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LysoSENSCells have a lot of reasons to break down big molecules and structures into their component parts, and a lot of ways to do so. Unfortunately, one of the main reasons to break things down is because they have been chemically modified so that they no longer work, and sometimes these chemical modifications create structures that are so weird that none of the cell's degradation machinery works on them. This situation is very rare, but in the long run these modified chemicals add up. Ultimately the chemicals end up in the lysosome, a special vessel that contains the most powerful degradation machinery in the cell; if something can't be broken down there, it just stays there forever. This doesn't matter in cells that divide regularly, because division dilutes the junk enough that it remains at harmlessly low levels, but non-dividing cells gradually fill up with this stuff, making them dysfunctional. The heart, the back of the eye, some nerve cells (especially motor neurons) and, most of all, white blood cells trapped within the artery wall all suffer from this. Eventually, these cells can't process any more of this junk, and they stop working correctly. This failure is the key cause of atherosclerosis (the unstable buildups, called plaques, that build up in the artery wall and eventually burst and cause heart attacks and strokes). As the cells responsible for clearing toxic fatty materials out of the blood vessels become engorged with indigestible materials, they cease functioning and die, leaving their corpses behind to build up in the vessel. Failure to process recalcitrant junk within the cell is also important in several types of neurodegenerative diseases (such as Alzheimer’s and Parkinson’s) and in macular degeneration (the main cause of blindness in the old). So it's very important that we find a way to prevent or reverse the build-up of these wastes within the cell. In neurodegeneration, aggregates also tend to form in parts of the cell other than the lysosome. There is, however, good evidence that this is a compensatory measure when neurons' lysosomes stop working properly as a result of the more modest accumulation of lysosomal toxins. Therefore, if we fix the lysosome then the non-lysosomal aggregates should disappear naturally. The solutionThe most promising approach, in my view, is to enable cells to break the junk down so that they don't fill up after all. This can be accomplished by equipping the lysosome with new enzymes that can degrade the relevant material. The natural place to seek such enzymes is in soil bacteria and fungi, as these aggregates, despite not being degraded in mammals, do not accumulate in soil in which animal carcasses are decaying, nor in graveyards where humans are decaying. This suggests that the micro-organisms present in soil have enzymes capable of breaking these aggregates down, and preliminary work in my old department in Cambridge, as well as work now being carried on at Arizona State University, has already confirmed this optimism. The concept is a logical extension of the replacement of a natural lysosomal enzyme in lysosomal storage disorders, such as Gaucher's disease, in which people are born either lacking the gene for the enzyme, or with mutations that render it dysfunctional. Replacement of the enzyme via injection is already used as an effective treatment for these diseases, and further work is underway to make these treatments even more effective using the gene instead of the enzyme. Gene therapy is still in its infancy, and its difficulty must not be underestimated, but progress is steady; it may not be overoptimistic to predict that by the time we have identified enzymes capable of degrading lysosomal junk and made them work in mice, gene therapy will be sufficiently advanced to allow their use in humans. Also, very importantly, the biggest application of this technology (in atherosclerosis) doesn't need gene therapy at all, because the cells that need to be given the microbial genes are macrophages, special white blood cells, which come from the bone marrow. So we can make the necessary changes to blood stem cells in the laboratory, and then give them to people as a bone marrow transplant, which is much, much easier than gene therapy. ProspectsWe still need more work on this project. It will take time to find the right enzymes in soil micro-organisms, to find the ones that work well in mammalian cells and are not toxic, to modify them so that the cell knows how to target them to the lysosome, and so on. Fortunately, each of these problems can for the most part be worked on independently (rather than having to master one problem at a time before going on to the next one in sequence), so the more laboratories are put to work on each of them the sooner we can get the whole project to succeed. Enthusiasm for this approach is growing, as demonstrated by the sponsorship of the fourth SENS roundtable (a meeting focused on this intervention which I ran in July 2004) by the National Institutes on Aging, and the calibre of the scientists who attended, contributed to the discussion, and signed on to the resulting detailed proposal for the development of the therapy. The Need for SamplesThe key to the success of this project is microbial diversity. Not all soil microbes are amenable to our screening methods, not all enzymes we discover will work in the human physiological environment, some will have deleterious side-effects, and so on. That's why we need as many different genetic sequences as possible to begin with. So how can you help fight age-related storage diseases?You can help by sending us environmental samples from biodiverse habitats in your area, or from places that you think are likely to contain microbes capable of degrading age-related aggregates (e.g. because the target substance gets degraded there naturally). 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 LysoSENS project. Bear in mind that in general, quality is better than quantity. Everyone will have a garden and a compost heap, and we'll get plenty of these. Not everyone will live next to a hot spring, or go on a holiday to the Great Barrier Reef - you get the idea. The more exotic and biodiverse your sample is, the more we will want it. In addition to such attempts to culture microbes on our target substance, we are also directly extracting genes from soil in order to make what is called a metagenomic library. This approach has two advantages: First, it includes non-culturable microbes, which some say account for up to 99% of all microbes. Second, the DNA samples can be copied, frozen down to extreme low temperature and thus stored indefinitely, which allows them to be used in the near and far future for other projects. So whatever you contribute now will become the foundation of a growing DNA library that will probably accompany us until the LysoSENS (and GlycoSENS) targets (intracellular junk, extracellular junk, and protein crosslinks) are out of the way. Hopefully, the construction of this most remarkable DNA library alone can show the scientific community that the public cares about this work, and inspire imitation among scientists worldwide. InstructionsLess than a handful of soil (50-100 grams) will be plenty. 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. Remember, exotic, biodiverse samples are key. Please send your samples to the following address: By regular mail: John Schloendorn (The above address cannot receive FedEx / UPS shipments) By FedEx / UPS: John Schloendorn (The above address cannot receive regular mail) LysoSENS Progress & Next StepsOur teams have now cultured bacteria capable of degrading 7-ketocholestrol (implicated as a major cause of atherosclerosis and also involved in Alzheimer's disease), A2E (responsible for age-related macular degeneration) and CML, a sugar-derived protein modification which accumulates throughout the body and is associated with many of the symptoms of diabetes (this last target, although technically part of the GlycoSENS strand, is presently being handled at our Arizona laboratory). The enzymes involved in A2E degradation have been identified and we are working with Professor Janet Sparrow to test them for therapeutic benefit in cellular models of macular degeneration. Our preliminary work on 7-ketocholesterol was recently published in the international journal Biodegradation, in the March 15th 2008 issue. Our microarray program, based at Rice University, has identified a series of enzymes implicated in 7-ketocholesterol degradation which we are now characterising and cloning into E. coli to allow more extensive testing. We will publish these results (and hopefully many others!) in the near future. Research Team
Questions and ContactIf you have any remaining questions feel free to join the Methuselah Foundation Research Forum, or email John Schloendorn at Zauberkugel@yahoo.com That's it folks, enjoy digging. ResourcesTalks on this topic at IABG 10: At SENS2: At SENS3: |
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