Aging tends to rob us of our ability to concentrate, recall facts, and reason, and this decline seems to stem from the fact that older brains generate fewer neurons than they did when they were younger. However, German researchers have discovered a molecule that accumulates with age that inhibits the formation of new neurons. This finding might help scientists design therapies to prevent age-related mental decline.
This molecule, Dkk1 or Dickkopf-1, accumulated in the brains of aged mice. If Dkk1 production was blocked, neurons were born at much higher rates. Dr. Ana Martin-Villalba, the senior author of this work and a member of the German Cancer Research Center in Heidelberg. Said, “We released a brake on neuronal birth, thereby resetting performance in spatial memory tasks to levels observed in younger animals.”
Aged mice that lacked Dkk1 performed just as well in cognitive tests that included memory and recognition tests as younger mice because of the ability of their neural stem cells to self-renew and generate immature neurons.
Younger mice that lacked Dkk1 were less susceptible to developing acute stress-induced depression than normal mice. This seems to indicate that in addition to slowing memory loss during aging, neutralizing Dkk1 could be beneficial in counteracting symptoms of depression.
Martin-Villalba said that there are ongoing clinical trials to test inhibitors of Dkk1 for other medical purposes. “The design of inhibitors that reach the brain might enable the prevention of cognitive decline in the aging population and depression in the general population,” she said.
Bernard Thébaud works at the Ottawa Hospital Research Institute (OHRI) and Children’s Hospital of Eastern Ontario (CHEO), and is also a member of the Ottawa Stem Cell Initiative. Dr. Thébaud has proposed a new therapy that utilizes umbilical cord stem cells to treat a lung disease called bronchopulmonary dysplasia (BPD), which was previously thought to be untreatable.
Thébaud described BPD in this way: “BPD is a lung disease described 45 years ago in which we have made zero progress. And now, with these cord-derived stem cells there is a true potential for a major breakthrough. I am confident that we have the talent and the tools here at CHEO and OHRI to find a treatment for BPD. These findings published today are helping us get there.”
Every year, BPD affects ~10,000 premature newborns in Canada and the US. The lungs of infants with BPD are not developed enough to function properly, and consequently the baby has to be placed on a ventilator in order to receive sufficient quantities of oxygen. Mechanical respirators, however, are very hard on such young, friable lungs, and the lungs then to fray and this prevents them from developing properly. The longer the baby stays in the neonatal intensive care unit, the greater the degree of multiorgan damage (retina, kidneys, and the brain). Therefore, the baby needs oxygen to survive, but the very act of giving them oxygen eventually hastens their death.
Thébaud’s research team used new-born rats that were given oxygen soon after their premature birth. Some were given stem cell treatments and others were not. These experiments produced five new findings:
1) Mesenchymal stem cells (MSCs) from human umbilical cord can protect the lungs when injected into the lungs as the animals were put on oxygen.
2) MSCs had a tendency to stimulate repair of the damaged lungs when injected two weeks after the animals were put on oxygen.
3) The medium in which the MSCs were grown (conditioned medium) was injected into the lungs instead of the cells, this medium had the same reparative and protective effects as the cells themselves. This suggests that it is the cocktail of growth factors and other supportive molecules secreted by the MSCs that provide their healing properties. Such a mechanism, in which the cells secrete molecules that affect nearby cells and tissue, is known as a “paracrine” mechanism.
4) When examined six months after treatment (the equivalent of 40 human years), the treated animals had better exercise performance and more normal lung structure.
5) MSC administration did not adversely affect the long-term health of the laboratory animals. None of the MSC-treated animals had any tumors and MSCs given to control animals that did not have BPD were also normal six months later.
Thébaud would like to conduct a pilot clinical (Phase I) study within two years with around 20 human patients in order to determine if this treatment is feasible and safe. If the treatment turns out to be safe, Thébaud would like to initiate a randomized controlled (Phase II) clinical trial.
See Maria Pierro et al., “Short-term, long-term and paracrine effect of human umbilical cord-derived stem cells in lung injury prevention and repair in experimental bronchopulmonary dysplasia,” Thorax 2012: DOI:10.1136/thoraxjnl-2012-202323.
The highly-regarded journal Science has published a review article by University of Rochester Medical Center scientists Steve Goldman, M.D., Ph.D., Maiken Nedergaard, Ph.D., and Martha Windrem, Ph.D. that argues that stem cell researchers are very close to human application of stem cell therapies for a class of neurological diseases known as myelin disorders. Myelin disorders consist of a lengthy list of rather nasty diseases:
1) multiple sclerosis, which is a disease that affects the brain and spinal cord and damages the myelin sheath that surrounds and protects nerve cells. This damage slows down or blocks messages between the brain and body, which leads to the symptoms of MS, which include visual disturbances, muscle weakness, trouble with coordination and balance, sensations such as numbness, prickling, or “pins and needles,” and thinking and memory problems.
