Ride For Life: ARE STEM CELLS IN YOUR FUTURE?

THE ROBERT PACKARD CENTER FOR ALS RESEARCH AT JOHNS HOPKINS

(Excerpts from a lecture sponsored by the Friends of the Johns Hopkins University Libraries on May 28, 2003 featuring noted stem cell researcher John Gearhart. Dr. Gearhart is the C. Michael Armstrong Professor of Medicine in the Johns Hopkins School of Medicine and an investigator and advisor for the Robert Packard Center for ALS Research at Johns Hopkins. A list of recommended readings is posted at the end of the transcript.)

Introduction: George Udvarhelyi

Our guest is an unusual man, bearer of revolutionary ideas in a revolutionary time. John Gearhart is the C. Michael Armstrong Professor of Medicine in the Johns Hopkins School of Medicine. He's a key member of Hopkins' Institute of Cell Engineering, the first of its kind in the country. He earned his doctorate at Cornell University, had fellowship training at the Fox Chase Cancer Center and joined the faculty of Hopkins in 1979.

Dr. Gearhart is a developmental biologist and his research over the last two decades has been directed at understanding the molecular and cellular basis of human embryonic development. He has over 200 research publications in developmental genetics. He's a leader in the development and use of human reproductive technologies and in the genetic engineering of cells.

In 1998, Dr. Gearhart and his research team at Johns Hopkins published a report, "The Development of Pluripotent Stem Cells from Primordial Germ Cells in the Human Embryo." These cells have the capacity to form all cell types and tissues in the human body. They're considered a starting point for the development of a variety of cell-based therapies in the new field of regenerative medicine. The possible applications to disease conditions are immense: Parkinson's disease, motor neuron loss, spinal cord injury, stroke, cerebral palsy, to name a few.

What we're witnessing is revolutionary. It's like Robert Koch discovering that a bacillus causes the disease tuberculosis. Or the discovery of antibiotics. But it's sad that stem cells have become a political issue. Things have become distorted and this is truly unfortunate. We hope people involved in intellectual honesty will succeed.

Here is Dr. Gearhart's talk:

I'm almost afraid to say anything after that glowing introduction. I appreciate the chance and the honor of giving this inaugural lecture for the Endowed Friends of the Johns Hopkins University Libraries.

What I wanted to do, as much as I can in a short time frame, is to give you a little of the science and to weave this into the issues on ethics, politics and public policy. This (the non-science) is something that I've spent an inordinate amount of time on in the last five years, and not by choice. It was as if, in 1998, I fell into the proverbial rabbit's hole. It's had this Alice in Wonderland quality to it. I've made 160 visits to Capitol Hill over this time. I've spent time in parliamentary chambers of other countries. It's also been an experience because I never thought I could touch as many people as I have -- either those who support my work, or those who have objections to it.

I've had some very emotional experiences, some of which I'll describe. Overall, though, I believe we're on the right course. I believe we will prevail; this work will go forward. I think we'll all benefit from it, though, for some of us in this room, the benefits may not be direct. (The audience is, for the most part, an older one.) The promises some make are aimed at politicians who are elected for two years, four years, six years, and who want something done during their tenure. I think you can appreciate that in biology, it takes many years for something like this to go from the lab bench to the patient.

(Shows a cartoon from 2001) This shows even then, stem cells were accepted by the public as a sure therapy. But that's not so. It's unfortunate. I could tell you, right now, that we can, in a laboratory dish, have a cell that can form any cell type in the body and that we can find, in that dish, all the cell types, what's the problem? Take the insulin-producing cells or heart muscle cells and apply them to patients. One of the take-home messages from this talk is that we're a way from that.

When you're dealing sometimes on the cutting edge of biology, particularly reproductive biology, you assume most people come to accept things like in vitro fertilization and the like. And when there's conflict, it's a surprise. It's brought to mind many questions: should we be working with human embryos, should we be creating them for research purposes, should there be cloning? How do we define life? How do we define personhood? These are things that now, even as a biologist, I'm confronted with in seminars and lectures. And it makes you think a lot. They're things I never really thought about before. Not an oversight, I think.

This is one area of questioning. Another is intellectual rights. Who has the rights to this technology? Who owns it? Because this is a library-devoted audience, I want to encourage you to read books that touch on many aspects of what we're doing.

John Turney's book puts into perspective biomedical advances, what the scientists did, how it was reported in the media and what the response of the public was to those reports and to the science.

Talk to a lay public. Our work is always against this background that conjures up images of Frankenstein. What are you mucking about with? people ask. They don't realize, much of the time that we're hoping to advance health-based issues.

Books like Brave New World touch on these things. Stephen Pinker's book challenges a lot of issues with respect to the nervous system and ties into the issue of when life begins.

More controversial reading, such as that by Leon Kass, the President's Bioethics Council's chair, essentially says that biotechnology is taking us to hell. Says we're on a slippery slope and should stop the research.

I encourage reading these books. There are arguments there, assertions there that are very concerned about where we're going with biomedical research.

Gregory Stock's new book looks at those and says the naysayers are wrong: we're going to go there anyway, we'll be designing humans, using genetics in ways nobody's even thought about and that you should get used to this and accept it.

Last three books are especially good reading because they're about what you should do in a democratic society to establish public policy when it comes to science. This is a very important issue. If you have a multicultural, pluralistic society and are dealing with research areas that are controversial, how do you establish a policy?

Those arguments go back to C.P. Snow's original lecture, The Two Cultures. That's your reading assignment.

So let's talk about the biology of stem cells.

