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Stem cell campaigner speaks out

ACT via IRG
Researcher Robert Lanza
wants the White House to
approve a new type of "no
embryo destruction" stem
cell for federal funding.


Embryonic stem cells can transform themselves into virtually any kind of tissue, holding out the promise of potential cures for spinal-cord patients, diabetics, heart-attack sufferers and many more of the world's afflicted. But how do you balance that promise against ethical concerns about the destruction of human embryos?

Some scientists have concluded that the potential benefits outweigh the ethical concerns, and are seeking to harvest the precious cells from surplus embryos or cloned embryos. Others avoid using embryos altogether, and instead work with adult stem cells, umbilical-cord blood, menstrual blood ... or even garden-variety cells that can be genetically reprogrammed to behave like embryonic cells.

And then there's stem cell pioneer Robert Lanza.

As chief scientific officer for Massachusetts-based Advanced Cell Technology, Lanza is building up a track record on both sides of the spectrum - and often hits upon controversy along the way.

Back in 2001, Lanza and his colleagues at ACT announced that they were the first to clone human embryos - but the cells died off soon after they were created, leading some to deride the development as "a publicity stunt."

In the same year, ACT notched yet another first by cloning an endangered gaur ox and implanting the embryo into a cow. The baby gaur died two days after its birth, due to dysentery - but at the time Lanza hailed the achievement as having "the potential to save dozens of endangered species."

Cloning isn't Lanza's only strategy: In the wake of last year's exciting revelation that skin cells could be made to act like stem cells, he's been researching ways to reprogram ordinary cells without the risky gene-transfer method that is the current state of the art.

But his main campaign nowadays is something completely different: a technique that takes a single cell from a human embryo at the eight-cell state to create stem cells - and keeps the embryo viable rather than destroying it in the process.

Back in 2006, Lanza and his colleagues reported in the journal Nature that they created new stem cell lines using the method, which is based on the procedure for diagnosing fertilized human eggs before they're implanted in the womb. Once again, controversy dogged the claim: The journal had to issue clarifications saying that the researchers removed several cells from the embryos to increase their chances of success - and destroyed the embryos in the process.

At the time, Richard Doerflinger of the U.S. Conference of Catholic Bishops said the method "raises more ethical questions than it answers."

"What we have here is hype, not hope," bioethicist Arthur Caplan wrote in his column for msnbc.com.

In a paper published online today by the journal Cell Stem Cell, Lanza and his colleagues address the scientific and ethical questions: They report that they developed five new lines, using single cells taken from eight-cell embryos, and that the embryos were then allowed to develop into a state where they could be safely be frozen for later implantation.

The fresh round of research led Lanza to call on the Bush administration to clear the new lines immediately for research purposes.

"This research has been held up for too long, and hopefully the president will approve these stem cell lines quickly," he told me this week. "There's an urgent health crisis out there, and we can't afford to hold this research up any longer."

In an extended Q&A, Lanza discussed the research and how he hoped its implications will play out. Will there be a fresh round of controversy? This could quite easily turn into another case of hype over hope. But even if the impact doesn't live up to Lanza's expectations, his findings - and the controversies that surround him - will surely factor into the larger debate over stem cell science and ethics.

Here's an edited transcript of the exchange:

Cosmic Log: Can you explain what exactly you did, for a layman who doesn't understand all this stuff about "blastocysts" or "ICM niches"?

Lanza: What we did is we removed a single cell - and one of the problems unfortunately whenever you're trying to generate embryonic stem cells is that those cells have a mind of their own. At that early stage, they like to become what's known as trophectoderm. That's basically the part of the embryo that's going to go on to become the placenta when the embryo implants in the uterus.

Before those cells can become these trophectoderm cells, they have to differentiate. And there's a molecule known as laminin which we found ... that if you added it actually inhibits that process, and basically shifts the cell into becoming an embryonic stem cell.

The early embryo – the blastocyst – is basically a hollow ball. The outer surface of the ball is going to become the placenta. Inside that hollow sphere is a tiny little group of cells clinging on the inside, known as the inner cell mass or the ICM. By adding this molecule we're basically re-creating that ICM environment, so that the cell that we've removed becomes an embryonic stem cell.

It really improved the efficiency dramatically. In our previous paper, the proof-of-principle study that we published in Nature a year ago, the efficiency was only 2 percent. We're now talking anywhere from 20 to 50 percent, which is exactly comparable to what has been reported for using entire embryos.

So basically what you're doing is you're trying to fool the cell chemically into thinking it's on that inner cell wall where it's expected to become an embryonic stem cell?