2) white matter stroke, a lack of blood flow to white matter, which is quite severe, since blood flow to the white matter far less than that of gray matter.
3) cerebral palsy, a group of disorders that involve the brain and nervous system functions, that include movement, learning, hearing, seeing, and thinking. There are several different types of cerebral palsy, including spastic, dyskinetic, ataxic, hypotonic, and mixed. Cerebral palsy is caused by injuries or abnormalities of the brain. Most of these problems occur as the baby grows in the womb, but they can happen at any time during the first 2 years of life, while the baby’s brain is still developing. In some people with cerebral palsy, parts of the brain are injured due to low levels of oxygen (hypoxia) in the area. It is not known why this occurs. Premature infants have a slightly higher risk of developing cerebral palsy. Cerebral palsy may also occur during early infancy as a result of several conditions, including: bleeding in the brain, brain infections, head injuries, infections in the mother during pregnancy, severe jaundice.
4) certain dementias, and
5) rare but fatal childhood disorders called pediatric leukodystrophies. Leukodystrophies are a varied group of diseases that primarily affect the white matter of the central nervous system (CNS). These diseases include both primary myelin disorders, axonal/neuronal degeneration and inflammatory disorders. There are two types of leukodystrophies: dysmyelinating diseases, which usually results from inherited defects in an enzyme pathway or organelle function that causes abnormal formation, destruction, or turnover of myelin, and demyelinating disorders that result in abnormal destruction of normal myelin and/or axons.
According to Goldman, “Stem cell biology has progressed in many ways over the last decade, and many potential opportunities for clinical translation have arisen. In particular, for diseases of the central nervous system, which have proven difficult to treat because of the brain’s great cellular complexity, we postulated that the simplest cell types might provide us the best opportunities for cell therapy.”
Myelin disorders share a common pathological factor and that is a cell that makes myelin, called an “oligodendrocyte.” Oligodendrocytes arise from a cell found in the central nervous system called “glial progenitor cells (GPCs). GPCs give rise to oligodendrocytes and “sister cells” called “astrocytes.” Both cells serve rather critical functions in the central nervous system.
Oligodendrocytes produce myelin, a fatty substance that insulates the fibrous connections between nerve cells that are responsible for transmitting signals throughout the body. When myelin-producing cells are lost or damaged in conditions such as multiple sclerosis and spinal cord injury, signals traveling between nerves are weakened or even lost.
Astrocytes are the unsung heroes of the central nervous system. They were largely neglected for some time, but are now coming into their own as one of the main glial (support cells) in the brain. Astrocytes secrete a cocktail of growth factors that keep neurons and oligodendrocytes healthy and help them properly signal to other cells.
Because they give rise to cells that are so central to the function of so many other brain cells, GPCs and their offspring represent a promising target for stem cell therapies. An added bonus of using GPCs is that (unlike other cells in the central nervous system) they are rather homogeneous and are also don;t mind being manipulated and cultured. Consequently, they are easy to transplant. In fact, several animal studies have established that transplanted oligodendrocytes will disperse and repair or “remyelinate” damaged nerves.
“Glial cell dysfunction accounts for a broad spectrum of diseases, some of which – like the white matter degeneration of aging – are far more prevalent than we previously realized,” said Goldman. “Yet glial progenitor cells are relatively easy to work with, especially since we don’t have to worry about re-establishing precise point-to-point connections as we must with neurons. This gives us hope that we may begin to treat diseases of glia by direct transplantation of competent progenitor cells.”
Several key technological advances have made these recent advances in neural stem cell protocols possible. First of all, superior imaging technologies with more advanced MRI scanners that provide sharper and more magnified images can provide more precise information about the specific damage in the central nervous system that result from myelin disorders. Additionally, once cells are transplanted, these new scanning techniques allow scientists to more precisely trace their implanted cells and determine what those cells are doing.
Another important advance are the major obstacles that have recently been overcome in recent work. First, there have been significant advances in the manipulation and handling of GPCs and their progeny. Goldman’s lab has pioneered the techniques for GPC manipulation. He and his colleagues have determined the precise steps used in the induction of GPC differentiation into either oligodendrocytes or astrocytes. Goldman’s lab has produced GPCs by reprogramming skin cells and he has also identified specific cell surface molecules that act as markers for GPCs. The identification of markers is a huge advance because it allows him and his co-workers to isolate the differentiated cells away from those that might potentially cause tumors.
