University Times

Few issues today are as potentially promising and simultaneously controversial as human stem cell research, two Pitt professors agreed.

"Imagine what would be possible," Alan J. Russell said. "Imagine Christopher Reeve walking. No more organ donor waiting lists. Curing diabetes with a single injection of cells. Scar-less healing of wounds. Countless other healing therapies using cells."

On the other hand, are scientists developing techniques that, in the wrong hands, will lead to human cloning for reproductive purposes? asked Alan Meisel. "Stem cell research, to the extent that it involves human embryos, gets implicated in the decades-old debate that includes issues of abortion, tissue research, transplantation — raising for some the most profound ethical questions," Meisel said.

Russell, director of the McGowan Institute for Regenerative Medicine, professor of surgery and professor of chemical and petroleum engineering, spelled out the state of the science involved in stem cell research, and Meisel, professor of law and psychiatry and Dickie, McCamey & Chilcote Professor of Bioethics, laid out what he called "a spectrum of ethical quandaries."

The tag-team spoke Oct. 18 on "Stem Cell Research: Hype or Hope?" at the Maryann F. Fralic Distinguished Lecture at Pitt's School of Nursing.

Fralic, who is professor and director of corporate and foundation relations at Johns Hopkins School of Nursing and a member of the original class of Pitt's legacy laureates, established the annual nursing school lecture to attract health care experts to address the University community.

The science of stem cells "I'm sensitive to the fact that the use of embryonic stem cells is a very ethically difficult thing to deal with," Russell said, acknowledging his personal opinion that human life begins at conception. "But I'm going to stick to the science and leave the ethical questions to my colleague."

Russell's overview included defining stem cell research; recounting some of the research successes in treating diseases in mice; making some distinctions, such as the differences between embryonic and adult stem cells and between therapeutic and reproductive human cloning, and noting what the most pressing challenges are for stem cell researchers.

"First, what is a stem cell? Imagine you're a single cell at the trunk of the tree of life and as you advance up the tree, every time you come to a branching point, you have to make a decision, am I going to become this kind of cell or a different kind of cell?"

This process, called cell differentiation, triggers a cell to become, for instance, a hair follicle or a heart muscle. It is not just the process by which an embryo becomes a baby, he said.

"The lining of the stomach wall, perhaps the most commonly injured part of our body, gets hurt just by eating a meal. How does the gut regenerate? It uses stem cells as a wound-healing substitute. It recruits stem cells to divide and tell your body how to heal quickly."

Harnessing the potential of these cells is at the core of stem cell research, doing what Russell termed chemically driven therapy and medicine by moving into biologically driven research.

There are two categories of stem cells, embryonic and adult. Both show promise in battling disease, but extracting embryonic stem cells requires the destruction of their source, so-called blastocysts. A blastocyst, or pre-embryo, is the hollow ball of about 50 – 100 cells that forms in the first 3 – 5 days following in vitro fertilization of an egg. A limited number of those cells, usually three or four, are stem cells, which develop into an embryo. The rest of the cells form the placenta.

"You can take one of these three or four cells and you can culture it. Because these cells continue to divide, you can culture them in large numbers, until they differentiate. The challenge is to turn them into the kind of cell you want and then use that cell to treat a patient. So embryonic stem cells in and of themselves are not clinically useful. In order to use them you have to actually convert them into adult-like stem cells."

Since embryonic stem cells divide naturally, they are relatively easy to guide chemically, Russell said. "In contrast, the adult stem cell is designed to repair damage and, in the meantime, it hibernates until it is needed," making it difficult to find and isolate. There are relatively few of them, as well; only about 1 in 100,000 adult cells are stem cells.

"There's something about adult stem cells that makes them a little too advanced and we haven't yet been able to make them 'go backwards' down that tree of life, but I'm pretty confident that we'll be able to do that eventually," Russell said.

To date, however, embryonic stem cell research has demonstrated more success in treating disease, including curing Parkinson's in mice.

Parkinson's disease is caused by the failure of brain cells to produce dopamine, a neurotransmitter that connects the brain with certain motor functions. "So, clearly, if you could produce dopamine at the right site, you might be able to reverse Parkinson's, and cure it. And yes, it can be done. You can take these embryonic stem cells, you culture them, you get them to turn into dopamine-producing neurons, you implant them in the brain and they make connections and they survive in the brain, and they are able to reverse Parkinson's in mice. It's a very impressive result that has been a powerful driving force in what could happen in future human clinical trials."

But Russell cautioned that researchers still need to bridge the gap between animal and human research, which he estimated will take about a decade.

"There are other challenges, too," he said. For example, how do you know whether the stem cells, which have varying degrees of potential to become other cells, can be converted into the needed cells? How do you trace where they go in the body once injected? How do you control cells once you inject them inside the body? How do you know the cells are working?

Researchers also can create blastocysts, and therefore embryonic stem cells, by cloning. "Actually, human cloning is simple. You take an unfertilized egg, remove the nucleus, inject an adult cell from another person into it, and the DNA in the signaling environment makes a blastocyst."

