BERAC Meeting Minutes November 5-6, 1998

MINUTES

Biological and Environmental Research Advisory Committee (BERAC) Meeting
Office of Biological and Environmental Research
Office of Science
U.S. Department of Energy

DATE: November 5-6, 1998

LOCATION: American Geophysical Union, Washington, D.C. The meeting was announced in the Federal Register for November 5-6, 1998 (Pub. L. No. 92-463, 86 Stat. 770).

PARTICIPANTS: A list of attendees showing all BERAC members who were present, guests, and participating Department of Energy officials and staff is attached.

November 5, 1998

Director's Comments - Dr. Martha A. Krebs, Director, Office of Science

Dr. Krebs discussed the success of the FY 1999 budget. The onset of the Spallation Neutron Source has put the Office of Science (SC) back in the billion dollar class business. However, the Climate Change Technology Initiative et al. were cut in half. The next generation Internet was damaged very badly coming out of conference $15M. Hopefully, Congress will recognize and continue to support this program.

Congress acknowledged efforts in the Office of Biological and Environmental Research (OBER) and added funding for low dose. Funding was also added to the Office of Environmental Management (EM), and Congress wants these two offices to work together. Dr. Krebs is pleased with the collaboration that has developed between the ER and EM programs.

Changing the Office's name to the Office of Science was a motive to help members of Congress and their staff better understand what we do. ER is the only office in DOE that was created in legislative language; in order to change that, an amendment would be required.

A framework was developed at the highest level on the Energy R&D portfolio activity. DOE will have seven white papers to represent seven activities; there are 100 subsets. These were used as a basis for SC's Strategic Plan and were limited to 4 or 6 pages so that the document is not too large. This document will be available for the 2000 document. Dr. Krebs and Under Secretary Moniz believe it to be an iterative document. For the 2000 budget, actions in Congress in 99 may give us concerns. Quite possibly, DOE has over-targeted for rebase line, rebase target which gives reasonable room to continue the Spallation Neutron Source and to have modest recognition of continuing the Climate Change initiative and the next generation Internet and to try to do some things for other recommendations for other various advisory committees.

Michael Knotek, Ed Oliver, and Jim Decker et al. have been engaged in the Strategic Simulation Initiative (SSI) since its beginning. They were involved in the preparatory workshops last winter and have made lots of progress in collaborations with the NSF; as well as OMB. It is anticipated that this will be an approximate billion dollar effort over a period of 5 years. There is some indication that the President will be ready to receive this. An assessment needs to be done on the state of computational and research: database issues and informatics.

What would we do without SSI? BER does not have to think about the climate side; but BER can help think through what the right kind of Charge needs to be done. This can be done via each advisory committee or via a consolidated assessment. Dr. Moniz questions why we have five studies. We need to prepare whether or not we get the SSI -- if we get it, we may need more Interagency Working Groups. Part of the response to the Pcast finding is about diversity and the President's direction to develop approach. We will have a report available by the end of January to respond to the President, then a second follow-on to that.

The Laboratory Operating Board (LOB) is a critical element being ensued by Dr. Moniz. This critical element was introduced by this Administration which needs to have a review. The LOB will receive a lot of attention from inside the Department. The Office of the Secretary is asking BERAC to do a lot of things in the coming year. One of those items we have not yet received a charge for. One will be a review of the BNCT program. BERAC will be asked how do we position DOE efforts on issues? The facilities are important but there probably needs to be more than facilities. BERAC's advice is needed on that too.