The Nedergaard lab has done a tremendous amount of work to understand the structure of the neural networks of the brain and their functional contributions to the brain as a whole. Together, these two labs have developed models of normal human neural activity and brain disease that are based on laboratory animals that have been transplanted with human GPCs. This enables the human neural cells to operated within a living brain instead of a culture dish. Such experimental has already opened several new strategies for modeling and potentially treating human glial diseases.
The authors contend that these advances have accelerated research to the point where human clinical trials for myelin disorders will probably occur soon. As an example, patients with multiple sclerosis would benefit from the invention of a new generation of stabilizing anti-inflammatory drugs, since multiple sclerosis results from thsensitizatione of the immune system to the myelin sheath. However, such drugs always have nasty side-effects. If you do not believe me, just examine this short list of side effects for one of these drugs. Instead MS patients would definitely benefit from a progenitor-based cell therapy that could repair the now permanent and untreatable damage to the central nervous system that results from this disease. Also several childhood diseases of white matter are also excellent candidates for cell-based treatments.
“We have developed a tremendous amount of information about these cells and how to produce them,” said Goldman. “We understand the different cell populations, their genetic profiles, and how they behave in culture and in a variety of animal models. We also have better understanding of the disease target environments than ever before, and have the radiographic technologies to follow how patients do after transplantation. Moving into clinical trials for myelin disorders is really just a question of resources at this point.”
StemCells, Incorporated is conducting a Phase I/II clinical trial in which the company’s proprietary stem cell line, their HuCNS-SC stem cell lines, which is a purified human adult neural stem cell line, is implanted into the spinal cords of patients who have suffered a spinal cord injury. This clinical trial is designed to determine the safety and preliminary efficacy of HuCNS-SC as a treatment for spinal cord injury.
The goal for this clinical trial is to treat 12 patients who have suffered thoracic (chest-level) neurological injuries at the T2-T11 level. In order to be candidates for this procedure, the patients must have suffered their spinal cord injuries recent enough so that they can have the stem cells transplanted into their spinal cords within three to twelve months after their injury. The clinical trial will assess the safety of the procedure and its efficacy. Efficacy will be specifically assessed by determining the recovery of such features as sensation, motor function and bowel/bladder function. The first three patients have already been treated and these patients have spinal cord injuries that are classified as “ASIA category A.” This is a shorthand for American Spinal Injury Association category A. Category A means that there is no sensory or motor function below the level of the injury. The next group of patients to be treated will have less severe injuries (ASIA-B – sensory but no motor function below the level of the injury) and the third group will be even less severe injuries (ASIA-C – motor function is preserved, but most of the major muscle have reduced function).
The trial is being conducted at Balgrist University Hospital, University of Zurich, which is a world leading medical center for spinal cord injury and rehabilitation, and is open for enrollment to patients in Europe, Canada and the United States. Enrollment for those patients in the second cohort with ASIA-B category spinal cord injuries is now underway.
As previously reported, StemCells, Inc. reported at a conference on the results of their clinical trial. They reported that in six months after the first patients were treated, the patients showed no severe side effects. Even more favorably, the patients showed considerable gains in sensory function in two of the three patients compared to pre-transplant baselines. The third patient remains stable.
Armin Curt, M.D., the principal investigator for this clinical trial, presented these data at the 51st Annual Scientific Meeting of the International Spinal Cord Society in London, England. This clinical trial represents the first time that neural stem cells have been transplanted as a potential therapeutic agent for spinal cord injury. The recovery of sensory function in the two patients is certainly a remarkable finding, and gives new hope to those with a spinal cord injury.
I lived in Great Britain for three years (1994-1997) and have first-hand experience with the National Health Service. Needless to say, I was not impressed. They do fine with child-birth and then abandon older people to their own fate. Nationalized health care is rationed health and do not let anyone tell you differently. When you become old enough, the health service you spent your whole life paying into abandons you in your time of greatest need. Now we have a stark example of this.
