Celling Out

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Dr. Eva Feldman, director of the A. Alfred Taubman Medical Research Institute and the Program for Neurology Research and Discovery, is confident stem-cell research will lead to effective treatments for myriad diseases. Photographs by Roy Ritchie

Don’t even try to keep up with Eva Feldman. By 8 a.m. on a chilly December morning, the University of Michigan stem-cell researcher and professor of neurology has already put in a few hours writing e-mails and making phone calls connecting with colleagues and patients. And it’s only Monday.

Now she’s suited up for a stint in her research labs at the A. Alfred Taubman Medical Research Institute, where she serves as director. Clad in a red sweater, gray slacks, and Brooks running shoes, Feldman dashes past a bank of some two dozen refrigerators filled with stem-cell and tissue samples.

“People say I’m the only woman who has more refrigerators than shoes.”

After an hour in the labs, she’s back in her office checking on post-doctoral candidates’ stem-cell research, reviewing budgets, and pushing along grant applications. When that’s done, she pulls out a pair of black leather shoes, a hand mirror, blush, and a tube of lipstick from a filing cabinet to quickly transform herself into “Dr. Feldman.” Pulling on her crisp white doctor’s coat, she says, “I always try to look a little better for my patients,” and she hurries from the Biomedical Science Research Building to the neurological clinic at the University of Michigan Medical Center, where she’s on-call for the month of December.

A few days later, Feldman will repeat the process as she heads over to see patients in a clinic for neurodegenerative diseases that serves as the epicenter for everything she and her team of researchers work on in the labs.

In harshly lit exam rooms, she takes notes about symptoms and checks the strength of patients’ legs, arms, hands, and feet. She listens to daughters as they talk about fathers whose shoulder muscles don’t seem as strong, and wives who’ve noticed a 20-pound weight loss in their husbands. By the end of the day, she’ll have to tell at least one patient (and possibly several more) that he has ALS — amyotrophic lateral sclerosis — better known as Lou Gehrig’s disease.

In almost two decades as a doctor of neurology at the University of Michigan, Feldman has diagnosed hundreds of people with ALS. She and a team of doctors personally care for about 150 ALS patients in the clinic annually.

Feldman knows there’s no cure and no effective treatment for this disease, which lays waste to people’s bodies as their muscles weaken and eventually become paralyzed when nerve cells die and aren’t replaced. But something sets her apart from other doctors diagnosing and treating patients with ALS and other neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases: She’s a doctor and a researcher — a not-so-common occurrence in medicine.

After the tough morning hours in the clinic, Feldman is back in the lab, looking at nerve stem cells that are growing slender ribbons of cells called axons. Those pulsating cells — stained vibrant red and green to show up on slides — could hold the answers to treatments for the diseases she sees in her patients.

“To be frank, I couldn’t go into the lab and work as hard as I work if I didn’t have my patients as inspiration,” Feldman says during a rare quiet moment in her office. “And yet … I couldn’t face them many days — giving them the diagnoses I give — without being able to say there’s hope. I can tell them, ‘We’re working hard in the lab, and I have 30 young people keeping it going 24/7, so I’ll have therapies to bring to you.’”

A Cure for the Economy?

Stem cell therapies hold great promise — and not just for Feldman’s patients.

The University of Michigan and many people in the state, including politicians, business leaders, and voters who approved stem-cell legislation in 2008, believe that biomedical research — including stem-cell research — has the potential to help revive the state’s foundering economy.

Stem cells, derived from both embryos and adults, can be used to treat diseases at the cellular level, making them a powerful economic force if and when those therapies are commercialized. Stem cells — in particular, those derived from embryos — are able to become any type of cell in the body, from a kidney to an eye retina. In the future, stem cells can be used to grow tissues and organs, making tissue replacement a major area of investment and growth.

Stacey Sakowski, postdoctoral fellow in the Program for Neurology Research and Discovery, examines a zebrafish being used as an animal model for ALS. Photographs by Roy Ritchie

Moreover, stem cells are important in the development of other treatments and drugs for diseases, such as cancer and diabetes. Stem cells for these diseases can be used to grow the disease in the lab, allowing researchers to conduct drug trials efficiently and rapidly instead of testing therapies on humans or large animals, which can take years. The multipronged possibilities for stem cells could be a powerful economic force in the same way that products created by pharmaceutical companies such as Pfizer were once mainstays of the Michigan economy.

