What was the strategy?
At first I thought we could isolate islets from cadavers or animals and protect them from rejection by putting them in little capsules. We managed to get around that with our first patient, a Boeing executive with pancreatitis. He had to have his pancreas removed, and instead of throwing his gland away, we took it back to the lab and got maybe 50,000 to 100,000 of these insulin-producing cells. We injected the cells back into his portal vein and they took up home in the liver and the guy was fine. It made a lasting impression on me because what it meant was that if you could deliver a person’s own cells, you would eliminate the risk of rejection, and you could give the patient insulin-producing cells without the need for insulin injections for the rest of his life.
How did you get from islet cells to embryonic ones?
Around 1990, when I was still at UCLA, I was approached by BioHybrid Technologies in Shrewsbury, Massachusetts. At first I thought, “Why would I leave sunny California to go back to the rain and slush and snow?” But I went out for the interview and the president, a brilliant man named Bill Chick, asked me what would make me happy. I threw out what I thought was a preposterous figure for a salary, and when I got home there was a message saying it had been accepted. I didn’t realize at the time that it was below the market rate. At the company Christmas party I met his daughter, and she said, “So you’re the one with the tacky tie. You’re the one my father stole.”
It turned out that Chick had suffered from diabetes since childhood. Now he was dying, but he wanted to save himself by using the encapsulation method I had proposed at UCLA. It was a race against the clock—Bill had so much angioplasty and heart surgery he was being glued together. After a while we actually succeeded in dogs. We got islet cells from the pancreases of healthy dogs, encapsulated them, and transferred them to diabetic dogs, who became insulin independent. That’s when I learned about Dolly, the sheep cloned by the Roslin Institute in Edinburgh, Scotland, and I said, “Aha! That’s it.” If you can create an embryo genetically identical to the adult—that is, a clone—you can harvest immune-compatible cells to replace any tissue you might want without fear of rejection.
In essence the clone would supply stem cells to the parent?
Right. You can do all kinds of tricks with embryonic stem cells, but if they come from another individual, you still have the problem of rejection. You still need powerful immunosuppressive drugs that cause cancer. My idea was to clone the sick individual, not for reproduction but for therapy. The stem cells produced through this therapeutic cloning would, like other embryonic stem cells, be capable of developing into many cell types and serve as a repair system for whatever part of the body required replenishment at the time. You solve the rejection problem, and you have unlimited amounts of tissue. I tried to convince Bill to try this, but he wouldn’t budge. In the end he had strokes and didn’t know what was going on. He died in 1998 in front of my eyes.
Then I learned there was a cloning company right up the street from BioHybrid that was the top in the world, called Advanced Cell Technologies, or ACT. It was almost like fate. By then I was attached to Massachusetts. I’d bought a little island, where I lived. I had all my fossils and dinosaur bones there, and I had landscaped it. My island had swans; it had a beaver and a beaver den 10 yards from my door. I wanted to stay around.
So you went to ACT and asked for a job?
Before they would hire me, they gave me a task that was like bringing back the witch’s broom. There was a question about whether the National Institutes of Health would allow the work. Even though this was for therapy and not reproduction, it still involved cloning embryos, and the public was totally against it. Many considered it murder. So I was asked to get all the Nobel laureates in the country to sign a letter to support embryonic stem cell research, addressed to Harold Varmus, the head of the NIH. This was in the old days, when everything was by fax. Actually, I had this whole drawer of all the letters signed by 70 Nobel laureates. The effort was published in Science, and a few months later, many college presidents also signed on.
At the time, ACT was a subsidiary of a poultry genetics company, doing work in agriculture. When I joined they made the move from animal cloning to human therapy, and we knew we would get hit, big-time. I may be the only person who’s had the [Catholic] Church, the pope, and a couple of presidents condemn my work. At one point we had bodyguards here. There was a bombing up the street; then a doctor at a local in vitro fertilization clinic was targeted. I didn’t think I would be alive for more than a few years.
And you, alone on your island, were so vulnerable to attacks.
I would go for a walk, listening for sounds. I was one of the most visible people in cloning and yet I was isolated. I figured there was more than a 50 percent chance that I would be knocked off. But I wanted to go out trying. I’ve always followed my heart.
Can you describe the original groundbreaking work at ACT?
We injected human DNA from an adult cell into an egg from which the nucleus had been removed. We managed to clone early-stage embryos that grew to four or six cells in size. This was obviously far short of getting stem cells, which require a blastocyst [an embryo with a larger cluster of cells]. In fact, even to this day, a decade after the cloning of Dolly, scientists still have not cloned human embryos developed enough to generate patient-specific cells.
You’ve been exploring other ways of producing patient-specific cells. What are they?
We recently published a paper on a cell we created called a hemangioblast, which exists only transiently in the embryo but not in the adult. I think of them like unicorns, these elusive cells that we had hypothesized and sought for years. With the ability to become all of the blood cells—including your immune cells, red blood cells, all of your blood system, as well as vasculature—hemangioblasts have been biology’s holy grail. What we discovered is that we can create literally millions or billions of these from human embryonic stem cells. Now that we have them, we are harnessing, for the first time, one of nature’s early, most profoundly powerful cellular building blocks. The point is, we can use transient, intermediate cells like hemangioblasts as a toolbox to fix the adult so you don’t have to have limbs amputated, so you may not have to go blind, to prevent heart attacks. We can direct their development into different cell types by adding certain molecules to them as they divide.
If you can create an embryo genetically identical to the adult, you can replace any tissue without fear of rejection.
How does it work?
We found that when we injected these cells into a damaged, ischemic limb, there was almost 100 percent restoration of blood flow in a month. Before, the limb would have been amputated, but now it was restored. As to heart attack, injection of the cells cut the death rate in half.
Since these cells give rise to the immune system, what about using them to treat autoimmune diseases?
There are more than 80 autoimmune diseases. What’s interesting is that when you do a bone marrow transplant for cancer, some of those with autoimmune disease go into remission, as if the immune system has been eliminated and allowed to rebuild from scratch. Using hemangioblasts that are the progenitors of the immune system, we’re hoping we can replace the immune cells too.
