Help find cures for major diseases

Join the Betterhumans Rosetta@home team
to determine protein shapes with your spare computing power

This is a thread for both technical and science related discussions and questions about the Betterhumans team at the distributed computing biomed project Rosetta@home. I may also use this thread to give occasional updates on events and milestones at the project - which hopefully will attract a few more Betterhumans to the team. ;-) Let's see how this will work out...

The team currently has 40 members (1.5% of the Betterhumans membership - so there is room for improvement ;-). Please do join the team if, after reading this, you think that Rosetta@home is a worthwile project. See the link section below for info on how to join. You don't need to be a Betterhumans member to join the team.

What is Rosetta@home ?

Rosetta@home is a distributed computing project, run by the Baker Laboratory at the University of Washington, aiming to solve the protein structure prediction problem. Its goal is to develop methods that accurately predict and design protein structure and complexes, an endeavor that may ultimately help researchers develop cures for human diseases such as HIV/AIDS, Cancer, Alzheimer's, Malaria, viruses and other pathogens. The project believes that they are getting closer to accurately predicting and designing protein structures and protein complexes, one of the "holy grails" of computational biology. This requires an enormous amount of computing resources, greater than the world's largest supercomputer. This is only achievable through a collective effort from volunteers. Rosetta researchers are relying on a technique known as distributed computing, which pools the resources of idle computers everywhere (quoted from Rosetta@home Wikipedia entry).

Why Betterhumans should be interested in Rosetta@home ?

Both protein structure prediction and design have immediate medical implications for fighting the major killer diseases and for live extension - as someone put it on the Rosetta forum, given enough computing resources  (yours !), Rosetta has the potential to wipe out disease as we know it. The Rosetta algorithm allows to design new proteins to order,  that don't exist in nature, to perform specific, novel functions in the body: one can think of these  'designer proteins' as nanobots that go into the cells to perform specific functions there, such as blocking disease causing processes, breaking up unwanted chemicals, or even fixing errors in the genome. And all of these things will happen sooner if lots of participants donate their spare computer time to Rosetta ! And in addition, participating in Rosetta@home is a great way to show your support for biomedical research !

Links:

Rosetta@home homepage,  What is Rosetta@home ?, disease related research, screen saver, Dr. Baker's science journal (several updates per week), WorkUnits log, previous Betterhumans post and  news article on Rosetta@home

Puting things into perspective: what other distributed computing science projects are there ? Betterhumans forum thread on Rosetta@home vs. Folding@home comparison

Statistics trivia: BOINCstats team and member pages, international teams ranking
 
How to join: download BOINC software and sign up for Rosetta@home, join Betterhumans team  (click on join).

Other BOINC projects ? Rosetta is based on the BOINC open source infrastructure for distributed computing. Since many BOINC participants like to donate computing time to several BOINC projects in parallel (eg., Rosetta@home and SETI@home), there may be a need for Betterhumans  teams at some of those other projects. If so, someone else would have to take the lead there (the team name needs to be exactly the same one for all projects, for the combined team statistics to work).

Posts in this thread:

Lecture on Rosetta@home
Letter to Rosetta@home participants: CASP
David Baker, 2004 Feynman prize
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
Protein design: a progress report from the Rosetta@home Science Journal
Download Rosetta@home video

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Hoelder1in
changed my username to make it consistent with Rosetta (used to be Hoelderlin)
LAST UPDATE: 2008-04-07

I thought you might be interested in this one hour lecture (audio/video) given by David Baker, head of the Rosetta@home project and Professor at the University of Washington, in which he explains the science behind Rosetta in laypersons terms.

Title: Computing structural biology

Abstract

I will discuss our progress in predicting the structures of biological macromolecules and interactions and in designing novel macromolecules with new structures and functions, with emphasis on the key computational challenges to fully transforming structural biology from an experimental to a computational science.

Hoelder1in, do you have anysuggestions on how to make the program run more effiently. I am about to install in on a new hard drive that will give it more HD space to work on but is there anything else I can do to make it work faster?

JoelStephenson:

Hoelder1in, do you have any suggestions on how to make the program run more effiently. I am about to install in on a new hard drive that will give it more HD space to work on but is there anything else I can do to make it work faster?