Indeed, life-sciences industries are already one of the few bright spots in Michigan’s economy. An analysis by the Anderson Consulting Group, using U.S. Census Bureau data, showed that the life sciences grew almost 10.7 percent from 1996 to 2006, while manufacturing dropped 24.7 percent during the same period. Nationally, economists predict — based on statistics compiled by the University Research Corridor, which includes the University of Michigan, Wayne State University, and Michigan State University  — that stem-cell research alone will receive private investments of $14.2 billion by 2012.

New investments by the University of Michigan could push those numbers even higher in the next several decades. In late 2008, the university bought the former Pfizer campus that had been left vacant when the drug giant pulled out of Ann Arbor. The site, now called the North Campus Research Complex, will house many different university research and development facilities, along with private companies. In mid-January, the university announced that the complex’s first tenants will be approximately 300 employees from the Michigan Institute for Clinical and Health Research, the medical school’s Institutional Review Board, the Office of Medical Development and Alumni Relations, the development and clinical trials offices for the UM Comprehensive Cancer Center, and clinical research billing.

But one of the complex’s main purposes is to provide world-class lab space for biomedical research, including stem cells — which the state lacks right now. The Pfizer campus formerly served as a global development research center that developed some of the company’s biggest drugs, such as Lipitor.

“Biomedical research will be the biggest initial player because the medical school itself has invested about $108 million for the purchase of the space,” says Stephen Forrest, the university’s vice president of research. “There’s little doubt that medical research will be one of the strengths of the campus. But you can look at the whole acquisition as a watershed moment for the University of Michigan. It’s the largest investment the university has made in 50 years, and it’s one that we will not fully take advantage of for another 50 years.”

A Cure or Controversy?

While Feldman and others are staking their careers and their futures on stem cells, this area of biomedical research is particularly fraught with political and ethical issues. Researchers consider stem cells derived from embryos to be the best to work with because they can be used to grow many different types of cells.

But some groups oppose destroying embryos to create stem cells, citing ethical and moral concerns. Under the Bush administration, scientists who received federal funding could only work on 21 existing stem cell lines, and no new lines were approved for federal research use. The Catholic Church, among other groups, has opposed most uses of embryonic stem cells, and its lobbying power has been felt throughout the country.

With the 2008 elections, however, the political tide began to turn toward supporting stem-cell research. In Michigan, voters passed Proposal 2, which allows people to donate their embryos left over from fertility treatments for scientific research — and possibly the creation of new lines. In the past, those embryos would’ve been thrown out as medical waste.  The proposal’s passage renewed hopes that the state would be a major player in what many researchers (Feldman included) believe will be one of the biggest breakthroughs in medicine in the first part of the 21st century.

In December 2009, the Obama administration reversed the Bush directive on stem cells and began approving new embryonic stem-cell lines that could be used in federally funded research. Stem-cell lines are created from taking cells from embryos and adults and growing them in the lab. Those lines can then be manipulated to grow into many different types of cells — and then into tissue and organs as the science progresses. Stem cells have the ability to develop into every type of cell in the body (usually the ones from embryos do this the best) or into replicas of themselves — these are often from adults and are used in research such as cancer stem-cell research in which cancer “stem cells” can be grown in the lab.

Private institutions must still create the lines, but the National Institutes of Health is already authorizing grants worth tens of millions of dollars to work on the new stem-cell lines.  These two changes could mean that the University of Michigan researchers will be able to create stem-cell lines that might be approved by the NIH under the new rules issued by the Obama administration.

Bhumsoo Kim, research assistant professor in the Program for Neurology Research and Discovery, prepares to run a test on neurons.
Photographs by Roy Ritchie

Yet even with Proposal 2 passed and the federal government in support of using taxpayer funds for stem-cell research, the ethical concerns of some groups remain. While stem-cell research may be allowed, there are big questions about how to control and regulate embryonic stem cells and subsequent research. In Michigan, a set of bills have been proposed by Sen. Tom George (R-Kalamazoo), one of two physicians in the Legislature, to implement Proposal 2.

