Genetic Medicine: A Prescription for Conflict

Although the ability to predict, prevent and treat disease with genetic technologies such as gene therapy, stem cell research, and xenotransplantation seems like a real possibility, it is not without controversies and roadblocks.

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The DNA Files:
Unraveling the Mysteries of Genetics

As heard on National Public Radio

Genetic Medicine: Prescription for Conflict

Hosted by John Hockenberry


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Last reviewed for accuracy: February 2002.
JOHN HOCKENBERRY: This is The DNA Files. I’m John Hockenberry. Sometimes it seems we are on the verge of a medical revolution brought on by genetic science.
DANIEL SALOMON: They’re all related. Gene therapy, xenotransplantation, stem cell biology. They’re all related. When we finally roll out mature therapies for disease, it will very likely involve some mixture of these three major biotechnologies.
JOHN HOCKENBERRY: From gene therapy to stem cells, it seems new cures for diseases like Parkinson’s and cancer are right around the corner. But amid the atmosphere of hope and hype, there’s also a difficult set of unanswered questions we’ve yet to tackle. And they’re not just about how safe genetic medicine might be, but whether it is ethical and aimed at the public good. A look at the frontiers of genetic medicine, when we return, with The DNA Files.

• • •

JOHN HOCKENBERRY: While nations debate the politics and ethics of human cloning, the biology seems to get lost in the fray. But scientists who clone animals say that biology is the ethical issue right now… because human cloning is just too dangerous, as Rusten Hogness reports.
RUSTEN HOGNESS: Pink-faced rhesus monkeys chase each other through their two-acre outdoor enclosure at the Oregon Regional Primate Center. Indoors, scientists are trying to clone a monkey.
Shoukhrat Mitalipov stares into a microscope at a tiny droplet.
SHOUKHRAT MITALIPOV: Although it’s very tiny microdrop, when we look at it under microscope, it seems like big pond.
RUSTEN HOGNESS: In his magnified pond, he performs microsurgery on a monkey egg cell, removing its genetic material and replacing it with the nucleus of a body cell from a donor monkey. This is nuclear transfer cloning.
If all goes well, the egg will develop into a tiny ball of cells that can be implanted in a female monkey, and 5 months later an infant clone of the donor monkey will be born.
But all has not gone well. Optimistic in the wake of the sheep Dolly’s successful cloning in 1997, a team at the primate center performed several hundred nuclear transfers.
DON WOLF: But we did not establish any pregnancies.
RUSTEN HOGNESS: Lead scientist Don Wolf.
DON WOLF: After about a year of taking this approach, of stepping to the plate and hoping to hit a home run because we wanted to get a pregnancy, we recognized that we really had to step back and say, well, we think there’s a problem here.
RUSTEN HOGNESS: They’ve proved their cloning techniques are not the problem, says Wolf. The problem is that the egg cell can’t get the new, donor nucleus to work quite right. It’s called reprogramming. And it’s not just a problem in monkey cloning.
Dolly was the only lamb born out of 277 nuclear transfers. And while the success rate in sheep has improved to about 4 percent, the vast majority of cloned embryos still die before birth.
WILMUT: And unfortunately, some of the lambs which are born alive will be found to be abnormal and will subsequently die or in some cases be euthanized because it’s kinder to do that.
RUSTEN HOGNESS: Ian Wilmut led the effort to clone Dolly at the Roslin Institute in Scotland.
IAN WILMUT: It’s true of all of the five species in which there are cloned animals. That’s not just sheep, but cow, mouse, pig, and goat. That the overall success rate is similar. But the exact time when they die seems to vary.
RUSTEN HOGNESS: A calf’s immune system collapses. A lamb fights for every breath. A bewildering array of reprogramming mistakes. And, says Rudolf Jaenisch, who studies reprogramming using cloned mice at MIT’s Whitehead Institute,
RUDOLPH JAENISCH: The biological problem of reprogramming is the same in humans as in mice and goats and sheep. So therefore one can predict that the great, great majority of human clones will die in utero. Some will survive to birth and will die, probably soon. Some other may survive longer and probably they will be kept alive by medical intervention.
RUSTEN HOGNESS: But why does the egg cell have to reprogram the donor nucleus? Because the donor DNA is folded up and crusted over with proteins, silencing all the genes except the ones the donor cell uses.
Think of the DNA as a musical score.
Ian Wilmut.
IAN WILMUT: Orchestral scores, you know, the full sound depends on the coordinated playing by everybody. And normal physiological functioning depends on normal functioning of, you know, a large number of the 30,000 genes that’s present in each cell.
RUSTEN HOGNESS: Body cells, like a skin cell or a mammary cell, don’t play the entire DNA score. They specialize, like a handful of orchestra members going off to improvise on just a single theme in the score. In cloning, the egg cell has to bring back the whole orchestra, ready to play the whole score. The jazz group can’t do it alone, says reprogramming expert Rudolf Jaenisch.
RUDOLOPH JAENISCH: If they’re now asked to go back directly out onto the stage and now get the whole symphony playing again. I think they will be hard fetched, even if they are well trained.
RUSTEN HOGNESS: Reprogramming has to be complete. If the violin section is missing, the embryo might not even begin to develop. But just the equivalent of a missing triangle player could be critical, especially in human cloning.
RUDOLOPH JAENISCH: They might be very subtle defects, which are not apparent in animals. We cannot test the brain function for example, of a mouse or a sheep. But of course in a human clone, those defects might become apparent when the baby begins to socialize or goes to school.
RUSTEN HOGNESS: And, says Ian Wilmut, the problems might not be subtle at all.
IAN WILMUT: It does strike me as being the supreme irony which escapes some people that one of the reasons they’re suggesting for copying people is to bring back a dead child. And yet one of the most likely outcomes or their cloning exercise is another dead child.
RUSTEN HOGNESS: These cloning researchers disagree about whether a person should ever be cloned, even about whether it will ever be safe. But they all agree that for now, it’s very risky business.
For The DNA Files, I’m Rusten Hogness.

