13 replies to this topic

[henri]

I would be very interested to hear any suggestions about good *postgraduate* programs for a student interested in matters relevant to SENS. English-speaking lands are preferred. America and Europe come first in the mind, but alternatives to these are welcome too.

Edited by henri, 24 December 2005 - 10:00 AM.

[John Schloendorn]

Hey Henri, who's the student, not you is it??
Well first, email Aubrey about it, haven't ya? Despite getting increasingly popular, my impression is that Lyso-SENS can always use a motivated hand. I'm at Bruce Rittmann's place in Tempe, AZ, but I will probably not be here for very long (summer) and I don't have a successor yet who would keep this thing alive over here. This is a great lab, the institute is like the showpiece of Arizona State Uni, all shiny new. One is very free to do what one wants, and the resources are great. If you can dream it, then you can do it at biodesign. I think it would be a shame not having a SENS person here in the future.

But other possibilities exist too, so it should also depend on the skills, interests of the student.

[henri]

Yeah, I'm the student. Thanks. What degree are you working on in the lab? Do you have plans as to what to do after you've left the lab? Have you found out anything really interesting? What aspect of SENS-lyso would you like to study now?

My focus isn't yet totally clear, quite naturally. Currently I'm doing MSc studies neurobiology (in the famous Kuopio university, http://www.uku.fi/aivi/ ). So, after getting the degree, I would be quite knowledgeable in that area. I guess one way I could take advantage of that would be to study how to replace neurons, or to study how to deliver stuff across the blood-brain barrier, or Alzheimer stuff (though research on that is often done from angles that aren't optimal for SENS).

[caliban]

Hello Henri,

I'd agree to stay with neurobiology/medicine. Thats where the music plays at the end of the day. Just be careful that if you are working a pathology you are not drawn into too specific functions.

Unless you see a job offer coming up at a 'true' anti aging company, I'd suggest you go for the PhD. Where you do the that should be determined less by the 'programme" and more by whose lab you'd be in.

Be careful there however: just because someone is prolific/doing good stuff does not mean that you will get along, and that I think is the most important consideration.

Also (and I keep saying that) if you don't want to have to pick a vaguely relevant project, don't leave it until gradudation. You need to start communicating with potential future employers as soon as possible.

ImmInst is a good place to work towards future projects. Even if you start doing something else, you can start writing the right grant proposals once you got a foot in.

[John Schloendorn]

What degree are you working on in the lab?

Not working on a degree. I'm volunteering my time, while the Methuselah Foundation is keeping me alive.

Do you have plans as to what to do after you've left the lab?

Get a PhD somewhere where I'm not completely out of touch with blood stem cells, because I will need that for my more long-termish dreams to go startup...

Have you found out anything really interesting? What aspect of SENS-lyso would you like to study now?

We now have enrichment cultures that robustly degrade 7KC. Next I need to take them apart and try to find the genes that allow them to do so. An A2E project will also come in to existence soon.

replace neurons, or to study how to deliver stuff across the blood-brain barrier, or Alzheimer stuff

The main reason these things aren't being promoted by the MF / would-be IBG is that everyone is already happy to do them without such promotion. What I would hate to see you do is something that would soon get done by any deathist/sleepwalker anyway. The reason I am doing Lyso-SENS research is not primarily fixing anything all by myself, but the hope to leverage all those mainstreamers into the field by generating some initial results.

My focus isn't yet totally clear, quite naturally

Good. Then you are still in the position of avoiding that critical mistake I was warning against.

If you become interested in Lyso-SENS, I would suggest to place your focus on brain-junk disease, i.e. target hyperphosphotau, b-amyloid, polyQ, a-synuclein and co with a lyso-SENS approach. This is currently not being worked upon and I for one will not have the chance to do so. There will be a LysoSENS meeting in February, where we will settle what precisely everyone will be doing in summer.

When will you finish your degree?

[henri]

Get a PhD somewhere where I'm not completely out of touch with blood stem cells, because I will need that for my more long-termish dreams to go startup...

I'll have a short introduction to bone marrow transplantation soon. It'll be about seeing how GFP-tagged monocytes (from transplanted marrow) go into the brain and start being microglia, in response to lipopolysaccharides or a-beta accumulation. I guess this touches on the topic, though it seems to me that microglia aren't the key to fixing brain aging. They can't degrade stuff that's inside the neurons. Though they could be made to degrade extracellular junk that they normally can't. But on the other hand, I don't know how severe a problem the interstitial junk is in the brain. For one thing, Alzheimer patients get lots of amyloid, but usually astrocytes and microglia are capable of degrading it without any augmentation (to my understanding). But maybe one could use the microglia to transport something into the brain?