Hi Joel

Other than upgrading or overclocking your CPU there probably isn't much you can do to make it run faster. Presumably you wonder why others with similar computers have higher credits/day in their stats ? Well, this is because they use non-standard BOINC clients which give them higher benchmarks. The credits for each WU are calculated simply by multiplying the execution time on your computer with the average of the float and real benchmarks that you see on your computer page. So higher benchmarks will give you more credits but this has nothing to do whatsoever with how much work your computer  is doing for the project. To find out how much work your computer actually does you need to go to the Result page of a WU to see how many structures (nstruct) were calculated. You then would have to compare these numbers with those of other users who were crunching similar WUs (same WU name except for the running number at the end).  Anyway, best not to take those credits all too seriously. ;-)

-H.

Wow ! I just got this banner, promoting the Betterhumans Rosetta@home team (and linking to this thread), instead of the usual Google ads at the top of the page:

Simon seems to have set this as the alternative that gets displayed whenever Google doesn't have anything else to display on the page. Thanks Simon - the design is excellent ! With all the attention this is bound to draw to the Betterhumans Rosetta@home team and with the offical endorsement from our Betterhumans manager, I can't wait to see the team membership skyrocketing... ;-)

The following is quoted from the first ever email the Rosetta@home team sent out to its 50,000+ contributers today:

Dear Rosetta@home Participants,
a wonderful aspect of Rosetta@home for me has been the marvelous contributions of the many dedicated volunteers around the world. We are about to begin the 7th biennial CASP Structure Prediction Experiment and from May 10th until August 1st our need for computing power will be even greater. In a bid to solicit more of your 'crunching time', R@H volunteers have put together the following letter which we are sending to all participants. With all of your collective efforts it should be possible to do wonders!
Thank you! David Baker

CASP7 is here - Be part of the competition and the winning team!

There are many science teams working on protein studies, and every 2 years they conduct a contest of sorts, to define the current state-of-the-art. Now the 2006 event is underway, and you can help. CASP will present proteins no one has ever seen before and ask the research teams to give their best structure predictions for this computationally intense problem. We are very hopeful the improved Rosetta software, now with the added power of distributed computing, will again find the most accurate predictions.

CASP7 runs from May 10th to August 1st. The more computing power we apply, the better the predictions become. Please be sure to run Rosetta@home, at least during the three month period of the competition. Read more about CASP7, and check for published results on the Rosetta@home website through the end of the year.

If you watched the lecture that I linked to in one of the previous posts, you heard that David Baker, head of the Rosetta@home project, was jokingly introduced as the "Terror of CASP" and his team as the "team to beat at CASP". So, if you enjoy to compete and like to be part of a winning team, now would be the time to join Rosetta@home...

A couple of days ago (May 11) the Betterhumans Newswire carried this news item:

Feynman's Birthday today: read his classic talk, then nominate for Feynman Prize

So I thought I should mention that David Baker, the person behind Rosetta@home, was in fact the 2004 winner of the Forsight Institute's Feynman Prize in Nanotechnology. He was awarded the theory prize for his part in the development of the Rosetta software.

The prize is awarded each year to the experimental and theoretical researcher whose recent work has most advanced the achievement of Feynman's goal for nanotechnology: molecular manufacturing, defined as the construction of atomically-precise products through the use of molecular machine systems.

Dr. David Baker (left) receives the theory prize from Dr. K. Eric Drexler, Foresight Founder and Advisor.

Of course, the best way to commemorate Richard Feynman's work is to read or re-read his classic after-dinner talk There's Plenty of Room at the Bottom. Well, perhaps that's the second-best way: the best way is to work to implement the vision in the talk by participating in the work of one of the Feynman Prize winners. (I borrowed this from Christine ;-).

Just out of curiosity, what is the policy on using the results? Is there any commitment to open access publishing of the results? Is the data guaranteed to be posted to a public data base? Who gets the patents? a public institution? a drug company? or the investigator? Who has access to Rosetta and is anyone profiting from selling that access? Is access being kept to one lab for a competitive advantage? If there are profits being made, then why can't they pay you for renting machine time?
    Okay, so I am a bit sceptical of apparently altruistic acts, but any good charity should be completely up front about how they are using their resources and this sort of project should answer these sorts questions before asking for help in the "selfless" battle against disease.