Here's the working definition, which is never agreed upon at any stem cell meeting. Essentially, a stem cell has two properties: It has the property in which it can renew itself. And it can specialize in some cell type. Some stem cellsCembryonic stem cells, can renew indefinitely. Some will only do that once. Some stem cells give rise to every cell type in the body. Others will only give rise to one cell.

So all we're saying, generally, is that it can divide and can turn into something.

Where do we get them? We can get them from early stage embryos; we can get them from the developing fetus and we can get them from adults. In all of these cases, it is removing these cells from their position in the embryo, fetus or adult, and placing them in a dish that allows you to see their capacity to divide and to specialize.

Sometimes what goes on in a dish isn't exactly what goes on in an embryo or an adult. But these are the most common sources of the cells.

I'll spend a few minutes talking about the more controversial sources of the cells.

The first involves early stages of embryonic development, in the first week after fertilization and that occurs, basically, in an IVF clinic as well. The second source is from a developing fetus.
And the third source, which receives no press at all, but which is the only source that's gone to clinical trials, comes from a special type of tumor, called a teratoma/teracarcinoma/mixed germ cell carcinoma that's found in ovaries or testes. Those tumors arise from a stem cell. The stem cell gives rise to the tumor, which contains a variety of cell types. That's why these tumors are often called "teratomas" from the word for monster. You can find tooth, bone and hair tissues here, glandular structure, neural structure if you examine these tumors. You can recover these cells, place them in culture in the lab, treat them with certain kinds of growth factors and derive neural cells out of them. And these neural cells were implanted into twelve stroke patients at the University of Pittsburgh.

The stem cells from the teratomas are not controversial, except that they do not have a normal chromosomal complement and are stem cells, not only of normal cell types, but of tumors. Obviously, we're very concerned about what happens in these patients.

Back to the first source:
(Shows diagram of human embryos from an in vitro fertilization clinic) If you remove the inner population of cellsCabout 15 cellsCfrom the 200-cell embryo (called the blastocyst at this stage) and place it in a culture dish, you can derive a stem cell. This was done in 1980 in mice. Martin Evans, the first person to do this will probably win a Nobel prize. That's because these cells have been extremely valuable in learning about mammalian biology with the mouse. This is where mutations have been introduced...the so-called "knock out" mice with certain genes out of commission. Truly important. In 1998, Jamie Thompson at the University of Wisconsin derived human cells by this route.

At Hopkins, when I approached the deans in 1992, they were very unhappy that I might work with pre-implantation stage humans and said go work with aborted fetuses instead. There's another way of deriving stem cellsCfrom aborted fetal tissue. In 4-5 week cadaveric fetuses, there's a developing ovary or testisCabout 2 mm. longCfrom which you can recover the germ cells. You can culture these cells which also have stem cell properties. That's what we use. From cadaveric fetal tissue. We also use the blastocyst cells as well.

We are learning of a number of properties of these cells, of what exactly makes a stem cell a stem cell. They must have certain genes expressed, certain proteins, etc. etc. We're trying to build a panel of what constitutes a stem cell. Why is that important? We want to know what "stemness" is at the molecular level. We're going to learn, eventually, what a stem cell is at a molecular level. Then we'll be able to take any patient's cells and transform them into stem cells: that's the future!

At this point, we know three genes associated with "stemness." If we can manipulate these genes in an adult cell, we can transform it into stem cells. And if we can do that, we can transform a person's cells into tissues they need. And we can even correct genetic mutations within those cells so, if they have a genetic or gene-based disease, they can produce new cells that are healthy.

That's the take-home message of the science. That's where we're headed.

Currently, the basic science of stem cell biology is the hard part. Everybody's talking about transplantation therapies. But here's the most difficult part of that: we have in a lab dish cells that can form any type. But how do you get cells that can do everything and convince them, direct them to form just the thing you want? This is developmental biology at its core.

You want to know what the genetic programs are, what the environmental cues are. This is difficult to find out. This is very hard science. This is what we need people to support.

Many years ago, a nobel laureate said, if you reach this stage, you should have thought about it ahead of time. But we haven't. The U.S. has a strange history in certain areas of science. We've convened panels over the decades to study these issues and make recommendations to the executive branch or to Congress, as to how the work should proceed/if it should proceed. Every one of these panels has been ignored. It's just not Mr. Bush. Every recommendation of these blue-ribbon panels has been ignored.

Ten years ago, a panel was talking about human cloning and made recommendations. Another about fetal tissue research, fetal tissue transplants. Much of it was ignored. It's not that we're not smart enough to get these panels together. It's that we haven't been alert enough to try to develop policy, as has been done over a decade in the United Kingdom. Now I'll get off that soapbox.

The strategy we use now in the laboratory is to try to mimic what has gone on in an embryo in a dish. We've "stolen" information from our molecular biology colleagues, who've worked out these techniques the hard way, and now we apply their knowledge to cells in a dish. So we'll treat these cells with various growth factors in a sequential fashion that've been found to be important. And we can now drive cells, in some instances very impressively, to a single cell type. And that's where our work is now.

Our success in producing dopaminergic neurons or insulin-producing cells is generally through that strategy. We don't know enough genetics to do it genetically. We don't know enough about the key first steps in many of these pathways. But we know a little about which growth factors to culture these cells in. We'll take our cells in culture, treat them in various ways. Then, in a second stage, using genetic markers and various cell-sorting techniques, we can purify stem cells for the blood, for muscle, for different neural lineages. It's a little inefficient: we'd like to take 10 million stem cells and convert them to 10 million neurons, but we're not at that point yet. That will come.