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Regenerative Medicine Regenerates Itself

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When Scott Noggle was an undergraduate student watching various PIs present their work to give students an idea of which labs they may want to work in, he saw a video of cardiac muscles developed from mouse embryonic stem cells. The cells were beating in the culture dish — contract, contract, contract — and Noggle's imagination was hooked. "Most things don't move around in the dish while you're looking at them," says Noggle, now a PI at the New York Stem Cell Foundation. "It was pretty wild."

Stem cell research has captured the imaginations of many people. Very few fields of scientific research are fraught with such misinformation, controversy, and hope — some spas offer "stem cell facials" to rejuvenate tired skin; stem cell opponents say that research destroys embryos and will lead to human cloning; and families of patients with neurodegenerative diseases wait for the day when their loved ones can be treated with stem cells to repair the damage wrought by ALS or Alzheimer's disease.

The field has also captured the imagination of many researchers. "Embryonic stem cells are a representation of a person in a dish," Noggle says. The cells, in their undifferentiated state, can be poked and prodded to become any cell in the human body. A PubMed search for papers from researchers that utilize stem cells or experiment on them returns more than 100,000 results — more than 700 in the last two months alone. That's quite a bit of interest.

Stem cells generally come in two forms: embryonic stem cells, which come from the inner cell mass of blastocysts and are pluripotent, can differentiate to become all the different tissues of the human body and can be replicated almost indefinitely; and adult stem cells, which come from — and are named after — various parts of the fully developed human body and cannot be changed into other kinds of cells. Adult stem cells are already successfully being used in medicine to treat blood and bone marrow cancers through bone marrow transplants. Researchers are also working with induced pluripotent stem cells, which are adult cells that are de-differentiated and reprogrammed to express specific genes. The first iPS cells were derived from adult skin cells by Shinya Yamanaka and his colleagues at Kyoto University in 2006.

A focus on disease

No matter which type of stem cells researchers work with, there is mounting pressure now to learn as much as possible about how they work, and how they can be used to improve the state of human health. Most stem cell experiments can be divided into two categories: using stem cells for drug discovery and finding ways to implant stem cells to fix problems in the brain, heart, bones, pancreas, or almost any other organ. For both kinds of work, most researchers say that embryonic stem cells are superior to adult stem cells. "The advantage that embryonic stem cells have over adult cells is that they're pluripotent — they can turn into any cell type in the body — whereas adult cells only develop into the cells they came from," Noggle says. "The other problem is that when you take adult stem cells out of the body, they become very difficult to expand and still maintain their properties, whereas you can expand embryonic stem cells almost indefinitely and they maintain their ability to differentiate themselves." To be used as a therapy, a lot of cells would be needed to fix the damage in the brain left by Parkinson's or Alzheimer's disease, or to create bone grafts for reconstructive surgeries.
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But even for drug screens, Noggle says, many cells are needed to properly test potential therapeutics. "It's very difficult to contemplate those kinds of screens using adult stem cells because they're hard to expand to the numbers that you need to do that," he adds. In the near future, the use of stem cells in drug screens is seen as the avenue with the most potential — especially when it comes to neurodegenerative diseases. Brain cells are the most complicated types of cells in the human body, and differentiating stem cells into specific brain cells is tricky, Noggle says. In the case of Alzheimer's, the disease kills neurons scattered throughout the brain, making replacing that brain matter with stem cells particularly difficult. Instead, NYSCF researchers and their collaborators are using iPS cell technology to generate cells from patients that have different forms of Alzheimer's and then replicating the cell biology of the disease in a dish to develop assays that can be used to screen for new drugs that block the pathways leading to Alzheimer's.

Another of NYSCF's projects is to try and figure out all the signals that an embryo would use to differentiate its cells, and try to mimic those signals to grow the cells found in the forebrain, Noggle says. "We can do that pretty well with motor neurons, and we can do it really well to get a general mix of the cells you find in the brain," he says. "What we're working on now is to get an exact match of the cells in the forebrain." Once they have differentiated cells, the researchers can generate assays, looking at disease-specific destruction of the cells and build screens.

Similar to the work being done at NYSCF, the more than 700 researchers at the Harvard Stem Cell Institute focus on directing the specialization of stem cells into various cells that are deficient in certain diseases, such as cardiomyocytes for the heart, nerve cells for the brain, or, in the case of Doug Melton's lab, the insulin-producing cells of the pancreas that are deficient in people with type I diabetes. Although the researchers are trying to ready the cells for transplantation, Melton says the larger part of his team's focus is on deriving stem cells that contain the genes responsible for these diseases in order to screen for drugs that could slow the degeneration process. "It's using stem cells as a product to put it into patients or stem cells as a tool to discover drugs," Melton says.

