A decade ago researchers believed that stem cells were active only in the early development of humans and animals. Thus embryonic stem cells were the rage, not only scientifically but ethically: because human embryonic stem cells can be procured only through the destruction of embryos, highly volatile moral questions were raised concerning continuing research. Ethical challenges remain; however, therapies derived from cell lines first generated from these sources are now moving toward human clinical trials.
Meanwhile newer discoveries have opened promising, pragmatic and noncontroversial ways to build, manipulate and use stem cells to better understand and possibly cure human disease. Called induced-pluripotent stem (iPS) cells, these are body cells that are reprogrammed in the lab dish to return to a stem-cell-like state. First developed in 2006, iPS cells have moved to the forefront of the research agenda.
A further discovery is that the adult body is dotted with stem cells through and through. Although not as generalized as embryonic cells, these cells are nonetheless important in maintaining adult tissues. Many cancers are now believed to arise when these wide-ranging, or endogenous, stem cells go wrong.
Clive Svendsen, Ph.D., says he has seen stem cells go from “rare to ubiquitous.” As director of the Cedars-Sinai Regenerative Medicine Institute in Los Angeles, Svendsen is one of the leaders in the new era of stem-cell research. At the heart of the institute is a specialized facility for the production of iPS cells that are capable of making all tissues in the human body from adult human skin biopsies. These cells are used in a variety of Cedars-Sinai medical research programs, including understanding the causes of and finding treatments for diseases of the brain, heart, eye, liver, kidney, pancreas and skeletal structures, as well as for cancer and metabolic disorders.
Svendsen spoke with Vision contributor Dan Cloer about the institute, about stem cells, and about scientific curiosity.
DC It’s been said that the iPS cell was developed to skirt the controversy over embryonic stem cells. Was it, or was iPS just a natural development of research?
CS It was the result of curious scientists. The ethicists were having a ball with things, but the scientists were just getting on with business. We were just growing the cells. Because of Dolly the sheep, we knew every cell had the potential to do everything. Each has all the DNA. So Shinya Yamanaka and James Thomson pushed the system and found that they could reprogram somatic [body] cells back to a pluripotent, embryo-like state.
Scientists don’t have time to listen to all of the moral arguments, and they are driven by curiosity and asking questions. That’s what we do every day.
DC Does science exist outside the moral argument?
CS Most scientists I know will work within the framework they are given. If President Bush says you can use these 20 lines, then fine, that’s what we’ll use and get on with it. But we will push the barriers. I do think that if you are in that area and are doing developmental biology, you will push the system as far as it will go.
DC So curiosity drives the “could,” but you don’t think about the “should” part of the equation?
CS For the “should” you have to go to your regulatory bodies. For example, if I was planning on putting a human embryonic stem cell into a primitive chimpanzee embryo it would have to go to many oversight committees. We would understand that this may be crossing a boundary and that it could result in a hybrid between a human and a chimp. And they would say: Here are the parameters. Here are the timing and the restrictions that have been established by previous committees.
So scientists understand that they should stay away from certain areas; usually we accept the policies that are in place and get on with it. Rarely are you pioneering the ethics. Thomson was in a new area when he began with human embryonic stem cells [in 1998], but it was mostly the ethicists who made guidelines, and he tried to follow them. He did not lead the ethical and moral arguments at all.
DC You have said that we need to “release the power of stem cells.” What is the mission of the Regenerative Medicine Institute? What is it you hope the public will understand and donors will support?
CS The main message is getting away from pills—treating the symptoms of disease—and really providing long-term solutions to problems such as Parkinson’s, ALS, cancer and other illnesses. We are going to try to do that through the regeneration of tissues.
“If drug companies gave you something that could cure your problem in three days, either that medicine would have to be phenomenally expensive . . . or they would have to come up with a completely different business model.”
Most drugs used today cause side effects and are only treating the symptoms of the disease. Anti-arthritis medicines are treating the symptoms of arthritis; they are not curing the arthritis. If drug companies gave you something that could cure your problem in three days, either that medicine would have to be phenomenally expensive (because otherwise they would not get back their investment in creating the medicine), or they would have to come up with a completely different business model (because you would no longer need to take that drug every day for the rest of your life). This is a real challenge.
