Future Directions for Metabolic Engineering (ME)

[Geoff Holdridge's notes from discussion session at ME interagency workshop, 1/31/03]

Fred Heineken started the discussion with one slide:

Molecular level understanding of life processes is one of Marburger/Daniels interagency priorities, per May 30 2002 memo to agencies about FY 2004 interagency R&D priorities. Fred proposed several possible options for future of Federal ME support:
-    Continue interagency activity another 5 years
-    Systems biology focus overlap -- see recent Science article (cover story for March 1, 2002 issue)
-    Other possibilities?

Lonnie: this group will say yes [to extending for another 5 years], of course.

Terry: Will this overwhelm more targeted ME activity if you broaden it to include systems biology? Suggests keeping systems biology activities separate -- this would be very healthy. Don't do away with core issues of ME activity.

Fred: is 5 years enough time, or is there room for a 10 year program?

Jay: Is the number of proposals still growing? If so why end at 5 years?

Mark: One of the issues is related to a question raised in Mary Clutter's presentation: ME is not an "entity" definable within any specific program for some agencies. It is related to various programs, but not dead center on any of them. Sometimes it is difficult to fund a project out of these programs if it is not "mainstream" [central to that program's focus]. Better to make this ME effort "more in the middle" than where it is in some agencies. Some agencies DO have ME specific foci, but not all. This is one of arguments for NOT continuing this group.

Harold: I am not sure in hearing the Marburger memo on 'molecular level understanding' if this is literally aimed at ME, or more a top down engineering systems view. Regarding the general "state of the union" in the present interagency Metabolic Engineering program, it is a curiosity in which very different agencies are being asked to co-fund projects, and yet the resulting projects are not multi-disciplinary. I believe that this field needs a huge amount of multi-disciplinary work. Imran's work, for example, should be coupled to a bio-organic chemist and a mechanistic enzymologist who knows how fundamental folds in protein are related to catalytic mechanisms. Small grants are not getting at this kind of multi-disciplinary problem. The big challenge is to understand these evolved systems, which often needs a much broader look by a top multi-disciplinary team.

Imran: Has recently identified an organic chemist to work with. Harold is right.

Harold: The MURI program at DOD requires proven multi-disciplinary teams. e.g., bioorganic, bioinformatics/genomics, etc. The basic problem is we don't give very large grants in this multi-agency program.

Fred: [reads from Marburger memo]: Talks about sequencing, new approaches with potential to unravel complexity of life at the molecular/cellular level.

Cristina: sounds more like systems biology

Peter Karp: Agree with need for multi-disciplinary work. Excited by seeing these ideas reduced to practice. Any way to help transition these ideas to industrial application? Can we include that thrust in this program?

Fred: The existing ME program announcement encourages industry to apply for grants -- NSF can't do that, but other agencies can support that.

EPA rep: EPA cannot make awards to industry.

Vassily: General comment: lost in the U.S. is quantitative physiology. Companies need such people. These kinds of groups are disappearing in U.S. [but perhaps not in Europe?]. This is closer to metabolic engineering than systems biology. A lot systems biology in Science, but not a lot of systems bioTECHNOLOGY. Process component is lost. Will systems biology accommodate looking at process, biotechnology? Only concern in merging these things is losing that technology emphasis, industrial application.

Terry: applications and translation into industry are almost all proprietary. Industry doesn't publish what they do. But this stuff is immediately applicable.

Lonnie: Agree. Industry is very interested in ME, but perhaps not so much in systems biology.

Fred: A lot of industrial papers were presented at last Engineering Foundation Conference on Metabolic Engineering. We still may not know about a lot of this industrial activity.

Terry: they will identify it.

Imran: On one hand, there are a few other programs out there that combine various disciplines in this area. This is one of the few programs that would entertain this sort of thing. NIH maybe would have, but not sure about now. This isn't the sort of thing that would survive study section: need a hypothesis. But when research goes beyond a certain point, you need to ask people to submit proposals that are collaborative.

Harold: Government activity like this with a budget relying on each contributing agency's existing funds is problematical -- "up to $X00K as funds available" is the language. Since we can't come up with large amounts to fund large inter-disciplinary efforts, could this program act as a catalyst to find collaborations with other programs, that is leveraging existing agency grants and new funding sources?

Bernhard: Agree to much of what has been said. Think of systems biology as different -- systems bio is understanding; ME is engineering. Can ME be broadened to go beyond micro-organisms -- e.g., understanding human disease? Metabolism is big part of understanding diseases. In particular, in cancer where metabolism is highly abnormal. So up to now program has been focused on microbial cells.

Fred: Not true; Quantitative Systems Biotechnology (QSB) is focused on microbes; in ME there is no restriction.

Bernhard: But that's what's been funded.

Warren [NIH rep]: 2 of 6 proposals funded last year were not microbes. No limitations.

Hal Monbouquette: go back to Harold's idea: There could be some effort at agencies to put together groups to tackle larger problems, go for larger chunks of funding.

Fred: how large a grant?

Hal: To go to post-genomics, this is a huge undertaking. Won't move very quickly with grants of a few hundred K, 2-3-4 PhD students.

Fred: current budget guideline is up to 550K for single investigator, up to one million dollars for 2-3 years, multi-investigator.

Hal: You could spend most of that on equipment that you might need. Think about leveraging and get other programs involved.

Peter Karp: Consider some technology development component of this program -- better metabolomic technologies to help people do their work faster and better. Second idea is enzyme genomics. Of enzymes we have identified, how many do we have sequences for? Only half. So one should consider effort to find sequences for these enzymes.