What is done with the blastocyst is crucial, Russell said. One choice is to make a human clone, while another is to take a stem cell from the blastocyst with DNA identical to its donor cell, turn the stem cell into a needed therapy cell and inject it back into the donor. "That's therapeutic human cloning, which is quite distinct from reproductive human cloning," Russell said. "But nobody's figured out how to go straight to a human embryonic stem cell without destroying the blastocyst. The reality is you have to go through a life — I think it's a life, anyway — to produce a blastocyst and then destroy it to get the stem cell."

Even with some of the known drawbacks, Russell said, no one knows which kind of stem cell is more promising in the long run, adult or embryonic stem cells.

"We're now 10 years into the research, and it will likely be another 10 before we'll see real broad clinical utility, and maybe another 3 – 5 years before we really know what the chances are that these therapies will work in humans," Russell said.

Ethical implications Russell's belief that scientists do not yet know which stem cells are preferable for research segued into Meisel's area of expertise. "Are we even going to have the opportunity to answer the question whether embryonic stem cells or adult stem cells are better?" the bioethicist asked.

Meisel said the political climate in this country is unclear. Last year President Bush partially lifted the ban on federal money for embryonic stem cell research on cell lines that existed prior to Aug. 9, 2001.

The policy says federal funds may not be used for: 1. the derivations or use of stem cell lines derived from embryos created after the August 2001 deadline; 2. the creation of any human embryos solely for research purposes, or 3. the cloning of human embryos for any purposes.

Moreover, research on existing stem cell lines requires the informed consent of the donors without any financial inducements, and can be done only on embryos created for reproductive purposes, in order to be eligible for federal funding.

In August and September 2002, the Pittsburgh Development Center, part of Magee-Womens Research Institute, received two of the estimated 78 existing stem cell lines identified by the National Institutes of Health, according to Christopher Navara, a professor in the Department of Obstetrics, Gynecology and Reproductive Sciences, who is a researcher at the development center.

The Pittsburgh Development Center, which specializes in the study of embryonic cells, is one of only 20 such centers nationally funded by NIH.

Although unlimited private funding is legal, Meisel said this federal policy likely will retard research efforts in this country.

"There is no ban on the research itself, except for federal funding. Right now it is theoretically illegal in Pennsylvania, the way state law is commonly understood, to create embryonic stem cells here, but we can get them from out-of-state and legally evade what appears to be a ban." This hasn't been tested in state court yet, he added.

"Embryonic stem cell research raises questions about the destruction of human life, the creation of human life, the problem of consequences, the problem of funding and some subsidiary issues," Meisel said. "I don't pretend to offer any answers, but maybe I can put some of the questions into focus."

Among the ethical issues Meisel pointed out are:

* "At least for now we can't get embryonic stem cells without the destruction of the embryo, which raises a basic ethical question: the claim that this research requires the destruction of human life," Meisel said. "To avoid this, the research has attempted to make stem cells from other means, but that raises a second ethical issue: the creation of human life for research purposes, and by that I mean therapeutic cloning."

The major disadvantage of that technique may be the name: cloning, Meisel said. "There's nothing you can do to make that word sound good, no matter what good may come from it. It's one of those hot-button words like suicide or euthanasia." Meisel pointed out that even though most people are familiar with human clones — identical twins — the word cloning still carries a strong negative connotation.

* "Is there a morally relevant difference between creating an embryo for the purpose of creating a child, and doing it with research in mind? What was the intent of the progenitors of the blastocyst? Most are originally intended for the process to conceive a human being."

And if that intent has changed, does the value of the blastocysts also change? Should we weigh the potential of one human life versus developing a cell line that potentially could save countless human lives?

* If blastocysts are human life, what about the sperm and the egg: are these human life? Can conception be the beginning of life, when both the egg and the sperm are alive, or is conception instead an increase in complexity?

"Some would say whether blastocysts are human life is unanswerable in any scientific way," which is essentially the position the Supreme Court took regarding the status of the fetus in the Roe v. Wade 1973 abortion case, Meisel said.

* The issue of respect. "Even if we assume blastocysts are not human life, can we do anything to them, since they at least have potential of human life? Or do we need to take into account their effect on existing human lives, including those suffering from certain diseases, and not the potential human life they represent? Or are there moral obligations not to use the therapies, because of the way they were developed?"

* Potential consequences. "Assume a blastocyst is a human life. Some believe it is always inherently morally wrong taking a human life. But many others believe that morality is determined by weighing the benefits versus the burdens.

"For example, President Bush's decision to shoot down the plane headed for Washington before that plane crashed in Pennsylvania, was looking out for the greater good, even if it would have meant taking innocent human lives."

There also are potential consequences for not doing, or of limiting, embryonic stem cell research, Meisel said. "One possibility is that we will miss out developing new therapies. Another consequence is we may be at a disadvantage in competition with other countries.

"Another is, if we make embryonic stem cells off-limits because of the way they were developed, wealthier people would be more likely to have access in countries where they are available. We could be creating a black market."

* Retrospective validation. Meisel said many, if not most, of the embryos that are stored in fertilization clinics will be destroyed if they're not used for research. "But because euthanizing them is morally objectionable (to some people), is to use them somehow to deny that the original act was immoral?" he said.

This is analogous to using data that the Nazis collected on human research subjects in concentration camps, data some people would call inherently morally tainted.

"Others would say that if some good can come from that, so much the better."

–Peter Hart