This is why so much of regenerative medicine is an academic enterprise—why Cedars-Sinai, as a nonprofit, has such an interest. Let’s say your heart is degenerating; rather than having 30 years of beta blockers, we could pop in a few cells, they could regenerate new heart tissue, and you could go home. It is a different way of thinking about diseases, and commercially it has a huge impact.
So the bottom line concerning what stem cells can do for patients is that we will come up with some novel ideas for regenerating tissues in academic institutions like ours. It is about enriching our environment with the correct mix of scientists and doctors. The core of this institute is stem-cell production, whether from iPS or embryos; and then all around the edge—physically arranged around that core within the facility—are the rest of us, not stem-cell biologists but doctors and scientists who know about the eye, the pancreas, the liver and so forth. As institute director I am feeding those groups with knowledge and information about how to possibly regenerate those tissues.
The wider context at Cedars is the clinics that are dotted all over the campus, through which we can push this out to the patients.
DC You’ve referred to a sliding scale of risk in the question of potential benefit and cost to patients.
CS If the disease is minor, why risk a tumor to try stem-cell therapy? But if you have a terminal disease like ALS with a three-year prognosis—a horrible death through paralysis—and someone comes out with a well-validated idea but without a clue how it works and some risk of tumor formation, it may be worth trying.
DC Animal studies show some level of proof-of-concept for cell therapies, but animal development, even primate embryology, does not follow human development exactly. News reports are often very optimistic about animal studies, but the base causes of these diseases in humans is still mysterious.
CS Animals are not humans. We don’t really understand what causes your disease, so how on earth are we going to prove whether our treatment is going to cure it? For brain diseases, I would argue that we have very poor animal models. Rats, for instance, do not get Parkinson’s, ALS, Alzheimer’s, strokes; we have to put genes in to create disease. Even when we force over-expression of these genes, the animals still do not get the disease as a human does. They get funny tangles in the brain, but they don’t lose the same neurons; they don’t have the same behavioral deficits. It has been very frustrating. Money is being spent trying to create new animal models that will be better predictors.
“You are using an animal model that you have designed to mimic the disease, but you know it has nothing to do with the actual cause of the disease.”
The best model for Parkinson’s uses a poison that kills the rat’s dopamine neurons in about four hours. But in Parkinson’s this loss happens over 20 years. So the model is woefully inadequate: it’s rapid, it causes inflammation—all very different from what happens in a patient. You are using an animal model that you have designed to mimic the disease, but you know it has nothing to do with the actual cause of the disease. We don’t know the cause of Parkinson’s. There are genetic links, but not in all patients. In just about every disease, there are genetic mutations clearly associated with the disease. But if you examine a hundred Parkinson’s patients, only three will have this mutation. The rest are normal. So then you move to the rat or mouse model and cause the same mutation. In some cases, the mice are actually happy with that; they don’t get the disease.
Everyone goes on about how our DNA is 97 percent the same as a chimpanzee’s. Big deal! It’s 3 percent different, and that defines us as being human. A mouse has even greater difference. We’ve cured cancer in the mouse a hundred times over, but not in a human. The war on cancer is still on; we can stop tumors in mice very easily with drugs, but none of them have translated into clinical efficacy. We still use shotgun approaches with massive doses of radiation and anti-division agents that we could have come up with without any animal models. Whole animal studies are definitely important for many reasons and in some cases have led to major advances in medicine, but I am skeptical that they are going to reveal all the crucial mechanisms of human disease.
“Everyone goes on about how our DNA is 97 percent the same as a chimpanzee’s. Big deal! It’s 3 percent different, and that defines us as being human.”
DC How are cells in a dish an improvement on this?
CS Look at it this way: How many brand new drugs are developed and come out in America in a year?
DC Not many. About a dozen?
CS Yes, that’s right. Billions of dollars on pharmacology are being spent by the big drug companies who use animals to develop drugs. This uses a huge number of animals and is obviously very expensive. I think this is because the animal models are so poor. What I am suggesting is that we can finally start looking at human tissues through the use of pluripotent stem cells.
The new idea is to model the human disease in a dish. If it’s a cardiac problem, you can show it with human cells and look at toxicology and efficacy: how will the drug affect human cells? That’s the power of the iPS technology, but it, too, is nowhere near perfect. Now you are in an in-vitro model with no vascular supply, no immune system. You may get a completely false readout.
