LINCOLN - The University of Nebraska Medical Center needs 40 cancer patients to help test a new "mini-transplant" procedure researchers think will be far less toxic than traditional allogenic bone-marrow transplants.
The technique developed by Drs. Steven Pavletic and Greg Bociek aims to reduce the risk and side effects of graft-versus-host disease - a potentially fatal side effect of allogenic transplants. In traditional transplants, bone marrow from related and unrelated donors is used to create a new, cancer-free immune system in the patient. The UNMC technique transplants bone marrow only from related donors, and uses much lower doses of radiation and very mild chemotherapy. Bone marrow is the source of the body's white blood cells, the immune system that fights infection.
Think of it this way: You've got two overlapping circles, with the patient standing in the middle of the overlap. One circle represents "graft vs. cancer," the good outcome doctors are looking for where donor bone-marrow cells attack the patient's cancer. The other circle represents "graft vs. host," the bad outcome doctors hope to avoid where donor cells attack other tissues in the patient's body. By carefully balancing transplanted cells, radiation and drug treatment, the UNMC doctors hope to have the patient touching as much as possible of the good circle and as little as possible of the bad circle.
"Our protocol is designed to be very non-aggressive," Pavletic said.
The UNMC approach also involves a new use for an old leukemia drug, pentostatin. "The drug plays an important role in suppressing the patient's immune cells during the transplant process," Pavletic said. This is another key thing to understand about the mini-transplants. Previously, doctors have used heavy doses of radiation and chemotherapy to essentially destroy a patient's immune system, so there will be a clear path for the foreign donated bone-marrow cells to do their work and not be rejected by the patient's own immune system. With mini-transplants, it's only necessary to suppress the patient's immune system -- putting him or her in far less danger of complications.
Those eligible for the study include patients who are responding to standard treatments, but whose disease is at a high risk of coming back; patients older than 60; those who can't tolerate high doses of radiation and chemotherapy; and those whose cancer returned after an autologous stem-cell transplant.
"We use this therapy with patients who otherwise have very little hope. Instead of no chance for survival, we hope we can achieve a 30 to 50 percent cure rate. We want to find something for these patients," Pavletic said.
For progress on cancer therapies to continue, Pavletic said, people need to continue to enroll in clinical trials like the one UNMC plans. He cited the Food and Drug Administration's recent unusually rapid approval of Gleevec, an oral therapy for some patients with chronic myeloid leukemia. Pavletic was the principal investigator for UNMC's portion of the national Gleevec study.
"The approval of Gleevec in two years was the most rapid FDA approval ever," Pavletic said. "This is one of the reasons why it is important for patients to participate in clinical trials.
"If we didn't have patients, we wouldn't have any of this information yet. Some people have reservations about participating in clinical trials like 'I'm going to be a guinea pig,' and so on. It's natural to have these reservations. But all these trials are therapeutic.
"The bottom line is we are doctors. We don't offer a trial if we think there is something better."
For more information about the study, call Karen Taylor at (402) 559-6729.
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This story originally appeared in Nebraska StatePaper on
Friday, June 8, 2001
Wednesday, May 30, 2001
UNMC Scientists Seek Patent for Potential Parkinson's Vaccine
LINCOLN - A University of Nebraska Medical Center research team including Dr. Howard Gendelman and a star graduate student are awaiting a patent on what could be a vaccine for Parkinson's disease.
Gendelman discussed his and graduate student Eric Benner's Parkinson's discoveries Wednesday at an Omaha seminar hosted by Nebraskans for Research. It was the first time Gendelman had publicly discussed the matter since December, when StatePaper exclusively reported limited details about the potential vaccine.
"This is kind of the first comprehensive effort to tackle Parkinson's research in this way," Gendelman said.
Parkinson's disease, a degenerative brain disorder, afflicts more than 1 million Americans with muscle stiffness, tremors, slowness of movement, poor balance and walking problems. Actor Michael J. Fox and former Attorney General Janet Reno have the disease.
Few new details about the potential vaccine beyond what StatePaper has already reported were available Wednesday. Gendelman said he must keep quiet about specifics or risk losing the patent. (As with all patents, approval isn't a sure thing.)
Unfortunately, things that must be kept quiet include how the vaccine would work, and on what kind of patient.
"The crux of how the vaccine works is all under patent," Gendelman said.
But Gendelman was able to release these new points of interest:
As StatePaper reported in December, the research into the potential vaccine got started with Benner's idea 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.
