It is my great pleasure to be here with you this morning and to thank Director Major General Tim Toyne Sewell for the conceptualization of this conference and for bringing us together. It is also a great delight to be back at Goodenough College, quite a remarkable institution here in London. I would also like to thank Brian Brock, Roger Lwellyn, and Tom Wilkie for putting together the program. It is indeed an interesting one.

The parallels between the first two talks you have already heard and my remarks are striking, I think. I am going to be talking about the role that the Office of Science in the U.S. Department of Energy is playing in genomics research.

As you have just heard from Dr. Robert Cook-Deegan, the issue of microbial genomics is beginning to develop in a way that has profound consequences – not only for health but, we believe within the Department of Energy, for the energy balance and environmental issues that the entire world is dealing with.

In terms of political economy, the consequences of this research, we believe, will be substantial. It is very important that this research be worldwide, be shared and understood, and carried out in a coherent fashion.

Let me begin with a few words about the Office of Science. We have a current budget of just over $3.3 billion. We are the primary supporters of the physical sciences in the United States. We provide over 40 percent of federal support in the areas of physics, chemistry, mathematics and computation, and about 90 percent of all of the federal government’s support for high energy and nuclear physics. Sixty percent of federal support for catalysis research comes from the Office of Science.

The Office of Science characteristically supports high-risk but high-payoff research, for the long term. The best example I can give for that is what we will be celebrating next month, namely the completion of the sequencing of the human genome. The human genome program began, some of you may not realize, within the Department of Energy in the mid-1980s. It required not only biology, but also mathematics, physics, chemistry – the entire panoply of the physical sciences to carry off, and it was the Office of Science and the Department of Energy that initiated those genome mapping and sequencing programs. Indeed a great deal of what is used now for sequencing technology was originated in the 1980s in the Office of Science. We have also played a fundamental role in visualization and imaging advances, in MRIs and the various PET scans that are now used routinely in medicine.
You may be asking yourself: Wait a minute, why is the Department of Energy involved in programs of this sort? It is because of the unique capabilities of our Office of Science. As you’ve heard already this morning, genomics is not just biology. One is dealing with huge data sets. But more importantly, one is dealing with a complexity that requires sophisticated mathematics and instrumentation in order to unravel.

We have been successful in sequencing not only the human genome, but as you have just heard, a number of microbial systems and plants as well. We have already finished “Arabidopsis thaliana,” which is the first plant (or weed) that has had its genome sequenced, and we are now working to sequence the poplar tree.

So what we have before us is a huge database now, representing the nature and structure of the DNA across a wide variety of systems.

However, that is not function. What we are interested in, in the Office of Science, is carrying forward this very complex static structure into the proteomics and cellular function that will give us an understanding of the characteristics of life and how it takes place – and from that understanding, an opportunity to genetically modify particular microorganisms and improve the quality of life on an international scale.

The way we are going about this in the Office of Science is through our program called Genomes to Life. Over the past three years, hundreds of scientists from universities, national laboratories, and industry have helped us frame this program. It is an international program, and it involves scientists from all over the world who use our facilities and join with us in this endeavor.

What we want to do is to create a predictive understanding of a microbe or microbial community and its interactions with the environment. Why microbes? Over billions of years of evolution, microbes, and communities of microbes, have found homes in every conceivable environment on earth, from boiling thermal vents at the ocean’s bottom to Arctic flows. These microbes live on and make diverse sources of energy, including biomass, methane, and hydrogen. They also use many different substances as energy sources, including some that we consider toxic wastes. Microbes comprise approximately 60 percent of the earth’s biomass, and more importantly, they contain and more than 90 percent of the active cell surfaces of all life on earth. Microbes are the foundation of the biosphere, controlling earth’s biogeochemical cycles and affecting the productivity of the soil, quality of water, and global climate. Indeed, the ability of this planet to sustain life is entirely dependent on microbial activity.

Understanding the microbial world is our key to energy and climate futures, to the development of sustainable modes of living and advanced industrial technologies, and, in no small part, to understanding how life on this earth functions. Individual microbes and communities of microbes have already found solutions for many of our current challenges in energy production and environmental cleanup. In the process of adapting to these diverse life challenges, nature has outfitted microbes with a remarkable array of multi-protein molecular machines, each with exquisitely precise and efficient functions and controls that make microbial biology, indeed all of biology, happen.

So the central goal of our Genomes to Life program is to understand microbes and communities of microbes so well that we can use and possibly even redesign them to address international energy needs. Success in the Genomes to Life program will require a predictive understanding of the multi-protein molecular machines in cells, the regulatory structures and processes that create and control these machines, the behaviors of communities of microbes, and of metabolites and environmental factors that affect and control microbial behavior. It is easy to see how this program will require the use and development of tools not only from the biological sciences, but from the physical and computational sciences.

We are taking another step, which was alluded to by Dr. Peter Robbins in comments earlier. We are integrating ethical practices within our research program. When we began a very challenging new program (with Craig Venter, who of course was one of the co-founders of Celera and led the private sector in sequencing the human genome), we started by putting together an ethics committee, formed of scientists, theologians, philosophers, and others from around the world who could advise us on the ethical issues that would be encompassed by this particular research project.

