Role Model

A few days ago, Matt White, who lives with ALS, addressed the Butler NCAA basketball team prior to their Final Four victory over Michigan St. Normally I don't care about basketball (I am a hockey fan) but a Facebook friend posted the Youtube link above and I viewed it. The thing that struck me about Mr. White's address was his promotion of Sir Ernest Shackelton as a role model. If you don't know who he is or don't know his story, please take a moment to read the previous link (most notably the portion on the Trans-Antarctic Expedition). Sir Ernest is a perfect role model for PALS because of his dogged determination, his cool ability to make rational choices in grim situations, and his use of those characteristics to survive a lethal predicament (multiple predicaments, actually). Not only did he survive but he ensured his men would as well. Contrast the experiences of Scott and, worse, Franklin. Even though Shackelton was forced to abandon his original goal, he achieved an even greater goal by surviving. I would like to thank Mr. White for including Sir Ernest in his address and would like to concur. Even though PALS may be forced to abandon their goals, it is my hope that many can join me in "pulling a Shackelton" and doing what is necessary to survive an impossible situation.

CD40L and the MAB

The ALS Therapy Development Institute is a non-profit biotech fully devoted to finding a treatment for ALS. A few years ago they undertook a genome-wide association study (GWAS) on the animal model of ALS (the G93A mouse).The results implicated the costimulatory pathway which links the innate and adaptive immune systems. In an attempt to address that pathway, TDI used a monoclonal antibody against CD40L. This decreased a specific T-Cell interaction which led to the body attacking the axons of the motor neurons. A very good description of the study can be found at the Alzheimer Research Forum (Alzheimers, Parkinsons, and ALS are selective neurodegenerative diseases so research in one can provide clues into the pathways of others). This finding is interesting for a few reasons. For the first, it marks a shift in looking at ALS as a motor neuron disease to seeing it as some other dysfunction in which the neurons are injured. Second, while the treatment described isn't a "cure", it does point towards a significant pathway of disease management. Another important point is the success reported by TDI. Since the development of the murine model of ALS numerous researchers have claimed varying degrees of success in preclinical work only to have the candidate substance fail in human trials. TDI undertook an internal study to figure out why and discovered numerous variabilities for which researchers must account when designing trials. TDI's mouse program is now recognized as the "gold standard" for that model. The fact that they can report measurable and repeatable results is significant. Of course mice aren't men and this isn't a cure, but it does give quite a bit of hope that a truly effective treatment may be within reach. [UPDATE 04-02-2010: TDI discusses this via MP3 podcast.] [UPDATE 04-05-2010: The study is now available free of charge in PDF format. Very good of Nature Publishing Group to make this available to PALS and CALS!

Stem Cells for Dummies

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.]

Sausage-fest!

Interesting things happen to one's body due to ALS. One of the most trivial effects I have noticed involves my fingers. I am quadriplegic so my hands spend all their time on a (relatively) flat surface. Grasping or any voluntary flexing of my fingers has been nothing but a memory for years. This allows the skin to tighten and smooth a bit. You know those little wrinkles over your knuckles on each finger? I don't have any anymore! I noticed this during physical therapy a few weeks ago and wondered what these little keratin-tipped bony alien hotdogs were doing at the ends of my hands. Truly a sausage-fest.

Letter from Lou

I recently received a handwritten letter from Lou Gehrig. Obviously it was not addressed to me as the people responsible for creating me had not yet themselves been created. But it does give an intimate glimpse into the life of a remarkable man (even without the disease his accomplishments are legendary). I was struck by the proof of his equally legendary kindness and generosity, and hope to approach that in my own life as I struggle with fellow PALS to achieve the goal that eluded Lou.

Kindle for PC

Back in November of 2009, Amazon released its Kindle for PC software. The program is free and available for Windows 7, XP, and Vista. A future version for Mac is promised. While I have never used a physical Kindle (holding anything but my breath is no longer an option for me), the software appears to recapitulate most of the function of the device. The most important part for me (and for all advanced-stage PALS) is that it behaves very well with my optically-controlled assisted communication system. I use the ERICA from ERT. ERT was recently purchased by Dynavox but the K4PC should still work on that platform as well as the Tobii. Downloading and installing is very simple. Once installed you need to register the "device" to your Amazon account (like the physical Kindle each registered software counts as one of the 5 devices on which you are allowed to share your purchases). If you don't have an Amazon account you will need to set one up (I recommend letting an assistant do the data entry here although I was able to do this myself). For those who already have a Kindle, you should see your previous purchases sync to the software. If this is your only device, new purchases from Amazon will appear within 30 seconds of purchase. Each page has large, easy to read type and the size and spacing can be adjusted for comfort. To either side of the page are white arrows to turn the page. They only appear on mouse-over, and if you click even near them you will hit the target. They are spaced far enough away from the text that accidental page turn is almost impossible. If you close the application with a book open your place is saved automagically. Other bookmarks are easily set. The software is considered beta at the time of writing this post but works very well for me. Updates are automatic but can be set to manual. For software not expressly written for handicapped users it satisfies some important requirements. I am very happy to be reading books again!

Stem Cells

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.