David Jay Brown Interviews Geneticist Dr Michael West, Founder of Geron Corporation

The Technology of Immortality 


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Human embryonic stem (ES) cells -- the primal cells that give rise to essentially all cell types in the body -- were first grown in culture last year. This breakthrough opens the door to an astonishing array of potential medical applications. ES cells can differentiate into all types of tissue and might be used to grow new organs. Since ES cells can be made using one's own DNA, the body will accept the new tissue as its own.

Michael West, PhD, is a driving force in ES cell research. He is the founder of Geron Corporation, a biotechnology firm in Menlo Park, California, and is currently the president and CEO of Advanced Cell Technology (ACT) in Worcester, Massachusetts. Geron funded the research that isolated human ES cells last November, and ACT is at the forefront of therapeutic cloning.

David Jay Brown spoke with Dr West about the potential therapeutic uses of ES cells. He got a strong sense that Dr West is truly excited by this research, as well as the impression that Dr West is on to something really big.

DAVID: How did you get involved in ES cell research?
 

DR WEST: It goes back to the fundamental interest that I've had in the cellular basis of what's called the "immortality of species." As you know, life continues generation after generation, in an apparently immortal fashion. This is because germ-line cells (our sex cells) come from the previous generation of germ-line cells, and there's an immortal lineage of these cells that connects the generations of all living beings on the planet. That lineage of cells is immortal in the sense that they have no dead ancestors and have survived all of the insults of life -- free radical damage, cosmic rays, and everything else that can injure living things.

These cells have survived all those sources of injury and, according to some estimates, have been evolving for over four billion years as a continuous life form. Of course, this immortal lineage of cells that connects the generations, and causes babies to be born young, is of great interest to gerontologists. This is because the cells that make up the rest of our body -- what's called the somatic lineages of cells -- clearly do not share in the immortality of the germ line. Our goal has been to learn from the immortality of the germ line and transfer these characteristics to somatic cells.

Telomerase was the first attempt to do that. Telomerase is an enzyme, a critical piece of which is a protein made by a gene commonly called a telomerase gene. The actual name for it is human telomerase reverse transcriptase, or hTERT for short. But that particular gene is turned "off" (it's inactivated) in mortal cells that age, and it's turned "on" (activated) in cells that are immortal. The gene is turned "on" in our germ-line cells and is turned "off" in somatic cells.

Embryonic stem cells can differentiate into all types of tissue and might be used to grow new organs.

DAVID: And unfortunately, our bodies are composed of somatic cells (except for the germ-line cells, of course).

DR WEST: Yes. You probably know that back around 1992, we began trying to track down the telomerase gene, and we managed to clone it. Having done that, we found that telomerase is useful for preventing somatic cells from aging. There are clearly cells in our body that don't age, simply because they don't divide. Heart muscle cells and neurons in the brain are two examples. It could be that they age as a consequence of other cells that are aging.

For instance, heart muscle cells do not divide and therefore do not age. But damage to heart muscle can occur due to a heart attack, arrhythmias, or other heart disease. Damage to the heart muscle could also be the result of the aging of cells of other biological structures, such as the cells that make up the vessels to the heart, or some other cells that have a finite life span and upon which the heart muscle is dependent for healthy functioning. When that tissue becomes diseased and the blood vessel can no longer feed the heart muscle, the heart muscle is damaged secondarily. But however you think about it, the point is that there are aging or damaged cells and tissues in our body that need to be replaced.

The ES cell research is an attempt to find a novel way of treating age-related disease. It's essentially a transplant therapy, replacing damaged cells and tissues, by going back to this immortal germ line. These ES cells are so primitive that they are still in the immortal germ line. So when you make a somatic cell from an ES cell, the cells that result are born young, as a baby is born young. We are creating a technology to replace damaged cells and tissues with young cells as a therapy for aging.


Dr Michael West

DAVID: Are ES cells currently being used to help repair damaged tissue?

DR WEST: No. It's a brand-new technology. It's so new that the first report of isolated ES cells is less than a year old.

DAVID: What are some of the future applications that you foresee?

We are creating a technology to replace damaged cells and tissues with young cells as a therapy for aging.

DR WEST: The ES cell is, as we say, "totipotent," which literally means "total power." These cells have the ability of becoming any cell or tissue type in the body, so the applications are endless. The Director of the National Institutes of Health, Dr Harold Varmus, has said that there is not a single area of medicine that these new technologies will not potentially impact. I think that's probably an accurate statement, because they can potentially be made into anything.

DAVID: How long do you think it will be before we'll be able to use ES cells to grow any type of tissue or organ that we need?