Formicus,

I just found this page, it might be of use to you: http://boinc.bakerlab.org/rosetta/rah_medical_relevance.php

Formicus, you are not the first person to ask these questions. They have been discussed on several occasions on the Rosetta forum, and I think they have been answered satisfactorily. Here are some anwers by David Baker in response to similar questions:

Everything will be public domain. No, I do not believe in patenting naturally ocurring genes, proteins, etc. 

And just recently:

 Just to reiterate what has already been said here, all work done in this project, and in our group generally, is for the public good and nobody will make money out of it. All of our software and results are freely available to all but corporations, who have to pay--all the money we raise in this way goes back into the project. For example, we may be able to use some of these funds to pay Laura for the Rosetta@home video she is planning to make. By far and away the major use is for our annual rosetta developers meeting held every summer in the cascades which brings in researchers from all over the country. 

You may also want to have a look at the software licensing information (free of charge for academic use) at the rosettacommons.org website as well as at the publications page of the Baker Lab at the University of Washington which provides the full text of all their research papers.

As to your question about paying for renting machine time, the project currently operates at a sustained computing power of more than 20 TFlops provided by volunteers and they have stated that they seek even more computing power and would like to reach 150 TFlop in order to meet their objectives. There are currently only 10 computers in the TOP500 list of supercomputers offering a computing power of more than 20 TFlop and just one which could provide 150 TFlop. So it seems completely out of the question for a small university research group to gain access to this level of computing resources through other means than public distributed computing. I am not sure drug companies could or would want to pay for this out of their own pocket but I think your point was exactly that it is better to have these activities out in the open at a university research lab where the whole community can benefit than behind closed doors.

If you have any remaining concerns you may want to go to the Rosetta forum and raise them there. David Baker is a very busy person these days but he usually tries to respond to all sorts of questions and concerns from participants in person. To give an example, after watching the lecture that I linked to in this thread, I asked the following question. The question was posted on a Sunday (!) and it was answered within a couple of hours.

Hoelder1in: There is one specific question I wanted to ask, though: right at the end of the lecture there was a statement which seemed to say that the work about cutting DNA at specific sites (as described on the "Disease Related Research" page) was already under way. I would definitely be interested to hear how far this work has proceeded (e.g., in terms of developing this for therapeutic purposes) and what is planed for the future. Thanks, -H.

David Baker: We have worked out the science/technology needed to create new DNA cleaving enzymes (if you ever look at the scientific journal "Nature" you will see our paper on this in a few weeks). We are currently hard at work trying to create enzymes that cleave within genes that cause disease and within pathogens. Once we have these they can be tested as therapeutics, but this is still a step or two away. 

And since this addresses enzymes, I thought this post from a few weeks earlier might also be of interest:

David Baker: sorry for not reporting earlier, I was away this past week with several people in my group at a meeting in Florida on designing new enzymes to catalyze any desired chemical reaction. This is a very exciting area and hopefully we will be able to run some of our design calculations on rosetta@home after CASP7 finishes.

Does anyone know how different this is from the Folding@Home by Stanford, of which there is a fairly large Longevity Meme group helping out with that?

liveforever22:

Does anyone know how different this is from the Folding@Home by Stanford, of which there is a fairly large Longevity Meme group helping out with that?

The two projects are indeed different. They have different goals and they use different methods:

While Folding@home wants to understand how proteins fold, by calculating the intermediate, partly folded states in sequence, Rosetta@home attempts to determine the endpoints of the folding process, i.e., the final 3-dimensional folded shapes of proteins, from their sequence of amino acids (the protein folding problem) - and by reversing this process, to determine amino acids sequences that fold into specific, pre-determined shapes (protein design). 

So how does this relate to medical relevance (finding cures):

Since Folding@home studies the details of the folding process, this approach seems particularly suited to study mis-folding which is at the heart of some diseases, Alzheimer's comes to mind foremost. Another would be Mad Cow Disease, I am not sure there are many more others but my knowledge on this may be incomplete.
In the case of Rosetta@home I think it is obvious that the capability to design proteins with specific shapes and active sites that are able to perform specific functions in the body has immediate relevance for drug design. Rosetta's capability to determine the 3D shapes of proteins from their amino acid sequence on the other hand helps to determine the function those proteins perform in the body and to identify potential drug targets. See the Disease Related Research page at the Rosetta website and the statements by David Baker about "enzyme design" that I quoted in my previous post. Info on Alzheimer's/mis-folding related research at Rosetta is available here.