• • •

JOHN HOCKENBERRY: Welcome to The DNA Files. I’m John Hockenberrry.
VOICE: If we could journey inside ourselves into a cell, we would see 23 pairs of chromosomes packed into a nucleus...
June, 2000. Scientists announce the successful sequencing of the human genome. In laying out our human genetic heritage, researchers say they’ll now have new tools for revolutionizing the practice of medicine. Think about it. Take a degenerative nerve disease, such as Parkinson’s. In advanced stages, Parkinson’s destroys motor control and can cause dementia. But what if scientists could rejuvenate the damaged tissue with a stem cell implant?
TOM OKARMA: These cells have two characteristics. First, they are immortal in their primitive form. The second is that they will grow into literally any cell or tissue in our bodies.
JOHN HOCKENBERRY: or... Say a patient needs a new liver. The probability of getting one from another human is slim. But researchers working in the field of “xenotransplantation” say that if they can overcome immune system rejection problems, this patient could be saved by an organ harvested from a bioengineered pig.
JULIA GREENSTEIN: We’re attempting to develop a strain of pig, which is called a miniature swine, and that miniature swine offers a number of advantages for use in human transplantation.
JOHN HOCKENBERRY: A genetic mistake, a mutation, causes hemophilia. Hemophiliacs lack proteins needed for blood to clot. Researchers are currently testing a “gene therapy” treatment to fix it. They use a virus, that’s been genetically altered, to deliver the dose.
INDER VERMA: I believe that gene therapy will become a predominant form of molecular medicine in this century. Its influence will be far more pervasive than any other technology in medicine.
JOHN HOCKENBERRY: This new scientific alchemy of programming the human body to repair itself has roots in basic research done decades ago. In the early 1970’s, Stanford University biochemist Paul Berg was studying viruses that, when injected into mammals, caused cancer tumors.
PAUL BERG: And when I began working with these tumor viruses and animal cells, I naturally wondered, could we adapt these viruses to carry foreign genes?
JOHN HOCKENBERRY: In 1971, Berg figured out how to do it.
PAUL BERG: It turned out to be relatively simple, and we made what was called the first recombinant DNA. That is a molecule of DNA which contained genes from one species and genes from another species all joined together in one molecule.
JOHN HOCKENBERRY Berg’s discovery won a Nobel Prize in chemistry. It also scared people.
VOICE: I have made references to Frankenstein over the past week and some people thing this is all a big joke. That was my way of describing what happens when genes are put together in a new way. This is a deadly serious matter...
PAUL BERG: The concern was voiced that this tumor virus genome might get into bacteria that inhabit our intestinal tract and bring on a plague of intestinal cancer or human cancers because of our carelessness, stupidity, of having created this molecule and having it inadvertently get out of the lab.
VOICE: ...if worse comes to worse, we could have a major disaster on our hands.
JOHN HOCKENBERRY: Berg says, back then, he found such fears a bit farfetched. But, he and other scientists couldn’t be sure. A series of meetings were convened at the Asilomar Conference Center in California, bringing in scientists from all over the world to talk about potential dangers and what to do about them. In February of 1975, the group issued its recommendations.
PAUL BERG: We did something which was very unusual, which was laid on ourselves a set of constraints on what kinds of experiments should be done and which kinds of experiments should not be done, and those that should be done, under what conditions.
JOHN HOCKENBERRY: The scientists who gathered back in 1975 focused exclusively on safety issues. Questions about the ethical propriety of recombinant DNA research were not addressed.
PAUL BERG: We knew they were out there, but had we gone to Asilomar and tried to address the ethical issues of doing this kind of research it would have ended up as a total disaster, with no consensus.
JOHN HOCKENBERRY: The scientific advances made possible by manipulation of genetic material have been extraordinary over the past quarter century. They’ve birthed a new biotechnology industry, aided in the development of new medical treatments, and given rise to hopes that many debilitating and deadly conditions, such as heart disease, Alzheimer’s, cancer, might one day be curable. The once worrisome – gene-splicing experiments mulled over by Paul Berg and his colleagues at Asilomar are now carried out in high school science labs. Still, questions about safety, ethics and morality persist. And each area of research has its own set of questions. We are after all, playing around with life itself.
In the early 1990’s, we started hearing about something called gene therapy. Scientists theorized it should be fairly easy to fix genes that make us sick by inserting ones that work properly.
INDER VERMA: The concept of gene therapy is so disarmingly simple. Introduce the gene and it should either alleviate the defect or kill the defect.
JOHN HOCKENBERRY: That’s Dr. Inder Verma of the Salk Institute of Biological studies in La Jolla, California. He’s been trying to unlock the secret of gene transfer since 1983. He was a bit skeptical at the ‘cures around the corner’ enthusiasm that emerged in the early 1990’s.
INDER VERMA: What they didn’t realize it that its not the concept, it’s the execution of the concept and the execution means that you have to learn how to deliver the genes.
JOHN HOCKENBERRY Enter again the virus. Think of that bit of nastiness known as the common cold. Something called the adenovirus makes us temporarily very miserable. On the other end of the spectrum, there are retroviruses that deliver diseases like Ebola and AIDS. Researchers in the lab are removing the parts that cause sickness, while retaining a virus’s remarkable capacity to invade the body. They hope to use these viruses as vectors to deliver good genes. Robert Langer of the Massachusetts Institute of Technology explains.
ROBERT LANGER: A viral vector is something that’s almost like an artificial virus, but not infectious, so that could deliver the gene to the cell, and that might have the advantages of being very effective, but there have been some issues of safety that one might be concerned with.
JOHN HOCKENBERRY: Patients joined up for gene therapy trials, signing consent forms saying they knew this was all experimental. Many were so sick that conventional treatments had been ruled out. No great breakthroughs occurred, but again, no serious harm had been done. That all changed on September 17th, 1999, when 18 year-old Jesse Gelsinger died in Philadelphia.
[sound of radio tuning]
VOICE: Jesse Gelsinger had a rare genetic defect that made it difficult for his liver to break down protein. Roughly half of babies born with the disease called OTC deficiency develop high levels of ammonia in the blood, fall into a coma and die. But Gelsinger, who was 18, had a mild form of the disease. Nevertheless, he volunteered to try out a new treatment as part of a clinical trial at the University of Pennsylvania.
JOHN HOCKENBERRY: Jesse volunteered because he wanted to help in the quest for a cure. Tests on animals had the Penn doctors expecting some minimal side effects. Flu -like symptoms, mild liver inflammation. Jesse Gelsinger’s body went into multiple organ failure.
PHILLIP NOGUCHI: This clearly was the first death in which it was so closely associated with the vector that one could not help but say, yes, Jesse Gelsinger died because of the infusion of the vector.
JOHN HOCKENBERRY: Dr. Phillip Noguchi oversees cellular and gene therapy for the federal food and drug administration…the government agency charged with overseeing the safety of all clinical trials. He says the head of Penn’s Institute for Human Gene Therapy, James Wilson, called as soon as Gelsinger began to fail.
PHILLIP NOGUCHI: Dr. Wilson was extremely cooperative, he actually called us and we were talking with him when Jesse Gelsinger was dying, so it was not like that part was hidden at all.
JOHN HOCKENBERRY: The death triggered investigations. Again, Dr. Noguchi.
PHILLIP NOGUCHI: When we went to examine the records and look into the situation more clearly, what we found was rather startling in the sense that the records seemed to be missing some facets, we weren’t sure which informed consent was being used and of course that led to more investigations about that.
JOHN HOCKENBERRY: There were congressional hearings…the University of Pennsylvania’s president convened a panel to look into gene therapy research at the school. Dr. Inder Verma of the Salk Institute, one of the most respected researchers in the field, participated in the review.
INDER VERMA: In hindsight a number of red flags were there which were not noticed either by the scientists or the FDA. And our recommendation was that the Institute for Human Gene Therapy should not do any clinical trials because they’re neither adequately supported nor adequately financed and not adequately staffed or trained for that reason.
JOHN HOCKENBERRY: And the FDA began scrutinizing other gene therapy trials. Red flags popped up again when they looked at an experimental trial aimed at treating patients with end stage heart disease. The research was put on hold. But some subjects of the trials—people who’ve actually had the therapy—maintain it’s a miracle. Reporter Kathy McAnally visited with two southern California residents who claim they’d be dead had they not offered up their hearts to some very experimental research.

