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Hope, fear, and politics

A UR scientist navigates the complexities of stem cell research

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For millions of people suffering with debilitating injuries and serious diseases like diabetes and Parkinson's, stem cell research offers hope. But as promising as the research is, it is also polarizing. And the Bush administration has taken a non-scientific view of stem cell research and turned it into public policy.

At the University of Rochester, cell biologist Mark Noble is trying to apply what he has learned about stem cells to deliver safer and more effective chemotherapy to cancer patients. But he, like many scientists, is concerned about the growing anti-science movement that is shaping the stem cell debate, often through false information.

The result, he says, is "a series of losses," in knowledge, in medical cures, and in economic opportunities.

Stem cells aren't ordinary cells. They are found in most mammals, including humans. What makes them unique is their ability to self-renew: stem cells create new stem cells. As they divide and mature, these specialized cells form tissue.

There are two types of stem cells: adult and embryonic. Adult stem cells are found in humans after birth --- in babies, children, and adults. Their ability to renew themselves is "tissue specific." An adult brain stem cell, for example, can only form more brain cells.

Embryonic stem cells, on the other hand, are not only self-renewing, but they also have the ability to form all cell types of the body. They can, for instance, form brain, heart, or liver cells.

It's the unique characteristics of embryonic stem cells, in particular, that has scientists like Noble so eager to conduct more research. Noble sees a time, for example, when "customized" embryonic stem cells could be used to repair a damaged liver using cells from the patient's own body. This would in theory eliminate the problem of tissue rejection, since the new liver tissue would be genetically the same as the old.

But the use of embryonic stem cells is controversial, partly due to where they come from: umbilical cord placenta, aborted fetuses, and unused fertilized eggs from fertility clinics.

And despite the revolution that understanding embryonic stem cells could bring to medicine, researchers have been stymied. The Bush administration is opposed to embryonic stem cell research, insisting that adult stem cells are equally suitable for research purposes. The administration has severely limited the availability of stem cells to scientists supported by the National Institutes of Health. In August 2001, the president announced that taxpayer funds could be used for research only on embryonic stem cells already in existence. And the administration has held funding for the NIH to the level provided during the Clinton administration. That funding limit has discouraged NIH officials from supporting research that could be considered controversial.

Despite the challenges, the University of Rochester has made a solid commitment to stem cell research. Joel Seligman, the university's new president, is trying to work with lawmakers in Albany to shape policies more favorable to the state's research community. He and a group of the state's college presidents believe that stem cell research will stimulate whole new branches of medicine. They are concerned that other regions --- California, Canada, Korea --- are aggressively supporting stem cell research, attracting the best scientists and developing a competitive edge.

In recent interviews, Noble spoke about his research at the UR, the debate over using embryonic stem cells vs. adult stem cells, and bills before Congress that, if enacted, would further restrain stem cell research in the United States. The following is an edited version of those discussions.

City: What are you currently working on?

Noble: Two aspects of cancer. One involves chemotherapy. The agents we use to treat cancers are very toxic for normal dividing cells in the body. We need to be able to do side-by-side comparisons in order to understand and identify ways of specifically killing cancer cells. Cancer cells use every trick of evolution [to survive].

In one of your papers, you described them as the "evil siblings."

Right. One of the things some cancers do is that they have a stem cell compartment. They represent maybe 1 to 2 percent of all the cells in the cancer, but they are the source of everything thing else. If you don't kill them, the cancer comes back. So we have extensive interest here at the University of Rochester. Dr. Craig Jordan [specialist in hematology and oncology] in particular and I have dedicated efforts to understand how to kill cancer in stem cells without killing normal cells.

I'm also working closely with [UR geneticist] Dr. Hartmut Land to understand the genetic programs of cancer.

Why are the restrictions imposed by the Bush administration so important?

The great majority of us who study development and do stem cell biology work with rats or mice, and we work with cells derived from animals of different ages. We've gained enormous knowledge about the capacity of different cells to do different things.