Collaboration between Gendelman, Benner and scientists in New York and Israel has been key in developing the ideas behind the potential vaccine. Benner has worked with the renowned Movement Disorders Division at Columbia University's Columbia-Presbyterian Medical Center in New York. Gendelman's contributions come in part from his Fulbright Scholar experiences studying spinal-cord regeneration at the famous Weizmann Institute of Science in Israel. Gendelman's ideas on the potential vaccine also are an outgrowth of his "Dr. Jekyll and Mr. Hyde" approach to other degenerative brain disorders like Alzheimer's disease and AIDS-related dementia.
You can read more about Gendelman's theories in this story, but here's the gist. Gendelman says brain cells called 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 classic story, the evil persona isn't permanent - Mr. Hyde turns back into Dr. Jekyll. The analogy to that story is fitting, because Gendelman's research has found ways to turn the evil glial cells back into good ones.
Also notable in this is the rarity of having a graduate student join a world-renowned researcher as co-discoverer of a patent. Even in the unlikely event the patent isn't approved, just being listed on the application will be one heck of a resume booster for Benner.
"He's unbelievable. We let this kid roll and he's performed spectacularly," Gendelman said. "He had a significant role in the discovery."
_____
This story originally appeared in Nebraska StatePaper on May 30, 2001.
Gendelman discussed his and graduate student Eric Benner's Parkinson's discoveries Wednesday at an Omaha seminar hosted by Nebraskans for Research. It was the first time Gendelman had publicly discussed the matter since December, when StatePaper exclusively reported limited details about the potential vaccine.
"This is kind of the first comprehensive effort to tackle Parkinson's research in this way," Gendelman said.
Parkinson's disease, a degenerative brain disorder, afflicts more than 1 million Americans with muscle stiffness, tremors, slowness of movement, poor balance and walking problems. Actor Michael J. Fox and former Attorney General Janet Reno have the disease.
Few new details about the potential vaccine beyond what StatePaper has already reported were available Wednesday. Gendelman said he must keep quiet about specifics or risk losing the patent. (As with all patents, approval isn't a sure thing.)
Unfortunately, things that must be kept quiet include how the vaccine would work, and on what kind of patient.
"The crux of how the vaccine works is all under patent," Gendelman said.
But Gendelman was able to release these new points of interest:
- If the patent is approved, proving the concept behind the potential Parkinson's vaccine will take about five years. Laboratory work on cell cultures is already underway. Experiments on mice that have been given a Parkinson's-like condition could begin soon. The timetable for human trials will depend, as always, on the Food and Drug Administration.
- The illegal trade in the street drug heroin actually has a positive side effect. A chemical used to purify heroin -- methylphenyltetrahydropyridine, or MPTP -- gives mice a condition close enough to human Parkinson's disease to be useful for research.
- Cells from aborted human fetal tissue are not being used in the Parkinson's vaccine research. (Gendelman uses fetal cells in other research projects.) If fetal cells were used in the vaccine research, Gendelman said, they would be used to prove the vaccine works, not to manufacture the vaccine itself.
As StatePaper reported in December, the research into the potential vaccine got started with Benner's idea 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.
Collaboration between Gendelman, Benner and scientists in New York and Israel has been key in developing the ideas behind the potential vaccine. Benner has worked with the renowned Movement Disorders Division at Columbia University's Columbia-Presbyterian Medical Center in New York. Gendelman's contributions come in part from his Fulbright Scholar experiences studying spinal-cord regeneration at the famous Weizmann Institute of Science in Israel. Gendelman's ideas on the potential vaccine also are an outgrowth of his "Dr. Jekyll and Mr. Hyde" approach to other degenerative brain disorders like Alzheimer's disease and AIDS-related dementia.
You can read more about Gendelman's theories in this story, but here's the gist. Gendelman says brain cells called 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 classic story, the evil persona isn't permanent - Mr. Hyde turns back into Dr. Jekyll. The analogy to that story is fitting, because Gendelman's research has found ways to turn the evil glial cells back into good ones.
Also notable in this is the rarity of having a graduate student join a world-renowned researcher as co-discoverer of a patent. Even in the unlikely event the patent isn't approved, just being listed on the application will be one heck of a resume booster for Benner.
"He's unbelievable. We let this kid roll and he's performed spectacularly," Gendelman said. "He had a significant role in the discovery."
_____
This story originally appeared in Nebraska StatePaper on May 30, 2001.
Saturday, March 10, 2001
$3 Million Grant Boosts Rapid-Autopsies Effort
LINCOLN - Dr. Howard Gendelman has received a prestigious national grant award that will help his University of Nebraska Medical Center research team continue developing rapid-autopsy techniques for brain-disease treatment.
The $3 million Javits Neuroscience Investigator Award is the second major award Gendelman has received in a year. Last March, Gendelman was named a Fulbright Scholar and studied nerve regeneration for eight months at the world-renowned Weizmann Institute in Israel.