Human Genome Program 5 Year Plan: Federal Agency Responsibility in an Area of Private Sector Initiatives - Dr. Elke Jordan (NIH) & Dr. Ari Patrinos (OBER/DOE)

Dr. Jordan : The 5-year plan for the human genome project is very ambitious. NIH and DOE had planning committees. There are significant changes in the goals, and a number of those goals were identified. The sequence time was shortened from the year 2005 to 2003. That was decided in response to a community interest which will develop a working draft of the genome to be completed by 2001. Goals were also identified for the focusing of regions for biological interests; these regions will be subject to a peer review process. The plan also includes goals for: sequencing technology development; for studying human genome sequence variation; for developing technology for functional genomics; for completing the sequence of Caenorhabditis elegans and Drosophila melanogaster and starting the mouse genome; for studying the ethical, legal, and social implications of genome research; for bioinformatics and computational studies; and for training of genome scientists. They will continue to support novel technologies and plan to start a new initiative for pushing along prototypes in the prototype stage. There is great interest between humans. Plans are to develop technologies, identify cSNPs, create an SNP map of 100,000 markers, and to stimulate the development of methods to analyze large data sets.

Specific Goals for 1998 - 2003

1) The Human DNA Sequence

2) Sequencing Technology

3) Human Genome Sequence Variation

4) Technology for Functional Genomics

5) Comparative Genomics

6) Ethical, Legal, and Social Implications (ELSI)

(These goals were developed by special groups -- ELSI research planning and evaluation is identified):

• Examine issues surrounding completion of human DNA sequence and study of human genetic variation
• Examine issues of integration of genetic technologies and information into health care and public health activities
• Examine issues of integration of knowledge about genomics and gene-environment interactions into non-clinical settings
• Explore ways for new genetic knowledge to interact with a variety of philosophical, theological, and ethical perspectives
• Explore how socioeconomic factors and concepts of race and ethnicity influence the use, understanding, and interpretation of genetic information, the utilization of genetic services, and development of policy.

7) Bioinformatics & Computational Biology

8) Training

- Training in genomics [shortage of people in informatics]

- Career paths in genomics

- ELSI scholars

NIH looks forward to continued strong collaborations with DOE. In the last 2 or 3 years, collaborations have become more intense.

Dr. Patrinos : Dr. Patrinos offered DOE perspectives and acknowledged the successful partnership with the National Human Joint Research Institute which is based on trust and mutual interest. Other groups have helped, and it is commonly referred to as the labor of love. The DOE team was led by Dr. Ray Gesteland. It is important for BERAC to recognize leadership by the people who helped set up JGI. Dr. Tony Caranno was on the sequencing front. DOE's portion was just to think through the ideas carefully. This was done very much in the context of a 5-year plan.

JGI / PSF Update - Successes, Challenges, and Opportunities - Dr. Elbert Branscomb (Lawrence Livermore National Laboratory):

Dr. Patrinos offered DOE perspectives and acknowledged the successful partnership with the National Human Joint Research Institute which is based on trust and mutual interest. Other groups have helped, and it is commonly referred to as the labor of love. The DOE team was led by Dr. Ray Gesteland. It is important for BERAC to recognize leadership by the people who helped set up JGI. Dr. Tony Caranno was on the sequencing front. DOE's portion was just to think through the ideas carefully. This was done very much in the context of a 5-year plan. - Dr. Elbert Branscomb (Lawrence Livermore National Laboratory)

Dr. Patrinos offered DOE perspectives and acknowledged the successful partnership with the National Human Joint Research Institute which is based on trust and mutual interest. Other groups have helped, and it is commonly referred to as the labor of love. The DOE team was led by Dr. Ray Gesteland. It is important for BERAC to recognize leadership by the people who helped set up JGI. Dr. Tony Caranno was on the sequencing front. DOE's portion was just to think through the ideas carefully. This was done very much in the context of a 5-year plan. - Dr. Elbert Branscomb (Lawrence Livermore National Laboratory)

Dr. Branscomb summarized last year's events. Anthony Caranno's charts shows that cumulative production surpassed the experimental goals of almost 21 million. All three sites contributed tremendously. All of this was done at separate sites. The monthly production rates were on the web. Cumulative production puts JGI in the top efforts in the world.

The data shows the number of lanes loaded per month which is up to 120,000 lanes. This is very impressive data. Two hundred thousand lanes per day are expected. This marker is a useful measure--what's needed to achieve high quality of sequencing in a mammal in a year.