It's not surprising to find that cells that function during early development are very special. They have the job of building the body in the first place. So except for those rare tissues where cell replacement goes on throughout life like the blood, the cells derived from a young animal are very different from the cells of an adult. They have a much greater capacity for division and tissue formation.

For embryonic stem cells, the problem that we have is that scientists supported by the National Institutes of Health could only use embryonic stem cells [that existed] prior to the date of the president's [August 2001] speech.

Although he initially said that there was something like 60 lines available, the actual number is much smaller. The numbers vary, but it's certainly fewer than 20.

It turns out that those [stem] cells have been grown using mouse cells as feeder layers, which means they are not suitable for human use.

For those of us who are trying to figure out how to do real pre-clinical studies --- not just experimental stuff, but want to move it to the clinic --- those cells are useless.

The cells that are suitable for clinical development have been generated entirely through private resources. You have to create a separate laboratory funding stream. You can't spend NIH money on them. That is very restrictive.

Can you give me an example of one of the diseases you're talking about?

I'll give you an example of one that was cracked right here. The disease is called Vanishing White Matter Disease. In this disease, the children are born normally and undergo a period of normal development. But if they have a particular mutation, the part of their brain through which impulses are conducted starts to degenerate. When this white matter --- which is the insulation around nerve cells --- breaks down, you lose impulse conduction. This is what happens when you have multiple sclerosis and severe spinal-cord injury.

We had a child here on life support, and the neurologist called me. The parents wanted to know if we would do research on this. It's a genetic condition. They have other kids. So the question was, could we figure out what was going wrong?

The brain has three cell types. There are nerve cells, which conduct impulses. There are cells called oligodendrocytes, which produce the insulation that is necessary for normal impulse conduction.

The third cell, the most numerous cells in the brain, is called the astrocyte. And this is a cell that does many things. It controls a lot of the metabolic functions in the brain.

When we started studying the disease, we thought there was going to be a defect in the oligondendrocytes, because they are the cells that make the white matter. And that's the area being destroyed.

The way it turned out, another set of stem cells from the child's brain were defective in their ability to make astrocytes. All of a sudden, we knew how to approach the disease. The transplantation that we would have done to replace all of the oligodendrocytes would have been the wrong thing to do.

Now through the work of [UR geneticist] Dr. Margot Mayer-Proschel, we already knew how to grow normal human renewing cells. So we actually have the cell types in the laboratory that one would want to transplant into these kids. This is a disease where at the moment what is going to happen is unstoppable, but this offers the possibility of changing the outcome.

But why is the scientific community so dependent on the NIH? Why can't you approach a venture capital firm for the money and start a company that is dedicated to stem cell research? You could circumvent the funding restrictions imposed by the NIH and the Bush administration. Isn't that's how Silicon Valley was created?

To start with, people don't really understand how researchers are paid and how labs are funded. They think the universities' teaching hospitals pay for it all. But there are 25 researchers here, and we have to come up with half of our salaries on our own. In some universities, it is more than half; it could be 100 percent. But the point is, we apply for the grants. The university doesn't.

We are more like artists than the public probably realizes, in terms of how we are supported. If the money isn't there, then labs shut down. And under this administration, you have billions going to the top 2 percent of the richest Americans, but the NIH is in a holding pattern. That's why you see labs shutting down in this country when we should be supporting more research.

Then you have to consider the amount of money we're talking about. There are very few sources for this amount of money. And even though government money is going to the NIH and then into research, the public gets the money back in terms of whole industries that wouldn't exist if it weren't for the NIH. The bio-tech industry wouldn't exist if not for the NIH. Companies like Amgen and Genentech wouldn't be in operation today without NIH help.

In this country, the NIH is by far the largest source of funding for bio-medical research. It is not the same as start-ups in Silicon Valley. Silicon Valley doesn't have an FDA body, and remember that a lot of the breakthrough technology that came out of there was a result of research at the university level. Venture capital money doesn't come into it until late in the game.

