Life Extension Interviews Michael West on new breakthroughs in anti-aging cloning research
Cloning: The word sounds like science fiction. But cloning is now science fact for many species, and it could hold the answer for the majority of problems of aging humans. Recent advances in cloning have come with remarkable speed, but doubts about their applicability to aging have remained. Now, in a major new paper published in the April 28, 2000 issue of the journal Science (1), a group led by Dr. Michael West has reported what may be the most revolutionary advance in cloning research so far. They have found that cloning can totally reverse cellular aging. To give you the inside story of this breakthrough, and on how it fits in with prospects for using cloning to intervene in aging, Gregory Fahy, Ph.D. and Saul Kent, President and founder of the Life Extension Foundation, interviewed Dr. West by telephone on March 18th, 2000. Dr. West is the founder of Geron. He is currently President and CEO of Advanced Cell Technology in Worcester, Massachusetts, where the research reported in Science was conducted.
Life Extension (LEF): Let's start at the beginning. Given that you left Geron to pursue cloning opportunities with Advanced Cell Technology (ACT), cloning obviously must be pretty important. But what is cloning?
Mike West: Cloning, as it is used in popular language, means the process we call nuclear transfer, which is an asexual way of reproducing an animal. Rather than using a sperm and an egg cell and getting a genetic mix between two animals, making a unique offspring, cloning uses an egg cell which is stripped of its DNA and a cell from the body of an existing animal. That body (somatic) cell is then placed into the egg cell.
LEF: The whole cell is placed in the egg cell?
West: Yes. This is the step we call nuclear transfer.
LEF: Even though it's more than the nucleus.
West: Yes. What we typically do is take the whole somatic cell and transfer it into an egg cell whose DNA has been removed. The result is a cell that has all of the DNA from an existing animal, so the resulting embryo and then, eventually, the animal is genetically identical to the original animal from which the cell was taken, unlike normal sexual reproduction, which leads to a unique new animal. In a sense it is being born again. It's a rebirth of a genetically identical copy of the original animal (2,3).
LEF: Are there different ways of doing cloning? Does it matter what the source of the cells is for example?
West: The technology has really only been used in a somewhat widespread manner over the last five years or so. So there hasn't been, to my knowledge, a complete survey of all of the different kinds of cells in the body from which we could clone an animal. But we do know that it is possible to clone an animal from cells that are usually easily accessible, such as skin cells or mucosal epithelial cells from the inside of the cheek.
LEF: How could cloning impact the field of anti-aging medicine?
West: Well, in the course of human aging, we have damage to the tissues and the cells in our body, not completely unlike the damage you see to your automobile over time. So, just like your carburetor needs to be replaced at some point, or your spark plugs need to be replaced, just through wear and tear you have organs that need to be replaced. I guess a striking example would be something like the loss of a tooth because of falling off a bicycle in a cross country race. Or a skin burn or other trauma. Also, of course, you can have an infectious disease, like a kidney infection which can damage the kidneys. Since the kidneys will not regenerate, they need to be replaced. So over the course of aging, we may need to have cells and/or tissues and organs replaced.
LEF: What is therapeutic human cloning?
West: Therapeutic human cloning is cloning for the possibility of recreating young cells and tissues (potentially of any kind) genetically identical to the person who needs them in order to replace worn out cells and tissues (4-7).
LEF: I think we need to clarify that when you are talking about therapeutic human cloning, we are now changing the definition of cloning that you gave us earlier. We are not talking about growing say a 12-year-old child and then taking the organs out of that child in order to replace old tissues in an adult, right?
West: Right. What we are proposing as an ethical and moral use of cloning technology in the arena of human medicine is the creation of microscopic balls of cells, called blastocysts. These are aggregates of about 100 cells that exist up to about 14 days of development. At 14 days, small aggregations of cells begin to individualize. By that, we mean the cells begin to become the various cells and tissues of the body, or that they've committed themselves to become an individual human being. Prior to day 14, the small ball of cells can still become two individual human beings. They can become identical twins, and indeed that is how identical twins form: the small ball of cells divides into two. So prior to day 14, this small ball of cells has not individualized, it has not decided to become one individual or two individuals.
LEF: Or even any particular part of any individual.
West: Yes. There is no skin, there is no blood, there is no bone, there is no tissue of any kind. So, because they have not individualized, they have not committed to becoming a person. And because there is no person there, and there are no differentiated cells of any kind, the blastocyst is often called a pre-embryo to distinguish it from an embryo which is committed to becoming a given individual. And because of that primitive state of the cells, the majority of ethicists have agreed that the creation of such an aggregate of cells to benefit people who are sick and in need of therapy would be a good and moral use of technology.