DR WEST: I think it's going to be a spectrum of opportunities. Some things will be relatively easy to do, and then other things are going to be harder to do. I guess some of the early applications of ES cells may be things like cartilage for arthritis, and blood cells for leukemia or other blood disorders. Maybe neurons for neurological disorders.

DAVID: Like Parkinson's disease?

Some of the early applications of embryonic stem cells may be things like cartilage for arthritis, and blood cells for leukemia or other blood disorders. Maybe neurons for neurological disorders.

DR WEST: Parkinson's disease, certainly, is a classic disease where you simply need those cells back. But any disease where there is a loss of cell or tissue function is a clear target for this sort of thing. There are all kinds of other possible applications. In heart disease, when you lose heart muscle, you need to replace it. A lot of arrhythmias could be treated this way. With just a little imagination, you can see there are literally thousands of applications. Until last year, we never had the ability to make any cell type in the laboratory. So it's obviously a very exciting development.

DAVID: The discovery that the tips of our chromosomes -- telomeres -- become shorter with each somatic cell division may have important implications for our understanding of how we age. What sort of potential for extending human life do you foresee as being possible by preventing telomeres from being shortened during cell division?

DR WEST: We still do not know the real answer to that question. It's amazing. I would put the blame for our lack of knowledge of this as simply the lack of funding that goes into aging research. As you know, Geron has been able to raise a fair amount of capital to promote aging research. Now, here at Advanced Cell Technology, we've been able to raise some money. The National Institute on Aging sponsors some research into aging.

But if you put all the biotech together, along with the federal government, it's still a small fraction of what's spent on AIDS, and, of course, the budget on AIDS is too small. We probably spend more in a week bombing Yugoslavia than we ever spend on aging research. That's where I put the blame. We simply do not know. What we do know is that telomerase abolishes aging on a cellular level -- what we call "cellular aging." So, for cells at least, we've solved the problem of aging. The lack of telomerase is what causes cells to age. When the immortalizing telomerase gene (hTERT), which directs the synthesis of telomerase, is turned off, cells become mortal.


Dolly of cloning fame.

Since we're made of cells, this should have an application to human medicine. I would bet that it does, but we simply don't know what percentage of human aging is caused by cellular aging. If you pinned me down on it, I would say somewhere between five and a hundred percent of human aging. I don't know whether it's closer to five or a hundred, but it's somewhere in that range. But even if it's only five, it's noteworthy that here we've tracked down the fundamental molecular cause of at least a part of human aging and have found a means of intervening in it and changing it. So even if it's just a small piece of human aging, at least it's some advancement.

DAVID: Have you found that any genes trigger the release of endogenous enzymes that may be able to benefit us now through some type of supplementation?

DR WEST: No, I don't know of any. There are some genes that have been reported that induce telomerase, but none of them give us any clues as to any supplementation that would help -- and that may be what you would expect. There are literally billions of people on the planet eating many different types of foods and supplementing their diet in many different ways. As of today, however, there's no known case of anyone who has dramatically affected their life span — maybe because there is no dietary means of fundamentally altering this biology.

The reason that we think this biology is in place is that it may be a powerful antitumor mechanism. Cancer is a runaway cell — a cell that's inappropriately growing without limits, like a runaway car that doesn't stop for stop signs. But all of the cells in our body can only divide a finite number of times. So the "car" has only an eighth of a tank of fuel. That way, if it becomes a runaway car, it can't go too far. Our bodies are actually littered with cells that have started to run away. If you look at your skin, you'll see little moles and splotches, which often represent some of the pigmented cells, where you can see the cells starting to run away in uncontrolled growth. But the mole, or the pigmented blotch on your skin, you'll notice, grows to a certain size and then stops.

The lack of telomerase is what causes cells to age. When the immortalizing telomerase gene, which directs the synthesis of telomerase, is turned off, cells become mortal.

We believe that this is a reflection of the mortality of cells -- that they have a finite life span. If there were a simple dietary means of unlocking a replicative immortality, it might allow those cells to just continue to grow. So the repression of telomerase may be an antitumor mechanism. Now that's not the same as to say that telomerase would induce cancer. The ability to refuel the gas tank of a car doesn't make it a runaway car. But it may be that allowing all the cells in our body to be immortal would raise the risk of cancer. Over the eons, natural selection has tended to "mortalize" the body, since in ancient times we rarely lived very long anyway. The average human being lived maybe 20 years in ancient times. So why would you need your cells to divide forever, when cancer or being eaten by a lion was much more of a risk?

DAVID: What are you currently working on?

DR WEST: What we've been working on here more recently is nuclear transfer or cloning. Having ES cells is great, but they're not you -- they're somebody else.

