it off so you won’t get it until you’re 101.” And we’ll give you certain exercises, certain dietary differences and some nutraceuticals so you can put it off. So molecular epidemiology will give you a profile so you can see who is headed for what disease. As it is now, we’re waiting until the horse is out of the barn.
Do you foresee any therapies that will be available more immediately?
We have these incredible mice that have Alzheimer’s, made by Dr. Veronica Galvan here at the Institute. Let me show you a film of these cool mice. This is the sort of thing I find really fascinating. [goes to his computer and brings up a movie; we see a tank of milky water, filmed from above; a mouse enters the tank and swims straight for a platform] These are normal mice that have been trained to find this target, a platform that enables them to get out of the water. They hate being in water. [a different mouse enters the tank and swims around and around in circles] This mouse has the same genetic mutation as humans that have Alzheimer’s. He can’t find his way out. We take him out after 60 seconds. [a third mouse enters the tank] This is our [genetically altered] mouse. He is identical to the one I just showed you, but we’ve changed one amino acid. It’s like two houses that are identical except for 1 percent of one brick. We put him in the water and here he goes! Just like the control mouse, he knows exactly where that target is. So our mice are just as good as the normal mice, even though they have Alzheimer’s. We have completely prevented Alzheimer’s in these mice. Everything is back to normal. We made a minimal change, but it’s absolutely crucial. Of course we’re now trying to develop drugs that have the same effect. We can cure the mouse genetically, but we definitely can’t take a human and mess around with his or her genes.
But it’s possible to come up with some sort of medication that can do this?
That’s exactly what we’re doing. We’re screening drugs that specifically have that effect. You can’t change the amino acid, but what the drug does is it gets in the way.
How far away do you think you are from being able to test it on humans?
I think the animal studies will go on for the next two-three years and my hope is that after that we’ll have something that will look pretty darn good for ultimately putting into humans. When I was working at the VA in San Francisco, this couple came in and the woman was sitting in the chair crying and she said, “He’s not mean any more.” And the guy said, “I feel fine,” he was just the nicest guy. Well, it turned out when I got the whole story, he had been one of these businessmen who was just a son of a gun [sneering, grinds his thumb down on the table], just a schmuck to everybody, and she knew when he stopped being a schmuck to everybody that something was wrong. And she was absolutely right. He was getting a neurodegenerative disease and his personality was changing. He was a relatively young guy, 62 or something. Spouses always see it coming. Some day we’ll be able to tell you, you’re not going to get Parkinson’s, or you’re not going to get Alzheimer’s—just like today we can tell you, you’re not going to get polio. Imagine the difference in the world. It’s going to be fantastic. I can’t wait.
PHOTO OF DALE BREDESEN BY ROBERT VENTE
ARCHIVES: More Pacific Sun Features
Lurking very close to the surface of the eminent Dr. Dale Bredesen—president and CEO of the Buck Institute for Age Research, professor of neurology and much-lauded expert in neurodegenerative disease—is a surf rat. Growing up in Fort Lauderdale, the young math-and-science whiz spent hours riding the waves and chose his college, Caltech, for its Southern California location as much as for its academics. You can still see the energetic, enthusiastic teenager in him as he talks about his life’s work. “Look at these cool mice!” he says, as he shows a film of some genetically modified mice he’s cured of Alzheimer’s disease. He’s planning on curing Alzheimer’s, Parkinson’s, cancer and other aging-related diseases in people, too.