• • •

KATHY MCANALLY: Jackie Braswell is preparing lunch in her kitchen in La Mirada, California for two guests, her gentleman friend Richard and me. Tuna and egg salad is on the menu. A couple of years ago, says Jackie, this simple hospitality would’ve been impossible.
JACKIE BRASWELL: My breathing was awful. I couldn’t walk from my bedroom to my kitchen without gasping for breath. Just turning over in bed, I just really would gasp. A shower that would just do me in.
KATHY MCANALLY: Braswell was first diagnosed with heart disease in her late twenties. At sixty, she had a major coronary, followed by four bypass procedures.
JACKIE BRASWELL: So I thought that was really the end of it until I was close to 70. And I kept saying, Lord, I don’t want to be 70; I don’t want to be 70. I had a heart attack and said just kidding. I did.
KATHY MCANALLY: Her doctors were not encouraging. They used phrases like “you’re a walking time bomb” and “you ought to get your affairs in order.”
An hour or so down the road in Escondido, things were looking equally grim for Dick Hooper. Back in 1993, he’d had 3 stents implanted in his arteries to keep them open.
DICK HOOPER: In 1998 I had another ten angioplasties in one year and now have 19 stents in my arteries holding them open. It got to a point where there was just not much they could do with me because of the continual blockage of the scar tissue blocking up with the stents, called restinosis.
KATHY MCANALLY: Hooper began thinking about final arrangements, where he’d have his ashes scattered. Braswell toyed with an expensive alternative therapy, ‘til someone told her it would take two years before benefit could be expected. One of her daughters kept calling clinics, refusing to accept that nothing could be done to help her mom. One night, they were dining at a Marie Callender’s. Jackie’s daughter overheard a conversation at a neighboring table, having to do with some work underway at the Scripps clinic in La Jolla, California.
JACKIE BRASWELL: My daughter, who has ears, she picked up and said ‘can I talk to you sir’ and he said ‘sure’. She said ‘well, my mother’s in a real bad way and we want to know if there’s anything going on at Scripps with heart’, and he said ‘oh yeah, all kinds of stuff’.
KATHY MCANALLY: It turned out doctors at Scripps were planning a gene therapy clinical trial. It would involve injecting patients with an engineered gene. The doctors would inject a single dose of altered DNA directly into a diseased region of the heart. Braswell wanted in.
JACKIE BRASWELL: And I was so worried, and then I thought, you know what, they don’t have a woman and I’m the only woman, I thought, they have to have one.
KATHY MCANALLY: Dick Hooper was eager to participate as well.
DICK HOOPER: I was up for it. I thought, what other choices do I have? And they thought we would have good success with it, although nothing was positive, and I signed away my life. Whether or not it would fail, I felt that I wasn’t going to last that much longer anyway. Death was on the horizon, so to speak, not to be dramatic, but it was, and I was willing to take the chance to go ahead with it.
KATHY MCANALLY: The gene was injected into the damaged heart muscle in a single treatment.
These days, Hooper is feeling pretty good. He can play with his Llasa Ahpso puppy bailey, in the beautiful new home he’s moved into with his wife. Plans for his memorial have been filed away. Braswell can keep up now with her own little dog, a Yorkie named Sweetie. She’s traveled to Europe with her daughter and played in Las Vegas with her friend Richard.
JACKIE BRASWELL: So we’re having a great old time, you know, it’s really nice. I got a totally, totally different life.
KATHY MCANALLY: Braswell and Hooper were both perplexed by an FDA decision in 2000 to put the clinical trials on hold. The FDA was concerned protocols for patient consent were not being followed. Dr. Phil Noguchi of the FDA.
PHILLIP NOGUCHI: There have been some reporters that have come up to me and said, I understand the FDA has alleged, and I point out that the FDA does not make allegations, we make statements of finding. We say ‘we cannot find evidence that so and so ever received an informed consent and signed it before this was done. That person is now dead. That is a series of statements of fact.
KATHY MCANALLY: According to Dr. Richard Schatz, of the Scripps Clinic in La Jolla, the treatment was eventually found not to have contributed to the patient’s death. As of late September of 2001, the trial remained on hold.
RICHARD SCHATZ: I think the more prudent thing would be for them to say, hey, we have some questions, they’re not scientific, they’re administrative, keep your trial going, at least treat the patients you promised to treat. We just have to work with them and hope that patients don’t die waiting—that’s always my concern. I care about the paperwork, but I sure care about the patients more.
KATHY MCANALLY: Dr. Phil Noguchi of the FDA bristles at the suggestion that the heart trials were shut down because the agency was wielding a new big stick in the wake of the Jesse Gelsinger death in Philadelphia.
PHILLIP NOGUCHI: We may put other trials on hold because we cannot necessarily guarantee why that trial wasn’t being done right. It’s really a stretch to say it was related to an incident outside that institution.
KATHY MCANALLY: Dr. Schatz sees the passage of time as the enemy, postponing the day when this therapy could cure millions. The small biotech company that created the gene treatment is in serious financial trouble. And Schatz has invested his own money to try to keep it afloat.