Those bills have been met with concern by researchers, investors, and university officials who say the proposed laws would restrict what embryos would be allowed for use in stem-cell research.

“We are concerned about current efforts to pass a package of bills that would undermine Proposal 2,” wrote University of Michigan president Mary Sue Coleman in an e-mail. “Since the passage of Proposal 2, the university has embarked on an ambitious new embryonic stem cell research program. This package of bills, if approved, would [block] our efforts to find new disease treatments and cures.”

In early December, those bills were up for discussion in committee. That got the attention of a lot of people, including Stephen Rapundalo, president and CEO of MichBio, an industry trade association. “You know a lot of heads turned when Michigan was able to change the constitution and allowed work that hadn’t been allowed before” says Rapundalo, who worked at Pfizer before it closed down. “I would hate to see us have to go back on that in any way. It will [affect] our reputation. It will [affect] our ability to recruit top-flight researchers, much less stem-cell researchers. Michigan needs to project an attitude … that [we’re] open-minded, that we have a favorable business climate for biotech, biomedical research.”

To project that attitude to the powerful Detroit Economic Club, Feldman donned yet another hat last December, when she gave a science lecture to members in a move designed to garner support from people outside the research community. The timing was critical, since it looked as though Sen. George’s bills would make it out of committee and possibly be voted on before the end of the year. (In the end, that didn’t happen, and as of mid-January the bills were still in committee.)

In addition to her science lesson, Feldman had big news to announce: The university’s consortium on stem-cell therapies would begin accepting unused embryos, thanks to an investment of $2.2 million from the Taubman research center she oversees and the University of Michigan.

Feldman was introduced to the Detroit Economic Club by Alfred Taubman, the shopping mall magnate and one of her patients. “I asked her for a second opinion,” Taubman said, “and she said, for a second time, “You’ve got diabetes.’”

He was joking, of course. Instead, Taubman says he was “fascinated by [Feldman’s] intelligence and her ability to ferret out my problems so easily.” The doctor-patient relationship evolved to one of friendship, and now Taubman is one of Feldman’s biggest supporters and the biggest private donor to her stem-cell research.

Back at the Economic Club, Feldman uses her teaching voice as she instructs members in the packed room to shift their chairs and turn their attention to a large screen. On the screen, she flashes slides about the basic biology of the human body, reminding the audience of cell division and growth. As Feldman explains how stem-cell research works, her audience looks at photos of brightly colored stem cells in lime green, brilliant pinks, and vivid reds.

Then come the slides that the businesspeople understand: numbers like the $6.8 million the university received in stem-cell research grants and the $99.7 million the university received as part of the Obama administration’s stimulus grant funds. Wayne State University professor of economics Allen Goodman estimates that stem-cell research could bring close to 4,000 new jobs to the state, with an annual payroll of $254 million.

A Cure?

Feldman is willing to spend some time away from her labs and patients if it means moving stem-cell research closer to finding therapies and potential cures for her patients. But, whenever possible, she prefers to stay close to the two places that provide inspiration for her, especially after working more than 20 years on diseases that, so far, have no cure and very few treatment options.

Feldman diagnosed her first case of ALS when she was a resident at Johns Hopkins University in the late 1980s. When she returned to the University of Michigan, where she had received her Ph.D. in neurology, as well as her medical degree, she continued to work with patients who had some of the most troubling — and yet fascinating — diseases.

By the early 2000s, Feldman was already an eminent researcher doing work on more traditional treatments for neurodegenerative disorders. She began looking at a growth factor, called insulin-like growth factor-1. It was something that had already showed promise in rodents. “We got all the way to phase three clinical trial with 330 patients, but the therapy failed,” she says. “It was one of the reasons that I decided we needed to expand our horizons.”

