Sniffing Out a Cure for Parkinson’s?
A decade has passed since James Thomson first showed how embryonic stem cells could be cultured under laboratory conditions. Long known for their embryonic potential—the stem cells’ ability to grow and differentiate into a complete human being—the cells’ healing and regenerative potential quickly came to the forefront of investigators’ interest around the world. If new stem cells could be grown in the lab, could a patient’s cells be cloned and used to replace or repair his degenerative disease?
While much controversy has surrounded the necessity of destroying human embryos to extract the stem cells (as well as the cloning of a patient embryo to begin the process), the potential of adult stem cells has often fallen to the back page. Since Vision last reported from the stem cell front in March 2007, it has become increasingly and enticingly clear that our bodies are outfitted with an array of stem cells. According to several research articles published in just the last month, adult stem cells may have a far more immediate impact on regenerative therapies than first imagined.
Round and Round
Part of the difficulty of considering adult stem cells (aSC) for therapy is the question of their “stemness.” Is a stem cell, say in the nose or the intestine, actually able to regenerate a different part of the body, the brain or heart, for example? One clue to an aSCs potential is the understanding that it exists in a kind of genetic flux. The life of an aSC is like a trip on that familiar traffic convenience called a roundabout: there are many exits to complete differentiation and if one is missed, not to worry, that path will come round again. “Stemness” is not a single condition; like cars circling on a roundabout, any one may exit at any time to follow separate paths or they all may move together down one.
This is the idea that aSCs are poised to differentiate. Individual cells within a colony are not all at the same place on the cellular roundabout. Running on an internal cycle, each cell is producing different marker proteins as it moves through its biochemical course. This suggests to the authors of a paper recently published in Nature that there is a “hidden multi-stability within one cell type.” In cultured blood stem cells, they found a variety of “distinct transcriptomes.” This indicated that even cloned stem cells—cells which one would assume are biochemically equal—are operating on independent genetic cycles. A transcriptome is the chemical signal that a cell produces as a primer to turn other genes on and off.
“Thus,” concluded the authors, “clonal heterogeneity of gene expression . . . reflects metastable states of a slowly fluctuating transcriptome that is distinct in individual cells and may govern the reversible, stochastic priming of multipotent progenitor cells in cell fate decision.”
The potential success of aSC therapy is in part reliant in our understanding how to direct the cell out of the loop and down the proper path that would heal a patient’s illness. Up until now the best bet on that task of directing the “cell fate decision” has been a process called reprogramming.
In November 2007 Thomson, at the University of Wisconsin-Madison, and Shinya Yamanaka, at Kyoto University in Japan, announced their separate successes at returning adult cells to a stem-like, or pluripotent, state. Hailed in the popular press as a way around the embryo problem, the process is not without severe drawbacks. These “induced pluripotent stem cells” (iPS) are created by using a modified virus to reinsert key genes to bring the mature cells back to a more flexible condition akin to, in our analogy, returning to the roundabout.
Viral gene insertion is, however, a random process so an iPS cell is also at risk of becoming cancerous. George Daly, an iPS developer at Harvard Medical School in Boston, told Nature Journal, “One of the next big milestones will be making these cells without the use of viruses—leaving the cells in a genetically pristine state.”
Progress toward this goal was recently described in a Cell Stem Cell research report. Yan Shi, at the Scripps Research Institute, La Jolla, California, and other coworkers were able to discover some of the chemical messages called transcription factors that actually do the reprogramming. If these could be added to the adult cells directly rather than through viral/genetic manipulation, the more “pristine” state Daly suggests may be available sooner than would have been imagined just one year ago.
“The use of additional small molecules or other nongenetic methods that could replace the function of the remaining transduced TFs [transcription factors] and/or improve reprogramming,” Shi writes, “could ultimately allow the generation of iPS cells or multipotent tissue-specific stem cells in completely chemically defined conditions without any genetic modification.”
Wake Up Call
Rounding out this brief overview of current stem cell progress are reports from investigators at the Schepens Eye Research Institute, an affiliate of Harvard Medical School, and the National Centre for Adult Stem Cell Research, Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane, Australia. Both concern neural stem cells and their potential to directly heal damaged brain tissue.
The first describes the discovery that rather than being few and isolated, the brain is loaded with stem cells. Working with mice, Jianwei Jiao and Dong Feng Chen determined the signaling system that keeps these cells inactive. This knowledge could enable us to direct cells to initiate healing.
“These findings identify a key pathway that controls neural stem cell growth in the adult brain,” says Jiao. Through stimulation with the transcription factors that would send them down the correct path, Jiao suggests that “it may be possible to reactivate the dormant regenerative potential.”
While the above papers are concerned with the biochemistry of stem cell function, Wayne Murrell and his team have jumped ahead to actually transplanting stem cells to address Parkinson’s disease. Could stem cells be moved directly from the roundabout and delivered to their therapeutic destination? Published online at Stem Cells Express, Murrell writes, “The relatively localized nature of this lesion [Parkinson’s affects a very specific portion of the brain] has led to it be considered a prime target for cell transplantation therapy by placing a source of dopaminergic cells into the striatum.”
Taking neural stem cells from the nasal lining of human subjects, Murrell first cultured the cells and through the addition of growth factors brought the cells to a dopamine-producing condition. These cells were then injected into rats that had had their dopamine-producing brain cells chemically incapacitated. Called a “hemi-parkinsonian rat model,” these rats show awkward turning behavior indicative of dopamine loss.
Although the study was small (only 18 rats were used), the results showed impressive improvement in the affected rats’ condition. Most interesting was the fact that even cells originally cultured from the nose of a human Parkinson’s patient brought healing to the rat. “Cells derived from a Parkinson’s disease patient were similarly effective in reducing amphetamine-induced rotation compared to cells from a healthy control,” Murrell writes. This is indicative, he says, of “a therapeutic effect of transplantation of these cells.”
“None of the transplants led to the formation of tumours or teratomas in the host rats,” Murrell notes, “as has occurred after embryonic stem cell transplantation in a similar model.”
Not the Final Word
Certainly none of these reports is the final word on stem cell research. But they each in their own way show how our understanding of the body’s capacity to heal is moving forward one small, often molecular step at a time. A final paper of note is Aaron Levine’s “Identifying Under- and Overperforming Countries in Research Related to Human Embryonic Stem Cells” in the June 4 issue of Cell Stem Cell. Levine, an assistant professor at the School of Public Policy, Georgia Institute of Technology, studies the interaction of ethics and governmental policy and the impact of what he calls the “regulatory environment” on stem cell research.
He writes that “Overperforming countries generally offered permissive policy environments for hESC research, while underperforming countries were characterized by protracted policy debates and ongoing uncertainty.”
The Scientist comments that the conclusions Levine draws may not be complete.
It is obviously true that regulations that prohibit a particular behavior will reduce that behavior. In this case the focus is the U.S. sanction on federal monies for human embryonic stem cell (hES) research that requires the continuing destruction of new embryos. That ethical pause, which Levine points up, may be coming to a close as the next election cycle passes.
Whether this pause was detrimental or beneficial will continue to be debated. Did the intermission encourage more effort toward adult stem cell research and thereby some of the fruits that are currently coming over the therapeutic horizon? As Walter Murrell notes, it would sure cut down the “logistics” of stem cell-based cures if we could use the patient’s own cells. The progress being made across the globe toward that end is not something to sneeze at and easily discard.