From a Basement Office to a World-Renowned Research Center

LINCOLN - Dr. Howard Gendelman has cried twice in his life - first at age 4 after receiving a severe scolding for breaking a lamp, and next after walking into his office in the basement of a building at the University of Nebraska Medical Center.

The cold winds and slick sidewalks of that day - eight years ago come January - didn't help one bit in erasing one word from Gendelman's mind: bleak. Bleak weather, bleak basement, bleak future.

"And I said to myself, I'll never make it. A lot of my colleagues told me, 'You'll fall off the face of the earth. The world is flat, and if you go to Nebraska you're going to fall off the edge of it,' " he said.

But Gendelman did make it. At UNMC he's built a world-renowned research center that draws millions in grants, employs 40 researchers and technicians and even helps plug the worrisome "brain drain" that sees so many talented young people leaving the state.

David Volsky, a Columbia University professor of pathology who directs his own AIDS research center, describes Gendelman's research center this way: "Top of the line. Top-notch."

"He established a very active center that is publishing a lot of first-class publications, doing cutting-edge research in neurovirology and neurobiology," Volsky said of Gendelman. "He's well-funded, well-recognized by his scientific peers. Essentially people are looking forward to work from his center."

How did a brain-disease researcher who'd held prestigious positions at three world-renowned institutions on the East Coast end up in Nebraska? How did he turn a basement office and one technician into a laboratory that boasts the latest technology and explores eight categories of scientific pursuit? What learning opportunities does this offer UNMC students, and fellow professional scientists? This story, the second in a two-part series, will answer these questions. (Click here to read the first story, which concerns the science behind Gendelman's use of human fetal cells in his research.)

Along the way, we'll tell you how research that started looking at one of the great scourges of our times, AIDS, branched out into Parkinson's disease and Alzheimer's disease. Could the three be related? How does that affect the prospects for cures?

Finally, you'll read about three exciting scientific achievements that offer hope for thousands of people. An Omaha woman consigned to die from AIDS-related dementia was saved, using experimental treatments derived from Gendelman's research. Rats with damaged spinal cords moved their legs again, after treatments inspired by Gendelman's ideas. And a UNMC graduate student is pursuing a vaccine for Parkinson's disease, drawing on technological resources and expertise he says are available all in one place at just one laboratory in the country - Gendelman's, in Omaha, Nebraska.

Planting a Seed

It all started in Gendelman's garden, at age 10. He would experiment with different planting methods, fertilizers, watering methods to satisfy his curiosity about why things are the way they are.

"I was interested in why things do what they do," he said. "The whole concept of how and why things developed was something that really fascinated me."

Gendelman turned to medicine relatively late in his life. He received his bachelor's degree in Russian studies and Russian literature; science was only a minor. He had many other interests, classical guitar and theology among them. He chose medicine for his graduate studies because he believed it could integrate his love for science, the humanities and theology.

"Medicine is a unique field where you can give of yourself to other people, while at the same time solving scientific problems," he said.

His third year of medical school was to begin a theme that has echoed throughout his life: He pursued the practice of medicine repeatedly as a physician, but was repeatedly drawn away from clinical practice by his research interests. In that third year, he spent the summer studying infections of the nervous system and the brain with a neurovirologist. "To me it sounded kind of interesting how viruses can attack the brain and cause various motor and mental malfunctions," Gendelman said.

That summer, all of Gendelman's childhood excitement about scientific research came rushing back. He realized that as a practicing doctor, he could apply what other people had discovered. "But as a scientist, you are moving the frontiers of the cutting-edge forward," he said. "You are setting the stage for how medicine is practiced on a global scale."

In a fellowship at Baltimore's Johns Hopkins University, Gendelman was supposed to split his time among treating patients and conducting brain research. But the research so fascinated him that clinical work took a secondary role.

"What I studied there really set the stage for everything that has come in the future, including everything that we're doing right now," he said.