 

In 2006, Feldman took a sabbatical  and went to the University of California-San Diego to take a look at the work of a researcher named Martin Marsala, who’s had success injecting stem cells into rodents after spinal cord injuries. “He has some fairly amazing movies where you would see a rat that was somewhat paralyzed begin to walk,” she says.

Feldman wanted to see what would happen if they injected stem cells into animals with ALS. The results were impressive, she says. “The stem cells incorporated into the spinal cord and maintained the nerve cells,” she says. “It kept them from becoming ill.”

Four years later, that work has evolved rapidly. The Food and Drug Administration approved the research team’s application to conduct a Phase 1 safety study of 18 ALS patients at Atlanta’s Emory University. If all goes well with the first phase, a second phase will be started to demonstrate the efficacy of the treatment. Feldman hopes to make it to the second phase in two years. A third and final phase, a Phase 3 trial would involve a large number of patients and, if that’s successful, the therapy will be approved.

Feldman knows that reaching such a goal is still a long way off. But, she says, “I’m over the moon that we’re in phase 1.” For her, this is just the first step toward a future where stem cells could stabilize people with a disease like ALS. “It’s like chicken soup for nerve cells,” she says, using an analogy she’s fond of to explain how nerve stem cells act as restoratives for damaged nerve cells. The second treatment would be for stem cells to actually replace cells that were lost because of diseases such as Parkinson’s.

Feldman’s passion and inspiration can be felt throughout her labs — and it even extends to her patients.

Researcher Stacey Sakowski began working with Feldman about three years ago, after finishing a degree in molecular biology at Wayne State University. Her grandfather had died of Parkinson’s, so she had some personal knowledge of what these types of diseases can do. Now she spends a great deal of her time watching zebra fish that have been given ALS, in hopes of better understanding how the disease works and what drugs and treatments might help conquer the disease.

The zebra fish are a critical component in Feldman’s lab. Thousands of them swim in tanks stacked in a basement lab. Zebra fish are vertebrates and share 99 percent of their DNA with humans, making them almost the perfect animal with which to work when it comes to human-stem-cell research.

Zebra fish can also be bred every week, resulting in hundreds of embryos and hundreds of fish within hours. Their short life cycles mean that the fish will start to show that they have ALS in just 24 hours; after 30 hours, Sakowski can see how the neurons are being affected. After just 15 hours, the fish begin to swim more slowly and exhibit other symptoms of the disease. That’s when, using nerve stem cells, Sakowski springs into action and watches to see how the treatment affects the infected zebra fish — and there’s some indication that the nerve cells are working to control the disease.

Sakowski also tests many drugs that have already been approved by the FDA to see if they have any effect on the fish. The rapid pace of the research — aided by the fast-growing zebra fish, as well as by using stem cells in the lab instead of in animals — gives Sakowski hope that treatments will finally be found for a disease that was discovered 70 years ago, yet is still incurable and untreatable.

But it’s Feldman’s patients who feel the impact of her passion for research the most. And some find ways to share that passion. Bob Schoeni, a University of Michigan professor and health researcher, first met Feldman when she diagnosed him with ALS in 2008. Schoeni doesn’t remember much from that day, he says, only that “she was someone who took charge, who saw something that wasn’t right and said, let’s get on it right away.”

After the news had settled in, Schoeni says he turned to his own work as a social scientist and researcher as a way of coping with the disease. “I wasn’t asking ‘Why me?’” he says. “But ‘What causes ALS?’”

In the past year, Schoeni has begun consulting with Feldman and other researchers who are looking at anecdotal evidence that shows ALS clusters in certain populations — Gulf War veterans, golf course superintendents, and Italian soccer players, for example. “I had written a book prior to my diagnosis about the connection between environmental, social, and economic factors and how they affect health,” Schoeni says. “It was natural for me to ask the questions of what may cause the disease.”

Feldman knows the work she’s doing now may not help patients like Schoeni, but she’s cautiously optimistic about the stem-cell trials being conducted at Emory University. “My hope is that early stem-cell therapy will lead to disease stabilization. Right now, ALS is a relentless disease. If I could tell patients like Bob that I could stabilize their disease, that it won’t progress, it wouldn’t be ideal, but I think he would be happy.”

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