Research published last week ushers in a new and highly exciting stem cell era. Two groups of scientists from independent laboratories have reprogramed human skin cells to turn into cells that have the same characteristics as embryonic stem cells. Dr Goodman reviews these studies and how they may have impact for Huntington's treatment.
Stem Cell Background: Up till now there had been two sources of stem cells, embryonic and adult. Embryonic stem cells (ES) could be obtained only from early stage embryos. ES cells have advantages; they can develop into any kind of cell, and can be grown in the quantities needed for treatment of Huntington's or other disease. Adult stem cells are present in all organs. Though more easily obtained (most often from bone marrow), this type of cell has disadvantages; they are difficult to grow in the quantities needed, and more specific to Huntington's, there has been more difficulty with inducing neuron cell development.
The Huge Breakthroughs: In earlier landmark studies, scientists from Japan showed that fibroblasts (deep layer skin cells) from a mouse could be programmed to turn into cells (called induced pluripotent stem (iPS) cells) that are nearly indistiguishable from embryonic stem cells [Takahashi K 2006]. This same group subsequently showed that iPS cells functioned like embryonic cells; iPS cells placed into female mice produced baby mice [Okita K 2007].
In the present breakthrough research, two independent groups of scientists, the same group of Japanese scientists [Takahashi K 2007] and another group from the U.S. [Yu J 2007] extended these findings by reprograming human skin cells to turn into iPS cells.
How was it done? Each group of scientists added 4 genes (known to be master transcription regulators) to skin cells. This was done by using viral vectors: Each gene was attached to a portion of a virus that can enter the cells and deposit the gene into the skin cell's DNA. Remarkably, it took only 4 gene combinations (out of a possible 20,000) to set this into motion. Two of the 4 genes were used by both groups, but the other 2 were different, showing that the process did not require (at least 2) specific genes.
Why is this important? Embryonic tissue (with attached ethical implication) is no longer required to obtain the best (pluripotent) stem cells. The technique is relatively simple and robust, making further research by other laboratories much more possible. The additional beauty is that iPS stem cells can be generated that are specific to an individual. This means that the strong medicines used to prevent rejection of stem cell transplants will not be necessary.
Next Steps: There are several more steps (and years) before stem cell treatments could be tried in people. First, we will need safer viral vectors that ensure that genes are inserted into the proper place in the DNA; or better, small molecules that activate the necessary 4 genes. But as David Melton, a leading stem cell scientist from Harvard (who works on these things) stated in Science Magazine "It's almost inconceivable at the pace this science is moving that we won't find a way to do this . . and "It's not hard to imagine a time when you could add small molecules that would tickle the same networks as these genes [Vogel G 2007]". Second, there will need to be improvements in the process that can induce iPS cells to develop into specific kinds of neurons. This step is already being done in biotechnology companies like StemCell Inc. that has a neuron cell product (derived from neural progenitor cells) in phase I clinical trial, and Neuralstem Inc. (that has submitted INDs for clinical trials in ALS and Parkinson's). These companies and independent research [Lepore AC 2006] have demonstrated incorporation and development of neurons and glia when implanted into model animals.
For Huntington's, the process may require additional steps because iPS cells from skin will also contain the mutant gene. It is possible that neurons produced from iPS cells (like other neurons in HD) would function normally for many years, even decades. Or it might be technically possible to knock down the mutant gene function in iPS cells before they are used for treatment. This type of procedure would be easier to accomplish in individual cells in a test tube than in people.
While all of the projects take years of time, remember that a lot of work has already been done.
Comments: If stem cell therapy works, these findings bring it much closer. Think of this analogy: In the past, the prospect for stem cell therapy was like a relay race where the starting line was hidden, but all the runners were training. This new research is exciting because it marks the starting line so that the race can finally begin. You can be sure that, backed by billions of dollars invested in this medical biotechnology, this race is on in earnest, with each subsequent runner getting ready to take the baton.
Though we don't know whether stem cell therapy can be a successful treatment for Huntington's (or any other disease), this research leads the way to answers. Sure it will take years of time, but remember that the the different parts of the process will be pursued urgently and simultaneously. I think stem cell answers, and hopefully stem cell treatments, aren't so many years away.
Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006 Aug 25;126(4):663-76. Epub 2006 Aug 10. PubMed abstract
Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature. 2007 Jul 19;448(7151):313-7. Epub 2007 Jun 6. PubMed abstract
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007 Nov 30;131(5):861-72. PubMed abstract
Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007 Dec 21;318(5858):1917-20. Epub 2007 Nov 20. PubMed abstract
Vogel G, Holden C. Developmental biology. Field leaps forward with new stem cell advances. Science. 2007 Nov 23;318(5854):1224-5. PubMed abstract
Lepore AC, Neuhuber B, Connors TM, Han SS, Liu Y, Daniels MP, Rao MS, Fischer I. Long-term fate of neural precursor cells following transplantation into developing and adult CNS. Neuroscience. 2006 May 12;139(2):513-30. Epub 2006 Feb 3. PubMed abstract