• • •

JOHN HOCKENBERRY: This is The DNA Files. I’m John Hockenberry.
At Stanford University, Dr. Mark Kay is working on treatment for the inherited disease hemophilia. It’s sufferers lack one of two proteins, called factors, that cause blood to clot.
MARK KAY: I thought that the concept was so simple, that you take the DNA and you put it in the patient, but there have been unpredicted obstacles and I think that we’re at a point now where we will start to see some successes and some therapies.
JOHN HOCKENBERRY: Dr. Kay has already completed one trial and is starting another. He’s partnered with a former research competitor, at children’s hospital in Philadelphia and a corporate one that manufactures the gene therapy vector. These arrangements are fairly common in the brave new biotech universe.
And they disturb Kay’s Stanford colleague Paul Berg.
PAUL BERG: Scientists do basic research; it’s like going through a maze. You run up into a lot of dead ends. Now if in every fork in the road, you have a choice, this way, it’s not clear where it’s going to lead; this way leads to a potential commercial application. I’m worried that more and more people will begin to think about the commercial applications, particularly if the incentives are given to you by the university or the institutions in which you’re in.
JOHN HOCKENBERRY: Under Stanford’s rules for the conduct of clinical trials, Kay as someone with a stake in the outcome, must remove himself from direct patient contact.
Researcher Mark Kay says while the hemophilia treatment shows promise, the field of gene therapy is still in its infancy.
MARK KAY: There’s lots of other diseases that we really need to do a lot more work on before they really, come to fruition. We’re still at the beginning, because there’s lots of diseases that are potentially treatable by gene transfer, but are going to be more complicated in the approaches that are used.
JOHN HOCKENBERRY: Notice that Dr. Kay uses the phrase “gene transfer. Not “gene therapy.” The scientific community, humbled by a combination of failure to cure and the demise of young Jesse Gelsinger, has taken a semantic hop backward.
DAN SALOMON: We’re not trying to oversell it anymore.
JOHN HOCKENBERRY: Dr. Daniel Salomon of the Scripps Institute in La Jolla, California is one of the country’s leading experts on new medical therapies.
DANIEL SALOMON: We’re trying to tell you we can deliver genes, and once we get really good at delivering genes and understanding how that’s best done, then perhaps it will be time to come back and promise therapy. Then we can talk about gene therapy again.
JOHN HOCKENBERRY: And what does Dr. Paul Berg, the Nobel laureate who devised the technology that makes gene splicing possible say? He thinks it’s all bunk.
PAUL BERG: As far as I’m concerned, gene therapy is a dead end. It’s still used as hype. The people working on it still have hopes that they’ll find the magic bullet whereas I think most people are beginning to concede that cell based therapies are more likely to be the solution.
JOHN HOCKENBERRY: Cell based regenerative medicine has emerged as the next really big thing. The human stem cell, we are told, brings the promise of healing everything from degenerative brain diseases to diabetes to spinal cord injures. These cells are self -renewing and can be coaxed, at least in the lab, to manifest into all kinds of different living tissue. Stem cells are in our skin, our body fat. They are in umbilical cord blood. These are called adult stem cells. But the stem cells that most excite researchers with their potential to heal come from very young tissue, cells made at the very beginning of an embryo’s life. Tissue that comes from aborted fetuses and fertilized human embryos. And that makes it controversial.
RICHARD DOERFLINGER: The real drive for human embryo research outside the womb kicked off very shortly after the first announcement of the birth of a test tube baby in great Britain, the birth of Louise Brown in 1978.
JOHN HOCKENBERRY: That’s Richard Doerflinger, Associate Director for Pro -Life activities at the United States Conference of Catholic Bishops.
RICHARD DOERFLINGER: We felt that in vitro fertilization had problems in and of itself, and one of the major moral problems we saw was that it did create these embryos out of the laboratory where they became vulnerable to being treated as research material by people in the fertility clinics.
JOHN HOCKENBERRY: In 1994, congress passed what’s known as the Dickey Amendment, banning the use of federal funding in embryonic tissue research. Then, in 1998, two scientists, James Thomson of the University of Wisconsin, and John Gearhart of the Johns Hopkins University, announced that they’d isolated what are called pluripotent human stem cells. Pluripotent means that they can give rise to many different types of cells. Dr. Thomson developed his stem cell line from material removed from embryos at the blastocyst stage. A blastocyst contains between 100 and 300 cells. It’s a tiny mass of cells, small enough to fit on the end of a pin. The frozen embryos were donated by their parents, who no longer needed them to achieve pregnancy. Dr. Gearhart’s cells, called germ cells, are harvested from aborted fetuses.
JOHN GEARHART: We take these cells, and we put them, in the laboratory into what we call culture dishes, plastic dishes that have special nutrients and growth factors in it, and we can then cause these cells, or permit these cells to actually grow, begin to divide in a dish.
JOHN HOCKENBERRY: The discoveries by Gearhart and Thomson captured the imagination of many other researchers. If scientists could figure out how to train stem cells to turn into needed replacement cells or tissue, new treatments might be created for Alzheimer’s and Parkinson’s disease…spinal cord injury...heart disease and stroke. Diabetes. Late in his administration, President Clinton lifted the ban on government funding of embryonic stem cell research. Upon taking office George W. Bush put it back on hold.
You’re listening to The DNA Files. I’m John Hockenberry. Let’s take a short break.

