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Conquering Aging with Cloning
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LEF: This takes us right to the paper that has just come out in Science (1). Please explain what was different about what you observed and how it relates to the practicality of using therapeutic human cloning.

West: Well, the story really begins with efforts to find cells that could be turned into cells that are used to treat age-related disease, so, for example, a patient who has lost heart tissue because of a heart attack and needs new heart tissue could receive tissue to restore normal heart function. My thought was that if we went back to embryonic stem cells, the mother of all cells in the body, we could potentially make anything for the patient, because these cells have the power to become any cell in the body. And because they are still in the immortal germ line, the reproductive lineage of cells, any cells you made from them would be young. The problem was, however, that the embryonic stem cells we now have growing in laboratories around the world are not you, so any cells that we made from them would be rejected by your body as foreign cells. So I set out to try to find a way of making an embryonic stem cell identical to the patient's cells by cloning, creating them just like you would if we were going to clone a human being, but instead of cloning a human being, we would make embryonic stem cells.

After I left Geron, they evidently agreed that therapeutic cloning was the way to go, and they set up the collaboration with Ian Wilmut, the man who cloned Dolly at the Roslin Institute. Dolly came from a sheep that I think was about six years' of age, from a cell grown in the laboratory from breast tissue. So obviously they named Dolly after Dolly Parton.

In 1999, they announced that cloning did not reset the clock of aging in cells (13). In other words, they claimed that Dolly is "a sheep in lamb's clothing." That she is older than she appears to be. Ian measured the clock of aging, the telomeres, in the blood cells of Dolly. The telomeres are like a burning fuse. They measure how many cell doublings have passed and the life span of these cells. And he said the telomeres of Dolly, or the cellular age of Dolly, was quite old. Her telomeres were shorter than would be expected for normal sheep of the same age. His data were very preliminary, and it has been difficult to pin down, but I guess the best estimate is that Dolly appeared to be older than six years of age, even though she was in reality only one year at the time her cells were analyzed.

LEF: I think everybody agrees that this is a burning issue.

West: Not only for animal cloning. As you know, there is a theory that human progeria is a condition of premature telomere shortening. This is not completely documented, but it is a theory that is out there. And no one would want to have all of these cloned animals that were made for agriculture, or as seeing eye dogs or whatever, age prematurely.

LEF: Well, if you really wanted to have something like a cloned cow, presumably you would want to clone the clone and then clone the clone of the clone and so on, which wouldn't work if the clones get older and older with each generation.

West: Correct. But for human therapeutic cloning, the condition is even more profound, because many of the people who need transplantable cells and tissues are elderly. So if we had an 80- or 90-year-old individual who had aplastic anemia and we needed to replace blood cells, or who had cirrhosis of the liver and you needed to make new liver tissue or heart tissue for example, obviously it would not be optimum to replace them by therapeutic cloning with old, worn out cells and tissues.

LEF: So, essentially, you would end up giving old tissues back to the old person.

image
Healthy young calves at five months of age, with telomeres longer than normal, all produced by cloning from highly senescent skin cells. Their nicknames are Lily, Daffodil, Crocus, Forsythia and Rose

West: Right. So we decided to do a very careful study of what happens to this clock of cell aging, the telomere, in the course of cloning. In our case, we used some novel approaches to cloning. Our technique differs considerably from the technique the Roslin Institute used to clone Dolly, for instance.

An additional difference is that we cloned from cells at the ends of their life spans, cells which we grew completely to old age in the dish. The cells grown old in the dish had shortened telomeres, and indeed we believe the reason cells grow old and stop dividing in the dish is because the telomeres become critically shortened, the fuse burns down. We took these senescent cells and we put them back in this time machine called nuclear transfer. What we observed and reported in the paper in Science is that a gene for the enzyme telomerase that normally keeps our reproductive cells immortal, was activated shortly after the transfer. The level of telomerase was increased far beyond the levels you see in some other immortal cells, such as cancer cells. The telomeres were extended in the same way that a key can be used to wind an old antique clock. Telomerase rewound that clock and interestingly, in our experiments, wound the clock beyond the normal starting point the cells had at the beginning of life, so the telomeres were extended beyond what a normal animal would be born with.

LEF: Wow!

West: So we then studied what happened to the cells that resulted from that cloned embryo, and we saw that their life span was longer than a normal cow cells' life span. Also, the animals that resulted from this work appeared to be healthy, even though they were cloned from senescent cells, cells that could no longer proliferate. The animals were born, the animals appear to be healthy, and the animals have telomeres longer than a normal animal of the same age, just the opposite of what Ian Wilmut reported. Will this lead to these animals having a longer life span than normal animals? That remains to be seen. We do not know.

LEF: How can you be sure that the cells that gave rise to viable clones were really senescent cells, and not rare, contaminating young cells?

