November 17, 2004
Sonic Hedgehog Gene Triples Brain Stem Cell Growth
The gene for Sonic hedgehog proves it can stimulate old adult neural stem cells to grow more rapidly.(same article here)
Now, a UC Berkeley bioengineer has devised a way to enhance the utility of adult stem cells that could steal some of the spotlight away from embryonic stem cells and eventually lead to treatments or cures for diseases such as Alzheimer's and Parkinson's.
Schaffer's team took DNA from a rat and isolated the gene that produces the Sonic hedgehog protein. They then cloned that gene, inserted it into a harmless virus which they then injected into the rat's brain. The virus delivered the Sonic hedgehog genes to the brain stem cells, stimulating them to divide three times faster than normal, which in turn tripled the production of new neurons.
The ability to make a lot of neural stem cells would be useful for the preparation of stem cell therapies.
Researchers discovered a couple of years ago that Sonic Hedgehog is a major regulator of neuron cells. The body uses the Sonic protein in multiple tissues for development, such as the skin, hair, intestine, pancreas and brain, from the embryo stage to the adult stage. Schaffer’s investigation focuses on Sonic’s role in the brain.
“To regenerate tissue, or replace a lot of neurons, you need to mass-produce the cell, and then you need to take those mass-produced cells and induce them to differentiate them into neurons. So we’re very interested in Sonic Hedgehog because we found it’s a powerful way to mass produce the cells initially,” Schaffer said.
Parkinson's Disease and other brain diseases will some day be treated with stem cell therapies. Since neural stem cell growth appears to slow in people suffering from depression it is even possible that stimulation of neural stem cell growth could become a treatment for depression.
Neural stem cell growth appears to slow with age as well. Techniques to stimulate of neural stem cell growth may well become standard therapies to prevent the age-related decline in the ability to form new memories.
A couple of cautions however: First off, stem cells programmed to grow much more rapidly might grow too much and turn into neurons in locations they are not needed and even potentially harmful. Scientists will need to develop methods to not only stimulate cell growth but also to turn off the source of stimulation once the needed cells have been produced.
Also, stimulating old stem cells to grow more rapidly might not be wise if the old cells have accumulated a lot of DNA mutations. Old cells are at greater risk of becoming cancer cells because of the damage they have accumulated. So considerable care will be needed to in selecting older cells that can safely be stimulated into acting young again. One way to try to reduce the threat of cancer on old cells will be to do gene therapies to old stem cells to fix growth regulation genes that may have gotten dangerously mutated over a period of years.
Randall, I think that the first link you provide in your description of the Sonic Hedgehog research might be incorrect. The quotes you give are not from the "Daily Cal" article. They are from an article that appeared in the Contra Costa Times that is available here.
I was surprised when I read the following sentence: "They then cloned that gene, inserted it into a harmless virus which they then injected into the rat's brain." The adjective "harmless" might be premature. The use of a virus to insert a gene into a cell can be very dangerous. For example, two children in France developed leukemia when gene therapy using a viral vector was performed on them. See the article Gene therapy 'caused T-cell leukemia' in "The Scientist". The French experiment used a "defective Moloney murine leukemia virus" and the Sonic Hedgehog research used an "adeno-associated virus" AAV. The AAV is apparently much safer because the payload integrates into one spot in the genome of the host (on chromosome 19 in humans).
But personally I hope some new strategy is developed to avoid brain viruses. ;-) In any case, congrats to Professor David Schaffer.
Randall, very interesting link. Thanks.
The bit about using a viral vector to insert the gene is also good news. Perhaps a viral vector could be designed that targeted specific cancer stem cells and inserted one gene that “healed” the cancer stem cell.
Sick Kids researchers confirm that cancer stem cells initiate and grow brain tumours
Fly said: "Perhaps a viral vector could be designed that targeted specific cancer stem cells and inserted one gene that “healed” the cancer stem cell."