The administration launched a PR offensive --- using the First Lady --- that took the position that the science is iffy and overblown in terms of its ability to one day treat diseases like, let's say, diabetes. Do you think the scientific community has not made its case clear enough to the public?

The scientific community has countered this, but you have to ask yourself who controls the media. We don't get invited to the Larry King show or to Oprah's, but opponents generally do.

There is a serious ethical debate here, and I think one has to divide it into segments to do it justice. The first question for me is: does any religious group have the right to impose its belief upon everyone else in the country?

[Some of the objections to stem-cell research come from people who believe that life begins once an egg has been fertilized and starts to undergo division. Actually, as the egg divides, it forms a ball of cells called a blastocyst. Inside the blastocyst are embryonic stem cells.]

If we simply look at when life begins, this is a very fuzzy concept. If the blastocyst doesn't implant to the uterus wall, you have no pregnancy. And the estimations are that between 40 and 80 percent of all blastocysts are simply washed out in the menstrual flow. We don't have this huge effort to save the blastocysts to reverse this, and we do put so much effort into rescuing premature babies. So on some level we know there is a difference here.

Here's a thought experiment: You're standing outside an in vitro fertilization clinic. In there is a liquid nitrogen tank, and in it are 10,000 stored blastocysts, which is what you use for in vitro fertilization. And there is a fire. Trapped in that room is one child. Who are you going to rescue? I have never met a person who would rescue the nitrogen tank. But if these people were true to their views, they have to take the position that there were 10,000 lives to one life, and they would have to rescue the tank.

There is a difference.

There's also the discussion about the discarding of blastocysts in fertilization clinics.

There are an estimated half a million kids that would not exist today without in vitro fertilization. The way this is done: extra blastocysts are generated and frozen. But once the mother becomes pregnant and has the child, it is very rare to have the mother or couple asking to maintain the extra frozen blastocysts. You have to pay for it. Insurance doesn't pay for it. So the blastocysts are discarded.

What we have been saying in the scientific community is, if they are going to be discarded, let's take 20 to 30 [embryonic stem] cells from inside of them and make [more] embryonic stem cells. From one blastocyst, you could generate enough [stem cells] to fill a room.

As the field of regenerative medicine matures, where are we here in New York and where is the US compared to competitors?

Some states like California and New Jersey are taking this seriously. They recognize the economic impact this will have, and the number of businesses that will come from this work. So they are not waiting for the federal government to come up with a sensible policy that would free more NIH money.

And then you have Canada, Australia, India, and Korea all making strides because their governments are putting more money behind it. The science is not getting caught up or being driven by the religious debate, some of which is misleading and not based on science.

The answer goes back to this question: can we build an ethical system that starts with dishonest information? The opponents to embryonic stem cell research, some of whom are raising important ethical questions, unfortunately have frequently made the choice to misrepresent the science.

This gets to the fundamental difference between science and non-science. Science is based on data. I don't have the option of deciding to believe something just because it makes me feel better. Science that stays the course, in the presence of data that tells you that you are wrong, is not respected. That is why it is science that has given us vaccinations, antibiotics, anesthesia, and successful surgery.

What do you say to opponents of stem cell research who look at the recent developments in Korea and say, ah-hah! See? Embryonic stem cells don't lead to anything that can't be accomplished using adult stem cells?

That is simply not true. We already know that there is a difference between the two. And what this actually proves is how effective science is at self-policing. It is the scientific community that has come down hard on this guy. It's the scientific community that has challenged his work, not the opponents.

And furthermore, this proves something that we've been saying all along. This work is going forward with or without the US. Wouldn't it make more sense to be in the lead position instead of reacting to it?

If the government is so worried about what could be happening in the lab, all the more reason to get in front of it. All the current policy is doing is pushing the scientific work offshore into the hands of people less ethical. And it becomes a series of losses: loss of the research and the knowledge, loss of the help that it can offer in curing and treating diseases, loss of good scientists because they are going to go where the work is --- and loss of economic opportunities.

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