Sheep, Goats and AIDS

Gendelman and other Johns Hopkins researchers were studying brain-damaging viruses in sheep and goats, as a way to ultimately make discoveries about a disease that damages the human brain and nervous system: multiple sclerosis. Gendelman and his colleagues were the first scientists to show that the virus wasn't directly attacking the brain's most important component, the neurons. Rather, the virus was affecting the neurons' support cells, called glia. These glia normally nourish and protect the neurons, the "thinking cells" of the brain. But somehow, the virus turned these glia against the brain, and made them damage the neurons.

The same thing can happen in humans, in a process Gendelman now uses the old story about Dr. Jekyll and Mr. Hyde to describe. The glia in the vast majority of cases act like the good Dr. Jekyll, helping the brain function. But sometimes the glia can be transformed into the evil Mr. Hyde, hurting the brain. In the story, the evil persona isn't permanent - Mr. Hyde turns back into Dr. Jekyll. The analogy to that story is fitting here, because Gendelman's research has found ways to turn the evil glial cells back into good ones.

Early in his career, Gendelman saw his ideas published in premier scientific journals. His future would have seemed bright, were it not for one big hitch: No other research institute would hire him. Johns Hopkins was one of the few institutions in the world studying these sheep and goat viruses, which came from far-flung Iceland.

"Other institutions said, 'What kind of market is there for studying sheep and goats?' " It was expensive to maintain the animals, Gendelman said, and there wasn't a sound, clear linkage between the animal viruses and the human disease multiple sclerosis.

So Gendelman had resolved to leave research and go into private practice as a doctor. But just then, to use Gendelman's description, BANG! Human immunodeficiency virus, or HIV - the virus that causes AIDS - was discovered. The lab in which Gendelman worked was given an early sample of the AIDS virus. Scientists in the lab discovered that the sheep and goat viruses they'd been studying were in the same family of viruses as HIV.

"It became very clear that many of the observations we made in the sheep and goats were clearly applicable to AIDS," Gendelman said. "I went from getting no job requests … to the phone was just continuously ringing off the hook."

Gendelman next went to the lab of a prominent AIDS researcher at the National Institutes of Health in Washington. There, he and other scientists discovered that just like the animal virus he'd studied earlier in sheep and goats, the AIDS virus could affect the glial cells.

Federal grants to study AIDS were limited in the early days of the disease, so there were not many studies ongoing. As a result, every time the NIH lab in Washington published a paper, it would be a major national news story. Gendelman's picture appeared in Newsweek, the New York Times, and other publications. "It was an incredible time where every movement in my scientific life played out in the national press," he said.

Several years later, money started flowing to research and there were a consequent number of new opportunities opening for Gendelman. He had to decide if he wanted to start his own AIDS research lab, or become a student again and learn more. So he joined the U.S. Army in 1987.

Not to fight in the infantry, mind you. He went to Walter Reed Army Medical Center, known as "the bastion of immunology."

"They gave me a commission, and a decent salary, and a place to study with one of the best scientists in the world," Gendelman said. He spent five years at Walter Reed studying the body's immunity systems. The lab in which he worked made pioneering discoveries about immune cells, the way viruses live in the body, and how they can be combated.

"My relationship with the (research on the) brain, for those years I was at Walter Reed, was put on the back burner," Gendelman said. But the interest remained.

After the Gulf War came a round of downsizing in the Army that affected everyone dramatically, including staff at Walter Reed. Fearing he'd be the victim of a budget cut, Gendelman started looking for another place to go.

There Was No Place Like Nebraska

"I had a lot of offers, but when I came to Nebraska, it was because I really felt there were boundless opportunities," Gendelman said.

"One thing that really impressed me of the faculty and the recruiters, they said that our job is to help you be successful, to take all the roadblocks away, to allow you to be successful beyond your wildest expectations.

"That they were more concerned about me and my research than they were about themselves. The sense that really drove me toward Nebraska was they were really interested in building the university as a whole."

At Columbia University and Johns Hopkins, Gendelman said, officials were more interested in what he could do for them. This was reflected in those institutions' offers of startup funds, lab space and support. Whereas Nebraska's proposal, he said, "was more generous than any other offer."