• • •

This is The DNA Files. I’m John Hockenberry. Next, Producer Kathy McAnally takes a look at the Geron Corporation, a company that’s led the biotech pack in advancing stem cell research.
KATHY MCANALLY: Geron began its life as a company committed to finding ways to slow the human aging process. As time went on, Geron, which means “old man” in Greek, expanded into research into what’s called regenerative medicine. They were looking for ways to prompt the body’s organs to heal. CEO Dr. Tom Okarma says the idea was to find the scientists who seemed to be doing the most promising research on stem cells and pay them to do more of it.
TOM OKARMA: We wanted to be sure we were successful, so we funded more than one lab, and two of them were successful.
KATHY MCANALLY: Okarma says he knew the research would raise questions. Geron was among the first companies to set up an advisory board made up of non-scientists to look at ethical issues.
LAURIE ZOLOTH: I remember the whole thing being explained to me on a napkin. What a blastocyst was, recalling for us meiosis and mytosis, and remembering those stages, and then explaining to us about the pluripotency of human embryonic stem cells.
KATHY MCANALLY: Laurie Zoloth, a professor of Jewish studies at San Francisco State University, is one of the board’s members. They’re paid an honorarium by the company, 2000 dollars a meeting.
LAURIE ZOLOTH: There is a need for wider social questions. There is a need to think through sincerely and rigorously the implications of scientific work. I think that it’s been an interesting learning process on both sides. What if we hadn’t liked the work? What if we find something we think is ethically reprehensible? We’d say that too, and that’s a risk they were willing to take. Because I think they’re sincerely interested in changing a lot about how medicine’s practiced.
KATHY MCANALLY: I’m sitting in John Gearhart’s laboratory, deep in the bowels of Johns Hopkins hospital. His research uses stem cells derived from fetal tissue. Gearhart fires up his computer, and beckons me over to look at a research video on the screen.
JOHN GEARHART: Let me show you something here. This is proof of concept so what we’ve done in this experiment, just an example, is we have a rodent model of a motor neuron loss in the spinal cord, …
KATHY MCANALLY: I’m looking at this poor rat; the front paws work, but the hind ones don’t. The animal’s lower body is paralyzed.
JOHN GEARHART: and that’s the way this rat will be the rest of its life. Now, let me just get another angle here, and I’ll show you what we’re... OK. So into this animal, into the spinal cord, into the fluid in the spinal cord, we placed about 300 thousand human cells, OK, that were treated in such a way such that they were going to form neurons and glia of the nervous system. If we then look several months later and here we have an animal that is at least ambulatory.
KATHY MCANALLY: The rat walks! Not perfectly, mind you, but it’s still pretty impressive to me! The next day, I visit Dr. Phil Noguchi at the FDA.
PHILLIP NOGUCHI: That’s all the good stuff.
KATHY MCANALLY: Noguchi reminds me that these are things that have never been tried on humans before.
PHILLIP NOGUCHI: We know that those human stem cells, what they actually do is they migrate through the body, and in the case of Dr. Gearhart’s animals where he cuts the spinal cord, goes right to where it’s cut, at least what he can detect. It fuses and fixes that lesion. What happens to the other cells? What if one of them kind of wanders into the heart? Boom boom, the person may walk but he may die of a heart attack.
KATHY MCANALLY: And those are the kinds of issues the FDA will ask about before any treatments are cleared for use in humans. A lot of very expensive animal research lies ahead for Dr. Gearhart. So far, Geron has paid for a good deal of it.
JOHN GEARHART: This seems to always happen, just at the end they come in and give you a dollar and take everything! They have funded our project and in return, they have the licensing rights.
KATHY MCANALLY: Geron’s Tom Okarma explains how this works.
TOM OKARMA: Patents are legal instruments that protect the owners or licensees of the patent from others commercially exploiting what was patented. The patent owners are the academic institutions in which they work, Jamie Thomson, University of Wisconsin for the ES cell, John Gearhart, Johns Hopkins University for the EG cell. We don’t own it, we pay license fees, and we supported the work and we paid for these licenses. Which gives us the legal right to exploit them commercially.
KATHY MCANALLY: If and when there is something to commercially exploit. It’s a gamble. Geron could reap enormous profits if stem cell technology pans out. But so far, they haven’t made a cent.

