I am just back from an amazing meeting in Cold Spring harbor….I’ve got so many things I want to write about, but here’s a couple of several nice things in Cell Stem Cell!
A few mice with a tremor-inducing genetic condition seem to have been almost cured by a transplant of human fetal cells, according to research published in Cell Stem Cell1. Steve Goldman, a neuroscientist at the University of Rochester Medical Center in New York, who led the study, believes it is the first time human cell therapy has rescued a genetic brain disorder. Neurons in so-called ‘shiverer’ mice do not develop robust protective myelin sheaths; the mice suffer extreme involuntary shaking and die before they are five months old. To try to compensate for this defect, Goldman and his colleagues obtained human glial progenitor cells from aborted fetuses and transplanted them into shiverer mice that lacked functioning immune systems, a trait that enabled them to accept the human cells.
The researchers transplanted 26 newborn mice with 300,000 human cells, inserting them into five sites across the brain. A control set of 59 mice received no treatment, and a second control group of 29 mice received sham injections containing no cells. All the mice developed the shiverer symptoms; seizures were observed by six weeks; by 19 weeks, the mice’s hindlimbs were so weak they could hardly walk. By the end of 23 weeks, all of the control mice and 20 of the 26 treated mice were dead.
The mice that survived, however, regained the ability to walk and stopped getting seizures. Four appeared cured and survived for over a year before they were killed so that their brains could be studied. These autopsies showed that while the neurons themselves were all mouse cells, at least a third of the myelinating cells were human. And these human glial cells myelinated just as many axons as were myelinated in wild-type controls.
Previous transplants of glial progenitor cells had little functional benefit, says Goldman. He thinks this attempt worked because of three improvements: a better way of collecting and purifying the glial progenitor cells; injecting the cells in such a way that more cells were better distributed about the brain; and a better way of preventing rejection of the transplanted cells. The shiverer mouse model could be relevant to a variety of myelin-related brain maladies, including cerebral palsy and Pelizaeus-Merzbacher disease.
Evan Snyder, a neuroscientist at the Burnham Institute in San Diego, California, who has published similar results with mouse cells2, calls the results “very encouraging,” particularly the extensive levels of engraftment. He notes, however, that it’s unclear how the shiverer model relates to human disease, and that overcoming immune rejection could be tricky.
Goldman says his next step is to better define why the treatment works for a few treated mice but not others, and to use that understanding to make the treatment more effective. He says he’s optimistic about one day using such a strategy for human disorders and is currently collaborating with Ian Duncan at the University of Wisconsin in Madison to transplant cells to dogs with a genetic myelin disorder to better understand how the cells disperse in larger animals.
1. Windrem, M. S. et al. Neonatal chimerization with human glial progenitor cells can both remyelinate and rescue the otherwise lethally hypomyelinated shiverer mouse. Cell Stem Cell 2, 553–565 (2008).
2. Yandava, B. D., Billinghurst, L. L. & Snyder, E. Y. “Global” cell replacement is feasible via neural stem cell transplantation: evidence from the dysmyelinated shiverer mouse brain. Proc Natl Acad Sci USA 96, 7029–7034 (1999).
Countries with less restrictive policies for deriving human embryonic stem (ES) cells produce more than their expected share of scientific publications worldwide, according to a study this month in Cell Stem Cell1. By this measure, the United States was the worst performer. Although 36% of scientific publications on human ES cells in 2006 had a US-based researcher as a corresponding author, that was compared to 46% of a control set of biomedical publications and 47% of publications on RNA interference (RNAi), a less controversial ‘hot’ technology.
To distinguish whether differences in countries’ performance were due to the general level of scientific enterprise or to factors specific to the field, Aaron Levine of the Georgia Institute of Technology in Atlanta categorized scientific publications published in 2006 that cited the 1998 paper describing the first derivation of human ES cells, or the initial paper describing RNAi, or one of 50 randomly selected papers published in 1998 that were in the top 1% most-cited papers. Unlike RNAi, human ES cell research is controversial because early-stage human embryos are destroyed to make the cells.
Nine of 16 countries showed significant differences for human ES cell research; four did for RNAi research. Levin notes that governments in the top five overperforming countries (Singapore, the United Kingdom, Israel, China, and Australia) both provide support for the research and permit derivation of new human ES cell lines. Levine believes that specific human ES cell support has paid off, with Singapore having a share of publications on the topic 8.8 times greater than its share of the control set.
“The study chips away at the question but doesn’t necessarily take into account a number of other factors,” says Stanford University’s Jennifer McCormick, whose work has also found that the rate of the US publications in human ES cell research was lagging relative to other countries2. For example, the study does not control for the fact that some countries invest more in commercial than academic research or that some countries recognize patents covering human ES cell research and others do not. Also, it’s possible that some of the publications citing the 1998 papers are not limited to only human ES cells or RNAi research. Overall, McCormick says, the study raises very interesting questions, and “policy-makers ought to be keen on having them empirically addressed.”
Besides the United States, other underperformers in Levine’s study included Japan (10% of human ES cell publications compared to 13% of the general control set), France (2.9% versus 5.1%), and Switzerland (0.3% versus 1.5%). Although human ES cell research is legal in the United States and Japan, Levin notes that these countries have had policy debates “forcing scientists to navigate an uncertain policy environment”. Germany and Italy have policies restricting the derivation of lines, and although their share of human ES cell research published was smaller than that in the control set, the difference was not statistically significant.
Both France and Japan also have less than the expected share of RNAi publications, and Levine suggests that science in those countries is less inclined to pursue emerging technologies. China overperformed in both RNAi and human ES cell research, which Levin ascribes to strong economic growth and investment in research. Though the connection between performance and policy is not always clear, the analysis strongly suggests that government policy can significantly help or hinder biomedical research.
1. Levine, A. Identifying under- and overperforming countries in research related to human embryonic stem cells. Cell Stem Cell 2, 521–524 (2008).
2. Owen-Smith, J. & McCormick, J. An international gap in human ES cell research. Nature Biotechnol. 24, 391–392 (2006).