DARPA Focus 2000 Keynote Address

It's a great pleasure to be here this morning and to address this very distinguished group-a group that is famous for its foresight and which, through its vision, has helped enable this new and wonderful world of communication. It has fuelled businesses beyond people's imaginations. And because of the infrastructure that has been laid by the people here at DARPA - the managers of many years ago - we live in a much more exciting world.

You would have had to be dead or in a coma not to know that this is a very exciting time for my field, the field of modern biology. More specifically, for the field of genomics. I can't recall a time, other than when man first landed on the moon, when science and technology of a particular sort has received such focus and such attention. It is fair to ask, when that happens, "Is this mostly a media phenomenon? Or is this about real accomplishment and real change?" As is true for almost all human endeavors, the answer is, "Some of both." We do things for multiple motives. But for those of us who identified, some years ago, this marvelous field of genomics - a modern, systematic application of technology to understanding life - it is a truly transforming time.

I thought I would make a few comments that relate, in some ways, to the mission of DARPA as well as to missions that lie far beyond DARPA's. We know that this organization has focused on technologies that have had broad-reaching applications and implications. I think there is an opportunity to do that again. It is a rare and timely opportunity, and one where an organization like this generally make a long-term difference to many aspects of our personal and corporate and civic lives. I will highlight what I think that is at the end.

But before I do that, let me put into perspective some of the changes that have occurred. For the first time, we will have a draft of the complete human genome. We do not have it available yet, but certainly, with the announcements, it is on its way, and quite soon.

What are the implications of having that sort of information? Well, the first implication is that we will know a lot more about what underlies differences amongst human beings. All we need to do is to look at each other in this room to know that we are all different from each other. We can now begin to quantify that difference. We have about 100,000 genes - actually each human has 200,000 genes, because we have one copy from each parent. Between any two genes in any two people (or even within the same person , comparing the same gene from different parents) there are about four substantive differences. So that makes about 800,000 substantive differences in the genes and the proteins the code for, which are the working parts of our bodies - the parts that makes us what we are. When we look at our bodies, we are either looking at protein or at what protein has made.

So "Proteins R Us" in a very real sense. We are looking at how those small parts-proteins that are collections of atoms precisely arrayed in three-dimensional space with an accuracy of one-tenth of an atomic radius-fit together. We are looking at how they build larger structures and how differences in where an individual atom may be (which is essentially what a genetic change is) are reflected in the whole organism. Of course, there are in the population as a whole many more substantive genetic differences than the mere 800,000 that we expect between two people. When you start building something as complex as a human being out of parts that are all slightly different, you get a wonderful diversity that is humanity. And we are beginning to measure and understand it.

What does that mean for the average person? For a long time, it is going to mean the acquisition of knowledge without much ability to change it. That is a certain sort of a curse. It is almost a classic Greek curse, to know your future without having the ability to change it. We will see an increasingly contentious societal debate about that kind of knowledge. The first and most fundamental question that we will ask is, "How much of a person's life is bound up in his or her genes?" And part of that answer, we already know, is very tied to your genes: your life span and your life trajectory are specified by your genes in important ways. A mouse is built to live two years; we are built, ideally, to live 125 years. That very basic feature of our anatomy and our physiology is because of our genes.

How much of what makes us individuals is in our genes? There is going to be room for debate for a very long time. We will seek to understand, and we will find some things very surprising. Maybe whether you like coffee or tea is encoded in your genes. Or even more minute details: whether you like Baby Ruths or Butterfingers. And then, maybe not. Modern studies show that the most adaptable, the most physically changeable organ in your body is the organ that gives rise to your sense of self and identity - the brain. It is probably going to turn out to be the least genetically determined organ, and the one that is most determined by environment. If you remember anything from your experience here today, it will be because your brain physically changed to remember. So even now, at our age, our brains are changing. So, too, we know that the brains of our children are actually formed by the stimuli they receive.