Exactly. It's in the right developmental environment to become an embryonic stem cell.

What do you think this will do to the debate over embryonic stem cells? We've seen that the debate has already been changing over the past few months. What do you expect to happen now?

Well, this is a working technology, so it's here and now, and it can be used to increase the number of stem cell lines available for federal researchers immediately. We could actually send these cells out to laboratories tomorrow. And in fact, this new methodology is so efficient that we could effectively double or even triple the number of lines available within a few months.

The research has been held up for too long. If we had more research going on with these lines, anything we learn from these real embryonic stem cell lines – say, for instance, how to generate specific cell types to treat patients – can also be applied to reprogrammed stem cells. You've heard of the recent breakthrough where researchers were able to use various transcription factors to create pluripotent cells. Once that technology is safe enough to use clinically, we'll be able to apply all the knowledge that we've learned. So no time would be lost while we wait.

There's another very important point to make, and that is that we still don't know if the new technology to reprogram cells – which we call induced pluripotent stem cells or IPS cells – is going to be able to do all the same things that normal embryo-derived stem cells can do. We don't even know all the properties of regular embryonic stem cells. These have to be studied.

It might be that these IPS cells can only make neurons, but not insulin-producing cells. Or even if they can, they may not be able to do it as well. Until we have these answers, we cannot afford to abandon any line of research. So I think that there's a strong consensus in the scientific community that we really need to proceed with all these lines of research, and every advance gets us that much closer to the clinic.

One of the concerns that was pointed out about the induced pluripotent cells was that genes had to be inserted into the cells using a virus, and that one of the genes could lead to cancer. Can you talk about how your approach differs in that respect?

Right. So the new IPS cells, the way these cells were generated was basically by genetically modifying the cell. In several of those experiments, they used something known as c-Myc, which is very closely associated with cancer. In many of the animals where they use these cells, there was a high incidence of tumor formation. There was a new paper that allowed the researchers to eliminate c-Myc, the most offensive of those factors. However, even those cells were genetically modified – which in and of itself is associated with an increased incidence of cancer.

The FDA would never allow us to use those cells to treat patients. So right now, a number of groups – including our own – are working on methods to create these pluripotent cells without genetically modifying the cell. There's obviously a great deal of excitement and promise in doing that. But we don't know how long that's going to take. So in the meantime for one is we need to find out once we create those cells, are they the same? Can they do all the same tricks? There was one paper that suggested there was a difference in gene expression profile, which means they are different in certain respects. That has to be studied.

These cells that we're talking about in this particular paper are the real thing. They're true embryonic stem cells, and they were derived from embryos. We have a considerable amount of data on these cells, and we know they can do all sorts of exciting things. Just to give you an example: We created some embryonic stem cells from a single blastomere, and actually turned them into what's known as hemangioblasts. We found that these cells were able to cut the death rate after a heart attack in a mouse in half. Also, in animals that otherwise would have had to have their limbs amputated because of lack of blood flow, we were able to restore that blood flow completely to normal within a month.

These very same types of cells could be used in patients. Again, these are the cells we generated from human embryonic stem cells derived from single cells. So there's a lot of exciting potential here. And as this new IPS cell technology develops, we will have learned how to turn those cells into the cells that can help people. Right now we're working on making biological bypasses, and making blood, so we're going to have figured out how to turn the pluripotent stem cells into replacement cell types that can help people. So no time is going to be lost.

In terms of having these cells approved for use in federally funded research, what would be the procedure? Do the limits on embryonic stem cell lines apply in this case?

None of the embryos in this study were destroyed, so for all five of these lines, the parent biopsied embryo was frozen down and remains alive. ... Clearly these embryos were not destroyed. Now there is a question of 'were the embryos harmed?' I think in that particular case, the burden of proof really lies with proving the embryos were harmed. You can't say that these stem cell lines violate federal law without any facts, and they should not be denied federal funding because of religious opposition.

It's very clear that the biopsy procedure had absolutely no effect on the subsequent development of the embryos. … There are very objective scoring criteria to assess the health of the embryos. They're the best method we have to assess whether the embryos were harmed or not.

So I think these lines clearly should qualify for federal funding, and my understanding is that at the White House they're waiting for this published paper before they assess what course they're going to take.

When it comes to developing new therapies, one of the things about the pluripotent cells is that they're created from the skin cells of the donor, so they could be custom-made to fit the donor's genetic profile – whereas with these cells, it's a little more complex. If these cells can be used for therapies, how would you match a person with the cell that is needed?