PSF Status and Plans: full function occupancy is expected in December. They are going to have to increase sequencing rates. Partnerships with the private sector have been significant.

Structural Biology Subcommittee Reports - Dr. Jonathan Greer (Abbott Laboratories)

- Dr. Jonathan Greer (Abbott Laboratories)

Dr. Greer referenced the second Charge letter dated May 28, 1998. Dr. Marvin Cassman (NIH) asked them to look at where crystallography could go. The Macromolecular Crystallography Synchrotron Structural Biology Report is playing an increasingly important role in biological discoveries. The Shen report reviewed DOE synchrotron facilities--most were not relevant, but the structural biology parts were relevant. Drs. Hodgson and Lattman assembled from the beam lines, their status and its worth, from the BioSync report. The Subcommittee took advantage of all three reports. In order to improve taking advantage of the existing beam lines so they will be more efficient, this would involve staff increases. Currently, there are 2 1/2 people, and it should be 3 1/2 to 4 people. The cost is estimated to be about $3M per year. This number includes sharing between of the beam lines. It does not assume heavy use of inexperienced or less experienced users. The second element of upgrade was harder. The upgrades included new detectors and back-up detectors. Another major issue is improved access: apply for time, get the application reviewed, and it takes about 6 months to get there. The current beam lines are inconsistent with competition. Define a process to accelerate and get roving reviews. The application is to become more standardized; this may apply to repeats. Get short rapid access. Get more common graphical interfaces. This is very important for less experienced users.

Bergeneau-Shen were seconded by the macromolecular crystallography perspective: an operating budget of a half million dollars per year. Future research efforts were discussed. Detectors are one of the most critical elements. Today, they cannot keep up with synchrotron beamline advances--detector development needs to continue to put in with existing facilities and add to tomorrow's.

Automation will further help if, for instance, the user back home in his lab is redoing a web-based facility. This would magically appear on their machine--the web-based tools, etc. The last area was new beam lines. There are a significant number under construction. What about new beam lines? Suppose that these need to be reviewed on a case-by-case basis. They should be focusing on new science and new discoveries. Figures used will explode in the coming year.

The first report was relatively easy. The second was more difficult because of the range of difficulties of structural biology.

(See attached for the Structural Biology Reportsand Members of the Structural Biology Subcommittee.)

High spots of recommendations:

Charge : A review is apparent since six years have elapsed since the previous report, etc.

The previous committee report was reviewed and endorsed. We reviewed the 1992 report, and basically the conclusion of the subcommittee is that the issues in 92 remarkably remained the issues in 98. Neutrons? Are they neutrons for the studies that need to be done? What is the role of computational biology and the funding for computational biology. This is not to say that progress was not made. In many areas, progress was made. One is the critical role that x-ray detectors play. It is true that with the third generation, these detectors cannot keep up. New detectors are necessary to work more efficiently. Long term research needs to be done. We need to think about funding necessary to put in detectors. Other instruments and computations need to be developed and need to be fostered. There was a detailed discussion of high speed access since it is not practical to send six people to work 24 hours for days when it should be 1 or 2 people doing it remotely. Automation is critical.

NGR has always been an interesting problem. DOE doesn't give much funding there. The problem: machines get higher and higher in megahertz rating, the cost rises and it becomes more of a facility-type operation. Balancing of machines requires use time by users. The NGR experiment may take weeks. The subcommittee had two recommendations:

1) foster research into higher larger magnets for high field instrumentations to improve resolution, and

2) noise, push limits of methodology.

We need to create regional facilities with more conventional machines--700MH--ten or a hundred of these machines for the users to use. In Japan, such a facility is being built. Users can do NGR structures. It is becoming more important to do structural biology.

Mass spectroscopy:

1. If thinking about genomics and structural genomics, mass spectroscopy provides an intermediate station--genomics gives gene sequence, the structure is less rapid. Think of a massive program; ask all the proteins how many are being expressed and fit. What forms, how many forms, etc.? Mass spectroscopy can play an exceedingly important role.