The cells are not only useful in finding new drugs to treat disease, but also in making those drugs safer. Noggle says NYSCF has a collaboration with a group at Columbia University studying long QT syndrome — a heart condition that can change the organ's rhythm — and the effects of certain drugs on stem cells derived with the genes for this condition. Many drugs fail in clinical trials because they ignore the physiology of the heart, Noggle says. And some drugs — he uses Vioxx as an example — can create cardiotoxicities not seen in trials, which can create problems once they are on the market. "There are projects to try and figure out what the genetic characteristics that predispose people to those toxic side effects are — there are a wide variety of therapeutically relevant projects that are going on in stem cell biology," Noggle says. "When everyone wants to talk about stem cells, it's always about transplants. But using stem cell biology, I think, is one of the best routes to finding drugs that are more specific and have lower side effects, and finding early markers of disease that you can catch completely."
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NYSCF is also researching transplantation therapies in projects like the foundation's collaboration with Lorenz Studer at Memorial Sloan-Kettering Cancer Center. Studer's work is centered around generating specific brain cell populations in vitro, such as dopamine, GABA, motor neurons, or myelinating oligodendrocytes, to treat ALS, Huntington's disease, or — in the case of the NYSCF collaboration — Parkinson's. The work has shown a mixed result of success and failure, Noggle says, likely because the researchers do not yet have the correct mix of cells for implantation.

Certain cells are simpler than others to generate and implant. Some researchers have had luck with implanting cells into the eye to treat macular degeneration and generating bone cells to make scaffolds for bone grafts. The NYSCF team will soon be joined by a third PI, Darja Marolt, whose work centers on building bone from stem cells for implantation into patients needing facial reconstructive surgery and soldiers returning from war with serious injuries. The research could also have implications for patients with osteoporosis. "I think that in the next 10 years there will be clinical trials that involve transplantation," Noggle says. "I think the interesting point is that there are so many different avenues that these cells allow for study and for so many different diseases and you need more people actually looking at it."

James Thomson at the University of Wisconsin derived and published the first paper on human embryonic stem cells in 1998, and he says he's never been a big proponent of using stem cells as a therapeutic tool. "I think it can work ultimately, but it's going to be a very long time, and I think the real legacy of these cells — both embryonic stem cells and iPS cells — is going to be as models for human disease and understanding the human body," he says. "This is the first time we've had access to all the bits of the human body. As much as we use animal models, there are specific species differences [and research can] come out wrong. And now, you can get human DOPA neurons in a tissue culture." His work is primarily focused on understanding the basic biology of the cells, finding what makes them so special that they can give rise to all the different cells in the body.

Using stem cells as tools for drug screens is medicine's best chance right now, Thomson says, adding that he expects to see Parkinson's patients being treated with therapies derived from stem cells in the near future, though not through direct implantation.

Melton is of a similar mindset. "I think using stem cells as tools will come first, and then that will be followed by stem cells as products," he says. "When people discovered the transistor, they didn't predict how long it would take to get personal computers or cell phones, but without vacuum tubes we would never have produced those things. I don't know how long it's going to take, but the effect [of stem cells] is going to be at least that big — it's going to change biomedicine and I can't predict it, because no one can predict the rate of discovery."
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Found in translation

Methods aside, many researchers currently working with stem cells are doing so in order to have a direct impact on human health and medicine. "We don't have a favorite disease, but what we do care about is translating this work as quickly as we can from the bench to the bedside," says NYSCF's chief executive officer, Susan Solomon. NYSCF, which has been in existence for five years, runs its own lab, employing more than 20 full-time researchers. Because it is a private institution, NYSCF can afford to do the kind of high-risk, high-reward work that Solomon says is integral to moving stem cells from the lab to the clinic. "Our process is very fast, so we get the money out as quickly as possible and as soon as we get results that merit moving to the next step, we move," she says. For example, in 2008, NYSCF's chief scientific officer, Kevin Eggan, was funded by the foundation to create a patient-specific line of ALS stem cells using iPS cell technology in order to model a familial form of the disease. The research, Solomon says, led to the discovery of a potential drug target, which the foundation is continuing to research. "We love basic science and we believe in basic science, but we believe we have to take the next step," adds Stephen Chang, NYSCF's vice president of research and development.