Javits winners make up a rather exclusive club. One of last year's Nobel Laureates in medicine, Paul Greengard, received the award in 1985.
Gendelman's research center is one of just a handful in the world pursuing rapid autopsies as an alternative source of brain tissue for research into Alzheimer's disease, Parkinson's disease and AIDS-related dementia. UNMC launched a search for alternatives after controversy erupted 16 months ago over Gendelman's use of aborted fetal tissue in his brain-disease research. Anti-abortion activists who think the research encourages abortions have lobbied the Nebraska Legislature to ban the use of aborted fetal tissue. A ban proposal failed last year, but a similar one is pending this year.
Gendelman said the Javits Award represented crucial national recognition and validation of his rapid-autopsy efforts, which he began a relatively short time ago in February 2000. When he was under consideration for the award last year, he said, the program he'd built from scratch was in its infancy.
"If I don't get the money at the national level, this research ends," he said.
Rapid autopsies performed within an hour of brain donors' deaths have yielded two of the three types of brain cells required in Gendelman's research. Gendelman and just a few other scientists have managed to derive viable astrocytes and microglia, two types of brain-support cells, from rapid autopsies. But the brain's all-important "thinking" cells, the neurons, have so far eluded everyone. Gendelman returned to Nebraska this week from Arizona, where he and his research team studied rapid-autopsy techniques at the science center that pioneered them, the Sun Health Research Institute.
A national committee of scientists reviewed Gendelman's entire body of work, rapid-autopsy efforts included, and decided to fund it for an unusually long length of time -- seven years. Grants other than the Javits Award normally don't run longer than five years.
"It puts a stamp of approval that we trust the quality of his research enough that we believe he will continue to be productive over the next seven years," said Al Kerza-Kwiatecki, program director for infectious diseases of the nervous system at the National Institute of Neurological Disorders and Stroke, a division of the National Institutes of Health. His institute administers the awards.
Kerza-Kwiatecki continued: "That's quite a benefit to give a scientist this kind of vote of confidence, as it's very time-consuming to make scientists submit new documentation every couple years so their progress can be monitored."
UNMC Chancellor Dr. Harold Maurer congratulated Gendelman and his research team. "I think the Javits Award sends a strong message that UNMC is making impressive strides in its research efforts on neurodegenerative disorders," Maurer said. "It is among the best in the nation, and we are very proud of this accomplishment. The fact that a large portion of the proposed work will come from alternative sources other than fetal cells demonstrates the commitment and progress made by our scientists."
The $3 million Javits Award doesn't end the financial challenges facing UNMC's practically brand-new rapid-autopsy program. The Javits grant fund scientific experiments on the brain tissue obtained from rapid autopsies, but does nothing to help in the extremely expensive and time-consuming process of conducting the rapid autopsies. The logistics are challenging; because brain donors don't always die during business hours, a large team of doctors, nurses, technicians and scientists must be kept on call 24 hours a day to collect brain tissue on a moment's notice. (For more on the challenges involved, see StatePaper's article "Rapid Autopsies the Tool in Arizona, Nebraska Quest for Neurons.")
UNMC has already spent $400,000 on developing the program, but more money is needed to fund the ongoing logistical needs. Gendelman said he's applying for other national grants to that end, and other fundraising efforts are still under discussion.
In 1983, Congress created the Senator Jacob Javits Awards in the Neurosciences. They were established to honor the late Sen. Jacob Javits of New York, who suffered from Lou Gehrig's disease. Awardees must have demonstrated exceptional scientific excellence and productivity in one of the areas of neurological research supported by the National Institute of Neurological Disorders and Stroke, have proposals of the highest scientific merit, and be judged highly likely to be able to continue to do research on the cutting edge of their science for the next seven years.
Gendelman said everyone at his research center, and people like the UNMC chancellor and University of Nebraska president who supported it, deserved credit for the Javits achievement. "Any award of this nature is never a single person. I would love to take credit for everything I do. But the truth is this is an award for our entire team, this research center.
"It's the team, again not me, who's turned the adversity into triumph. I couldn't be more proud of the people who have worked with me."
_____
This story originally appeared in Nebraska StatePaper on March 10, 2001.
The $3 million Javits Neuroscience Investigator Award is the second major award Gendelman has received in a year. Last March, Gendelman was named a Fulbright Scholar and studied nerve regeneration for eight months at the world-renowned Weizmann Institute in Israel.
Javits winners make up a rather exclusive club. One of last year's Nobel Laureates in medicine, Paul Greengard, received the award in 1985.
