It must be that fast machine of yours that you're running it on, AP. My machine, being having a CPU that's over six years old, is not crunching nearly as fast.

Mr. Farlops:

It must be that fast machine of yours that you're running it on, AP. My machine, having a CPU that's over six years old, is not crunching nearly as fast.

In a previous post in this thread I quoted from David Baker's Rosetta@home Science Journal, describing the ongoing/upcoming protein design activities and their potential medical implications. Since a number of new developments/updates were reported in the Journal in the last couple of weeks, I thought it's time for another digest from the Science Journal.

If you don't yet know about Rosetta@home and are considering to donate some of your spare computing power to help develop potential treatments for many serious diseases by predicting and designing protein shapes, go to the link section at the bottom of this post to learn more.

The new HIV vaccine design project is starting to come into full swing. We now have computationally designed amino acid sequences for 15 potential vaccine candidates, and we will start the process of making them next tuesday; the first step is to synthesize genes which encode these proteins. We have also designed a whole series of novel enzymes which catalyze a wide variety of reactions, and are starting the gene synthesis process for these as well.

In our vaccine design and enzyme design calculations, the end result is an amino acid sequence for a protein predicted to be a good vaccine or catalyst of a chemical reaction. The next step is to make a gene--a piece of DNA--that codes for the amino acid sequence. Due to advances in technology, rather than having to laboriously synthesize each gene in the lab, we can buy genes for any amino acid sequence for not to much from DNA synthesis companies, and we are lucky to be collaborating with a startup company in Boston called Codon who can make them for us quite cheaply. Today we ordered genes for 16 potential HIV vaccines, 15 potential new enzymes, and 4 potential new protien-protein complexes. I say potential above because our design calculations are not perfect, and we won't really know if these proteins act as designed until after we get the genes back in a month or so. Then we take advantage of modern molecular biology techniques to put the genes into bacteria where they direct the cells to make large amounts of the designed proteins. We can then separate the designed proteins from the rest of the stuff in the bacteria using a special tag we include in each of them that provides a good handle. Once we have the purified designed proteins, we can see whether they bind the desired antibodies in the case of the vaccine designs or catalyze the desired reactions in the case of the enzymes. In this way, we will learn about both the strengths and weaknesses of the rosetta design methodology, and hopefully have created proteins that can have a very positive effect on the world!

In collaboration with several other research groups, to trying to cure human diseases caused by mutations in critical genes in cell populations that are capable of self renewal. An example of such a disease is sever combined immunodeficiency, which is described at http://www.scid.net/. The idea is that if we could correct a crippling disease causing mutation in for example the blood cell population or the immune cell population in even a very small number of cells, then these now normal cells could divide and eventually repopulate the body with healthy normal blood or immune system cells.

To accomplish this, we would need to target specific DNA sequences around the site of the disease causing mutations in the critical genes. We are doing this using the computational design methodology we described in the Nature paper earlier this summer that I mentioned in an earlier post. We are now designing enzymes designed to cut precisely in the genes responsible for SCID and other diseases. When we have succeeded in creating enzymes that cut specifically within these genes, and not in other parts of the genome, our collaborators will introduce these designed enzymes into mutant cells with a copy of the normal gene that doesn't have the mutation. Cells repair breaks in their DNA by copying from identical or near identical sequences elsewhere in the genome, and it is likely that this introduced DNA would be used to repair the break, in which case the mutation would be corrected. Of course, it would still be a very long road before such an approach could be used clinically, but it is an exciting road to be getting started on!

We have not quite gotten the design methodology to the point we can run it on rosetta@home, but this should be coming in not too long as several people in my group are now focusing on this. Before this, look for protein-protein docking calculations where we are trying to predict the structures of the complexes between proteins which mediate much of the basic processes important to life. Chu Wang, a graduate student in the group, is close to having his docking methodology compatible with distributed computing, and we anticipate breakthroughs in this importnat problem as it also seems largely limited by cpu power.

What is Rosetta@home ?
A lecture on Rosetta@home
Letter to Rosetta@home participants: CASP
David Baker, 2004 Feynman prize winner
Rosetta@home is not for profit
Rosetta@home vs. Folding@home comparison
AP/CNN article on Rosetta@home
Design proteins and enzymes on your computer
The Scientist: Porteins by Design
Gates Foundation supports Rosetta@home HIV reserach

AidanSonoda:

Glad to be on board. Thanks for the warm welcome.  With a little luck I'll be able to recruit the computer I'm building for a client now (an athlon64 4000+ San Diego) and perhaps some cycles from the OpenMosix cluster I'm servicing as well.  Not sure, but that might get me close to your numbers Hoelder1in.

Great thread btw, I'm glad to be working with someone so obviously empassioned by the project.

AidanSonoda:

http://www.faqs.org/docs/Linux-HOWTO/openMosix-HOWTO.html#AEN81

Sorry for the delayed response, Russell. Since you didn't crunch for Rosetta in the last couple of weeks, perhaps your problem still persists? I don't have any real experience with running multiple projects on BOINC, but it seems the agorithm that decides when to run WUs from which project is fairly complex (and un-intuitive at times), involving such things as Long Term Debt, Resource Share, Average Tunraround Time, and Deadlines. You can look up the details by following the links on this BOINC-Wiki page. Presumably you have tried to shut down and restart BOINC or even reboot? Well anyway, it is probably hard to diagnose the problem from a distance without more detailed information...

Thanks Aidan, I have passed on the information that openMosix seems to run fairly stable with the 2.6.12 and 2.6.17 kernels. I am not sure yet whether I will be able to convince our computer people to run some tests on openMosix. I will keep you posted.

I guess I agree with your points on computer nerds vs. transhumansits. As to the size of our team, it is probably worth mentioning that we more then tripled our throughput over the last month or so, thanks to new members and upgrades, and the team now contributes close to 1/1000th of Rosetta@home's total computing power. While this may not sound like much, wouldn't it be wonderful to contribute 1/1000th of the computing resources needed to eventually design an HIV vaccine or Alzheimer's or Cancer treatment from which thousands would benefit...

Hoelder1in:

Welcome to Rosetta@home and the Betterhumans team, McCoy, great to have another fellow-European in the team - and even one with three computers crunching for Rosetta ! :-)

PS: You seem to have had one or two errors among your first Rosetta WUs. It might perhaps help to set "Leave application in memory while preempted" to "yes" in your general Rosetta preferences - should be no problem in your case since you seem to have lots of memory.

Chironian:

Given how much processing power is necessary for this project, does it occur to anyone that the computational firepower of a protein itself is being underestimated, if not completely disregarded? As in, the protein itself is a conformational instance of its computational equivalent?

Secondly, if I understand it correctly, Rosetta isn't attempting to solve the protein folding problem, which is as computationally intractable as the many body problem in gravitation. It doesn't need to. You're concerns don't really apply.

Among other things, its trying to sort through huge number of protein shapes to find ones that especially useful for particular problems, say, drug applications. Read the FAQ and read how Rosetta results might benefit medical research.