That is a fine idea Fly and it is being tried now. "In about one-half to two-thirds of all cancers, a protein called p53 is defective." A common cold virus has been modified to contain a correct version of the p53 gene. Here is an article about an experiment at Stanford reported in 2002. The virus appears to heal a cancerous cell or force it to commit suicide - apoptosis. "The virus is also being studied as a potential treatment for head and neck, ovarian, and pancreatic cancer."
(Viruses are still dangerous. If the payload integrates into the wrong location in a genome it can cause a normal cell to become cancerous as noted above in the French experiment.)
Fly, Garson beat me to it on the dangers of the viral vectors. When you read a research study on animals that does gene therapy keep in mind that they come up with this neat result on an animal that has a short life anyway and they are just trying to see if they can achieve this specific effect.
It is quite possible that the gene therapy messed up the cells in this experiment in ways that would not become apparent in humans until years after the initial gene therapy. We really need safe ways to deliver genes. But this sort of work provides many useful insights and should and does go on in parallel with the efforts to develop better delivery mechanisms.
A couple of months ago I caught a cold. A virus invaded my body and hijacked the cellular machinery. I couldn’t determine where in my genome the viral code was inserted. I couldn’t determine what cells would be infected. Contrast that natural infection with using AAV that inserts in a specific location, doesn’t cause massive cell destruction, and only targets the desired tissue. Seems to me that using AAV to insert a gene in specific genome location in specific cell is less dangerous than that cold I caught. (Clearly a virus that targets brain tissues for destruction could lead to brain inflammation and death. I don’t believe AAV causes inflammation.)
To the extent that the gene change has powerful effects such as tripling neuron generation, the danger of harmful consequences is greater. One possibility is to activate the gene only in the presence of an antibiotic. Drug triggered activation of inserted genes has already been demonstrated in mice.
Gene engineering is advancing rapidly.
I agree that non-viral approaches to gene engineering are also promising. I like the idea of adding an extra enhancement chromosome to stem cells that target specific tissues. Verify their quality, grow as many as you want, and inject them into appropriate tissues. Perhaps a drug trigger could be used so that the stem cells would only divide when desired. You could even include a drug triggered “kill” switch to eliminate the modified cells as needed.
PS Garson, thanks for the link to the cancer paper.
Interesting post ... I am a little unclear why this study is connected with stem cell research. Are we writing science fiction?
The mechanisms forwarded by this research outlines a potential approach that is not linked to stem cell research and its host of mechanisms that need to be ironed out. A couple of the comments outline the open issues associated with this research project. This line is complicated enough.
The secret to good science is simplicity and solid causal linking. Bad science, but good science fiction is convoluted logic and complexity (how else can you write 400 pages).
Let's stick with good science.
I am a little unclear why this study is connected with stem cell research.
I am a little unclear on why you are a little unclear. So let us review some basics:
1) The research reported in this post was done on adult stem cells. Adult stem cells are a type of stem cells.
2) One problem with adult stem cells is that they do not divide as fast as embryonic stem cells. So getting sufficient supplies can be a problem.
3) These researchers found a way to produce more adult stem cells.
Are you still unclear?
R, I should have inserted "embryonic" infront of stem cell (my omission) ... My point is that the casual linkages necessary to execute the current research project needn't be complicated by introducing more complexity.
Hi I'm a Sonic the Hedgehog fan I'm surprised there's a gene called Sonic Hedgehog... do I have it? Anyway, I'm glad it's useful!!!
i am a student in the medical field and i want more info on the benifits and disadvantages of this gene (i am also a fan of sonic the hedgehog games) please send me any info. you have at firstname.lastname@example.org
I am a v victim of traumatic brain injury. Luckily my intellect is intact, as is my education and training. but I do have a left side visual field defect. according to an MRI, the nerve connecting my left side visual field was damaged. my right side visual field is fine. My neurologist did mention stem cell therapy, but none seems to be done in the U.S. Also, he mentioned that that stems cells might not work due to the nature of the nerve injury. My question id why wouldn't the stem cells simply create a new nerve rather than try to repair the existing one? If anyone knows is anyone snows anyone doing work in this field I'd appreciate a contact, Thanks, email@example.com