2. Neutron crystallography has had a difficult history. We can=t find neutrons suitable to do it. Large crystals are needed to collect data for a long time. Result: estimate 10 protein structures being done. You only do it when you define a question. High resolution crystallography now allows answers. The sense is, NGR is not where the action is today. There was lots of discussion about this.

Our recommendation is not to build a stationary instrument at IML. There is such a user population. If not, think about what one might do with that station. There is a community for this in Europe. There needs to be evaluation of where it is going, in addition to a broad range of structural biologists to think creatively. We see no need for neutron crystallography today.

There was lots of enthusiasm for neutron scattering and x-ray scattering. People want to look at proteins that don't crystallize well. One might have high resolutions of structures of each element. Use them to model into an assembly to look like atomic-type resolution questions--use this type of data to bring it together. There's a large group doing this in Europe. We need a multi-agency workshop. In many ways, x-ray absorption spectroscopy mirrors what's going on in crystallography.

There was quite a discussion on Acomputational biology. The sense was that it's easy to justify putting money into beam lines, etc., in light of limited budgets, rather than see dollars go into synchrotron beam lines, etc. If doing structural things--compromise in 1992--BER should invest in this area. Looking at it in 1998, areas where BER could be most useful are the areas of genomics, especially structural genomics. This led to: What do we do about structural genome? Should we be doing it? The subcommittee did not come to a conclusion about structural genomics. We need cross-agency effort to try to decide what needs to be done. What role should national laboratories and the DOE facilities play in this before others do it in a less useful or less efficient way? There needs to be a panel of scientists to do this. There needs to be a computational biology network.

Lastly, the subcommittee recommends coordinating funding between BER/BES:DOE, NIH, NSF, and NIST.

Dr. Hodgson commented:

Lower energy storage rings don=t adequately provide x-ray truth--not true. He gave examples. It has come about via innovative high field specialized magnets. The issue is really one by Dr. Mina Bissell that these rings can and do serve an important component and should be in case of discussions with the subcommittee. He suggests that we try to look and find some ways to address this.

Science Talk - Dr. Phil Gordon (NIDDK, NIH)

Dr. Gordon, a foremost expert in diabetes, was introduced by Dr. Michael Viola, Director of OBER's Medical Sciences Division. Dr. Gordon stated that diabetes is a common disease, and he cited four topics he would address: the public health issue, pathogenesis, etiology, prevention and therapy. Mouse farms contain mutations. The national laboratories bioengineering programs are very heavily involved. DOE has an investment in diabetes.

The State of BER Report - Dr. Ari Patrinos (OBER/DOE)

Dr. Patrinos pointed out the two Division name changes in OBER: the Life Sciences Division and the Medical Sciences Division. He emphasized that the change in name does not change the scope. He welcomed the new staff people, and publicly thanked Roland Hirsch for the tremendous role he played as Acting Director, Medical Sciences Division.

Budget:

- Life Sciences: genome structural biology: budget shows small increase from 1998-1999: in the genome program and low dose

- Environmental Processes: also small increase: climate change initiative; sequencing of microbial genome; sequencing of marine microorganism that could be useful for ocean

- Environmental Remediation: NABIR & EMSL

- Medical Sciences: small increase mostly in areas of instrumentation

- Study of marine animals in Hawaii

Human Genome Program:

There have been significant new hires. A major force in evolving the genome national program

will be to celebrate the opening of the sequencing factory in January being held in Oakland; it is hopeful to have Secretary Richardson there to cut the ribbon .

The Lehman review used tough scrutiny of plans [used to be construction]. This was an opportunity for BER to show ourselves--BIOLOGY. There are trained smart physicists in the genome program--JASON studies.

Being cognizant of the Informatics Charge, Dr. Patrinos is hopeful that the BERAC subcommittee will give some guidance. Regarding Intellectual Property Issues: exploring the impact of patenting in the genomics area; there is general recognization that we may quickly be approaching a tragedy. Too many patents will bring the research to a screeching halt. There's a move on the part of White House to Asolve the problem. Senior people should become more active. Re: CELERA are consistent; our cooperation with be an open exchange of information. What we do jointly will be along the lines of the international human genome program.