So now we're back to that lonely basement office at the University of Nebraska Medical Center, where Gendelman stood alone on an icy January day and felt rather depressed.

"I had to decide what I wanted to do," Gendelman said. "I decided I wanted to take everything I'd learned so far, and get Hyde back into Jekyll."

In four years Gendelman went from just himself and a technician to $800,000 in federal grants and a well-respected, nationally-known laboratory. He spent the money on the best equipment possible, in fulfillment of his vision that he and the other researchers in the center should never be limited by technology.

"The only thing that should limit us in our science is our ability to think," Gendelman said.

Using fetal brain cells from elective abortions was just one of nine approaches Gendelman and his colleagues developed to discover how HIV crossed into the brain from the blood, and turned those good Dr. Jekyll glial cells into evil Mr. Hyde ones. As you'll recall reading in the first part of this two-part series on Gendelman's research, the fetal cells are used to create simulations of the human brain so that concepts first tested in animals can be proven to work in humans.

Many more techniques were created on the animal-testing side of things. The scientists found a way to afflict mice with human-like dementia, and study the behavior of the diseased mice. "We had to become mouse neuropsychologists, so to speak. That didn't exist before," Gendelman said.

Gendelman's team also developed a brain bank to accept donations of autopsied brains, because some concepts had to be proven in a whole brain, not just a reconstruction of it. They found a way to measure the conductive qualities of nerve cells, to see how well the brain's electrical commands were being transmitted in the body.

"So all these different techniques had to be developed, and it's not like we had it across the street," Gendelman said.

Saving a Life

In 1996 came a critical turning point. Gendelman was serving part-time as a clinical professor at Creighton University in Omaha. One Saturday morning while making routine doctor's rounds at Saint Joseph Hospital, Gendelman saw a woman with profound HIV-related dementia.

"It was clear that this case had possibly two or three weeks left to live," Gendelman said. This was before the sophisticated anti-AIDS drugs of today were available. "Someone said to me, 'Dr. Gendelman, there's no way you're going to fix this woman, because dementia is a direct damage to nerve cells. And if it's direct damage to nerve cells, it can't be reversed, it can't be fixed.' "

But Gendelman knew better. After all his research on how viruses affected the brain, research that had started way back with the sheep and goats at Johns Hopkins in Baltimore, he knew that the AIDS virus did not directly damage neurons. It acted on those Dr. Jekyll and Mr. Hyde glial cells, which then turned from helpful to harmful and poisoned the neurons. Gendelman's approach was not to cure the AIDS virus; that's a feat that still hasn't been accomplished today. Rather, he went after the glial cells and, with some novel experimental treatments based on his research, convinced them to abandon their evil ways and stop poisoning the woman's brain.

It worked. The woman, consigned to death, survived. She lives today, back at the teaching job she loves. She hasn't been publicly identified because of the stigma of AIDS; she goes by the pseudonym Karen. After recovering, she wrote of her experience and treatment in a foreword to Gendelman's 1998 textbook, "The Neurology of AIDS."

Karen wrote this: "It is nothing short of a miracle that I am alive today. Just two months ago my viral count was over one million and I was given two months to live. Today, my viral count is barely detectable. Dr. Gendelman always tells me that I am medical history in the making. This is the first time where the virus has fully produced so much damage in the brain and then reversed itself. I don't need to be a doctor to know this is a huge breakthrough.

"… Secondly, I still can't believe that of all the places in the world, Dr. Gendelman, with his expertise in HIV that affects the brain, is in Omaha, Nebraska."

For Gendelman, there was the profound joy of saving a life. But there was also the satisfaction of seeing his theories work in a real person. "It taught us scientifically that our hypothesis was right," he said.

By now Gendelman had an $800,000 research program, with 15 or 20 investigators working for him. He began to think that if HIV dementia affected the brain through the glial cells, maybe Alzheimer's and Parkinson's disease did the same. "It seemed to me like we had a moral and ethical obligation to pursue these diseases," he said.