Gendelman's research center is one of just a handful in the world pursuing rapid autopsies as an alternative source of brain tissue for research into Alzheimer's disease, Parkinson's disease and AIDS-related dementia. UNMC launched a search for alternatives after controversy erupted 16 months ago over Gendelman's use of aborted fetal tissue in his brain-disease research. Anti-abortion activists who think the research encourages abortions have lobbied the Nebraska Legislature to ban the use of aborted fetal tissue. A ban proposal failed last year, but a similar one is pending this year.
Gendelman said the Javits Award represented crucial national recognition and validation of his rapid-autopsy efforts, which he began a relatively short time ago in February 2000. When he was under consideration for the award last year, he said, the program he'd built from scratch was in its infancy.
"If I don't get the money at the national level, this research ends," he said.
Rapid autopsies performed within an hour of brain donors' deaths have yielded two of the three types of brain cells required in Gendelman's research. Gendelman and just a few other scientists have managed to derive viable astrocytes and microglia, two types of brain-support cells, from rapid autopsies. But the brain's all-important "thinking" cells, the neurons, have so far eluded everyone. Gendelman returned to Nebraska this week from Arizona, where he and his research team studied rapid-autopsy techniques at the science center that pioneered them, the Sun Health Research Institute.
A national committee of scientists reviewed Gendelman's entire body of work, rapid-autopsy efforts included, and decided to fund it for an unusually long length of time -- seven years. Grants other than the Javits Award normally don't run longer than five years.
"It puts a stamp of approval that we trust the quality of his research enough that we believe he will continue to be productive over the next seven years," said Al Kerza-Kwiatecki, program director for infectious diseases of the nervous system at the National Institute of Neurological Disorders and Stroke, a division of the National Institutes of Health. His institute administers the awards.
Kerza-Kwiatecki continued: "That's quite a benefit to give a scientist this kind of vote of confidence, as it's very time-consuming to make scientists submit new documentation every couple years so their progress can be monitored."
UNMC Chancellor Dr. Harold Maurer congratulated Gendelman and his research team. "I think the Javits Award sends a strong message that UNMC is making impressive strides in its research efforts on neurodegenerative disorders," Maurer said. "It is among the best in the nation, and we are very proud of this accomplishment. The fact that a large portion of the proposed work will come from alternative sources other than fetal cells demonstrates the commitment and progress made by our scientists."
The $3 million Javits Award doesn't end the financial challenges facing UNMC's practically brand-new rapid-autopsy program. The Javits grant fund scientific experiments on the brain tissue obtained from rapid autopsies, but does nothing to help in the extremely expensive and time-consuming process of conducting the rapid autopsies. The logistics are challenging; because brain donors don't always die during business hours, a large team of doctors, nurses, technicians and scientists must be kept on call 24 hours a day to collect brain tissue on a moment's notice. (For more on the challenges involved, see StatePaper's article "Rapid Autopsies the Tool in Arizona, Nebraska Quest for Neurons.")
UNMC has already spent $400,000 on developing the program, but more money is needed to fund the ongoing logistical needs. Gendelman said he's applying for other national grants to that end, and other fundraising efforts are still under discussion.
In 1983, Congress created the Senator Jacob Javits Awards in the Neurosciences. They were established to honor the late Sen. Jacob Javits of New York, who suffered from Lou Gehrig's disease. Awardees must have demonstrated exceptional scientific excellence and productivity in one of the areas of neurological research supported by the National Institute of Neurological Disorders and Stroke, have proposals of the highest scientific merit, and be judged highly likely to be able to continue to do research on the cutting edge of their science for the next seven years.
Gendelman said everyone at his research center, and people like the UNMC chancellor and University of Nebraska president who supported it, deserved credit for the Javits achievement. "Any award of this nature is never a single person. I would love to take credit for everything I do. But the truth is this is an award for our entire team, this research center.
"It's the team, again not me, who's turned the adversity into triumph. I couldn't be more proud of the people who have worked with me."
_____
This story originally appeared in Nebraska StatePaper on March 10, 2001.
Sunday, February 25, 2001
Rapid Autopsies the Tool in Arizona, Nebraska Quest for Neurons
Editor's Note: This is Part Two of a two-part story on rapid autopsies. Part One reported that University of Nebraska Medical Center scientists are traveling next week to observe rapid-autopsy techniques at a research institute in Arizona.
LINCOLN - Rapid autopsies used to obtain brain tissue for medical research are exceedingly complicated and difficult, but offer fascinating scientific rewards for the effort.
Scientists at the University of Nebraska Medical Center are in the intermediate stages of developing a rapid-autopsy program, so they can stop using aborted fetal tissue in trying to treat Alzheimer's and other diseases. Anti-abortion activists and politicians have put pressure on UNMC to stop using the aborted tissue, and are trying again to ban its use after a legislative attempt failed last year.
