NIH scientists find that restocking new cells in the brain’s center for smell maintains crucial circuitry.
For decades, scientists thought that neurons in the brain were born only during the early development period and could not be replenished. More recently, however, they discovered cells with the ability to divide and turn into new neurons in specific brain regions. The function of these neuroprogenitor cells remains an intense area of research. Scientists at the National Institutes of Health (NIH) report that newly formed brain cells in the mouse olfactory system — the area that processes smells — play a critical role in maintaining proper connections. The results were published in the October 8 issue of the Journal of Neuroscience.
“This is a surprising new role for brain stem cells and changes the way we view them,” said Leonardo Belluscio, Ph.D., a scientist at NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and lead author of the study.
The olfactory bulb is located in the front of the brain and receives information directly from the nose about odors in the environment. Neurons in the olfactory bulb sort that information and relay the signals to the rest of the brain, at which point we become aware of the smells we are experiencing. Olfactory loss is often an early symptom in a variety of neurological disorders, including Alzheimer’s and Parkinson’s diseases.
In a process known as neurogenesis, adult-born neuroprogenitor cells are generated in the subventricular zone deep in the brain and migrate to the olfactory bulb where they assume their final positions. Once in place, they form connections with existing cells and are incorporated into the circuitry.
Dr. Belluscio, who studies the olfactory system, teamed up with Heather Cameron, Ph.D., a neurogenesis researcher at the NIH’s National Institute of Mental Health, to better understand how the continuous addition of new neurons influences the circuit organization of the olfactory bulb. Using two types of specially engineered mice, they were able to specifically target and eliminate the stem cells that give rise to these new neurons in adults, while leaving other olfactory bulb cells intact. This level of specificity had not been achieved previously.
In the first set of mouse experiments, Dr. Belluscio’s team first disrupted the organization of olfactory bulb circuits by temporarily plugging a nostril in the animals, to block olfactory sensory information from entering the brain. His lab previously showed that this form of sensory deprivation causes certain projections within the olfactory bulb to dramatically spread out and lose the precise pattern of connections that show under normal conditions. These studies also showed that this widespread disrupted circuitry could re-organize itself and restore its original precision once the sensory deprivation was reversed.
However, in the current study, Dr. Belluscio’s lab reveals that once the nose is unblocked, if new neurons are prevented from forming and entering the olfactory bulb, the circuits remain in disarray. “We found that without the introduction of the new neurons, the system could not recover from its disrupted state,” said Dr. Belluscio.
To further explore this idea, his team also eliminated the formation of adult-born neurons in mice that did not experience sensory deprivation. They found that the olfactory bulb organization began to break down, resembling the pattern seen in animals blocked from receiving sensory information from the nose. And they observed a relationship between the extent of stem cell loss and amount of circuitry disruption, indicating that a greater loss of stem cells led to a larger degree of disorganization in the olfactory bulb.
According to Dr. Belluscio, it is generally assumed that the circuits of the adult brain are quite stable and that introducing new neurons alters the existing circuitry, causing it to re-organize. “However, in this case, the circuitry appears to be inherently unstable requiring a constant supply of new neurons not only to recover its organization following disruption but also to maintain or stabilize its mature structure. It’s actually quite amazing that despite the continuous replacement of cells within this olfactory bulb circuit, under normal circumstances its organization does not change,” he said.
Dr. Belluscio and his colleagues speculate that new neurons in the olfactory bulb may be important to maintain or accommodate the activity-dependent changes in the system, which could help animals adapt to a constantly varying environment.
“It’s very exciting to find that new neurons affect the precise connections between neurons in the olfactory bulb. Because new neurons throughout the brain share many features, it seems likely that neurogenesis in other regions, such as the hippocampus, which is involved in memory, also produce similar changes in connectivity,” said Dr. Cameron.
The underlying basis of the connection between neurological disease and changes in the olfactory system is also unknown but may come from a better understanding of how the sense of smell works. “This is an exciting area of science,” said Dr. Belluscio, “I believe the olfactory system is very sensitive to changes in neural activity and given its connection to other brain regions, it could lend insight into the relationship between olfactory loss and many brain disorders.”
This work was supported by the NIH Intramural Program.
For more information about brain research, please visit http://www.ninds.nih.gov
NINDS is the nation’s leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.
About the National Institute of Mental Health (NIMH): The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit http://www.nimh.nih.gov.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
Making “scents” of new cells in the brain’s odor-processing area
Adult-born cells travel through the thin rostral migratory stream before settling into the olfactory bulb, the large structure in the upper right of the image. Courtesy of the Belluscio Lab, NINDS.
A stroke therapy using stem cells extracted from patients’ bone marrow has shown promising results in the first trial of its kind in humans.
Five patients received the treatment in a pilot study conducted by doctors at Imperial College Healthcare NHS Trust and scientists at Imperial College London.