• • •

JOHN HOCKENBERY: This is The DNA Files. I’m John Hockenberry. As spring turned to summer in 2001, the research community awaited the president’s decision on stem cell funding. While the president pondered, the public debate rose to a crescendo. For weeks on end, the stem cell debate took up more of the daily news cycle than Middle East bloodshed , even the state of the economy.
VOICES: ...nobody knows how many out there—in vitro fertilization clinics. They’re not gonna get adopted. They’re gonna get thrown away, or they’re gonna get kept in some freezer somewhere..
...I think that the problems that we get into with harvesting embryos for stem cell research far outweigh the potential benefits.
...the point of how it’s helping people. I mean, wouldn’t you want to save Michael J. Fox?
JOHN HOCKENBERRY: Actor Michael J. Fox, who suffers from Parkinson’s disease, pleaded for funding.
MICHAEL J. FOX: If I had the good fortune to share a room with President Bush, I would not say, let’s talk about stem cells, I’d say President Bush, you have the opportunity to oversee the cure of a major disease.
JOHN HOCKENBERRY: This celebrity driven lobbying campaign frustrated Richard Doerflinger. He points to other, non-famous people living with disease and disability who are against embryonic stem cell research.
RICHARD DOERFLINGER: Those people have been largely ignored, to such an extent that one woman with spinal cord injury who was testifying against this research, the reporters wouldn’t even make way for her wheelchair to let her out of the hearing room because they were too busy crowding around the movie stars with diseases.
JOHN HOCKENBERRY: As the debate heated up, a number of prominent pro-life politicians broke ranks to support embryonic stem cell research.
VOICE: ...but I also spent a lot of time on my knees praying and trying to make the right decision here. And I believe that it is one of the most right-to-life, pro-life positions to take to extend human life...
RICHARD DOERFLINGER Well, it’s a bit of a surprise to find that various politicians who said they were pro life were merely anti-abortion.
JOHN HOCKENBERRY: Pollsters were busy. They reported that a majority of Americans, including Catholics, agreed with Senator Orrin Hatch, a pro- life Mormon, that life didn’t begin in a freezer. Professor Laurie Zoloth.
LAURIE ZOLOTH: For Jewish religious thinkers, the pursuit of healing, to save a life, is mandated, and in precisely this arena because for Jewish thinkers these blastocysts don’t have the same moral status, moral weight, as living human persons.
JOHN HOCKENBERRY: Meanwhile the United Methodist church, with liberal views on abortion, came out against embryonic stem cell research. That church opined that it would turn human life into a commodity. And the Catholic Church, so staunch in opposition to destroying embryos, seemed more flexible on the use of aborted fetal tissue in research.
RICHARD DOERFLINGER: We’re not in favor of the federal government making arrangements with abortion clinics to obtain tissue. At the same time we think embryonic stem cell research poses an even more direct moral problem because the embryos are actually destroyed, they’re alive, and they’re destroyed by researchers for the sake of their stem cells, so that’s not an abortion that happened for other reasons and done by other people.
JOHN HOCKENBERRY: But, should the fetal tissue be available due to a spontaneous abortion, or miscarriage, those stem cells may be used in research with the church’s blessing.
JOHN HOCKENBERRY: On August 9th 2001, President Bush made his first prime time address to the nation to, finally, announce his decision on embryonic stem cell research.
GEORGE W. BUSH: I have concluded that we should allow federal funds to be used on these existing stem cell lines, where the life and death decision has already been made.
JOHN HOCKENBERRY: It was a decision that pleased almost no one. Richard Doerflinger conveyed the dismay of the catholic hierarchy. Scientists questioned the number and provenance of the existing stem cell lines that could be used in federally funded research . Legal squabbles began immediately over who owns what. More hearings will be held. The controversy lives on. Laurie Zoloth, a supporter of embryonic stem cell research, finds the continuing public debate quite extraordinary.
LAURIE ZOLOTH: I mean, we could be thinking about a whole number of frivolous, unimportant, essentially silly issues and here we are having a national debate about the meaning of human life, and about the meaning and fate of the human future.
JOHN HOCKENBERRY: Geneticist Inder Verma finds the debate extraordinary for different reasons.
INDER VERMA: What an interesting society we live in, when a thing like that is taking such an enormous proportion of our time, and not worrying about the thousands of homeless or the thousands of children who are born and no one takes care of them. And we are much more interested in the ones which are lying in a test tube and will be thrown away.
JOHN HOCKENBERRY: Even the most enthusiastic advocates of stem cell technology admit that this research is still in its infancy. It could be ten years or more before viable treatments hit the market. And there are no guarantees that the technology will lead to anything medically useful at all.
DANIEL SALOMON: The day someone sends me a little bottle of stem cells and readable directions about how to use those stem cells to grow all these different organs that we want, I promise to never mention xenotransplantation again, but the fact is that that’s just the latest hype.
JOHN HOCKENBERRY: That’s Dan Salomon of the Scripps Institute. He hopes that the much- hyped stem cells do eventually morph into cures. But why not also look to a technology that might get us some livers or hearts or kidneys much sooner…without having to wait for people to die and leave their organs for transplant.
Consider the pig. Specifically, carefully bred, bio-engineered miniature swine born surgically by sterile C-section. In a new twist this little piggy goes to market… these little piggies are monitored for disease, fed a carefully calibrated diet, so as to develop size appropriate organs for transplant into people. In the United States alone, 75 thousand people are on organ waiting lists...and there are an estimated hundred thousand more who aren’t wait listed, but could benefit from a healthier organ. There is a big need for product here. Dr. Julia Greenstein is President and CEO of Immerge Biotherapeutics in Massachusetts.
JULIA GREENSTEIN: The mission of the company is to evaluate, in a pre-clinical scenario, the safety and efficacy of solid organ xenotransplantation, so trying to use pig organs as replacement organs for human transplantation.
JOHN HOCKENBERRY: In the constantly shifting biotech landscape, Immerge is a new company. It’s a joint venture funded by several other biotech firms to explore the feasibility of xenotransplantation. Using animal organs to replace human ones isn’t exactly a new idea.
HUGH AUCHINCLOSS: Well, in various ways, people have been experimenting with it literally for centuries.
JOHN HOCKENBERRY: Dr. Hugh Auchincloss is a transplant surgeon and professor of medicine at Harvard University.
HUGH AUCHINCLOSS: But the modern era of xenotransplantation clinical trials really did start in 1963, with a series of kidney transplants from non human primates, and there have been, over the course of the years, 50 to a hundred efforts at clinical xenotransplantation ranging from heart transplants, kidney transplants, several liver transplants...
VOICE: The infant, identified only as Baby Fae, received the heart of a young baboon in a five-hour operation that took place yesterday morning. The baboon heart started beating on its own...
JOHN HOCKENBERRY: Baby Fae died not long after receiving her baboon heart in 1984. Her own immune system waged a war with the intruding tissue. Our bodies have a variety of weapons poised to drive out invaders. Dan Salomon.
DANIEL SALOMON: The minute you put that cell in, that antibody has been circulating in the blood just waiting for it, it hits it, activates the body’s other immune defenses, kills it.
JOHN HOCKENBERRY: That’s what’s called hyper acute rejection and it’s can destroy the transplanted tissue in minutes. By the mid 1990’s the development of transgenic pigs seemed to overcome the hyper acute rejection barrier. These pigs expressed certain kinds of human proteins on their blood vessels. The discovery set off a biotech stampede. Big pharmaceutical companies, initially slow to climb onto the genetic medicine bandwagon, poured millions into xenotransplantation.
DANIEL SALOMON: Unfortunately, as often happens in science and medicine, right on the other side of the barrier was another barrier that had not been predicted, and that was this acute vascular rejection.
JOHN HOCKENBERRY: None of the immunosuppressive drugs on the market were effective. Many companies pulled out of xenotransplantation. Safety issues were emerging. In 1995, scientists were worried about the possibility that a virus carried in the genes of animals could be spread, via tissue or organ transplant, into people. In that climate of concern, a 38-year -old San Francisco man, dying of aids, pressured regulators to allow an experimental therapy.
VOICE: ...Doctors hope the baboon’s bone marrow cells will help strengthen the man’s ravaged immune system. The experiment is controversial because of fears that animal to human transplants could spread animal diseases to people.
JOHN HOCKENBERRY: Kathy McAnally recently spoke with Jeff Getty, who fought to win approval for this experimental therapy.

