Religious Taboos Against Stem Cell Research: No Cure for Lou Gehrig’s Disease 32 Years After My Cousin Died Torturously

by on October 5th, 2015
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When Bob and I were both 15, we went to the wedding party of my dad’s littlest brother. Bob was dad’s sister’s second-oldest son. We lived in southwestern Minnesota and they lived north of Minneapolis near Bob Dylan’s home turf. Consequently, I only saw Bob at family reunions-or once or twice a year.

But his round face topped off with a shock of blonde, messy hair and decorated with an unending grin spelled fun and mischief. I loved him.

My uncle’s wedding was the last time I saw my cousin as a whole, healthy person. He and I teased the bartender, trying to sneak a beer. The barkeep wouldn’t give us one. Finally, the combination of my innocence and Bob’s stealth grin forced the man to top off a beer for each of us with strawberry soda.

We had our beer and could drink merrily in front of our parents. Another rite of passage.

Shortly after high school graduation, I heard that Bob had incurable Lou Gehrig’s Disease (amyotrophic lateral schlerosis or ALS). My dad’s sister began flying with him all over the U.S. and to some other countries with money they didn’t have to try exotic or fraudulent cures. This was the early 1970s.

The last time I saw Bob was when I arranged with one of his sisters for her to bring him to a small restaurant on the outskirts of his home town. We were both about 25.

I recognized him only by the sparkle in his eyes. He sat in a wheel chair curled into the shape of a sea horse or a 93-year-old woman with osteoporosis. He was 99 percent paralyzed. The only parts of his body he could move were on his face and a bit of his right arm. I had to shake the one finger he could move instead of his whole hand, or instead of the jovial bear-hug we would have executed as 15 year olds. His sister had to interpret his speech, which came out as mumblings only someone who knew him intimately could decipher.

He died when we were both about 28. I’m 57 and there still is no cure-and barely any ameliorative measures-for ALS. I believe that one of the main reasons has been the religious taboos against adult stem cell therapy or research. Too many people believe research on adult human stem cells is condemned by God.

Well, this is another confused human rationale that will have to fall. Leonardo DaVinci, revered today, faced similar religious taboos when he first drew the human body in great detail, including the inner organs. However, many of us nowadays are able to live into our 80s and beyond because DaVinci broke those taboos, thus permitting development of many medicines and surgeries we now rely on and don’t realize would have been impossible without DaVinci’s courageous act.

Recently, I had the opportunity to ask some questions of Tom Maniatis at Harvard, who is a first rate scientist and past chair of ALS Association’s Research Committee

My questions included:

1) What is the primary research focus w/r ALS now in the U.S.?
Dr. Maniatis:
ALS is a complex disease, and is therefore being approached on many different fronts. From my perspective the following are the most exciting and promising:
A. Genetics – two directions:
1. Identification of genes that when mutated cause ALS.
This is generally considered the most exciting recent advance for two reasons. First, mutations in two genes have recently been shown to cause ALS, and both genes have been implicated in RNA expression or processing (they both bind RNA). One gene, called TDP-43 is important because it links, for the first time familial and sporadic ALS. The role of TDP43 was first recognized in the analysis of protein aggregates in post-mortem samples of patient spinal cords. Analysis of these cytoplasmic aggregates revealed the presence of TDP43. Subsequently genetic studies revealed the presence of mutations in the TDP43 gene in both familial and sporadic ALS patients. The second gene, called FUS/TLS was discovered more recently, and is also associated with both familial and sporadic ALS. Intense studies of the normal function of these genes are in progress, and efforts are being made to generate mouse models and to study motor neurons derived from patient fibroblasts (induced pluripotent stem cells (iPS – see below).
2. Genetic Linkage studies: Thousands of patient DNA samples have been analysed for genetic linkage to sequence polymorphisms, and a few candidate genes have been identified. However, I think it is fair to say that the field has been disappointed by the lack of clear candidate genes.
B. Stem Cells:
Two directions:
1. Therapy – the most promising avenue is to introduce genes encoding trophic factors into stem cells. The idea here is to introduce genes that encode growth or trophic factors into human embryonic stem cells, differentiate these cells to generate motor neurons, and then introduce them into the spinal cords of ALS patients. The idea here is to populate the spinal cord with cells capable of secreting factors that slow motor neuron death. Animal studies have been carried out and efforts are underway to develop this approach for clinical trials. An alternative, and in my opinion, much longer term approach is to actually replace dying motor neurons in ALS patients with functional stem cell-derived motor neurons. The greatest challenge here is to correctly rewire motor neurons so they function normally. This is an enormous challenge that will require significant technical advances, and may simply not work. However, the potential benefit is so great this effort should be supported.

2. Disease Mechanisms: This is the most promising immediate benefit of stem cell research. The idea here is to collect skin cells (fibroblasts) from ALS patients, turn them into iPS cells using well established methods, and then use these cells to generate motor neurons and glia for studies in cell culture. In fact, the first two steps have been achieved – that is the generation of patient derived iPS cells and their differentiation in culture to motor neurons. The last step – observation of disease properties has yet to be demonstrated in long term culture. If this does work, this approach will provide an excellent system for studying ALS disease mechanisms in cell culture, and will provide an excellent cell based assay for drug screening. An encouraging note, this approach has worked with mice – that is it was possible to generate motor neurons from stem cells taken from the SOD! ALS mouse model, and show that they display disease properties in long term culture. We are currently using this approach to study disease mechanisms and test potential drugs. Another benefit of this study was the important discovery that cells other than motor neurons plan an important role in disease progression. Specifically, it was possible to show that astroglia (the cells that surround, contact, nourish and support motor neurons) play an essential role in the disease, at least in the SOD1 mouse model of ALS. In fact, it appears that astroglia derived from the SOD1 mouse stem cells secrete toxic factors that kill motor neurons. Efforts are underway to identify these toxic factors.

2) How does stem-cell research rank in importance? And what kind of stem cell research are we talking about?
Dr. Maniatis: Answered above – I consider stem-cell research to be of great importance, both in the development of treatments for ALS and for understanding disease mechanisms.
a) If it’s not the ultimate path to a cure, what could be?
Dr. Maniatis:
Too early to answer – best hope is to identify small molecule drugs that prevent neurodegeneration – the best current assay system is stem cell-derived motor neurons and glia.

b) How do religious or cultural taboos affect research in the U.S. and around the world?
Dr. Maniatis:
The implications in the US are obvious. The restrictions on stem cell research have severely hampered progress. Although iPS cell technology may be successful, the use of these cells for therapy is not possible without further advances. No progress has been made with alternative approaches such as nuclear transfer because of the restrictions. Even though more human embryonic stem lines can be used for NIH-supported research, the development of new lines will be difficult considering the guidelines.

c) Is there a cost or cost per year estimate of both current research and current attempts with today’s drugs?
Dr. Maniatis:
I am not in a position to answer this question – it depends on the focus of NIH and private foundations.

3) What do you and ALS think of adult stem cell therapy? Will it be the ultimate path?
Dr. Maniatis:
I think it is way to early to predict the ultimate path – all directions (adult and embryonic stem cells) should be aggressively pursued.

a) Q Therapeutics has a product called “Q-cells” used in “autologous” stem cell therapy. They claim significant success. Is this true? If not, why?
Dr. Maniatis:
I think the idea is sound – that is to provide myelin and trophic support to dying neurons, but it is currently much too early to get excited. The results in animal models have been positive but modest, and much more work will have to be done before they can be tested in the clinic. Basically, I think this is a positive direction, but we have a long way to go, and to make value judgements on which approach is better or worse are premature.

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