Next week UNMC scientists will visit a research institute in Arizona that became a pioneer in rapid-autopsy techniques because of a ban on fetal-tissue research in that state. Arizona's ban has since been ruled unconstitutional, but Sun Health Research Institute's experience continues to be of interest to scientists around the country. The Sun City, Arizona institute's lineup of visitors includes researchers from UNMC Tuesday through Friday, Wayne State University in April, and New York University sometime in the spring.
Rapid autopsies are performed on people who have agreed to donate their brains to science. In the case of Sun Health's around 2,800 donors, they're people who have put stickers on their driver's licenses and medical charts that indicate they're brain donors. They've also informed friends and family so that as soon as they die, someone will call Sun Health's 24-hour autopsy-team hotline.
They're called rapid autopsies for a reason, after all. It turns out that when brain activity ceases and person is clinically dead, many brain cells die off and become useless for research. But, some cells can survive if doctors can extract them within an hour of death. So a team of doctors, nurses, technicians and others must be on call 24 hours a day, 365 days a year -- because people don't always die from 8 a.m. to 5 p.m. on business days.
"You have to have attended to every detail in advance as far as possible," said Joseph Rogers, president of Sun Health.
When brain donors die, they're brought to Sun Health. Doctors remove a 40-gram sample of brain tissue, about half the size of your fist. The procedure is not disfiguring; donors can still have an open-casket funeral.
The sample is immediately plunged into an ice-cold nutrient solutions. Chemicals are then used to disassociate, or dissolve, the tissue sample into its several different component cell types. These cells are then centrifuged -- spun around at extremely high speeds -- so that they clump together in different groups, based on their weight and other properties. Three types of cells are put in fancy test tubes with nutrient solutions that approximate conditions in the living brain, and the test tubes are placed in incubators that keep them at body temperature. The cells attach to the bottoms of the test tubes -- and survive.
"Now we've got for the first time living cells from Alzheimer's patients that we can test," Rogers said. "You can't test drugs on dead tissue. They don't do anything."
There are three cell types Sun Health works with: Neurons, microglia and astrocytes. These are the same kinds of cells UNMC now gets from samples of fetal brain tissue, but would like to obtain from rapid autopsies.
Unfortunately for the UNMC researchers, studying Sun Health's techniques won't mean an instantaneous ability to abandon fetal tissue. "With microglia and astrocytes, it took us six years just to work out the details," Rogers said. "The neurons are still a work in progress."
And there's the problem. UNMC's five reported rapid autopsies have yielded the support, or helper, cells called microglia and astrocytes, but not the all-important "thinking" cells, the neurons. (For more on the roles of these cells, see StatePaper's article, "Gendelman Explains Science Behind Fetal-Tissue Research.")
"We don't get very many nerve cells that are still alive," Rogers said. They're many times more fragile than astrocytes, which Sun Health has managed to keep alive for several months; and microglia, which last for two months.
The neurons can be kept around for one month, but they're not functional like the astrocytes and microglia. The process of separating the neurons from the other cell types amputates the nerve fibers, the all-important connections between neurons that form the basis for how the brain functions.
"We can't get the nerve fibers to re-grow," Rogers said. It's been a major achievement just to keep the neurons alive for short periods of time. "The nerve cells are extremely fragile. But in some ways, they're the prize. It is loss of nerve cells, and the connections between nerve cells, that cause Alzheimer's disease."
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This story originally appeared in Nebraska StatePaper on February 25, 2001.
LINCOLN - Rapid autopsies used to obtain brain tissue for medical research are exceedingly complicated and difficult, but offer fascinating scientific rewards for the effort.
Scientists at the University of Nebraska Medical Center are in the intermediate stages of developing a rapid-autopsy program, so they can stop using aborted fetal tissue in trying to treat Alzheimer's and other diseases. Anti-abortion activists and politicians have put pressure on UNMC to stop using the aborted tissue, and are trying again to ban its use after a legislative attempt failed last year.
Next week UNMC scientists will visit a research institute in Arizona that became a pioneer in rapid-autopsy techniques because of a ban on fetal-tissue research in that state. Arizona's ban has since been ruled unconstitutional, but Sun Health Research Institute's experience continues to be of interest to scientists around the country. The Sun City, Arizona institute's lineup of visitors includes researchers from UNMC Tuesday through Friday, Wayne State University in April, and New York University sometime in the spring.
Rapid autopsies are performed on people who have agreed to donate their brains to science. In the case of Sun Health's around 2,800 donors, they're people who have put stickers on their driver's licenses and medical charts that indicate they're brain donors. They've also informed friends and family so that as soon as they die, someone will call Sun Health's 24-hour autopsy-team hotline.
