It’s been over a month since my last post. A couple of interesting things have come over the transom but nothing really compelling for me to write about. Also I have been busy in other areas.
Something compelling did show up today. An article on Nature Magazine’s website concerning the controversy around stem cell medical tourism and the difficulty in regulation. While stem cells offer tremendous potential, the science necessary to fully and safely exploit that potential is still in its infancy. However, because of the potential, the desperation of people afflicted with horrible disease, and the ability to conjure and proliferate medical buzzwords over the Internet, the unwary and uninformed are preyed upon by the immoral and unscrupulous.
As can be demonstrated by reading my previous entries, I am a firm believer in stem cell technology. I am anxious to participate in one or more procedures in the hope of regaining function. But the science needs a little more time to develop. Anyone offering or advocating a stem cell “therapy” is either lying or deluded. Several clinical trials are underway or will soon commence (some of which I have previously discussed). But for now, I urge the reader to save your money and preserve your health by not succumbing to the siren song of an exotic “miracle cure”.
Today (10/12/2010), Geron began a Phase-I clinical trial using embryonic stem cells to treat spinal cord injury. While not directly applicable to ALS, a successful safety trial should open up approvals for similar subsequent trials utilizing human embryonic stem cells. Already there is favorable preliminary information coming from the Neuralstem trial (which uses fetal neural precursors, not embryonic stem cells) and several more are in the approval pipeline.
Meanwhile, in Israel, Brainstorm received approval to begin its trial for ALS. As discussed previously, Brainstorm engineers autologous cells to secrete neural growth factors and then implants them in muscle to promote axonal growth and nourish the cell body via axonal uptake. It’s a novel approach which doesn’t require risky surgery.
These are just a few very interesting things going on in research and clinical trials. But keep in mind that they are happening now.
I recently came across a video of a talk given by Dr. Hans Keirstead, whose work I have mentioned in a previous post. In the video, posted June 29, 2009 (almost exactly a year ago), Dr. Keirstead showcases his research on a stem cell therapy for SMA. He shows how he was able to grow functional motor neurons (proving it by showing them innervating muscle fibers) and explaining the then-current status of a proposed human trial to replace damaged tissue.
The proposed trial is for infants who suffer from Type 1 SMA. SMA (Spinal Muscular Atrophy) occurs from a malfunctioning SMN gene and the Type 1 (infantile) version is rapidly fatal. Like with a form of ALS called PMA (Progressive Muscular Atrophy), the motor neurons between the spinal cord and muscles die leaving the person paralyzed. When the diaphragm muscle is eventually denervated the person dies of respiratory failure. Regenerative medicine offers a way to replace lost tissue and restore function. In lab and animal tests it appears Dr. Keirstead has been successful. now for the next step.
There seem to be good reasons to try this in SMA infants. I am going to be coldly blunt but I beg the reader to take a breath and stay with me. First, the infants are going to die very soon so the trial length is short; you will see quick benefit or have rapid access to post-mortem tissue (also the reason Neuralstem included late-stage ALS patients in its trial). Because of the infants small size, the grafted neurons don’t have far to go to innervate muscle. In an adult such as myself motor neurons would have to grow a bit over a meter to reach fingers and toes. Even the phrenic nerve (the “money” nerve in neurodegenerative disease) would need to grow nearly half a meter to innervate my diaphragm muscle. Nerves grow slow so that could take as much as two years (for the more distal muscles). Infant bodies are still also in a rapid growth mode which may assist the grafts (mentioned in the Stanford study in a previous post). I could also guess that an immature immune system may be beneficial for anti-rejection purposes (pure speculation on my part). Time is in critically short supply in SMA (and ALS) so having short trial lengths is crucial. June 22, 2010 update on program progress.
Because SMA is so similar to ALS, if this trial goes well it would be huge news for PALS. In fact, ALS is the next disease in line for this treatment. With this program and the concurrent ongoing programs by Brainstorm, TCA, and Neuralstem either soon to be or currently in trial, I have great hope for regenerative medicine.
As always I invite responsible comments or questions.
I really love the Public Library of Science because they encourage and publish research articles in the Public domain. This gives a dilettante like myself access to current peer-reviewed medical research without emptying my bank account.
A couple of fascinating (if not immediately applicable) studies recently showed up in my search results. First was a study which researched how embryonic stem cells (ESCs) are not necessarily all created equal (good summary here). I rubbed that against this study which tracked how cells convert from Inner Cell Mass to ESCs. This is just basic research, so what? Well add this study from Stanford (mentioned in an earlier post) and that basic research gets more exciting. There is one company already developing methods to use placental stem cells for pharmaceutical purposes. Knowing how these cells change themselves, thereby facilitating in vitro manipulation, would be crucial.
