Monday 14 March 2005

Novel strategy just now being explored would avoid the use of transplanted cells.

(Image: HealthDay)

    Like many neurodegenerative illnesses, Alzheimer's disease is characterized by the uncontrolled death of precious brain cells. But in their unique ability to develop into any cell type, stem cells have long held out the tantalizing hope of replenishing neurons lost to the disease, a process called neurogenesis.

    Unfortunately, transplanting these stem cells from outside sources - such as embryos or bone marrow - carries its own risks and complications.

    But one researcher believes the best solution to Alzheimer's may lie closest to home: within the brain itself.

    The activation of dormant stem cells in the patient's own brain could someday allow doctors to re-grow lost cells without resorting to surgery, and in ways that target exactly those areas of the brain - and specific types of cells - damaged by disease.

    "We're developing maps so that we'll know exactly which stem cells give rise to every cell subtype in the brain," explained Dr. Mark F. Mehler, chairman of the department of neurology at Albert Einstein College of Medicine, and neurologist-in-chief at Montefiore Medical Center, New York City.

    "That means, we'll be able to say the equivalent of, 'OK, in sector three of sub-zone 7, we need to activate that cell.' And not only activate it, but activate it in a specific way," he added.

    The technique - still years away from clinical trials - is called endogenous (meaning sourced from the patient) stem cell activation.

    While stem cells sourced from embryos or bone marrow have received the most media attention, residual amounts of these regenerative cells exist throughout the body. According to Mehler, about 0.3 percent of brain cells may be dormant stem cells.

    Just why they so often remain dormant - even when the brain experiences injury - remains a mystery.

    According to Mehler, experiments suggest that inflammation at the site of injury may dampen signaling sent from injured cells to brain stem cells, or weaken the stem cells' response to those signals.

    "We also believe that evolution has built in a series of controls on stem cells, to prevent them from getting activated from trivial injuries," he said.

    Still, it's frustrating to know that endogenous stem cells have the potential to repair damaged brain tissue - if only scientists knew how to turn them on.

    Much of Mehler's work over the past few years has been focused on identifying a host of potential "on" switches that might activate stem cells, pushing them to develop into specific brain cell subtypes.

    Some of these activating or signaling events could be triggered by gene expression, he said, while other may be linked to natural chemicals called growth factors.

    "We know, though, that the signals will be there - not just for the expansion and maturation of these stem cells [into brain cells], but their integration into neural networks, which is really important," he said.

    "Because, with a transplanted cell, even if you could transplant a cell that looked like the cell that was lost [to disease], it's almost impossible to conceive that it would have all the elaborate signals that would allow it to integrate into neural networks," he said. "In all likelihood, it would be killed."

    According to Mehler, the Holy Grail of endogenous stem cell activation is a non-invasive means of introducing genes or chemicals into the brain that are targeted to only re-grow those cells lost to Alzheimer's or other brain diseases.

    The technique would also get around so many of the problems inherent in stem cell transplants - from issues of immune system rejection to the ethical concerns that dog the use of embryonic cells.

    But another expert cautioned the success of this strategy is far from assured.

    "Stimulating neurogenesis is a very interesting area, but one of the questions will be, 'Can the cells that you ultimately stimulate survive in an Alzheimer's brain?' We just don't know what's going to happen," said Dr. William J. Netzer, a research associate at Rockefeller University and scientific liaison at the Fisher Center for Alzheimer's Research Foundation, in New York City.

    Netzer explained that the brains of Alzheimer's patients are characterized by inflammation and the buildup of unwanted proteins. That's a potentially hostile environment for all cells, let alone newly activated stem cells, he said.

    "There are still lots of questions about this," Netzer added. "Can we specify particular targets, and is that even necessary? And if it is necessary, is the target you've chosen the right target?"

    "I think that the way it's going to go is that people will put in one or another of their favorite growth factors and see what happens," he said.

    According to Mehler, just such a clinical trial may take place in the not-so-distant future. Using safe, noninvasive infusion techniques already used in cancer chemotherapy, his team plans to use growth factors to jump-start sleepy brain stem cells in human subjects, sometime over the next five years.

    "It would be even better to do this using gene manipulation, because it would be even less invasive," he said, but gene therapy remains a more distant goal.

    Still, treatments that rely on the brain's own secret store of stem cells might come sooner than anyone can imagine, Mehler said.

    "Whenever anyone asks me to predict these things, I'm always wrong - in a conservative direction," he said. "Because if you follow the field of biomedical research, you realize that every two years or so some extraordinary new thing comes out of nowhere to revolutionize the field."