Cells 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 is very rare, but in the long run it adds up. The place where it adds up is called the lysosome, a special vessel that contains the most powerful degradation machinery in the cell; if something can't even be broken down there, it just stays there forever. This doesn't matter in cells that divide regularly, because division dilutes the junk away, but non-dividing cells gradually fill up with this stuff -- different types of stuff in different types of cell. 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 take any more and they stop working right. This is the sole cause of atherosclerosis (the formation of lumps, called plaques, in the artery wall, which eventually burst and cause heart attacks and strokes). It is also important in several types of neurodegeneration and in macular degeneration (the main cause of blindness in the old). So it's very important to fix it.

[Note: In neurodegeneration the main aggregates tend to form in other parts of the cell than the lysosome, but there is 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, so if we fix the lysosome then the non-lysosomal aggregates should disappear naturally.]

So what's the solution? The most promising approach, in my view, is to enable cells to break the junk down in situ so that they don't fill up after all. This can be accomplished by giving the cells extra 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. Preliminary work in my department in Cambridge has already confirmed this optimism. The concept is a logical extension of the replacement of a natural lysosomal enzyme in people who are congenitally deficient for it, something that is already being done. Such deficiencies cause lysosomal storage disorders, such as Gaucher's disease, and replacement of the gene is an effective treatment. 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 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.

We need a lot more work on this project. It will take time to find the right enzymes in the soil microorganisms, 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. This is a project that is very "parallelisable" -- if lots and lots of laboratories work on it, it will succeed sooner. Enthusiasm for it is growing, as demonstrated by the calibre of the fourth SENS roundtable, a meeting focused on it which I ran in July 2004.

Talks on this topic at IABG 10:
Archer

Talks on this topic at SENS2:
Rittmann      Sparrow      Jerome      Jessup      Rubinsztein      Nixon      Cuervo      Brady