Harvard's Melton says his lab has a similar mission. "This is not a department where we're simply trying to find out how nature works," he says. "We will fail if we don't get products into people. … This is not an academic department; it's an exercise in applied biology."

Both institutions are also looking into partnerships with pharmaceutical companies and biotech firms. Melton says he is already in talks with several companies, such as Eli Lilly and Roche, to discuss partnering on some of his research. NYSCF's Solomon says the foundation is open to working with anyone who is interested in using stem cell technology and research to treat human disease. NYSCF is also establishing a screening lab to do preliminary drug screens on stem cells — not to substitute for a drug company, but to take the research as far as it can go in the lab, Solomon adds. Although partnering with industry is the ultimate goal, companies often have priorities and time limitations that are not always conducive to intense, basic research. "A challenge for pharma companies is that they have market-driven priorities which can shift," Solomon says. "But what we can do is make sure we keep the focus on achieving clinical results."

Chang says the disconnect between the research world and industry can be a problem. "There is this huge 'valley of death' in that we discover something and we can't figure out how to get it into the clinical scenario," he says. "Yet the pharmaceutical and biotech houses are saying that because of funding pressures, unless something works, [they're] not really that interested." Corporations are driven by a three-month success rate, Chang adds — something he calls the "quarterly mentality" of corporate America. "I don't think a board of directors of a publicly traded company can think beyond a year. If research took only a year, it would be called just 'search,'" he says. Because experiments sometimes take months to set up, and research takes time, it is often hard to fit that into the timeframe of a commercial enterprise; hence the gap that sometimes exists between bench and clinic.
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The funding problem

But for all their commitment to the work and for all the allure of stem cells themselves, researchers working in this field face some large obstacles, not the least of which is the continual threat of having to stop their work for lack of funding. For nearly a decade, public funding for stem cell research in the US through NIH has been subject to the political whims of the reigning administration and Congress. In 1996, Congress passed the Dickey-Wicker Amendment, a law that bans the use of federal money for any research that destroys or otherwise harms human embryos, and which has been renewed by the legislative body every year since. In 2001, former President George W. Bush enacted tough restrictions on stem cell research, again blocking federal funds from being used to study human embryonic stem cells except for the 21 cell lines that had already been developed. When President Obama took office, he lifted the restrictions, signing an executive order in 2009 that expanded the number of cell lines available for research using federal dollars and gave stem cell researchers all over the country a little more breathing room. Obama's order didn't directly address Dickey-Wicker, making a distinction between work that leads to the destruction of embryos and research done with the products of embryonic destruction.

But these same researchers were dealt yet another blow in August when federal judge Royce Lamberth ruled that using federal money for embryonic stem cell research was against the law. He called the Dickey-Wicker Amendment "unambiguous" in its prohibition against the destruction of embryos and concluded that the new NIH guidelines violated the amendment, saying that deriving stem cells and hESC were not "distinct pieces of research" as the Obama administration had argued. NIH told its staff scientists to stop any work they were doing with stem cells, and canceled reviews of several new grants. Extramural investigators with NIH funding were allowed to continue their work, but were told by the agency that once their money ran out, additional funds would not be forthcoming. A federal appeals court has since lifted Lamberth's injunction pending a review of the case, but in the meantime, federally funded researchers are working under a sword of Damocles.

"The legislation on stem cell research is terrible," Solomon says. "It's a disaster. You want your thrillers in your novels and in your movies, not in your medical research funding." NYSCF is not funded through NIH, so its researchers are safe from the decisions of administrations and judges, but they have several collaborators in other institutions who are terrified that their funding will stop. "Scientific research doesn't exist in a bubble," Solomon says. "When our collaborators can't work, it's not a happy moment for us. It's a problem."