They're called rapid autopsies for a reason, after all. It turns out that when brain activity ceases and person is clinically dead, many brain cells die off and become useless for research. But, some cells can survive if doctors can extract them within an hour of death. So a team of doctors, nurses, technicians and others must be on call 24 hours a day, 365 days a year -- because people don't always die from 8 a.m. to 5 p.m. on business days.
"You have to have attended to every detail in advance as far as possible," said Joseph Rogers, president of Sun Health.
When brain donors die, they're brought to Sun Health. Doctors remove a 40-gram sample of brain tissue, about half the size of your fist. The procedure is not disfiguring; donors can still have an open-casket funeral.
The sample is immediately plunged into an ice-cold nutrient solutions. Chemicals are then used to disassociate, or dissolve, the tissue sample into its several different component cell types. These cells are then centrifuged -- spun around at extremely high speeds -- so that they clump together in different groups, based on their weight and other properties. Three types of cells are put in fancy test tubes with nutrient solutions that approximate conditions in the living brain, and the test tubes are placed in incubators that keep them at body temperature. The cells attach to the bottoms of the test tubes -- and survive.
"Now we've got for the first time living cells from Alzheimer's patients that we can test," Rogers said. "You can't test drugs on dead tissue. They don't do anything."
There are three cell types Sun Health works with: Neurons, microglia and astrocytes. These are the same kinds of cells UNMC now gets from samples of fetal brain tissue, but would like to obtain from rapid autopsies.
Unfortunately for the UNMC researchers, studying Sun Health's techniques won't mean an instantaneous ability to abandon fetal tissue. "With microglia and astrocytes, it took us six years just to work out the details," Rogers said. "The neurons are still a work in progress."
And there's the problem. UNMC's five reported rapid autopsies have yielded the support, or helper, cells called microglia and astrocytes, but not the all-important "thinking" cells, the neurons. (For more on the roles of these cells, see StatePaper's article, "Gendelman Explains Science Behind Fetal-Tissue Research.")
"We don't get very many nerve cells that are still alive," Rogers said. They're many times more fragile than astrocytes, which Sun Health has managed to keep alive for several months; and microglia, which last for two months.
The neurons can be kept around for one month, but they're not functional like the astrocytes and microglia. The process of separating the neurons from the other cell types amputates the nerve fibers, the all-important connections between neurons that form the basis for how the brain functions.
"We can't get the nerve fibers to re-grow," Rogers said. It's been a major achievement just to keep the neurons alive for short periods of time. "The nerve cells are extremely fragile. But in some ways, they're the prize. It is loss of nerve cells, and the connections between nerve cells, that cause Alzheimer's disease."
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This story originally appeared in Nebraska StatePaper on February 25, 2001.
Saturday, February 24, 2001
UNMC Scientists to Study Rapid Autopsies in Arizona
Editor's Note: This is the first part of a two-part story. Look for Part Two in Sunday's StatePaper.
LINCOLN - Dr. Howard Gendelman and a team of University of Nebraska Medical Center scientists are traveling to an Arizona institute next week to further their search for research alternatives to aborted fetal tissue.
Scientists at the Sun Health Research Institute in Sun City, Arizona, have extensive experience with rapid autopsies. That's the technique UNMC started pursuing last year so it can stop using tissue from elective abortions in its effort to treat Alzheimer's disease, Parkinson's disease and AIDS-related dementia. For more than a year now, UNMC's research has been at the center of controversy and attempts in the Legislature to ban it.
Sun Health researchers have had limited success in keeping alive neurons, the brain cells that are key to Alzheimer's research at UNMC and other institutions. They've had far more success working with two other types of brain cells, astrocytes and microglia, that UNMC researchers have also successfully obtained from rapid autopsies in Nebraska. UNMC so far hasn't reported success in finding living, scientifically useful neurons.
Rapid autopsies must be conducted quickly, within an hour or two of the donor's death. The science behind rapid autopsies is some fascinating stuff; you'll find some interesting details in the second part of this story, appearing in Sunday's StatePaper.
UNMC isn't the only institution interested in Sun Health's work. Scientists from Wayne State University will visit in April, and New York University researchers sometime this spring, said Joseph Rogers, president of Sun Health. His institute has perfected a brain-donor program which works so fast that it allows doctors to obtain small amounts of still-living tissue from a person who is clinically brain dead.
"I think the same methods should be applicable in any laboratory setting, and we are more than willing to share these techniques, especially with talented people like Dr. Gendelman and his scientists," Rogers said.
Gendelman said he and four other UNMC staff would learn about Sun Health's approach to the complicated logistics involved in brain-donor programs and rapid autopsies, and share their logistics ideas and scientific discoveries in return.