West: We specifically addressed that issue. First, the entire population of cells was able to grow for less than three doublings, so the cells were within three doublings from senescence. Second, we grew individual cells from that population. In the paper we show data on about 300 cells that were individually studied, and out of these 300 cells, not one of them would go more than 3 more doublings. Nevertheless, we had the same efficiency of cloning animals from the senescent cells as we did with an entire population of cells that were young.

LEF: That's fantastic.

West: So it's a simple matter of statistical analysis to demonstrate that it is very improbable that we had a very young cell in the dish from which we were cloning these animals.

LEF: It sounds extremely improbable. But did you also attempt to clone from an old animal, or just from cells that were old by cell culture standards?

West: We did not. However, Mark Westhusin's lab, at Texas A&M University, has done it. Mark, incidentally, is participating in a project to clone a dog, the Missyplicity Project (the dog's name is Missy). Mark has also been involved in cattle cloning. He managed to clone a steer that was 21 years old, which is an old animal. There was evidently a piece of skin that was removed from the animal and frozen away. Years later, and long after the steer was gone, it was remembered how great an animal it was. The original animal was called "Chance." They thawed some of the cells from this 21-year-old steer, years after it had died, and managed to clone it. They named the new animal "Second Chance," and again, it appears to be normal.

LEF: Did they look at telomere length in the cells of Second Chance?

West: I believe they have, and I believe that in Second Chance the telomeres were shortened, consistent with the Dolly results.

LEF: So we need to get a clear idea of why your method allowed for a reversal of the cellular aging clock, and why the method used by Westhusin and by Ian Wilmut did not.

West: I don't think we want to elaborate on that at this time.

LEF: Could you at least confirm that the cloning technique that Wilmut used was based upon cloning from quiescent (non-dividing) cells, and that the cloning technique that ACT owns (14) is based upon cloning from non-quiescent (dividing) cells?

West: Sure. The patent has issued (15). Second Chance, as far as I know, was cloned from a quiescent cell.

LEF: Okay, so both of the quiescent-cell nuclear transfer experiments led to a negative result (no rejuvenation), whereas one infers that perhaps your cells were not quiescent.

West: Oh, ours were definitely not quiescent because, as you recall, senescent cells block late in the G1 phase of the cell cycle near the G1-S boundary, whereas quiescent cells are arrested at early or mid G1.

LEF: In other words, cellular senescence arrests cells in a state that is not defined as "quiescence" even though senescent cells are not actually dividing or able to divide.

West: Yes, senescence is very distinct from quiescence.

LEF: Are you doing or planning to do an experiment using your method to clone from an old animal?

West:
Yes, we are. We're expanding out and doing a lot of different kinds of studies with this. But of course the most exciting thing is applying this technology to human medicine and being able to give the patient any kind of tissue that they need as a result of disease, such as heart tissue, kidney failure or whatever. Being able to give them back their own cells which have the full proliferate capacity they were born with, would be a real boon to medicine.

LEF: It would be terrific. How much of aging do you think could be addressed with that approach?

image
Persephone, an older clone made from a senescent cell, still going strong at the age of 10 months.

West: I think theoretically a very large part of aging. One can think of an extreme example, I guess maybe a thought experiment. One could imagine creating in vitro, in a laboratory, virtually all of the components of the human body by cloning, making you a new heart, a new kidney, new lungs, new skin and replacing virtually your entire body in parts or in conglomerate. Cloned animals, even when they are made from very old animals, appear to be young and are able to reproduce. There is no evidence of premature aging. There is no reason we couldn't find ways of applying this technology to transplant cloned young cells and tissues into an aged person.

New stem cell technologies actually offer the promise of distributing new young cells throughout the body. One could imagine, for instance, the transplantation of mesenchymal stem cells into the bone marrow. Those cells have been shown to travel throughout the body to seed muscle tissues with new muscle cells, bone with new bone cells and so on.

LEF: So in other words, you would inject a particular kind of cell that is not muscle and not bone, and it would then find places where there is a deficiency in muscle cells and bone cells, somehow sensing this deficiency, then turning into muscle or bone cells to overcome the deficiency?

West: Correct. That is all published data (16,17). These technologies could potentially allow you to restore back into aging patients stem cells that are the patients' own cells and would not be rejected, which have their whole life span ahead of them, and have the potential of distributing themselves throughout the body, seeding cells and tissues with new, young cells to replace those that are worn out. There are potentially many applications for diseases that are not normally thought of as a part of aging. One could think of muscular dystrophy as an example, or even diseases such as AIDS. We think both are examples of cells reaching the end of their life span in a premature manner because of an accelerated turnover of cells.

LEF: Are you also talking about eventually growing organs in culture, not just cells, but organs that consist of several different types of cells?

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