Perhaps I should also explain what got me to crunch for Rosetta: I originally participated in Folding@home for a number of years but decided to switch over to Rosetta, shortly after Rosetta went public, when Vijay Pande had spoken favorably of Rosetta and of David Baker's work on the Folding@home forum. Here are my reasons for the switch-over:

• Rosetta at the time was (and still is) the much smaller project in terms of participants - so I felt my contribution would make more of a difference there and it also seemed to be sort of fair that both projects should have access to similar amounts of computing power. So in fact lots more Folding@home participants would have to switch over to Rosetta. ;-)
• over the years I never really understood how the science done at Folding@home would eventually lead to treatments or cures. With Rosetta the connection to identifying drug targets and to drug design seemes much more obvious.
• somewhat related to the last point, I never really understood the science behind Folding@home. I mean what is it that we really learn by following the folding path of a protein - I understand the intellectual challenge and fun of being able to do that, but what is the point ? With Rosetta it seemed much easier to understand what the poject was after.
• after participating in Rosetta for a while I also began to enjoy the direct contact to David Baker and the other team members. David Baker is very good at making everyone feel a part of the team and whenever I had a question about the project it was immediately answered. The project is also very willing to take up suggestions by team members. In fact the text at the top of the Rosetta@home homepage (Rosetta@home needs your help...) seems to be partly based on a suggestion I made in the forum. ;-) And by the way: since a few days the Rosetta@home homepage also contains the statement Rosetta@home is not for profit, printed in bold, right at the top. So I am wondering whether David Baker actually reads our Betterhumans thread where we were discussing these issues at just about the same time (Hi David ;-).
  

So, since the longevity meme team at Folding@home currently seems to have about 35 active members I can't see any reason why we shouldn't be able to attract similar numbers of members to the Betterhumans Rosetta@home team. If anyone has any ideas or suggestions how to promote the team and make more Betterhumans join (or even better, attract new members to both Betterhumans and Rosetta@home - Simon will like this), please post them here...

See this Associated Press report on Rosetta@home ! The article is quite enthusiastic about the project which is portrayed as kind of special in terms of its communication and team spirit. AP supposedly reaches half a Billion people around the globe each day, so let's see what effect this will have on Rosetta's crunching power - probably more than this humble thread. ;-)

Reduced memory requirements for Rosetta@home: The Rosetta team invested a lot of time recently into reducing the memory requirements of the Rosetta client such that now machines with only 256 MB of RAM and slow modem Internet connections should be able to participate without problems. Note that by setting the target CPU runtime to its maximum value of 24 hours, the daily download requirements can be reduced to about 2 MB.

Go to the first post of this thread for more info on Rosetta@home and details on how to join if you are considering to put your spare computing cycles to good use...

I am delighted to report that this little team finally managed to attract its fifth member. Welcome Silento ! I am not sure you are a Betterhumans member or are reading this thread, but it would be great if you could let us know how you heard of Rosetta and Betterhumans and what made you join - and if some of the other team member would want to chime in, that would be even better...

Update: The Rosetta@home AP article appeared in more than 140 online (including CNN) and print media in the US and around the world, causing the new Rosetta@home participants to spike from below 200 to more than 2000 per day. Assuming that many of the readers of the AP article will go on to search for Rosetta@home on the Web, Betterhumans may also benefit: it turns out that the first page of more than 2,000,000 Google search results contains a link to this thread with the full text of the Betterhumans mission statement printed on the search page. Amazing !

Update on Rosetta@home vs. Folding@home comparison: I wanted to point you to this thread in the Rosetta@home forum (which includes links to a similar thread on the Folding@home forum) where the different merits of the two projects are discussed.