So Gendelman went to the dean of the college of medicine with the idea of creating a research center of excellence (that's academic jargon for an extra-special research program). The NU Board of Regents approved, and the Center for Neurovirology and Neurodegenerative Disorders was born. The notoriety of Gendelman's research increased significantly with the opening of the center, and special recognition from the National Institutes of Health brought in even more grants and people.

As if this were not enough success, exciting news came from Israel. There, scientists had applied some of Gendelman's ideas about glial cells to reverse spinal-cord injuries in rats. These rats, which had been rendered quadriplegic, moved their legs again after the treatment.

"So first the hypothesis I'd been studying for 15 years was proven in the woman, in her brain, and then in the rat, in the spine," Gendelman said. "And all of a sudden, this is making some sense. This is not some pie in the sky, Dr. Gendelman in Nebraska idea. This is something that people accept."

'And then the sky fell'

In November 1999, an article appeared in the state's largest printed newspaper revealing that Gendelman received donations of fetal tissue from a Bellevue abortion doctor. The political reaction in heavily conservative Nebraska was instantaneous, and highly critical of Gendelman and the medical center. The governor spoke against the research, anti-abortion groups picketed the Board of Regents, and state senators made plans to introduce legislation banning the use of fetal cells in science.

"This is like a bomb," Gendelman said. "When this fetal-cell thing broke, it was like one day we were top of the universe, and the next day we were questioned in terms of our ethics and morality."

Gendelman had undergone scrutiny before, from fellow researchers. Scientists can be particularly blunt in telling their peers whether an idea has merit, or is pure bunk. But now, criticism of his science was coming from politicians and political activists who knew little or nothing of glial cells and immune factors and nourishing neurons. Especially troubling was the accusation that he was anti-life, that his use of fetal cells was leading to more abortions.

"I consider myself very pro-life. My whole life is pro-life. That's what I'd been doing," he said.

The controversy dominated Nebraska politics during the 2000 legislative session, where attempts to ban fetal-cell research ultimately failed. UNMC promised to pursue alternative sources for the brain cells needed in the research, first saying that miscarriages or ectopic pregnancies might be viable sources. They weren't, so Gendelman and his colleagues set to work creating a new set of technologies and procedures to get the cells from rapid autopsies. Terminally ill people, or the parents of terminally-ill children, allowed Gendelman's team to quickly collect brain tissue after death. Rapid autopsies have produced two of the three types of brain cells needed; the all-important neurons still elude the scientists.

The Quest Continues

Research has continued through the controversy at Gendelman's research center, in eight different areas of pursuit. A professional scientist leads each of the research programs, which makes for a lot of expertise packed into one floor of a building.

The diversity of experiments in the center has opened unique opportunities for the UNMC graduate students who study there. One of them is 29-year-old Eric Benner, a San Clemente, California native learning in a joint M.D./Ph.D program.

"I have had an absolute wonderful experience here," Renner said. "The project I am working on contains a lot of my own ideas. I don't think that there are a lot of labs here on this campus that would be able to support those ideas the way the center has."

In collaboration with Columbia University, Renner is helping create a way to simulate Parkinson's disease in mice. Renner's idea is to use a vaccine to get immune cells, called T-cells, into the area of the brain affected by Parkinson's. Once in the damaged environment, these T-cells actually secrete chemicals that reduce the damage that's occurred. For reasons that are still unknown, these T-cells only do this in damaged areas, not healthy ones.

"I think it's really important for grad students to pursue their own ideas," Renner said. "I think in order to fully pursue my own ideas, I literally could not have done this without the huge amount of integration that is going on here."

The loads of top-notch equipment "right down the hall" don't hurt, either. "I would imagine that there's certainly no place that's more technologically advanced than us," Renner said.

A scientist who's worked at Harvard Medical School and The Cleveland Clinic heads one of the research programs at Gendelman's center. Dr. Tsuneya Ikezu is deputy director of the center, and also chief of the Alzheimer's Disease Pathology unit.

"The unique thing of this research center is that the program of each individual is highly interactive," Ikezu said.

The center often invites other professional scientists to visit and see the laboratories. "They always say that they haven't seen such a research program which is so highly interactive and highly successful," Ikezu said.