In a recent paper we suggested three pillars for modern drug discovery: first, regular cell lines that express a certain receptor to a disease-related cellular pathway that you can investigate pharmacologically; second, animal models in which to test the drug in vivo, a living system; then, third, is iPS cells. If you get your drug working in an animal model, as poor as that model may be, then it could be tested on human cells relevant to the disease. Now, if you could check all three boxes—works in vitro, in an animal, and on human cells—you could take the drug forward. If the drug fails in any one, then it won’t work.
DC One of the complaints regarding the previous federal funding limitations was that institutions using stem cells would have needed to segregate lab space into areas receiving funds and those not receiving funds.
CS That was true only if we derived new human stem-cell lines on site. If we used the federally approved lines, then we could use NIH [National Institutes of Health] funding. But if we wanted to make our own lines, then yes, we would have needed to have separate areas. It becomes complex, because you can’t intermix the federal funding. The Dickey-Wicker amendment  is still law. Nothing has changed for 15 years. No new laws have been passed on embryonic stem cells.
DC Then why all the fuss over the Bush executive order in 2001? He did not change anything?
CS In some ways nothing, as the law remained the same. But as president he could restrict what type of embryonic stem cells the NIH would fund, which has an effect on everyone’s research. The politicians realized that the research would go ahead with other funding outside of the NIH, and companies and investors went crazy pouring money into it. If you are a private company with $20 million, you can still work with embryos and do many experiments in America. That is the irony. When I moved here from England in 1990 I completely understood this. In England they actually have laws concerning human embryos; I participated in developing the 14-day rule [by which researchers may not experiment with human embryos that are more than 14 days beyond the time of fertilization] and licensing requirements. It is illegal to grow embryos in England unless you have a license and training.
America decided to do it differently—to restrict funding, which cuts one off from doing the research. For instance, you still cannot pay for IVF [in vitro fertilization] treatments using Medicare, because the Dickey-Wicker amendment says no federal money can go to any embryo research in any shape or form in America. That’s why the IVF clinics in this country are all private.
DC But there is a constituency in America that says people’s taxes should not pay for this research. Should there just be a box on the tax form to check if you do not want your taxes used this way?
CS Yes, this would seem appropriate, but it did not happen. We still cannot create new stem-cell lines using NIH money. The restriction on using only the lines available in 2001 has been lifted by Obama, but that is all that has changed. There are no grants to create new lines from human embryos at this point. However, new lines that were created with private funding over the past nine years under certain conditions of consent are now available for research with NIH funding.
“In 10 years it’s possible that no one will even talk about embryonic stem cells other than as a crucial step toward making iPS cells.”
In the last two years the whole area has been taken over with pluripotent stem cells, so the need to use embryos has almost disappeared. My lab now very rarely uses embryonic stem cells. The pluripotent cells are practically identical. They come from adult skin cells; there is no debate, no ethics. We need the embryonic stem cell lines that already exist to serve as a benchmark, but my brain has completely switched to iPS. Get your stories out quick, because the whole era is disappearing. In 10 years it’s possible that no one will even talk about embryonic stem cells other than as a crucial step toward making iPS cells.
DC How much do you think our lifestyle contributes to degenerative disease? As you have said, we look for genetic connections to disease, but the attribution is unclear. Aren’t factors of stress and how we live also important?
CS Stress will accelerate these things, but even if you live a perfect life, you will still die. Remember, we are programmed to die. As a species, reproducing and adaptation are what evolution is all about. Once you have procreated, you are useless biologically; one generation dies to make room for the offspring with new variations, new adaptations. Until we became civilized about a thousand years ago, unless you had genetic variability to adapt, you were potentially wiped out by any new condition.
We are now in a new phase of cultural evolution, where variations are no longer necessary. We can just go to the doctor and get a pill or maybe something regenerative. So it does not matter what disease you get; we are going to try to work out a way to cure it. In a sense, natural selection has disappeared and we really don’t need to die anymore. Regenerative medicine is also helping us understand that we can repair ourselves. I am convinced that aging is a program to help evolution; it makes so much sense biologically. Making iPS cells in a way is like making old cells young again and so supports the idea that aging can be reversed or prevented.
When we look at the fight against aging, we are fighting something that has been very successful in bringing our species to where we are today. Although winning this fight will take many years, it may not be as difficult as we first thought. Sometimes the biggest questions in life are the easiest to answer.