The main reason these things aren't being promoted by the MF / would-be IBG is that everyone is already happy to do them without such promotion. What I would hate to see you do is something that would soon get done by any deathist/sleepwalker anyway. The reason I am doing Lyso-SENS research is not primarily fixing anything all by myself, but the hope to leverage all those mainstreamers into the field by generating some initial results.

Yes, the research I mentioned is being conducted in another context. It would be great if you could find those genes you're looking for (the xenohydrolases). One thing I've been uncertain about lyso-SENS is if it would be beneficial to wait for some time so that people would have more microbial species sequenced (and do something else in the meantime). But obviously you see a way of proceeding right now?

When will you finish your degree?

That should happen in about 2 years, or maybe 3.

The meeting you're talking about - is it via the net or in person? Is it a meeting of some organization or some private people?

[olaf.larsson]

Will there be any A2E culturing? I have made progress in the task assigned to me.
An organism name would, be helpfull though. If you are going for A2E you could try with cyanobacteria, they use retinoic acid.
Unfortunatly I have much other things to do hopefully i will get more spare time for this in the spring.

[henri]

Okay, now I've read the topic on the lyso-sens project. Great stuff.

[John Schloendorn]

GFP-tagged monocytes (from transplanted marrow) go into the brain and start being microglia

Woah, they can do that in the adult? If so, do you have some references at hand where I could read up on that?

use the microglia to transport something

Yes, such as xenoenzymes tagged for uptake by neuron. But I just read a nature neuroscience review on neural stem cells as delivery vehicles, which also seem very well suited[1].

Alzheimer patients get lots of amyloid, but usually astrocytes and microglia are capable of degrading it without any augmentation

Yes, they can do it very well, they just don't seem to want to in the Alzheimer diseased brain. This is demonstrated by the success of the vaccines that encourage them to do it [2])

obviously you see a way of proceeding right now?

Oh yes, there are lots of ways to get unknown genes out of unknown organisms. It's actually hard to decide among them! The most promising seems to me right now to go for cholesterol oxidase with degenerate PCR and then retrieve the rest of the pathway by "walking" or inverse PCR types of strategies... (Though from a therapeutic point of view it would be best if that lead to the discovery of non-cholesterol oxidase dependent 7KC degraders.)

in about 2 years, or maybe 3

Good, so you have some time to think about things. But you might also need some lab work for your degree that you can do at interesting places/topics. You may consider trying to persuade one of your supervisors into a lysoSENS approach. Once people fully understand it, they tend to like it a lot (unlike most other SENS ;-)

The meeting

It's very small and informal. Hopefully it will include most scientists/students working on LysoSENS at this time or the immediate future.

[John Schloendorn]

Will there be any A2E culturing?

Yes, there definitely will be, soon! I have already received a shipment of A2E, but am having some difficulties with it that need to be resolved first... as usual.

[henri]

Woah, they can do that in the adult? If so, do you have some references at hand where I could read up on that?

Have a look at the following:

Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to beta-amyloid deposition in APP/PS1 double transgenic Alzheimer mice

[henri]

Caliban, what kinds of things have you done?

[olaf.larsson]

Though from a therapeutic point of view it would be best if that lead to the discovery of non-cholesterol oxidase dependent 7KC degraders

Sorry I dont really understand why it should be so.. could you explain it more.

[John Schloendorn]

Mainly two reasons:
- Many cholesterol oxidases produce H2O2, which can react unspecifically and promote free radical formation, which would probably be a bad idea to do in the lesion. However, some exist that produce harmless or beneficial NADPH instead.
- The other product of cholesterol oxidase (when in acts on cholesterol), cholest-4-ene-3-one has been shown to be cytotoxic and under some circumstances even pro-atherogenic. So one would need to try to either find, or mutagenise one to lose its affinity for cholesterol, or implement excess downstream enzymes.

But remember, the current objective of LysoSENS (as long as it is run only by half a handful of hypermotivated grad students) can only be leverage, not fixing death just yet. So we might not need therapeutic applications of everything we do, (which would be years ahead anyway) and still get the effect we want (although we'd sure prefer to get them).

Edited by John Schloendorn, 04 January 2006 - 02:24 PM.