Ways to get involved and the Stanford Connection

13 Mar
Published by MatTodd

Subject 

Request for Help

Community 

general open research

A few of us have recently been talking via email about exciting developments at Stanford, and Ginger prompted me to post this on the site so others could comment. Here are the emails, edited down…

Marc originally visited Stanford to talk on what he's doing in the area of neglected diseases (http://www.salilab.org/~marcius/home/?page=talks). His talk was hosted by Achal Acrol.

In response, Achal wrote:

 

“I think it was clear that today's audience was very excited by your talk, and in general through my work with ADEM [Access and Delivery of Essential Medicines] I have noticed a growing interest here at Stanford among young researchers to carry out their training and career development in traditional ways while somehow finding some other way to simultaneously apply those skills/resources to affect some amount of positive change in the world.

 

I see probably the most effective collaboration of our efforts to be that while I continue to sign up labs that would be willing to provide certain resources and services, you could provide us with a wish-list of biological/chemical resources you would need to fully test any of the computational work your team does. In essence I would work to provide (the other 95%) 'beta-testers' that could respond to your computational biologists 'programming core' and perform the wet lab experiments and cell culture and in vivo experiments to verify in an open source manner the efficacy of those agents.

 

If we choose wisely and limit what we wish to test initially to just the most robust computational findings and are able to design specific wet lab experiments that do prove successful regardless of how effective the drug is, TDI will have proof-of-principle and instant credibility that the pipeline works - and hopefully this will spark similar collaborations for each disease at various institutions across the country.

 

ADEM is not interested in credit or fame or anything of the such - we just hope to mobilize the right people and increase access to the right resources to get the ball rolling in the hopes of sparking widespread adoption of the kind of work that has been neglected for too long. Achal”

 

This was all pretty exciting, and got us thinking about specific ways of mobilising volunteers. We asked Achal about this, and he replied:

 

“It is our goal to be as responsive as we can to whatever physical lab needs SynapticLeap may have with our efforts here at Stanford. Pat Brown, MD, PhD, inventor of the gene microarray and founder of PLoS open-access journal, and Terry Blaschke, an associate dean of Stanford Medical School, are supporting our efforts to sign up labs toward this cause.

 

For toxicity and pharmacology studies along the lines needed to bridge Marc's computational work with any clinical trial work further downstream that organizations like DNDi and IoWH could perform, you may need to add another partner such as SRI here in Menlo Park (a nonprofit that focuses on this kind of work), which has very strong connections to Stanford and many of the faculty advising our group - so that is a possibility we can help with. It would be great to have a clear pipeline of sponsors in mind up-front: from modeling to wet-lab validation to preclinical animal toxicity/pharmacology to clinical trial so there are people in line ready to run with it when they are given the handoff.

 

For more basic lab related testing such as in vitro and in vivo validation of compounds identified via in silico modeling, that is definitely something we can do on campus here. A number of labs are willing to help out and provide tangible services and resources and make specific donations (e.g. 10% effort, 15% effort, etc)... there is a lab on campus that is using high throughput techniques to test over a billion compounds in vitro for drug discovery for Dengue Fever. That is a model we can try to mimic for NDs. There are a number of other translational drug discovery efforts here on campus that we can siphon off a little overhead from to feed into a sustainable pipeline to support your efforts. At this point I have just been working on building a 'virtual institute' of collaborators willing to donate certain resources toward the work of neglected disease research. As we become project specific it will be easier to know what exact resources to focus in what ways. The response from most people at this points to be 'sure I would love to help, what exactly do you need me to do?'

 

Regardless of the project, if we can go over the needs and the gaps in the pipeline, we can work on filling in the right people for you and designing the specific studies these labs can perform. Achal”

 

I began thinking about what we could do on the chemistry side of things:

 

“Achal, I just wanted to add that I share Ginger's enthusiasm for what you describe, and hope that it equally applies to having people help with the wet chemistry. Part of my involvement in Ginger's group is to push the importance of compound synthesis, both in terms of lead compounds and scale-up at low cost (the subject of my current project). Mat.”

 

Achal was very encouraging:

 

“I agree that our efforts can easily be tweaked to include recruitment of wet chemistry labs. If I can get up to speed on an 'ideal' study design you would love to have executed here if Stanford was giving you a blank check to 'have at it' with any of their wet chemistry labs and researchers - I can better understand what to get mobilized for you. Achal”

 

To get a handle on the specifics, I asked:

 

“Achal - OK, thanks for your note. I guess I'm assuming that people will get involved in two ways. The first is the armchair way of thinking up new ways to make molecules, or offering advice to those attempting reactions in which they have experience. The potentially more significant way of being involved is open to those with access to a wet chemistry lab. In that case students can attempt reactions of relevance to those already posted, and try out new routes they are suggesting from scratch.