"I would say this is one of the most successful programs within the UNMC and in the whole U.S. in this field."

Outside scientists agree. Dr. Subhash Dhawan is chief of the immunopathogenesis section of a research laboratory at the Food and Drug Administration's Center for Biologics Evaluation and Research.

"I think he's doing very important work in neurological diseases," Dhawan said of Gendelman. Of the research center, Dhawan added: "I think it's a fantastic, it's a remarkable center. To my knowledge I don't think any other center exists in the United States that is addressing these issues. And these are very critical issues."

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This story originally appeared in Nebraska StatePaper on December 22, 2000.

Gendelman Explains Science Behind Fetal-Tissue Research

LINCOLN - When Dr. Howard Gendelman searches for cures to brain diseases like Parkinson's and Alzheimer's, he's working with cells that act like Dr. Jekyll and Mr. Hyde.

Gendelman has spent more than 15 years, the last eight of them at the University of Nebraska Medical Center in Omaha, puzzling over a central question. It's this: Why do certain cells, known as glia, act good in most people, nourishing the brain, but in some people turn evil, destroying the brain?

A second question: Can Mr. Hyde be turned back into Dr. Jekyll? Can Hyde's evil work be reversed?

Until now scientific questions and answers about these diseases have been buried under a mountain of political questions about one of five major tools Gendelman uses in his research: brain cells from aborted fetuses. The revelation last November that Gendelman used cells donated by a Bellevue abortion doctor created a controversy that dominated public attention this year, and almost certainly will do so again in the coming year. He no longer receives cells from the Bellevue doctor, but the cells he uses still come mostly from elective abortions.

Seeing only political responses to this most interesting of topics may have generated new questions from people on both sides of the fetal-cell debate. Those who abhor the cells' use because of their connection with abortion, and those who believe using the cells is proper because lives may be saved, may well wonder:

• How are the cells used? Do they play a minor or major role in the research? Aren't there alternatives that are less morally objectionable to some?


• How did research that started looking at one of the great scourges of our times, AIDS, branch out into Parkinson's disease and Alzheimer's disease? Could the three be related? How does that affect the prospects for cures?


• How did a researcher who'd held prestigious positions at three world-renowned institutions on the East Coast end up in Nebraska? How did he turn a basement office and one technician into a laboratory that boasts the latest technology, employs 40 researchers and assistants and explores eight categories of scientific pursuit? What learning opportunities does this offer UNMC students?

In an interview with StatePaper on Wednesday, Gendelman considered these questions. You'll find the answers about fetal cells in this story; look to Friday's StatePaper to discover how AIDS research branched out, and how Gendelman found his way to Nebraska.

Recreating the Brain

You want to study diseases that damage the brain; diseases like AIDS-related dementia, Parkinson's and Alzheimer's that rob their victims of the ability to think and function. You've got an idea that maybe the glial cells that nourish the brain's key component, the neurons, can turn against the brain and become its enemy. You've even got ideas about how to reverse this process - how to change the evil Mr. Hyde to the good Dr. Jekyll. But how to test your idea? How do you recreate the human brain in a test tube?

Simulating the brain in a test tube requires having three types of brain cells: neurons, glia and astrocytes. Gendelman and his colleagues in Gendelman's Center for Neurovirology and Neurodegenerative Disorders have five methods for getting these cells. One of the methods involves fetal tissue.

• Donated blood: This first method examines how white blood cells, the disease-fighting component of blood, get into the brain - and what they do when they get there. Gendelman's center receives donations of blood for these studies.


• Surgical resections: From hospitals in other states, the center receives the tissue left over following surgical removal of brain tumors. Some of this tissue is usable for science, as is some of the tissue removed from the brains of people with epilepsy.


• Rapid autopsies: This is the center's newest method, being pursued in an attempt to eliminate the need for using aborted human fetal cells. "That is going pretty well," Gendelman said of the effort. It involves getting permission to extract brain tissue very quickly after a person's death, so the three cell types needed will not deteriorate. So far, the center has succeeded in getting the astrocytes and microglia - but not the all-important neurons.