The therapy was found to be safe, and all the patients showed improvements in clinical measures of disability.
The findings are published in the journal Stem Cells Translational Medicine. It is the first UK human trial of a stem cell treatment for acute stroke to be published.
The therapy uses a type of cell called CD34+ cells, a set of stem cells in the bone marrow that give rise to blood cells and blood vessel lining cells. Previous research has shown that treatment using these cells can significantly improve recovery from stroke in animals. Rather than developing into brain cells themselves, the cells are thought to release chemicals that trigger the growth of new brain tissue and new blood vessels in the area damaged by stroke.
“Our aim is to develop a drug, based on the factors secreted by stem cells, that could be stored in the hospital pharmacy so that it is administered to the patient immediately following the diagnosis of stroke in the emergency room.”
– Professor Nagy Habib
Department of Surgery and Cancer
MRI scans showing brain damage in the stroke patients before treatment. Source: Stem Cells Translational Medicine.
The patients were treated within seven days of a severe stroke, in contrast to several other stem cell trials, most of which have treated patients after six months or later. The Imperial researchers believe early treatment may improve the chances of a better recovery.
A bone marrow sample was taken from each patient. The CD34+ cells were isolated from the sample and then infused into an artery that supplies the brain. No previous trial has selectively used CD34+ cells, so early after the stroke, until now.
Although the trial was mainly designed to assess the safety and tolerability of the treatment, the patients all showed improvements in their condition in clinical tests over a six-month follow-up period.
Four out of five patients had the most severe type of stroke: only four per cent of people who experience this kind of stroke are expected to be alive and independent six months later. In the trial, all four of these patients were alive and three were independent after six months.
Dr Soma Banerjee, a lead author and Consultant in Stroke Medicine at Imperial College Healthcare NHS Trust, said: “This study showed that the treatment appears to be safe and that it’s feasible to treat patients early when they might be more likely to benefit. The improvements we saw in these patients are very encouraging, but it’s too early to draw definitive conclusions about the effectiveness of the therapy. We need to do more tests to work out the best dose and timescale for treatment before starting larger trials.”
Over 150,000 people have a stroke in England every year. Survivors can be affected by a wide range of mental and physical symptoms, and many never recover their independence.
Stem cell therapy is seen as an exciting new potential avenue of treatment for stroke, but its exact role is yet to be clearly defined.
Dr Paul Bentley, also a lead author of the study, from the Department of Medicine at Imperial College London, said: “This is the first trial to isolate stem cells from human bone marrow and inject them directly into the damaged brain area using keyhole techniques. Our group are currently looking at new brain scanning techniques to monitor the effects of cells once they have been injected.”
Professor Nagy Habib, Principal Investigator of the study, from theDepartment of Surgery and Cancer at Imperial College London, said: “These are early but exciting data worth pursuing. Scientific evidence from our lab further supports the clinical findings and our aim is to develop a drug, based on the factors secreted by stem cells, that could be stored in the hospital pharmacy so that it is administered to the patient immediately following the diagnosis of stroke in the emergency room. This may diminish the minimum time to therapy and therefore optimise outcome. Now the hard work starts to raise funds for this exciting research.”
The study was funded by OmniCyte Ltd and the National Institute for Health Research Imperial Biomedical Research Centre.
The Baldwin County doctor that treated former Alabama football players with adult stem cells also has treated at least two people diagnosed with amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease.
One of the ALS patients, former NFL football player and college coach Frank Orgel, recently underwent a new stem cell reprogramming technique performed by Dr. Jason R. Williams at Precision StemCell in Gulf Shores.
Former NFL football player and college coach Frank Orgel has been struggling with ALS for about eight years. (photo courtesy Precision StemCell)
Before the injections, Orgel’s health had declined. He could not move his left arm or leg. He couldn’t walk or stand on his own, he said.
Within a few days of having the stem cell treatment, Orgel’s constant muscle twitching diminished, said Bob Hubbard, director of stem cell therapy at the practice. Within weeks, he was able to walk in a pool of water and stand unassisted.
“I think it’s helped me,” said Orgel, who was a defensive coordinator at Auburn under former head coach Pat Dye. “I’m walking in the pool and I used to drag my feet. Now my left leg is picking up.”
ALS is a progressive neuro-degenerative disease that affects nerve cells in the brain and the spinal cord. The progressive degeneration of the motor neurons in ALS eventually leads to death, according to the ALS Association.
Stem cells, sometimes called the body’s master cells, are precursor cells that develop into blood, bones and organs, according to the U.S. Food and Drug Administration, which regulates their use. Their promise in medicine, according to many scientists and doctors, is that the cells have the potential to help and regenerate other cells.
While Williams’ treatments are considered investigational, he has said, they meet FDA guidelines because the stem cells are collected from a patient’s fat tissue and administered back to that patient during the same procedure.
