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Removing toxic aggregates that our cells can’t break down Aubrey de Grey Department of Genetics, University of Cambridge Email: ag24@gen.cam.ac.uk Website: http://www.gen.cam.ac.uk/sens/. The lysosome: the cell’s garbage disposal machinery of last resort. Amino acids. P. Lyso-some. R. ?.

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slide1

Removing toxic aggregates that our cells can’t break down

Aubrey de Grey

Department of Genetics, University of Cambridge

Email: ag24@gen.cam.ac.uk

Website: http://www.gen.cam.ac.uk/sens/

slide2

The lysosome:

the cell’s garbage disposal machinery of last resort

Amino acids

P

Lyso-some

R

?

M

slide3

The problem: the lysosome is not omnipotent

Liver’s solution: exocytosis

Lyso-some

Lyso-some

Not done elsewhere: kidneys would suffer?

slide4

All other cells’ “solution”: sequestration

Obviously fails eventually

Cellular function impaired

Cell becomes toxic

Cell dies

slide5

Lysosomal junk:

The four major types

Lipofuscin. Universal marker of postmitotic cell aging; reaches 10% of total cell mass in heart and motor neurons. No clear proof of pathogenesis, but in vitro evidence is strong

slide6

Lysosomal junk:

The four major types

2) A2E -- weird molecule created by reaction of the membrane lipid phosphatidylethanolamine with the photoreceptor pigment retinal. More or less proven to be pathogenic: causes age-related macular degeneration.

slide7

Lysosomal junk:

The four major types

3) Hyperphosphorylated tau in neurons. Widely believed to be a major cause of Alzheimer’s disease. Similar aggregates form in other neurodegenerative diseases and normal aging.

slide8

Lysosomal junk:

The four major types

4) Oxidised (etc) cholesterol and cholesteryl esters (oxysterols) in arterial macrophages. Causes them to become “foam cells”, then fatty streaks, and eventually atherosclerotic plaques.

slide9

Why don’t graveyards fluoresce?

de Grey 2002, Trends in Biotechnology 20:452-455

These (often fluorescent) materials do not accumulate in nature, even in areas rich in the remains of animals that produce them. Thus, something degrades them. They are energy-rich, so micro-organisms could live off them.

Bacterial strains exist with astonishingly varied catabolic activities, and are being used by many groups for bioremediation purposes. They degrade rubber, TNT, PCBs, dioxin, ... Some fungi are similarly versatile.

Can micro-organisms capable of degrading lysosomal junk be isolated from the soil???

slide12

Some FAQs

Q: Aren’t foam cell lysosomes mainly native cholesterol?

A: Yes - the major lysosomal component is not necessarily the culprit - the culprit may impair lysosomal trafficking of normally benign things

Q: Won’t we need an awful lot of different enzymes?

A: Probably not - degradation is synergistic - one step will often form a substrate for an enzyme we already have

Q: What about immune rejection?

A: Same problem/solutions as for normal gene therapy

slide13

Steps to biomedical application

Isolate competent strains; select by starvation

Identify the enzymes (mutagenesis, chemistry, genomics)

Make lysosome-targeted transgenes, assay cell toxicity

Assay competence in vitro (more mutagenesis/selection)

Construct transgenic mice, assay toxicity in vivo

Assay competence in disease models (apoE-/- mice, etc.)

Test in humans as for lysosomal storage diseases

slide14

Funding: the story so far

2001, 2002: Kronos deem it too “sciencey” :-(

2003: Archer wows NIA officials at IABG10 :-)

2004: “SENS 5” (July 26th, NIA offices, Bethesda)

Jay Jerome: atherogenic junk

Ralph Nixon: neurotoxic junk

Janet Sparrow: ophthalmotoxic junk

Ana Maria Cuervo: gene engineering for lysosomal targeting

Roscoe Brady: protein engineering for lysosomal targeting

Bruce Rittmann, Perry McCarty, Pedro Alvarez: biorem.

Fingers crossed….