The University of Wisconsin's Thomson says the majority of his grants are funded by NIH, and though he is optimistic that Lamberth's order will be overturned once the appeal is heard, he says it would "a disaster" if the order is upheld. "Historically, it's been very nerve-wracking, and the disappointment now is that I thought we were past it," Thomson says. "Obama opened it up considerably and now we're in a much more supportive environment, and yet everything's come to a screeching halt." What a lot of people are missing, he adds, is that stem cell research has come a long way since Dickey-Wicker was written, citing innovations like iPS cells. But human embryonic stem cells are still needed to make a comparison with the new iPS cell lines to determine whether they are really acting like natural stem cells, to see where they are deficient, and to determine a way to correct any deficiencies identified. However, what worries Thomson and others is that in order to keep away from the constant back-and-forth uncertainty about funding, many researchers will skip the comparison step and go straight to working with iPS cells. "I think it's a mistake because they're clearly not identical right now and we have to make them better," Thomson says.
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Melton says he believes human embryonic stem cell funding is not an issue that should be decided in the court system — Harvard's Stem Cell Institute is funded through a number of different grants, some of them federal. The only proper decision is going to be a legislative one, he adds, and the nation should pass a law that makes things like human cloning — something most researchers are opposed to — illegal, but legally codifies stem cell research as a legitimate field in which to spend federal research dollars. "Until we do that, we're going to be on the seesaw — 'Yes, you can,' 'No, you can't' — which is no way to do difficult, long-term projects," Melton says. "It's as if you're writing a story and you write a page, and then I tell you to wait a few days. Then you go back and write another paragraph, and I make you wait a month, and then you go back and write another paragraph and then have to wait again. At some point, you're going to say, 'This makes no sense,' and you're going to go do something else." At the moment, there probably has not been any permanent damage done, he adds, but researchers cannot continue to work with this uncertainty for much longer.

The chilling effect of these on-again-off-again legislative shenanigans also extends to the pharmaceutical and biotech companies that may be looking to partner with stem cell researchers, says Alan Trounson, president of the California Institute for Regenerative Medicine, which funds stem cell research in that state. "Any ethical issues are always a concern for companies who require funding investment from the community or from major investment institutions. They feel there's a certain risk, and it's a risk that many of them want to stay away from," he says.

In Europe, lawmakers have traditionally been more open to stem cell research than in the US, and promises of funding are more common. But in recent years, it seems that interest in the field has waned, forcing stem cell researchers to band together to demand the government keep up its end of the bargain and help researchers create viable medical therapies from their work. All government departments in the UK, including the Ministry of Science, have been told to expect budget cuts of 25 percent, despite letters from researchers and chairman of the House of Lords' science and technology committee, Lord John Krebs, that such deep funding cuts could drive researchers to leave — and take their investigations elsewhere.

In the US, Solomon believes that the solution to the federal funding problem must come from the legislature. "We can't keep fooling around," she says. "It's too important. We've got people with cancer, diabetes, heart disease, and they're in their doctor's office right now, and the doctor is saying, 'Well, I'm really sorry, but we don't have anything else that we can offer you right now.' And that's a bad answer." This is especially true considering the pace of research. Stem cells are already used to treat certain cancers, and are highly anticipated to be drug discovery tools. "If we keep taking our foot off the gas pedal and slamming on the brake at the federal level, that doesn't help the pace," Solomon says.

Now, researchers are looking for ways to circumvent federal funding. NYSCF has private donors, but the foundation's researchers also have several grants from New York State, which set money aside in its budget to fund stem cell research.
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In California, CIRM was formed in 2004 by the voters of the state through a referendum called Proposition 71. The ballot measure enabled the state to sell general obligation bonds up to $300 million a year for 10 years, the proceeds of which go to CIRM to fund researchers, Trounson says.

But these are options few researchers have. The New York State stem cell fund may provide a safety net for researchers in New York, but across the river in New Jersey, researchers are not as optimistic, Chang says. And in California, CIRM's future — after it uses up its $3 billion — is also up in the air. Trounson says the institute's board will likely ask for another proposition to be put up for a vote, but depending on the political mood and — more importantly for CIRM — the health of the economy, a fresh infusion of money is not a certainty.

Most researchers agree that progress in stem cell medicine is going to require more people who are passionate and committed to the field — something that is going to be hard to find if these federal funding problems keep cropping up. "There are a lot of people already [doing this research], but restriction are keeping others from looking at it, and it's delaying progress and it's a shame," Noggle says.

However, despite the current problems, researchers remain hopeful. "I think a lot of researchers did stay on the sidelines during the Bush administration because they didn't want to get involved," Thomson says. "I think with the new iPS cells and the Obama administration, people have jumped in, so it's taking off kind of logarithmically. There's been a surprising amount of progress in the last 10 years despite the small number of people working in the field." Medicine is not going to change tomorrow, he adds, "but drugs are already being screened on these cells, and they're already getting to the clinics faster, and they'll be safer because of it."

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