Orgel, 74, said Williams told him it would take between eight months to a year for his nerves to regrow. He is traveling to Gulf Shores from his home in Albany, Ga., this weekend for another stem cell treatment, Orgel said: “I need to get to where I can walk.”
In recent years, Orgel has gone to Mexico at least three times for different types of treatments, not sanctioned in the U.S. At least once, he said, he had placenta cells injected into his body. “That didn’t work,” Orgel said. “I didn’t feel any better.”
These days, he’s lifting weights and swimming twice a week as part of a physical therapy regimen.
Stem cell therapies
The technique performed on Orgel is called InVivo reprogramming, Hubbard said, which is described as reprograms adult stem cells into neural stem cells.
The procedure involves harvesting adult stem cells from the patient’s own fat, which Williams obtains through liposuction. Then, he uses image-guided therapy to insert the stem cells into the patient’s spine.
The patient is prescribed an oral medication that, as laboratory research has shown, causes stem cells to reprogram, converting them into neural stem cells, according to a written statement from the Gulf Shores medical practice.
Because of their experimental nature, stem cell injections to remedy conditions such as damaged knee joints or injured muscles are not covered by insurance. A typical stem cell therapy with Williams costs about $15,000. The collection of the cells through liposuction, he has said, makes up about half of the overall price.
Williams, a board-certified radiologist, said in a previous Press-Register interview that he spent about four years researching various stem cell therapies, including those collected from bone marrow. He said that the adult stem cells derived from fat tissue seemed to bring fewer chances for complications.
Harvesting stem cells from a patient’s own fat removes the need to culture cells, Williams said earlier this year, explaining that culturing stem cells can be a weeks-long process that may expose patients to risks such as infection.
In recent years, professional athletes such as Denver Broncos quarterback Peyton Manning and New York Yankees pitcher Bartolo Colon, among dozens of others, have acknowledged seeking stem cell injections outside the U.S. to try to help heal injuries.
FDA urges caution
Earlier this year, the FDA issued a consumer warning about claims regarding stem cells. In it, Stephanie Simek, deputy director of the FDA’s Office of Cellular, Tissue and Gene Therapies, said that stem cells from bone marrow or blood are routinely used in transplant procedures to treat cancer and disorders of the blood and immune system.
The document cautioned consumers, however, to make sure that stem cell therapy treatments have been approved by the FDA or are being studied under a clinical investigation allowed to proceed by the agency. “There is a potential safety risk when you put cells in an area where they are not performing the same biological function as they were when in their original location in the body,” Simek said.
Cells in a different environment may multiply, form tumors, or may migrate elsewhere in the body from the spot where they were placed, according to the FDA warning.
While several dozen clinical trials involving various forms of stem cell therapies are under way or have been announced around the world, few have included adult stem cells found in fat tissue.
Williams has said that universities and research groups have been slow to move forward because research funding tends to steer toward new drug therapies. He said that he is up front with his patients, telling them that results cannot be predicted.
“This new technique of InVivo reprogramming shows great promise for possibly repairing or regenerating nerve cells,“ Williams said in a written statement. “That means it may open up opportunities for treating several neural conditions such as spinal cord injury, stroke, Parkinson’s and Alzheimer’s disease.”
Williams said the new technique has been shown to help increase the number of neural stem cells that are transferred back into a patient.
“We are hopeful this will indeed help us heal or regrow nerve cells,” Williams said. “However, it is still too soon to really know.”
By Eleanor Bradford
BBC Scotland Health Correspondent
The first patients to take part in a clinical trial of a stem cell treatment for stroke have seen reductions in their disability, according to doctors.
Six patients in the west of Scotland had human stem cells inserted close to the damaged part of their brain.
After receiving the treatment, they saw improvements in the limb weakness they suffered as a result of their stroke.
Howeve, doctors have cautioned against reading too much into the early results of the clinical trial.
It is the world's first trial of a neural stem cell therapy for stroke.
Stroke is the third largest cause of death and the single largest cause of adult disability in the developed world.
The trial is being conducted at the Institute of Neurological Sciences at the Southern General Hospital in Glasgow, and is being led by Glasgow University neurologist Professor Keith Muir.
He said: "So far we've seen no evidence of any harmful effects. We're dealing with a group of people a long time after a stroke with significant disability and we don't really expect these patients to show any change over time.
"So it's interesting to see that in all the patients so far they have improved slightly over the course of their involvement in the study."
Patients had human stem cells inserted near the damaged part of the brain
Professor Keith Muir was intrigued by the results
All six patients suffered a stroke six months to five years before they were recruited to the trial, and all had been left with limb weakness.
The patients were assessed using the National Institutes of Health Stroke Scale.
Prior to the study, the first five patients had a median score of eight. Three months after treatment their median score had fallen to four.