"I look at this as a mutual exchange of ideas between two of the premier groups in the country who are using these types of techniques," Gendelman said. While there are many institutions across the country using fetal tissue in medical research, Gendelman's Center for Neurovirology and Neurodegenerative Disorders is one of just a handful seeking alternatives to using fetal brain tissue.
Going on the four-day trip starting Tuesday will be Gendelman, two technologists, a graduate student and William H.C. Brown II, coordinator of UNMC's rapid-autopsy program. The trip is the latest development in UNMC's search for alternatives; earlier, the medical center hired Brown, and before that purchased a highly specialized and expensive microscope to aid the rapid-autopsies program.
Rogers and his team in Arizona have some unique advantages in finding brain donors, which Gendelman's team may not be able to match. Sun City is a retirement community of 140,000 people northwest of Phoenix where the average age is 72 and the minimum age is 55.
"You need a mature and personally generous community to make this work," Rogers said. "Senior citizens are much more mature about their earthly body; they're not so concerned about a beautiful funeral service as they are in getting to heaven.
"The people in our community have signed up for our program in droves." Specifically, two percent of residents -- or about 2,800 people -- have taken steps to ensure Sun Health's 24-hour rapid-autopsy team is notified immediately when they die. They need not be concerned about a beautiful funeral, however. Rogers said his team's technique for removing brain tissue is not disfiguring, and allows for an open casket at the funeral.
Rogers said that when he worked with a brain-donor program in Massachusetts, he had to draw on an eight-state area to find the number of elderly donors he now has in an eight-mile radius. A comparison of elderly populations between Sun City, Arizona, and Nebraska isn't entirely appropriate here, however, because Sun Health's and UNMC's approaches to curing Alzheimer's differ.
Sun Health looks more toward working with tissue already impacted by Alzheimer's, Gendelman said, while UNMC takes healthy tissue and "gives" it Alzheimer's in order to find ways to stop the disease before it begins. So UNMC wouldn't necessarily be looking to the same donor population for its rapid-autopsy program. In fact, three of the five rapid autopsies UNMC has reported performing so far have been on infant donors.
The UNMC trip to Arizona will be an intermediate stage in developing a rapid-autopsy program Gendelman hopes will be around for the long haul. His team consulted with people at Sun Health by telephone while starting the program, but the Nebraskans had a lot of groundwork to do on their own.
"We had to start a brand-new research program, totally from scratch, that involved a complex logistical network and, more importantly, a complex scientific network," Gendelman said.
The scientists at Sun Health will be able to offer experienced advice on how to enroll people in a brain-donor program. When research scientists approach a family whose loved one will die of a terrible disease, the scientists face a big challenge.
"The last thing that family is thinking of is donating a brain to science," Gendelman said. The Arizona rapid-autopsy team will help UNMC personnel understand how to approach grieving family members.
Another goal of the trip is to ensure the long-term viability of UNMC's rapid-autopsy program. Things have gone well so far, Gendelman said -- his research team has received enormous financial and logistical support from people in all levels at the medical center. "Virtually every person in this university has been phenomenal," he said.
But despite the program's achievements so far, basic arrangements still must be made. Where will the program get the long-term funding necessary to keep an autopsy team on call 24 hours a day, 365 days a year? How will the medical center gain the community support necessary for such a massive undertaking?
These are questions Gendelman hopes to get answers for not only in Arizona, but from Nebraskans when he returns to Omaha. Gendelman said he and the medical center are sincere in saying, "Look, we're in this together."
"It's our medical center," Gendelman said. "It's a medical center for all Nebraskans."
_____
This story originally appeared in Nebraska StatePaper on February 24, 2001.
LINCOLN - Dr. Howard Gendelman and a team of University of Nebraska Medical Center scientists are traveling to an Arizona institute next week to further their search for research alternatives to aborted fetal tissue.
Scientists at the Sun Health Research Institute in Sun City, Arizona, have extensive experience with rapid autopsies. That's the technique UNMC started pursuing last year so it can stop using tissue from elective abortions in its effort to treat Alzheimer's disease, Parkinson's disease and AIDS-related dementia. For more than a year now, UNMC's research has been at the center of controversy and attempts in the Legislature to ban it.
Sun Health researchers have had limited success in keeping alive neurons, the brain cells that are key to Alzheimer's research at UNMC and other institutions. They've had far more success working with two other types of brain cells, astrocytes and microglia, that UNMC researchers have also successfully obtained from rapid autopsies in Nebraska. UNMC so far hasn't reported success in finding living, scientifically useful neurons.
Rapid autopsies must be conducted quickly, within an hour or two of the donor's death. The science behind rapid autopsies is some fascinating stuff; you'll find some interesting details in the second part of this story, appearing in Sunday's StatePaper.