Structural Biology

- BERAC Reports

- Interagency Working Group Report: in hopes of issuing report very soon--Cassman report-- it will be used as a blueprint in investments that NIH and GM will make.

- Proteome Initiatives: BERAC Charge (maybe the next most important initiative in Biology).

Charge will be given to BERAC very soon; it will involve many agencies: NIH/DOE/NSF. It is a broadly based scientific initiative. Lee Hood thinks that proteomics is analog to genomics. Henry Wagner says it comes between genomics and physiomics.

One earmark is the ALow Dose research. The BERAC Plan: it will be pursued with EM promoting synergism between both offices--a matter of expediency. Congress ran out of money for us so they put it in another appropriation. We cherish, promote, and encourage this and view it as an opportunity to get closer to our customers.

Bioengineering

- Moniz and Varmus: an opportunity for us to join the bioengineering consortium

- Bioengineering Consortium (BECON)

- National Lab Directors Meeting: offer to serve as a liaison of the capabilities in DOE national labs in areas of bioengineering that are necessarily funded by OBER--either through LDRD or other sources. OBER is offering to serve as a clearinghouse.

Global Change

- BERAC Report

- USGCRP Reinvention: re-engineering and fixing, another area of continued partnerships among many agencies

- National Assessment: There is new emphasis in this program. It started about a year ago and has consumed a lot of time and energy from a lot of people. It is connecting us to our customers who are the American people.

Scientific Simulation Plan

- DOE and NSF have the lead

- Climate (Global Systems) and Combustion

Carbon Sequestration

- Roadmap Exercise

- December Deadline

- SC and FE Partnership

- BER and BES

- Implementation Plans

Looking to the Future of the OBER Medical Sciences Program -

Dr. Mike Viola (Director, Medical Sciences Division, OBER/DOE)

Our program is responsible for radiopharmaceuticals/nuclear medicine, BNCT, instrumentation (we relate to the other Divisions and have a wide spectrum of interests), and structural biology.

The Division's Medical Sciences Initiatives include: Boron Neutron Clinical trials, imaging of gene expression, bioengineering, and molecular biology of treatment-related leukemia.

The Boron Neutron clinical trial is ongoing at the Brookhaven National Laboratory and at the MIT/Beth Israel Deaconness Medical Center and is a phase I trial to determine the safe, optimum dose of drug and radiation to treat patients with glioblastoma multiforme. To date, the phase I trial has shown that BNCT is: 1) safe at the doses employed; 2) doses of drug and radiation are approaching maximum tolerated. DOE has the Federal responsibility to monitor this trial and may be headed to a national BNCT data bank. DOE will not devise the trial, but will monitor it using an independent monitoring organization. Dr. Peter Kirchner, also of the Medical Sciences Division, is concerned about how to develop more effective boron-containing drugs. He says that the same rigorous procedures have to be applied in this area as was used in cancer chemotherapy. The Phase II BNCT trial is being developed and will be done in consultation with the NCI. We need BERAC's help to guide us through this, and a subcommittee will be formed.

The nuclear medicine and pharmaceuticals field has changed dramatically in the last few years. Much of our effort is in cancer imaging. We have a large program in studying the brain -- PET (positron emission tomography)--and also a strong radiochemistry effort. Imaging of gene expression will be a way to join efforts between OBER's Life Sciences Division and Medical Sciences Division and will be the subject of an upcoming workshop.

Bioengineering at the National Laboratories

Utilizing the principles of engineering, chemistry, and physics.

Goal : To develop innovative biologics, processes, instruments and informatics for the prevention, diagnosis, and treatment of disease, for patient rehabilitation and for improving public health.

Many profound changes have come from very simple types of devices. We like simple devices to export to other foreign countries who perhaps cannot handle more sophisticated ones.

Bioengineering:BER Interagency Activities