• Rat and mouse fetal cells: Most of the center's tests are run first on rats and mice, Gendelman said. "We only use the human cells as proof of concept. All the diseases we study - Alzheimer's disease, Parkinson's disease, AIDS dementia -- are human diseases. They're not mouse diseases."


• Human fetal cells: This is the only source of healthy neurons which will help answer the questions Gendelman and his center's researchers are asking. Neurons transmit the electrical impulses with which the brain tells the body what to do. They're the thinking cells. They're supremely important.

As you've read before, but perhaps not all in one place, the sample of brain tissue Gendelman receives from aborted fetuses is the size of a pea. The samples used to come within hours of the abortion from the Bellevue abortion doctor, but now come via overnight delivery from a facility in Seattle, Washington. The samples do not come from the abortion procedure its opponents call partial-birth abortion. Only cells from first-trimester abortions are usable, Gendelman said, because they grow and develop too much after that stage. There's a misconception that the cells come from late-term abortion, or even living infants, Gendelman said, and that's not true.

Now the statement that fetal cells are the only source of neurons that will answer these specific questions raises more questions: Why? What makes Gendelman's research so special? Read on, and you'll find out.

Food for Thought

Gendelman's science revolves around those glial cells mentioned earlier. They produce chemicals and substances that provide the food and nourishment the neurons to function effectively.

For many years, Gendelman said, scientists thought glial cells had no major role in disease. But years of work at several different institutions helped Gendelman and his various colleagues prove otherwise. Somehow, an "insult" to these glial cells - from a virus like the human immunodeficiency virus that causes AIDS, or from an abnormal protein associated with Alzheimer's disease - could turn the glial cells from nurturing to destructive.

So Gendelman and his partners would take different components of the brain, infect them with HIV or afflict them with Parkinson's, and try to get these purposely disease brain parts to mimic a whole brain. "Obviously to do that, you need all the players," Gendelman said. "You can't have the play without the principal stars."

Taking top billing in this play is the neuron. Once again, Gendelman gets neurons from aborted human fetal tissues, and only from that source. Critics of this approach have said neurons can be obtained from stem cells, thus eliminating the need for using morally objectionable fetal cells. Stem cells are the body's precursor or ancestor cells; they develop into all the body's different parts. Scientists have found ways to transform them into many different forms. It's a promising, exciting and highly publicized area of research.

The Whole, Not the Parts

But, Gendelman said, stem cells won't answer the questions he's asking. Here's the problem: Stem cells could be transformed into neurons, sure. But if you did, you'd get just that - a neuron. You wouldn't get a test-tube simulation of a working brain, which is what's necessary to prove that ideas for disease treatments would actually work in the real world.

You can produce the individual parts (with stem cells), but you can't produce the whole," Gendelman said. "It would be like Star Wars without the spaceships."

Recovering neurons from human fetal brains brings not just the neurons, but the supporting glial cells. The neurons can't live by themselves because they depend on the nourishment of the glial cells. The result is a more accurate test-tube representation of the human brain, a place where treatments can be tried with more assurance that they'll work in living people.

One of these proposed treatments is a novel approach: A vaccine for Parkinson's disease. It's being studied right now in Gendelman's research center. Other big successes at the laboratory involve doing just what was mentioned before: Treating brain-destroying diseases by turning "evil" glial cells back into good ones. It's already saved one Omaha woman's life, and helped inspire researchers in Israel to cure heal normally irreversible spinal-cord injuries in rats. Look for more on all those discoveries in the second part of this story, in Friday's StatePaper.

Gendelman thinks his ideas have promise. He thinks treatments or cures for diseases that rob people of their thoughts could come from his ideas. He uses human fetal cells as one of his tools because he believes finding cures for disease requires many different approaches. Other scientists take their paths, and he takes his.

"We're approaching things differently," Gendelman said. "We're all moving toward the same goal.

"That's a fundamental tenet of science, I mean, the search for the truth. You don't know if one approach, both approaches, no approaches, is going to work."

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This story originally appeared in Nebraska StatePaper on December 21, 2000.