 

I suppose that I was envisaging that grad students would have a go at some of the problems while doing their studies. But there is the more formal mechanism of organizing student projects to contribute. i.e. it could become a final year undergrad project to crack one of our routes. For example, take a look at http://thesynapticleap.org/?q=schisto/projects where I describe a simple project which is of current interest in organic chemistry. We have posted a route to this compound (PZQ) based on a reaction of current interest in the literature. It might be appropriate for a group of students to investigate the key step (the asymmetric aza-Henry step) as part of a project to design new catalysts for this reaction. i.e. our project gives extra impetus to an otherwise purely academic program. Alternatively there could be a competition to design an alternative route on paper for those students doing a literature project. So short answer - how about an organized student project for a 3/4 year undergrad lab program? This would be a very interesting case study. Mat”

 

And Achal replied:

 

“Sure this would work great and I can think of a few ways I can get it implemented by next Fall. Here is another possibility as well, and perhaps of greatest interest for scalability - it relates to your 'arm chair' way of thinking up new molecule synthesis techniques....

Stanford's greatest strength may be that it can do high-throughput identification of potential targets not just through computational means (using the Bio-X informatics infrastructure here) but also through chemical evolution means (Dr. Pehr Harbury's unique technique that allows for the fabrication and testing of billions of potential small-molecule compounds via combinatorial library synthesis in remarkably short order) - specifically I think the latter is probably our most powerful new 'armchair' tool we can put to use, which is most effective in 2 cases:

1) A particular target protein of interest on the parasite/virus has already been identified

2) A target protein and therapeutic agent exists, but there is a desire for more effective binding or a less toxic alternative or cheaper-to-synthesize solutions etc.

 

With computational work there are limitations of the type of protein structures you can simulate and a lot of computational time to account for lowest energy conformations, fluid interactions, etc that are instantly taken into account in real life.

The computational evolution technique can be used to test cultured wells in high throughput with over a billion compounds synthesized in a 'brute force' manner using combinatorial techniques for better binding to a known target. Pehr Harbury's unique technique employs an iterative process that allows the library of compounds synthesized to evolve with each round of in vitro testing to come up with the most successful candidate small molecule drugs.

There is a lab that is using the technique toward the development of a Dengue Vaccine. I am engaging this lab to work with us to expand their efforts to involved a handful of NDs.

Once these candidates are identified, they can be made immediately known to the SynapticLeap community, which can jump on them or give feedback.

 

In that way we could conceive some pipeline where:

1) protein targets are identified in parasites/viruses; or existing targets and problematic therapeutic agents are referred

2) Stanford's volunteers: new small molecule therapeutic candidates are identified via high-throughput means and tested in vitro; findings are made available open-access

3) pharmacology/toxicity preclinical trial work is done before handoff to iOWH and DNDi. Achal”

 

I clarified the position on PZQ as follows.

 

“The situation with Praziquantel (drug for schisto) is that we need a cheaper way of synthesizing it. Help with this is the first project. The target is not known (though there are the usual suspects). Once we know the target then a whole bunch of stuff becomes do-able. What you mention below would be a knockout approach that I would love to do when we know the target.

 

In the meantime, if there is any interest in a distributed-student project in synthetic chemistry, let me know. The paper chem. is simple, and self-explanatory from the web page. The wet chem. projects would need a bit of description from me, but are pretty simple to do, in that the molecules involved are small and inexpensive (that's the point) and the interesting chemistry is confronted early in the route, so the students would actually do it, rather than spending their time making precursors/intermediates. Mat”

 

Now we're hoping we can develop something in this area, and would welcome any comments on likely ways to make this happen. If anyone else has methods of mobilizing volunteers in this way, please let us know.

 

Cheers,

 

Mat

 

Comments

jcbradley's picture

Mat, you mention that you have posted a synthetic route that you would like to see implemented - can you provide a link to that?  Although we are currently mainly focussing on anti-malarials at this point, I may have a few more students coming on board.  If you have some very specific reactions in mind we can consider contributing at http://usefulchem.wikispaces.com

It is great to see more people contributing resources under open science conditions!

Jean-Claude

MatTodd's picture

Hi Jean-Claude,

 It's here. This is one route we've only just started, and we're still evaluating catalysts. The key is the asymmetric step. We'll be able to offer more guidance once we've got stuck into the chemistry. But if you wanted to have a go, that would be excellent. The most important criterion is cost.

Cheers,

Mat