The research project itself is quite spectacular. It is taking one of the smallest microbes – one actually living in your small intestine, one which has about 500 genes – understanding how it lives, and then addressing the question, How many genes do you need to sustain life? Literally, it means taking the entire DNA out of the cell and putting the genes back in one at a time to see what life means at this molecular and genetic level.

Of course that is not the end of the task. What Craig is intent on doing is using, from other organisms, the genes that produce hydrogen or sequester carbon dioxide or clean up toxic environments that I referred to earlier. In other words, what we are trying to do is create living machines that will deal with the environmental issues which this world faces – and will do so in a clean and environmentally secure fashion.

Now the ethicists reviewed this program in all of its detail before the grant was made. The result was a set of criteria and conditions that in fact informed the research process.
I refer to this as Integrated Ethics Management (IEM).

IEM means not, first of all carrying out the experiment, and then running to see “My goodness, what have we done? and how do we deal with it?” – or even worse, inhibiting what we are going to do by a set of ironclad rules that were irrelevant for the research at hand. Rather, IEM means an integration of the ethical and public issues that this research could entail with the design of the research program.

What emerged was a fascinating interaction between the two groups, the researchers and the ethicists. The process led to a pathway for research rather different than it might have taken without the informing power of the ethical considerations at the beginning.
I suggest that this is an approach which has an application far beyond microbial genomics. As we pursue many of the research avenues available to deal with the world’s issues in health, energy and environment, I suggest that this integration – we will call it IEM, for the purposes of this conference – should take place at the beginning, so that everyone has an understanding of what the issues may be – and so that the research design is carried out in such a way that those concerns are addressed head on and not some consequence of patchwork at the end to try and respond to issues which have developed.

This IEM approach has an implication, I believe, for all of us, and I think that this conference will give us a sense of the interplay between this incredible opportunity that mankind has and the issues that have to be dealt with in that process.

We have also initiated, within the United States government and in particular in the Office of Science, a nanotechnology initiative which recognizes the need to work at molecular scales in the construction and operation of these molecular machines. So we shall be working to develop microscopic methods for creation, support and control of microbial communities from a microscopic and fundamental perspective.

As we move forward in this new ear of biological research, it is important that we consider pathways that will benefit all of mankind – and that these pathways are understood and explained and explicit before the research is undertaken. Our approach in the Office of Science will be to continue pushing the boundaries where the physical, computational, and biological intersect to develop the research tools and the fundamental knowledge needed to find new, biology-based solutions to many of our most pressing challenges in energy and the environment.

Thank you very much.

Question and Answer Session:

Q: [Unintelligible]

Dr. Orbach: There is no question that there could be a very chilling effect on discovery if there are controls that are set arbitrarily for researchers in the laboratory. The practice that we have encouraged and developed, we hope, will not inhibit free discovery and free ideas and moving out into the areas that we could not predict from the beginning. Let me give you one example of where that might have developed and how we dealt with it. One of the issues of this microbial genomics is what happens if the microbes get out. That could be seen as a very limiting process. You don’t want to do anything to a microbe so that, if the thing gets out, you have an uncontrolled problem on your hands. The way Craig Venter responded to that was that he designed a death process in the microbe so that, if it leaves the laboratory, the microbe dies. What this does is to respond to the very serious not only ethical but fundamental issue of control while at the same time using the tricks of the trade in order to continue a line of research that now is protected from extra-laboratory experiences or release.

The question you raise is the fundamental question that we always deal with: Should scientists be able to pursue their intuitive paths regardless of the consequences? As a scientist, I can tell you how I feel about that. We are cleverer than that. I think that it is possible to construct a situation where the ethical issues that develop can be understood by all parties and still not inhibit the science. It will be a very interesting experiment to see what happens in that regard. It is a very fine question, thank you.

Q: [Unintelligible]

Dr. Orbach: That’s the other side of the coin, and we will see. The ethicists in this case, by the way, are a very distinguished group, and they don’t get pushed around very easily. When this was first publicized, there was concern over exactly this kind of question and whether the scientists could be controlled. The ethics group made it very clear that they would play a controlling role in this regard, and we as the funders – after all, this is government funding – insisted that this take place. What’s happened is that, because of this Integrated Ethics Management approach, we can avoid the pitfalls of either unconstrained research leading to unintended consequences or simply limiting the research perspective. So it depends on the strength of both the ethicists and the researcher to carry this out in a congenial and collegial fashion. The answer in this case was that there could be pathways that were closed. You can see by my example of how we are attempting to deal with some issues that could in fact be handled in a way that would not inhibit research.

Q: [Unintelligible]

Dr. Orbach: This is a very troubling issue because, as was discussed, some of these microbes have profound consequences for health and other purposes and, under certain circumstances, could be very detrimental to quality of life, if I can put it in the large scale. The issue you raise is one of open publication and free dissemination of information. Our going-in premise is that everything is for publication, but one can ask at what point does that cross the boundary of national interest and security interest. We have yet to define that boundary. I am personally very reluctant to start putting boundaries on things like that. We are truly an international community, and everybody is as bright as everybody else in every other country. It is foolish to believe that we could sequester some component of our scientific knowledge and information and thereby deny that to the rest of the world.

Q: [Unintelligible]

Dr. Orbach: I would like to expand on the word “ethics.” Ethics means different things to different people. What I mean by it is the public interest. We are a government agency and are responsible for acting in the public interest. So the ethical issues we deal with are focused on the public interest.