The sixth patient was treated less than three months ago. Six further patients will be treated as part of this Phase 1 trial.
Professor Muir said he was "intrigued" by the early results.
He added: "We know that if you're involved in a trial you are going to see patients change in behaviour, particularly if you're doing something invasive, so we need to be very cautious indeed in interpreting these results.
"However, that said, it is not something we'd anticipated seeing in this group of patients."
Further trials are needed to establish whether stem cells actually help the brain repair damaged tissue.
Michael Hunt, chief executive officer of the company developing the treatment, ReNeuron, said: "The clinical trial is primarily a safety study and we must therefore treat any of the observed early indications of functional benefit with considerable caution at this stage.
"That said, we remain encouraged by the results seen in the study to date and we look forward to providing further updates."
Now 13, he is still getting better and better.
Lisa Biermann has been dedicated to the improvement of her son’s quality of life. Thus far, she has experienced the miracle of hearing her son speak, as well as many other accomplishments, after she was told he would never be able to perform everyday tasks.
THANX TO PAMELA COTE
Tyler Biermann is a lot like other sixth grade boys. He loves working on his computer, playing video games, riding a bike and watching television. He has a silly sense of humor and is very curious about the world around him.
What makes Tyler so very special is the great physical hurdles he has overcome in the past 12 years of his life to be able to do the things that most boys his age seem to do so effortlessly.
When Tyler was born, the umbilical cord was wrapped around his neck, causing a lack of oxygen to his brain that led to Tyler suffering a stroke during delivery. The stroke caused damage to the back of Tyler’s brain. Tyler was diagnosed with cerebral palsy and his mother, Lisa Biermann, was told to expect the worst: a child who would never walk, talk, or have any chance at a normal life.
Lisa refused to give up hope. She tried everything she could to help Tyler. Tyler could not walk because his feet would not sit flat on the floor. She tried botox injections every three months, braces, casts and even ankle cord surgery. Nothing worked.
Lisa said Tyler could not communicate with her at all. She never knew when he was in pain because he was unable to tell her.
Tyler was considered to be blind, with a prescription that was over nine units nearsighted, and his eyes jumped around. Even with glasses, he could not focus his vision, and doctors did not believe he could see, or ever would see.
Until he was 8 years old, Lisa would carry Tyler from his classes at Woodland Park Elementary.
When Tyler was 8, he had a seizure. A USA stem cell doctor heard about Tyler and offered to help him with umbilical cord stem cell therapy. Lisa said she thought hard about it, and because she had tried everything else and nothing had worked, she decided to try the stem cell therapy, which she was assured (correctly) that it had no serious side effects.
In December 2007, Lisa took Tyler to Mexico for the treatment, which had to be done in Tijuana because stem cells injection was not legal in the United States.
Nor is it today, five years later. Nor will it be anytime this decade, according to Don Margolis . Three months later, they went for a second injection.
The stem cells were given to Tyler intravenously for a period of approximately 45 minutes.
Lisa said within weeks, she saw monumental changes in Tyler. All the milestones he never reached as a baby, he began reaching.
Within three months Tyler could put his feet flat on the floor and could walk independently. At six months post-treatment, he no longer needed the painful braces that gave him bunions.
Also within the first three months, Tyler took off his glasses and told Lisa, “no see, Mom.” When Lisa took Tyler to the eye doctor, his vision had improved from nine units nearsighted to 5.5. At six months post-treatment he had improved to four units. He is now at about 1 unit nearsighted and his doctor does not believe that he needs to wear his glasses. Even more impressive is that he can communicate and answer questions posed by the eye doctor.
In fact, Tyler, who could not communicate at all before his stem cell treatment, can now say hundreds of words. He can recite the alphabet. Tyler can spell and is even starting to read. He makes the honor roll and has received two spotlight awards from school for his progress.
Tyler helps with household chores, can walk up and down the stairs and pour himself something to drink. In December, he decided that he wanted to ride a bike and could not be discouraged from trying. To her great surprise, Lisa said Tyler not only climbed onto his friend’s bike, but he started peddling as well.
There have been setbacks along the way. Last April, Lisa took Tyler to the doctor because his blood pressure was very high. The doctor noticed that Tyler had no pulse in his legs and had an MRI performed.
The MRI showed that Tyler had a rare birth defect. He only had two heart valves and his aorta was pinched. The MRI also showed that Tyler’s veins and arteries had formed a web around his heart and major organs to supply them with blood. Lisa credits the stem cells for protecting Tyler’s organs.
Tyler had surgery to repair his aorta and has recovered well.
“He improves every single day,” Lisa said.
Lisa hopes to take Tyler for another stem cell treatment this summer. She wants everyone to know that there is hope and shares her experiences and links to others’ stories on her website, www.stemcellhelps.com