I am extremly thrilled about the capabilities of the Rosetta software to design proteins and enzymes that don't exist in nature, to perform beneficial functions in the body. Once this technology is perfected, the possiblities seem endless. I particularly like this kind of "engineering approach" to molecular biology, kind of like the car repair paradigm applied to molecular biology: if something breaks in your car/your body, design the tools and replacement parts needed to fix it, and you will be able to keep your vintage car/aging body running forever... ;-)

The Engineering Life article in the June issue of Scientific American, which is co-authored by Rosetta@home lead scientist David Baker, discusses engineering principles, applied to molecular biology, from a somewhat different angle. And to touch on another issue that was discussed in this thread, the article also proposes "open source design libraries" of bio-molecular parts to jump-start what the authors call a "Moore's Law" of molecular bio-engineering.

There has been a lot of discussion of Aubrey de Grey's SENS approach to aging research on this site, lately. I am certainly not qualified to judge the feasibiity of SENS, but I do think Aubrey de Grey has to be given credit for popularizing an engineering approach to medical research. And I actually believe that for SENS to ever fulfill its promises, Rosetta's capabilities to predict and design protein structures and enzymes would be a prerequisite.

Below I collected some recent quotes from the Rosetta@home website where lead scientist David Baker describes the current status and future directions of their protein and enzyme design work. It is exciting to see how the Rosetta team is forging ahead and producing results with the research described on the Disease Related Research page:

Here is a press release from the scientific journal Nature on an article of ours that is appearing in the June 1 issue. I'll explain a bit more about the applications of this new Rosetta methodology in future posts; these jobs should start running on rosetta@home after CASP is completed in early august.

One of the great remaining problems in computational protein design involves the redesign of a DNA-modifying protein so that it recognizes, and alters, a new DNA sequence. For example, changing the specificity of a nuclease, a protein that cuts DNA at a specific site, could be beneficial for a range of biotechnological and medical applications.
In this week's Nature, David Baker and colleagues have shown that it is possible to modify the sequence specificity of a homing endonuclease called I-MsoI. They used a computational approach to screen a virtual library of mutant proteins and predicted which amino acids needed to be changed to re-engineer this enzyme so that it recognized, and cleaved, a new DNA sequence. The mutant protein was highly active and was able to cleave the new DNA sequence, but did not modify the original sequence. The authors hope to redesign this and other DNA-modifying enzymes to alter a range of DNA sequences, so that they could specifically target almost any sequence in the genome. These computationally designed proteins may be useful in a range of medical and biotechnological applications, including gene therapeutic and other targeted genomics applications.

And somewhat earlier:

We have worked out the science/technology needed to create new DNA cleaving enzymes (if you ever look at the scientific journal "Nature" you will see our paper on this in a few weeks). We are currently hard at work trying to create enzymes that cleave within genes that cause disease and within pathogens. Once we have these they can be tested as therapeutics, but this is still a step or two away.

I think it is great that some of the work described on the Diseae Related Research page at Rosetta@home has already made it into one of the most prestigious scientific journals and will shortly also run on Rosetta@home participants' computers.

Here is another recent quote about Alzheimer's/mis-folding related work at Rosetta (I highlighted the sentence that specifically addresses protein design):

A significant fraction of human diseases are caused by proteins misfolding to form long "amyloid fibrils". These diseases range from Alzheimer's disease to infectious diseases from amyloid forming prion proteins. A huge breakthrough in the understanding of the process of protein misfolding to form amyloid fibrils was published in Nature last year from David Eisenberg's research group at UCLA. They reported the first high resolution structure of an amyloid forming peptide. It revealed a set of interactions which seem very likely to be general to most if not all amyloid structures.
We have been collaborating with Eisenberg's group to try to predict the portions of proteins known to form amyloid structures responsible for amyloid fiber formation. We use the rosetta-design method to identify sequences compatible with a generalized model of their amyloid structure. You can read about the promising results of this work in the collaborative paper with Eisenberg's group that is posted on the "2006" portion of our home page publication list mentioned in my previous post. The next challenge which we are collaborating on is to design "caps" that will add on to fibers and prevent them from growing further. This is a good example of how basic research development can have applications to pressing medical problems that were entirely unanticipated.

And just for completeness sake, I think HIV vaccine design, as described on the Diseasa Related Research page, is also on the short list of things to be run on Rosetta@home (I can't find a recent statment by the Rosetta team in the moment to back this up).