DAVID: I thought the whole idea was to use your own DNA?

So, theoretically, it looks as though we should be able to take a very old person and make new, young, transplantable tissue for that person, just like their own tissue when they were born.

DR WEST: Right, that's what the nuclear transfer idea is. The ES cells that exist were embryos made during in vitro fertilization. That's from taking a sperm and an egg and then making this little microscopic ball of cells we call a blastocyst. This contains the ES cells that can become anything. They're sort of like a raw material for life in some respects. They can be grown in a dish and made into the cells and tissues in the dish. But those cells are not you. If implanted in a uterus, they would become another human being, distinct from you. Your body will reject cells that are not your own.

So any cells or tissues that are made from an ES cell that's not your own, your body would reject. But your body doesn't have any ES cells -- they're long gone. So what we're working on is a cloning technology to make ES cells for you. We just scrape some cells off your skin and put them back into an egg cell whose DNA has been removed. What you then get is this little ball of cells -- ES cells that have your DNA. So what you're doing there is cloning, but you're not making an embryo that would be put in a woman. That would lead to a cloned copy of yourself. Rather, you're doing it just for the cells.

You're just making cells, not people. That's called "therapeutic cloning," as distinct from "reproductive cloning." So we're trying to make that work. The wonderful thing about this -- which isn't widely known -- is that we've actually shown that you can take an old cell that's at the end of its life span, and if you put it into an egg cell, it's like taking the cell back in a time machine. The cell is actually made young again.

Dolly, the sheep that was cloned, was made from an adult animal but was obviously born young.* In the same way that she wasn't prematurely old (despite starting out as an old cell), we've shown that we can take old cells in a dish, and when we do this cloning technique, the cells we get are young: they have their whole life span ahead of them again. We believe that somehow, that step of putting the cell back into an egg cell winds the clock up again and takes the cell back to the beginning of life. So, theoretically, it looks as though we should be able to take a very old person and make new, young, transplantable tissue for that person, just like their own tissue when they were born.


* As this issue goes to press, it has just been announced by Dr Paul G Shiels and his colleagues in Scotland that Dolly's telomeres have beeen found to be appreciably shorter than expected for a sheep her age. This has led to speculation about Dolly's "true" age  and what it means for the long-term viability of cloned animals. Dr West cautions that the results are preliminary, and the jury is still out on what these findings really mean.


DAVID: And give them a new heart?

DR WEST: Potentially. Under certain conditions, we've observed ES cells actually forming complex tissues, such as intestines.

DAVID: I read in Science that a dog's bladder had been engineered.

DR WEST: That bladder was made using tissue engineering, which is a little different: it was manufactured. But the ES cells will actually form themselves. They self-assemble into complex tissues that are obviously young. No matter how you think humans age, here is a technique that will allow us to create young, transplantable tissue. We honestly believe that we will be able to make new liver tissue, or maybe even young whole organs that are composed of your own cells, to replace the old worn-out ones. It's a long-term project, and it's years away from being available for people. But it's an exciting prospect.

Glossary

Differentiation The process of acquiring individual characteristics, as occurs in the progressive diversification of cells and tissues of the embryo.

Embryo In humans, the developing organism is an embryo from about two weeks after fertilization of the egg to the end of the seventh or eighth week.

Endogenous  Developing or originating inside the cell or body.

Germ-line cells  The body's sex cells (sperm and ovum), whose function is to propagate the species through sexual reproduction. 

Somatic cells The differentiated cells that constitute everything in the body, except for the germ-line cells. 

Stem cells The body's "parent" cells, from which all other cells of the body are derived through cell division and differentiation into various kinds of tissue, such as skin, muscle, liver, and heart.

Telomerase  An enzyme that protects the telomeres from the shortening process caused by repeated cell divisions. The activation of telomerase allows the cell to keep dividing without the telomeres' shortening. If activated telomerase continued to be present, the cell would become immortal.

Telomerase gene  The gene responsible for synthesis of telomerase in cells. This gene is activated ("turned on") in stem cells, but it becomes inactivated ("turned off") as these cells divide and differentiate into the somatic cells.

Telomere The protective end segment of the DNA strand that constitutes a chromosome (each chromosome has two telomeres). The length of a cell's telomeres is associated with cell division, aging, and cell death. Most cells need to keep dividing in order to stay alive. The longer a cell's telomeres, the more divisions the cell has remaining, and the longer it has left to live. As a cell divides, however, its telomeres get shorter, and its life expectancy diminishes. When the telomeres can no longer protect the DNA from damage, the cell dies.


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