• • •

KATHY MCANALLY: At first Jeff Getty didn’t want to talk to me. He said he was tired of the same old questions about the baboon bone marrow transplant he had years ago. Then, he agreed to do the interview, because Getty believes passionately in the promise of xenotransplantation.
JEFF GETTY: I wanted to speak in terms of activism and cross species research. There isn’t a lot of activism in terms of individual patients who have the diseases, and the problems that require cross species procedures to possibly save their lives.
KATHY MCANALLY: Getty says, having had the procedure, he’s a target of animal rights activists.
JEFF GETTY: The harassment includes such things as death threats, having your character assassinated in their magazines, phone calls in the middle of the night where people hang up, basically they turn their hate towards you.
KATHY MCANALLY: For Getty, lobbying for support of xenotransplantation research is a natural outgrowth of being an aids activist.
JEFF GETTY: Most people who have HIV are not allowed to have organ transplants, although many of the drugs we take to treat HIV destroy organs over time. A lot of people with HIV also have hepatitis, and that destroys people’s livers, as we know. We’ve had the doors slammed in our face for many years for organ, regular human organ transplants.
KATHY MCANALLY: It angers Jeff Getty that what he terms a miniscule risk of transmitting an animal virus into people is thrown up as a reason to stop it.
JEFF GETTY: The message that the government and the people who oppose cross species research is sending to those patients is, you’re better off dead than you are alive, it’s a very remote chance that you could have a pig virus that could be passed on to other people, and because we can’t quantify that risk, unfortunately you’re expendable, you die.
KATHY MCANALLY: The 1995 baboon bone marrow transplant didn’t succeed in knocking the AIDS virus out of Jeff Getty’s system. But it didn’t kill him either. Getty still regularly submits samples of his blood to the National Centers for Disease Control in Atlanta, so that scientists can screen for viral abnormalities. Thus far, nothing has turned up.