UNMC isn't the only institution interested in Sun Health's work. Scientists from Wayne State University will visit in April, and New York University researchers sometime this spring, said Joseph Rogers, president of Sun Health. His institute has perfected a brain-donor program which works so fast that it allows doctors to obtain small amounts of still-living tissue from a person who is clinically brain dead.
"I think the same methods should be applicable in any laboratory setting, and we are more than willing to share these techniques, especially with talented people like Dr. Gendelman and his scientists," Rogers said.
Gendelman said he and four other UNMC staff would learn about Sun Health's approach to the complicated logistics involved in brain-donor programs and rapid autopsies, and share their logistics ideas and scientific discoveries in return.
"I look at this as a mutual exchange of ideas between two of the premier groups in the country who are using these types of techniques," Gendelman said. While there are many institutions across the country using fetal tissue in medical research, Gendelman's Center for Neurovirology and Neurodegenerative Disorders is one of just a handful seeking alternatives to using fetal brain tissue.
Going on the four-day trip starting Tuesday will be Gendelman, two technologists, a graduate student and William H.C. Brown II, coordinator of UNMC's rapid-autopsy program. The trip is the latest development in UNMC's search for alternatives; earlier, the medical center hired Brown, and before that purchased a highly specialized and expensive microscope to aid the rapid-autopsies program.
Rogers and his team in Arizona have some unique advantages in finding brain donors, which Gendelman's team may not be able to match. Sun City is a retirement community of 140,000 people northwest of Phoenix where the average age is 72 and the minimum age is 55.
"You need a mature and personally generous community to make this work," Rogers said. "Senior citizens are much more mature about their earthly body; they're not so concerned about a beautiful funeral service as they are in getting to heaven.
"The people in our community have signed up for our program in droves." Specifically, two percent of residents -- or about 2,800 people -- have taken steps to ensure Sun Health's 24-hour rapid-autopsy team is notified immediately when they die. They need not be concerned about a beautiful funeral, however. Rogers said his team's technique for removing brain tissue is not disfiguring, and allows for an open casket at the funeral.
Rogers said that when he worked with a brain-donor program in Massachusetts, he had to draw on an eight-state area to find the number of elderly donors he now has in an eight-mile radius. A comparison of elderly populations between Sun City, Arizona, and Nebraska isn't entirely appropriate here, however, because Sun Health's and UNMC's approaches to curing Alzheimer's differ.
Sun Health looks more toward working with tissue already impacted by Alzheimer's, Gendelman said, while UNMC takes healthy tissue and "gives" it Alzheimer's in order to find ways to stop the disease before it begins. So UNMC wouldn't necessarily be looking to the same donor population for its rapid-autopsy program. In fact, three of the five rapid autopsies UNMC has reported performing so far have been on infant donors.
The UNMC trip to Arizona will be an intermediate stage in developing a rapid-autopsy program Gendelman hopes will be around for the long haul. His team consulted with people at Sun Health by telephone while starting the program, but the Nebraskans had a lot of groundwork to do on their own.
"We had to start a brand-new research program, totally from scratch, that involved a complex logistical network and, more importantly, a complex scientific network," Gendelman said.
The scientists at Sun Health will be able to offer experienced advice on how to enroll people in a brain-donor program. When research scientists approach a family whose loved one will die of a terrible disease, the scientists face a big challenge.
"The last thing that family is thinking of is donating a brain to science," Gendelman said. The Arizona rapid-autopsy team will help UNMC personnel understand how to approach grieving family members.
Another goal of the trip is to ensure the long-term viability of UNMC's rapid-autopsy program. Things have gone well so far, Gendelman said -- his research team has received enormous financial and logistical support from people in all levels at the medical center. "Virtually every person in this university has been phenomenal," he said.
But despite the program's achievements so far, basic arrangements still must be made. Where will the program get the long-term funding necessary to keep an autopsy team on call 24 hours a day, 365 days a year? How will the medical center gain the community support necessary for such a massive undertaking?
These are questions Gendelman hopes to get answers for not only in Arizona, but from Nebraskans when he returns to Omaha. Gendelman said he and the medical center are sincere in saying, "Look, we're in this together."
"It's our medical center," Gendelman said. "It's a medical center for all Nebraskans."
_____
This story originally appeared in Nebraska StatePaper on February 24, 2001.
Friday, December 22, 2000
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."
_____
This story originally appeared in Nebraska StatePaper on December 22, 2000.
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."
_____
This story originally appeared in Nebraska StatePaper on December 22, 2000.
Thursday, December 21, 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:
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.
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."
_____
This story originally appeared in Nebraska StatePaper on December 21, 2000.
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."
_____
This story originally appeared in Nebraska StatePaper on December 21, 2000.
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