Two major hurdles have plagued transplant medicine for the last several decades: One is the shortage of the cells and the tissues, and two is the problem of immune rejection. With any embryonic stem cell, the hope is that we can create unlimited numbers of these cells, and perhaps using tissue engineering, even grow up entire organs. But we still are confronted with the question of how you put those tissues back in the body. Say we have insulin-producing cells. You can't just plunk them back in the body because your body will reject them. The great thing about the new reprogrammed cells is that you're starting with the patient's own skin cell so you won't have to worry about immune rejection.

But the other thing to consider here is that if you do a little arithmetic, you quickly realize that a lot of this technology becomes economically prohibitive. If there over 200 million people with diabetes, and several hundred million people with cardiovascular disease, you'd be talking about literally creating billions of patient-specific cell lines. Whether that's going to be done through the reprogramming or cloning, it's a bit impractical.

Here's the way that'll probably be solved: If you look at the tissue types for the American population, you'll find that 100 tissue types would actually provide complete matches for 50 percent of the population. You could have cells that you expand – and of course the beautiful thing about embryonic stem cells or pluripotent cells is that they're immortal. They grow forever. Once you have a cell bank, you could use it for virtually everyone with that tissue type.

So say you had a heart attack, and you have a narrow window of opportunity, and you want to inject certain of these cells that repair the heart. You could have those all ready, and then once you know the patient's type you just thaw out a vial of those cells and use them.

Would you compare this to tissue typing for a bone marrow transplant?

Absolutely. The beautiful thing here is that we could pick people who are homozygous – that is, they have reduced complexity of their tissue type. To some extent it's like blood. And on that front, we can now create entire tubes of blood from embryonic stem cells. If we started with a line that was O-negative, it would be a universal blood type that would match everybody. So whether we use the reprogramming cells or we found a line that was basically O-negative, once you have that line – because it grows indefinitely – you could then use that to create literally unlimited amounts of cells that would be basically a universal donor to you, me, and everyone in the country. A similar kind of thing would apply to tissues. There are certain major tissue types, and by identifying the ones that are most common, we could make a very substantial dent in matching a large percentage of the population.

Since this still involves extracting cells from an embryo, I suppose people might ask the ethical question about what happens to those embryos that are sampled. Could you get into a situation where you're creating life to save a life, then have an open-ended fate for that life that you've created and frozen?

Actually, we're rescuing embryos, because these embryos would be slated to be destroyed, and we're not harming them so they're frozen down. By generating these lines, those embryos will be protected and will not be harmed. Period.

That's one thing. But the other thing to consider here is if you just look at PGD [preimplantation genetic diagnosis], these are couples who will have one of the cells from an embryo sent off to the lab to be tested. And of course when it goes off to the lab, that cell is destroyed.

What we could do is, before you send that cell off for testing, just let it divide overnight. Then send one cell off for testing, and you create a stem cell line from the rest of those cells. So you then have a genetically matched line for that child without any additional risk to the embryo. In other words, it has no impact on the clinical outcome of that procedure - but yet, there's a benefit in that you have a line that matches the child. And that line can also be used by the whole world.

What's next for your research? It sounds as if you're going to be doing some work with induced pluripotent stem cells as well as the cells described in this latest paper. Do you have a particular term for these cells?

In our paper we're calling them NED1, 2, 3, 4, 5 – because there's "no embryo destruction."

So if they came to be called NED cells, you wouldn't be opposed?

No, not at all. But also, you have to realize that as we move toward the clinic with these technologies, these studies can be very expensive. It could easily cost upwards of $100 million to bring some of these technologies through clinical trials. And pharmaceutical companies are going to be very wary before they invest money in something that's so controversial. So having a technology where they're actually using cells where the embryo was not destroyed might actually help in that regard.

We're going to be speaking with the FDA in a few weeks, and we're hoping to get permission to proceed this year to file an IND [investigational new drug application] for clinical trials, for using retinal cells to treat or prevent blindness. We also have some other projects that we're hoping in the next year or two to get into clinical trials. I know Geron, for instance, is hoping to use embryonic stem cell technology for spinal cord injuries.

So while we're moving ahead with developing these different cell types, we're still confronted with the challenge of moving into the clinic. For instance, I mentioned earlier that we can generate these hemangioblasts that can keep people from losing a leg or a foot. But we don't know how to use them without powerful immunosuppressive drugs. The hope right now is that we can use these reprogrammed cells, or therapeutic cloning, to create cells to bypass the problem of immune rejection. Either of those approaches would allow us to apply this technology and translate it into the clinic.