• • •

JOHN HOCKENBERRY: This is The DNA Files, I’m John Hockenberry. Jeff Getty’s experimental treatment back in 1995 still resonates with scientists who were caught up in the debate. Dr. Dan Salomon was a member of the FDA Advisory Committee that reviewed the therapy plan. He says that in response to fierce pressure from the patient, his family and the AIDS community, the committee caved in.
DANIEL SALOMON: It made us realize that we were not prepared. It made us realize that regardless of whether we were prepared or not, there were people out there who were going to begin to propose studies like this and that it was only a matter of time that there would be others.
JOHN HOCKENBERRY: In the years after Jeff Getty’s baboon bone marrow transplant, the relevant government agencies, FDA, CDC and the National Institutes of Health, devised stricter guidelines governing xenotransplantation research. Dr. Louisa Chapman of the Centers for Disease Control says there are enough dangers in human-to-human transplants.
LOUISA CHAPMAN: Anytime you transplant tissue between two organisms there is a possibility that you will transplant with that tissue something you didn’t intend, usually infections or cancer. We can do the same thing when we transplant living tissue from non -human animals into humans. Non-human animals have infections that can infect humans.
JOHN HOCKENBERRY: Its called xenosis. Rabies, Hantavirus, West Nile fever, Ebola, AIDS ; all are animal viruses that can make people very sick. So, strict rules are now imposed on animals bred for xenotransplantation experiments. They live in special colonies. Food is carefully monitored, and they are tested regularly for infections.
HUGH AUCHINCLOSS: The worry is about a virus that doesn’t currently exist, which is something very hard to come to grips with.
JOHN HOCKENBERRY: Dr. Hugh Auchincloss says that pigs, for example, carry the genes of inactive viruses within their DNA. They don’t affect the pig, and don’t seem to be transferable to humans. But.
HUGH AUCHINCLOSS: The concern that people have is, supposing these genetic sequences got transferred to human cells and mutated or recombined with genetic sequences within the human cells and made a brand new virus that nobody’s ever encountered before or seen before that turned out to be deadly pathogenic for humans and spread from one human to another. Now I can tell you this sequence of events that I’ve just described, any expert I’ve talked to thinks it’s exceedingly unlikely. But how exceedingly unlikely do you want it to be before you undertake clinical xenotransplantation?
JOHN HOCKENBERRY: So, xenotransplantation brings up a whole new set of ethical and safety questions. How does a society balance the potential of lifesaving animal organs against the seemingly tiny risk that some weird new disease might be unleashed on an unsuspecting public. It raises the issue of community consent.
ALAN BERGER: I think that if you have someone who is dying and you show them an animal organ and you say, this is your only chance, they’re probably going to take it.
JOHN HOCKENBERRY: That’s Alan Berger, executive director of the animal protection institute in Sacramento, California. He thinks it’s ethically wrong to use animals for human replacement parts. After all, a pig or a sheep can’t give consent to be used in this fashion. Alas, says Berger, he and the rest of the public can’t either.
ALAN BERGER: If you get that transplant, I’m not consenting to that, because you have the possibility to spread that disease to myself, my daughters, to my family, and I don’t want that to happen.
DANIEL SALOMON: There is no good way to do informed consent for the public.
JOHN HOCKENBERRY: Dr. Dan Salomon says there’s no way we can be 100 percent sure that a disease won’t be spread by xenotransplantation.
DANIEL SALOMON: We have to be careful and we have to be cautious and if we’re going to do any sorts of trials, they have to be really done under highly supervised situations with experts in infectious disease around.
JOHN HOCKENBERRY: A few years back, says Salomon, doctors in Russia were treating patients with pig spleen infusions. He says that animal to human experiments are going on in Mexico.
DANIEL SALOMON: Right now there are also a series of what we call rogue xenotransplant programs in Mexico. One is doing shark, fetal shark neural cells into patients with spinal cord injuries at over 50 thousand dollars a treatment, not bad, and these are advertised on the web. The scary thing is that there’s nothing stopping these people from doing this.
JOHN HOCKENBERRY: Dr. Julia Greenstein at Immerge Biotherapeutics says her company is working on several fronts to produce pigs that could provide safe organs for transplant.
JULIA GREENSTEIN: We’re genetically modifying the miniature swine to control some of the immunilogical hurdles of pig to primate transplantation, so we’re doing nuclear transfer cloning with a company called Infigen in Madison, Wisconsin.
JOHN HOCKENBERRY: Stem cell researchers are also looking at using certain cloning techniques to combat immune rejection. Geron’s Dr. Tom Okarma.
TOM OKARMA: The ES cells we now have do have tissue antigens, because they were derived from human embryos. So nuclear transfer, therapeutic cloning, is a potential way to circumvent that immune rejection.
VOICE: Scientists in Scotland say they have, for the first time, cloned an adult mammal. They’ve created a genetic replica of a sheep. Clones could be useful in science and for commercial purposes, but the research also raises enormous ethical questions because the same techniques could be tried in human beings...
JOHN HOCKENBERRY: The whole idea of trying to clone a human being is scorned by the scientific establishment. Dr. Ian Wilmut, who gave us Dolly, can present a long list of physical problems in cloned animals. Dolly herself is abnormally large, for a sheep. Wilmut says babies cloned using existing technology could have horrific physical problems.
IAN WILMUT: My concern is that if people do attempt to clone a person at the present time this will create so much public revulsion that they will then prohibit all research with human embryos to provide cells to treat human diseases and it would be a great shame if we lost out on that opportunity.
JOHN HOCKENBERRY: Wilmut’s lab, the Roslin Institute is in Scotland. In the United Kingdom, Parliament has passed laws that allow therapeutic cloning research on embryos up to 14 days of age. Several years ago, the Geron Corporation bought into Roslin. In addition to therapeutic cloning, the companies are looking at other ways to make human stem cells that don’t trigger rejection. Again, Dr. Wilmut.
IAN WILMUT: Whether it’s possible to change the cells so they become appropriate for everybody, to in some way modify the molecules of the cell surface to make them universal treatment cells, and there are some ideas as to how that modification might be brought about.
JOHN HOCKENBERRY: In the end, says Dr. Dan Salomon, the treatments that may one day emerge from all this research will probably take a variety of forms.
DANIEL SALOMON: they’re all related. Gene therapy, xenotransplantation, stem cell biology. They’re all related. When we finally roll out mature therapies for disease, it will very likely involve some mixture of these three major biotechnologies.
JOHN HOCKENBERRY: And exciting though the promise of these therapies might be, Audrey Chapman of the American Association for the Advancement of science sees the potential for trouble.
AUDREY CHAPMAN: In the early stages of the capacity to undertake genetic engineering, scientists were cautious. The major example is the Asilomar Conference, where they decided to voluntarily impose a moratorium on research. And then, as it appeared that some of the worst fears about that research were not coming to fruition, people, I think, have become increasingly incautious.
JOHN HOCKENBERRY: Dr. Paul Berg, the Nobel laureate who helped convene the Asilomar conference back in 1975, points out that as tantalizing as the new science is, genetics will never provide us with all the answers.
PAUL BERG: I think we’re in for some really exciting developments in biology. Having the genome sequence in hand is a first step. But I think we have to be a little circumspect, and say, “we don’t know.” Scientists will always say, we know this, but we don’t know that. And that’s the challenge.
JOHN HOCKENBERRY: I’m John Hockenberry. Thank you for listening to The DNA Files.

This series, The DNA Files, was produced by SoundVision Productions with funding by the National Science Foundation and the Alfred P. Sloan Foundation.
This program, Genetic Medicine: Prescription for Conflict, was produced by Kathy McAnally, and engineered by Rima Snyder. The editor was Catherine Stifter, and our host was John Hockenberry.
Our opening feature, “The Human Cloning Race,” was produced by Rusten Hogness, and edited by Gemma Hooley.
The DNA Files is: Managing Editor, Rachel Ann Goodman. Science Consultant, Sally Lehrman. Research and Production support by Adi Gevins and Noah Miller. Technical and Music Director, Robin Wise.
Original music composed by Jesse Boggs and performed by the Stanford Woodwind Quintet, Anton Schwartz, Tom Hayashi, and Jesse Boggs.
Project Director, Jude Thilman. Marketing by Murray Street Enterprise. Legal services by Walter Hansel and Spencer Weisbroth.
You can visit our website at Send your responses and letters to For tapes and transcripts, call 866-DNA-FILE (866-362-3453).
The Executive Producer is Bari Scott.
This has been a SoundVision Production, distributed by NPR, National Public Radio.