The second study demonstrated making functional neurons out of astrocytes without first reverting them to a pluripotent state (as is done with skin cells to create induced pluripotent stem cells). Sounds great, except harvesting the astrocytes can be a bit tricky. While I consider that there are multitudes from whom whole lobes could be removed with no appreciable cognitive or behavioral impact, poking holes in the brain for experimental raw material probably isn’t a good idea. And the study used retrovirus to deliver the genetic information, which for in vivo application could cause problems. (apologies for the inaccurate humor stretch)
While these studies don’t appear to be immediately applicable to human disease (and regenerative medicine), they demonstrate how far knowledge has advanced at an extremely rapid pace. This continues to give me hope for an effective treatment very soon. While the word “soon” has been used for decades (resulting in much cynicism among PALS), the techniques explored above are extreme changes in paradigm. And as human trials with stem cell technology are already underway, the time from basic research to effective therapies is now being greatly compressed.
In a previous post I made mention of the Neuralstem clinical trial currently ongoing at Emory University. Recently, CNN ran a story on the trial which provided welcome news to the ALS community. Three implantations had been performed with no complications so far.
Today I received a press release which carried forward the good news. Based on the results so far with the first three, they are going ahead with a fourth with double the injections (both sides of the spine). This is great news as it is showing the procedure and product to be safe (the primary objective of this trial). It is still too early to determine any efficacy and the trial isn’t designed to measure that anyway.
With each success the barriers are pushed back a little further. The success of the Neuralstem trial will pave the way for other trials.
Stem Cells for Dummies is authored by Lawrence S.B. Goldstein, PhD. Dr. Goldstein also co-authored the legislation which created CIRM.
The book does, IMHO, a rather good job of presenting complex science in terms which laypeople can easily digest. It starts with a primer on biology as it applies to stem cells and a brief history of their discovery and initial uses. The differences between adult and embryonic cells is explored with frank discussion of the attributes and limitations. The role of these cells in the research and treatment of various diseases is discussed along with a review of the current state of the art (my previous post on stem cells deals with some cutting-edge techniques). There is a detailed section on the ethical and moral controversies surrounding this sensitive topic, and a section on common myths and misconceptions.
Stem Cells for Dummies is written from the scientist’s viewpoint but takes effort to present in a neutral tone. It is written for anyone who wants to understand stem cell technology without requiring a PhD. Rather than spend weeks cuddling with Google and sifting through the inevitable dreck, drop $10 and receive a great resource from a recognized expert in either dead-tree or electronic form.
[disclaimer: I linked to Amazon for convenience and because I use their Kindle for PC application. If you can, support your local bookstores.]
There has been a bit of action recently in terms of stem cells, with one human trial in MND which commenced this month and another which hopes to commence soon. There are a two ways for stem cells to be of benefit: Trophic support where the grafted cells support existing neurons by secreting nourishing (trophic) proteins such as GDNF and BDNF and regenerative where new replacement neurons are grown. Each approach has advantages and technical (biological) hurdles.
As I said, trophic is secretion of neurotrophic (“nerve-feeding”) factors. It can also occur from the implanted cells just being a close friend to the diseased neurons. A benefit of trophic therapy is that the graft cells do not need to differentiate or grow. Cells modified to become GDNF “mini-pumps” have been shown to fully protect motor neurons in animal models of ALS. Unfortunately, however, in that study the protection did not extend to the axon. While the cell body was healthy, it made no contact with muscle which is functionally the same thing as the whole cell dying. In the trial underway in the United States, Neuralstem is using fetal stem cells. While they claim their product will differentiate into neurons and glials, they only claim to be pursuing a trophic therapy. In at least one animal trial, the implanted cells extended the life of the model (it is worth noting that due to variability in the model, the ten extra days could just be statistical noise). The cells were found to fully integrate into the host central nervous system. Another group, TCA Cellular Therapy is using autologous cells taken from the bone marrow. Both of these trials involve spinal implantation. A planned trial in Israel will also use autologous cells but will do the implantation in muscle to try axonal uptake.
Regenerative therapy has its own set of issues. While the ability for stem cells to become neurons has long been demonstrated, the new neurons still need to make proper axonal connections to muscle (spine -> muscle) and within the brain to other neurons (motor cortex -> spine). In 2006, a study by Johns-Hopkins achieved that in test animals. The process required not only implantation of prepared cells but also significant treatment on the muscular side of the connection (sharp readers may notice similarities to procedures discussed above). A much more recent study from Stanford showed that proper preparation of the stem cells is critical for proper behavior of the cells after implantation. The cells prepared with retinoic acid (as in the Johns-Hopkins study) failed to create proper connections whereas cells prepared by co-culture with stromal cells grew robustly and made proper connections from the motor cortex to the spinal cord, bypassing neurons from other cortexes (visual, etc.). Caveates of the Stanford study is that the work was done on very young animals (about a week old) so fully adult animals may present a different environment, and that requirements for cortex -> cord connections may be different from spine -> muscle.
On most of the studies above, the links are to press releases. This is done to indicate existence and to give limited information. Copyright prevents me from republishing any studies (except for the PLOS link which is intentionally placed in the Public Domain. The reader should also note that my technical training is in hardware and software, not wetware.