As most of you know, Lyso-SENS is a recent effort by the Methuselah Foundation to target age-related storage diseases, which are caused by the accumulation of some pathogenic chemical substance in the body with age. Examples of age-related storage diseases are Alzheimer's disease (amyloid and tau aggregates), heart disease and stroke (cholesterol and oxidized cholesterol species in the artery wall), age-related macular degeneration (lipofuscin of the retinal pigment epithelium) and skin wrinkles (advanced glycation end products of the extracellular matrix). As such, Lyso-SENS targets three of the seven SENS pillars: Intracellular aggregates, extracellular aggregates and extracellular crosslinks.
Lyso-SENS works by using methods from environmental bioremediation to find soil microbes capable of degrading the target substance. We then hope to isolate the enzymes used by these microbes to do so and use them for therapy in a way that is similar to current enzyme replacement treatments for congenital lysosomal storage diseases. However, not all soil microbes are amenable to our screening methods, not all enzymes we may discover will work in the human physiological environment, some will have deleterious side-effects, and so on. So we need many sources of different microorganisms to begin with.
This is where you come in. Please send us soil samples from your area, from places that you think are likely to contain microbes capable of degrading age-related aggregates. About a handfull of soil (100-200 grams) will be plenty. The more microbial diversity we can put into these experiments, the better will be our chances of sustained success. So your participation will truly increase the chances of success of the Lyso-SENS project.
Now what kinds of places would be the right choice? We do not know for sure, but one can speculate. As a rule of thumb, age-related aggregates get degraded in nature, whereever aged vertebrates die and rot on a regular basis. There are animal graveyards, places where farms or slaughterhauses drop their excess or simply forests or lakes rich in wildlife.
Initially, we have also thought of human graveyards, and I still have not completely rejected the idea. However, please remember to be responsible when obtaining samples from anywhere, and always uphold local regulations and traditions.
Another possibility is industrial wastewaters. Chemistry plants generally have a high diversity of organic compunds in their effluent and some of them may by chance resemble age-related aggregates enough to drive the selection for enzymes we can use.
In general, highly biodiverse regions are preferrable over ones dominated only by a few species. I would be happier to have a sample from the great barrier reef, rather than one from a pond that is overgrown with only one type of algae.
There is also no need to obtain samples from recently deceased animals, since at first it is the nutricious, easily digestible stuff that gets degraded. Recalcitrant, age-related aggregates will follow only when most other parts are gone. We do not know the exact timeframes of these processes, so it is best to choose a region where decomposition takes place continously or regularly.
The highest priority targets we are pursuing right now are 7-ketocholesterol (7KC) and A2E. The chemical structures of these compounds are shown below.
7KC is a major troublemaker in the atherosclerotic lesion. It can impair the removal of cholesterol from such lesions, can trigger apoptosis in arterial smooth muscle cells and macrophaes and has a number of other pathogenic effects. Chemically, it resembles cholesterol, steroid hormones and (to a lesser degree) also bile. 7KC occurs naturally in some vertebrate arteries, but most animals do not get as bad atherosclerosis as humans do, so it should be most abundant in human remains. Though it should also be worth checking out places where animals rot that did not move a lot and had a bad diet, such as high-throughput farm dumps. I think wastewater or chemical outlets may be worth going for, too.
A2E is a pathogenic fluorophore of the lipofuscin of the retinal pigment epithelium in the eye, that has been shown to cause a whole bunch of pathological effects in age-related macular degeneration, the leading cause of blindness in the elderly. It has vitamin A derived side-chains, which also occur in plants and some synthetic chemicals. Another part of the molecule is a pyridinium ring, which also occurs in diverse molecules of life and synthetic chemistry, so therapies may in principle come from any places that are rich in such compounds. However, the combination of the two features is rare, and except for places where eyes rot I am not sure where to find A2E specifically in nature. Use your imagination.
If you choose to send us samples, please do so immediately after you obtain them. Do not store them unnecessarily. For packaging we would recommend to wrap solid samples in plastic, liquid samples in some sort of screwcap bottle and put them in a suitably sized parcel. 100-200 grams ("a handful") will be a plentiful amount. Cooling or sterile handling will not be necessary. And of course be sure to add some chocolate, packaged separately. Please also add a brief description of where and when you took the sample. We will be ready to receive samples from Nov 28, 2005.
Please send your sample(s) to:
By regular mail:
John Schloendorn
The Biodesign Institute
PO Box 875701
Tempe, AZ 85287-5701
USA
(The above address cannot receive FedEx / UPS shipments)
By FedEx / UPS:
John Schloendorn
The Biodesign Institute
1001 South McAllister Ave
Tempe, AZ 85287-5701
USA
(Apparently, the above address cannot receive regular mail -- sorry about the trouble)
I can reimburse you for the cost of shipping if required, but you can also donate shipping to Lyso-SENS. I will make sure you get appropriate credit for this somewhere.
If you are unsure whether the sample source you are having in mind is a good choice, you are most welcome to ask here. And even if you are sure, you are cordially invited to share your ideas and story.
Also, if you like to collaborate in other ways, please get in touch with me. There are opportunities to put skills in sequence bioinformatics and/or synthetic organic chemistry to good use.
[Edit: spelling, fixed address, minor details]
Edited by John Schloendorn, 07 May 2007 - 05:43 PM.
