Fishing for a Cancer Cure

Richard Mark White, M.D., Ph.D., an instructor of Medical Oncology at Harvard Medical School in Boston, Mass., talks about using the zebrafish in cancer research.

How can fish help you understand cancer?

Dr. White: We work in a field that sort of fits in the intersection of being cancer and genetics. As you know, this is a disease of altered genes and we work with a fish called the zebrafish to try and understand early events in how tumors form and how they spread.

Why is the zebrafish useful in cancer research?

Dr. White: Zebrafish have been used now for probably 20 years because people figured out that fish have genes that are amazingly similar to human genes. They turn on and off in different ways -- that is why a fish does not look like a human -- but the genes themselves are pretty similar. We started studying fish in cancer because cancer is fundamentally a disease of altered genes, so it sort of came together that if we can study genes in fish, that will probably tell us something about cancer.

What enabled you to be able to look at this cancer?

Dr. White: The thing that we had not been good at looking at was, 'How does cancer start and how does it spread?' I became interested and thought, Could I do this in a living animal in a way that we cannot do otherwise? A few of us had the idea that – 'What if we could make a fish that was fairly transparent so we could see the origins of just when the tumor is starting and how it spreads within the body over time,' which is pretty analogous to what happens in a human -- it starts small and gets bigger. We started out with some fish that were already slightly see-through but not nearly transparent. They just had a slight translucency to them. Then we started bleeding types of fish -- each had a slight abnormality in their pigmentation or their color genes. Eventually we came upon a combination of two different mutants so that when you put them together the fish is fairly transparent throughout its entire adult life cycle.

Did you at all alter the DNA in the zebrafish?

Dr. White: I did not myself, but other groups had done the previous work where these pigment mutants that started the whole process were isolated initially by changes in their DNA content or genetic mutations.

Did it start out with some researcher or scientist genetically altering the DNA and then you took it one step further?

Dr. White: Exactly. It was sort of like taking the genetic changes that already occurred and then putting them together and figuring out, 'Why did that combination do this uniquely?'

When you first got the correct combination, what did you think?

Dr. White: It was like one of those ah-ha moments where it became fairly obvious as soon as we looked in the tank. They were about seven weeks old and it was one of those moments of ah, this one is clearly different than all the others.

How did you feel?

Dr. White: It sort of was one of those moments where I realized what we could do with this pretty quickly. At first we were a little concerned whether it would stay transparent, but it stays pretty transparent through its life, so by the time they are four months old, they are still pretty transparent.

What do you physically do so that you can see the cancer cell grow?

Dr. White: The thing that we are really interested in is, 'How does the tumor go from being a couple of cells to eventually growing and spreading?' The way we do this is what is called tumor transplantation where we take an existing tumor from one animal -- just a very few number of cells -- and transplant that into say, the belly of one of the transparent fish. Initially, you do not see anything. Then, over the course of five to seven days you start to see that tumor grow. Probably most remarkably is within a week to ten days, we start to see cells break off and go to other parts of the body, other parts of the skin, its head, tail, and things like that. It's really an amazing picture of how tumors grow and spread in a very rapid time in a way you could never do in an animal or obviously in a human.

What have you concluded so far?

Dr. White: I think it's pretty early but what we are sort of realizing pretty quickly is that when tumor cells spread they do it in a pretty organized way. I think there is an impression that you know, 'Oh my God, tumors have metastasized.' That is common language, right? 'Tumors have gone all over the place,' and what I am really interesting in is I do not think it's a random process. I think when tumors spread, they do it in a highly organized way. It may not seem organized and what we are trying to get at is -- What are the sort of genetic underpinnings of that? Why do tumors spread the way they do? Ultimately that is what kills the cancer patients, is spread tumors.

What are your hopes with this research?

Dr. White: The ultimate goal of this is, it could take a lot of science. If we could figure out, 'Why do tumor cells do this, and what makes them susceptible to metastasizing and can we find drugs or chemicals that prevent that from happening?' Because most cancer therapy is really aimed at shrinking tumors, this is different in that, 'Can we find drugs that prevent them from spreading or metastasizing?' You can then sort of think about ways that people might have tumors but they do not just spread anywhere and they do not ultimately kill the patient. It's a slightly different way of thinking about cancer therapy.

What I find remarkable is the fact that cancer cells are not as disorganized as we think...

Dr. White: I think that cancer cells have an amazingly organized way of moving around the body and we are sort of realizing that from other people's research as well. Understanding how they do that will be the critical thing to figure out how we can find drugs to stop or prevent that from happening.

What about stem cell research?

Dr. White: It's linked in a lot of ways. The other way that a lot of people use this fish is to ask questions about stem cell biology. One of the things we do not do very well in stem cell biology is understanding how the stem cell grows into lots of other cells, like blood cells or muscle cells, and things like that.  Part of the difficulty in the field is that we do things in a dish, but what happens in a dish is very different than what happens in a living animal. I think that the casper fish gives the unique opportunity to see stem cells growing and giving rise to other cell types in a living animal, which is really very difficult to do in any other system.

What is the ultimate goal with the stem cells?

Dr. White: For a lot of people in my lab, I think it's to find genes that regulate things like for example, blood stem cells. As you know, lots of patients with cancer ultimately get bone marrow transplants because they need new blood cells essentially to get rid of their leukemia, but this is a very toxic thing that we do to people when we do bone marrow transplants. One of the goals is to find better pathways or drugs that will make bone marrow transplants far more efficient or more tolerable for patients. Bone marrow transplant is a good therapy but it is an extremely toxic therapy, and we need to find out how we can harness stem cells to make that therapy better.

Explain how you try to get the stem cells at their infancy.

Dr. White: If we use the example of blood stem cells – we are trying to find things that either make their blood stem cells grow more effectively and alternatively, maybe make the bad blood stem cells, like the leukemia cells, grow less effectively. A simple way to put it is, we are trying to find things that help the good cells and hurt the bad cells.

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