Wesley Smith has a blog entry on this. It will make you sick. According to the British newspaper, The Daily Mail, a desperate hospital patient died after he was denied hydration by the hospital. To get hydration, he called the police and begged them to bring him a drink. The patient, Kane Gorny, 22, needed drugs to regulate his hormone levels after successfully beating brain cancer months earlier. However, during a further hospital stay nurses forgot to give him his medication and he became so delirious he was forced to call 999 (the UK equivalent of 911) to ask for help. The police officers went to St George’s Hospital in Tooting, south London, but were turned away by staff who insisted that Mr Gorny was fine. Gorny had been admitted in May 2009 to undergo hip replacement surgery after his bones became brittle. This was a side-effect of his prescribed steroids. Kane’s mother, Rita Cronin, said she spent hours trying to convince hospital staff that Kane needed urgent attention but was repeatedly “told he was alright.” See http://www.dailymail.co.uk/news/article-2167643/Patient-dying-thirst-rang-999-Inquest-hears-mothers-fury-nurses-neglected-son.html for the article.
An inquiry into the matter has been initiated by the Crown Prosecution Service at the behest of Gorny’s parents. Kane Gorny had surgery on his pituitary gland, and he had problems regulating his levels of salt and water in his system. Pituitary surgery commonly damages that back part of the pituitary gland and this prevents the release of antidiuretic hormone (ADH, also known as vasopressin). Without ADH, patients have a condition called diabetes insipidus, and they need to take exogenous ADH. Without exogenous ADH, the patient will urinated themselves to death. The nurses failed to give him his medicine, and dismissed his concerns and the concerns of his mother. Because he was so dehydrated, Kane called the police to get some fluid, but the nurses at the hospital dismissed them. He died from dehydration and abnormally sodium levels. His death was almost certainly a painful one.
The inquiry will probably result in some nurses being sacked (British for fired), but the status quo will probably be maintained. This kind of abuse is more routine in the British Health System than they would probably admit. Doctors have even started to prescribe water to elderly patients to prevent them from dying from dehydration. Is this what we want for the US?
Palliative sedation is a medical technique for terminally ill patients who cannot receive adequate pain relief while they are awake. Palliative sedation uses sedative medications to make the patient unaware and unconscious while the disease takes its course. This relieves extreme suffering by placing the patient in a kind of sleep. The sedative medication is gradually increased until the patient is comfortable and able to relax. Palliative sedation is not intended to cause death or shorten life (Erin Brender, MD; Alison Burke, MA; Richard M. Glass, MD. JAMA. 2005;294(14):1850.)
This has not stopped euthanasia advocates from asserting that palliative sedation is euthanasia. The inimitable Wesley Smith has a blog post on this and he refers to an article in the Journal of Pain & Palliative Care Pharmacotherapy that takes this deliberate conflation of these two very different things to the woodshed. It’s a great read. Check it out here.
According to the publication New Scientist, estimates by the Israeli medical profession postulate that there have been at least 600 ‘wrongful life’ lawsuits since the first case in 1987. A ‘wrongful life’ lawsuit occurs when the parents of a child with some kind of developmental abnormality or genetic disease sue the doctors who helped birth the child in the name of the child. The lawsuits allege that had the parents known about fetus’ severe genetic problem, they would have chosen to terminate their pregnancy.
“Wrongful life” claims are generally brought by the children, or much more typically, parents acting on behalf of the children. Essentially, the lawsuit specifies that the children are suing for the right to have never been born. They are suing doctors for NOT putting them to death. According to an article in BioNews, the psychological implications of such lawsuits on the children named in them have been noted by several medical ethicists. Professor Rabbi Avraham Steinberg of University Hadassah Medical School, Jerusalem, commented: “I find it very difficult to understand how parents can go on the witness stand and tell their children ‘it would have better for you not to have been born. What are the psychological effects on the children?”
Now in the state of Oregon, a “wrongful life” lawsuit in Portland was put forward involving a Down syndrome child. According to the newspaper, the Oregonian, in June 2007, Ariel and Deborah Levy were excited by the birth of their daughter, when then experienced profound shock and anger when hospital staff told them their daughter had Down syndrome. When asked if she had had a prenatal test in the form of a chorionic sampling test, Mrs. Levy answered in the affirmative. Unfortunately, the results showed that they were going to have a normal, healthy child. Several days after being born, a blood test confirmed that the Levy’s little girl, Kalanit Levy, had Down syndrome. Therefore, the Levys filed suit against legacy Health, claiming that they would have aborted the pregnancy if they had known that their daughter had Down syndrome. The Levys say that they “dearly love their daughter, who is now 4 years old, but they want Legacy to pay for the extra life-time costs of caring for her, which are estimated to be about $3 million.
With all respect to the Levys, but this, “We dearly love her but would have killed her before she was born” schtick does not wash. What if she learns that her parents brought this case. Doctors cannot guarantee outcomes. We do not have a right to a particular child and no one should have to be legally declared wrongfully born. If the jury has any sense in this matter, they will throw this case out. It is a clear-cut case of chasing deep pockets with a detestable premise.