So what we envision is that the cloning step, the nuclear transfer step, is a bit like a time machine. We believe we can take a cell from a patient, even from a very old patient, and put it back into an egg cell, and that egg cell would be like a time machine, taking what was once a skin cell back in time, making it young again and erasing its memory of what it was, taking it back to the state of complete power, or as we say, "totipotency," such that the cell can then become any cell in the body. So once we've taken the cell back in time, and we have this small little ball of cells that can form anything, we can go in two directions. First, we could implant this small ball of cells into a uterus, and it could become a human being, or two human beings, forming identical twins. That would be reproductive cloning of a human being. The second path, which is the path that we are advocating, would be to use the cells to create specific cell types that a particular patient needs. So if the patient has Parkinson's Disease, rather than creating a human being, we would create just the dopaminergic neurons that they have lost, the loss of which is causing their Parkinsonian symptoms (8).
LEF: But the pre-embryo, in and of itself, doesn't spontaneously form wanted tissues. You would have to coax the pre-embryo cells to turn into the types of cells you want to form. Could you do that in tissue culture?
West: Yes. We believe that all of this could be done in tissue culture, growing individual cells, without creating a cloned human being.
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| Young and old cells show dramatic differences. Cloning can convert old cells into young cells. |
LEF: What are embryonic stem cells?
West: Technically, an embryonic stem cell is a cultured inner cell mass. So the blastocyst is a little ball of cells, and inside it is a cluster of cells called the inner cell mass, and surrounding them is a shell of cells called the trophectoderm. The trophectoderm will become the placenta, and the inner cell mass will become the entire animal or, in the case of humans, the entire human being. The inner cell mass cells are totipotent. They have complete power. And because they have not yet committed to either becoming the germ line or the body (soma), they have not yet committed to the mortality of the soma, so they still have the immortality of the germ line. As you know, germ line cells have the ability of proliferating indefinitely, and that is why the species is immortal. We keep making babies generation after generation, so these cells are in this immortal germ line in a state of total power. When they are grown in the dish, they are called embryonic stem cells.
LEF: Has anyone taken these embryonic stem cells and turned them into specialized cells in tissue culture?
West: Yes.
LEF: Has this been published?
West: The first demonstration that human embryonic stem cells could be grown was published in the collaboration that I set up while I was at Geron with James Thomson at the University of Wisconsin at Madison (9), and then also in a collaboration with John Gearhart at Johns Hopkins University Medical School (10). That was in the Fall of 1998.
LEF: And what was done in this study, exactly?
West: It was the first time human embryonic stem cells were ever grown in vitro ("in the dish"). Also in this publication was evidence that they could be shown to differentiate into skin, neurons, heart muscle cells, blood cells, and all of the many different kinds of cells in the body.
LEF: But in that case, was the differentiation random, or was it directed in some way?
West: The initial work, of course, was random. The cells were either just allowed to haphazardly differentiate in the dish, or they were injected into mice which had an impaired immune system. Since the mice could not reject the human tissue inside them, the human cells grew into what is called a teratoma, which is a conglomeration of different kinds of cells and tissues.
LEF: We recently met a scientist who said he was able to transform skin cells into neurons. Our impression was that they weren't embryonic skin cells.
West: They were probably adult stem cells such as mesenchymal stem cells.
LEF: So to summarize what you've said, basically you can take a totipotent cell and instead of letting it commit itself to form of an individual, you can take that cell and, at least in principle, direct it to become any type of cell. As you said, you can make brain cells to treat Parkinson's disease or perhaps skin cells to treat facial aging, that sort of thing.
West: I think that is an accurate statement. A good example was reported just in the last couple of weeks or so. There was a paper where mouse embryonic stem cells were differentiated into beta islet cells. That is one of the more difficult examples. In normal embryological development, you are pretty far along before you get the gut, and then the gut evaginates into a pancreas, and then out of that pancreatic tissue a beta cell finally forms.
LEF: Yes, that is impressive.
West: It would be much easier to get, you know, a cardiac myocyte, which differentiates very early in embryogenesis, or neurons, or skin cells, but nevertheless they were able to develop embryonic stem cells into beta cells, isolate the beta cells in relatively pure form, and put them into a mouse and cure diabetes (11,12).
LEF: That's fabulous!
West: Yes, and I think the demonstration that you could go and do such a difficult project is good evidence that there are going to be many, many applications of this technology.
LEF: Are you doing any work in the area of directing the differentiation of cells in your company?
West: Yes, though the majority of the work at Advanced Cell Technology has been focused on taking the cells back in time. It is relatively easy to take a cell at the beginning of life, one of these totipotent stem cells, and steer its development through the differentiated lineages, like the branches of the tree, because that's the normal path of development. What's almost miraculous is that you can take a differentiated cell and take it back to a totipotent state, because that's taking differentiation in reverse. It's a bit like if I were to tell you that I had taken a baseball bat and hit a ceramic vase and broken it into a million pieces on the floor, and then that I could, through a magic wand, have that go in reverse and have all of the pieces of the vase fly together and fuse back into a vase and then go back up on the table top, like reversing a video tape. That would be near miraculous. And to have development go in reverse, which it never does in nature, through cloning is pretty amazing, and that's why the scientific community was so amazed that you could actually clone an animal from a body cell. But what I think is the second level of amazement is the fact that not only does the development go in reverse, but the animal is actually made young again in the process, and I think that's what impressed us even more.