So there will be a fundamental debate. To what extent is it going to be practical? There certainly will be those - friendly or not so friendly - who seek to understand this level of knowledge in order to manipulate leaders, individuals and populations. That will be a very interesting area of study, whose boundaries we can only dimly see. So as we begin to look at what sociologists and geneticists do together, we have to remember that there are some very broad implications of that type of knowledge. We should pay a great deal of attention to what those limits are. What are the limits of the knowable?

In an individual context, we will have to make decisions. How much of our fate do we want to know ourselves? How much do we want to share that knowledge with our spouses? With our families? How much should we know about our children's fate? And if we do know it, should we share it with them? How much should society know? How much should insurance companies know? What are the limits of privacy? What can be protected? Because, as you know, a whole story can be told in genetics by a single hair or by a few cells left on a glass once you have drunk from it. So if somebody really wants to know that story, a little snippet of hair, less than a lock, is all it takes to learn a great deal about you. These are going to be the questions that arise from the particular part of the Human Genome Project that seeks to understand humans as inheriting creatures.

That is part of the story. It is almost all of the story the public sees. If you talk to somebody who is not a biologist - an intelligent, well-informed person - about what a gene is, the conversation will be almost entirely about inheritance. Genes are what determine our inherited traits, our susceptibility to disease, and, for example, whether we look like our relatives. This is not what I do, and it is not what 95% of the pharmaceutical world does with genes. I am a molecular biologist. I come from that wonderful new tradition that has united an abstract concept of inheritance with a physical definition. That is what modern biology is about.

We are seeing, now, a new flowering of the classical view that genes are inheritance. But what has really been happening over the last 50 years is something very different: it has been the putting of a "face," a physical and chemical reality, on the idea of a gene. A gene, we have learned, is an instruction to build a protein. The protein is the irreducible operating element of a living system. We have moved beyond the cell theory of life to something deeper. We now have a gene-and-protein theory of life. The molecular biologist comes from a very different tradition than the geneticist. We look at a living system as a wonderful, intricate machine. It is a machine made of a lot of parts: organs, tissues, cells, organelles. We humans are a 100,000-strong collection of genes that can give rise to proteins (with each gene actually giving rise to several proteins tailored slightly differently). This is the view of an anatomist. It is a practical view that has immediate applications.

If you think of the contributions to our own health today of genetics and anatomy (including anatomy's modern incarnations, physiology and biochemistry), it is anatomy, not genetics, that has transformed our lives. Anatomy gives rise to our marvelous surgical techniques, our understanding of human physiology through measurements of heart rate, temperature, blood pressure, respiration rate, and blood chemistry. And it is anatomy that gives rise to an ever-increasing chemical pharmacopoeia that interacts with our biochemistry. The biochemist and the physiologist, who are both essentially anatomists, led the way to this marvelous medicine. And I believe that they-in their modern incarnations of the gene anatomist, the gene physiologist, and the gene pathologist-will lead the way to a new revolution in medicine. In fact, that transformation is well on its way.

For the last five years, the pharmaceutical industry, by focusing on genes, not the genome, and by working through collaborations with companies like my own, has had a virtually complete set of genes to work with. So we can look to the recent past to see what people will be doing in the future with a complete set of human genes. Because whether or not we have had all the genes to work with, we thought we had all the genes, and we behaved accordingly.

So the post-genomic era has not only begun-we are already well into it. I do not have to speculate about the future. I can just describe the present to tell you something about what that post-genomic world looks like. It is a fascinating world. The fundamental change that has been wrought is that our desire to treat and cure disease - almost any disease -now has a series of starting points

When we began our work in 1991-1992, the linkage between a desire to treat and cure a disease and a credible starting point was very tenuous. It relied almost exclusively on the work of talented academicians throughout the world who would investigate problems when they wanted, where they wanted, and how deeply they wanted-if, of course, they could get the funds to do so. That was not a systematic approach. All the pharmaceutical companies generally did in planning research projects was to look at the scientific literature. So they would all start the same sort of projects at about the same time. That may be an exaggeration, but there is a good deal of truth to it. If you were to look at the major programs in the big pharmaceutical companies, you would have found there was about an 80% overlap. There were all working on more or less the same 65 targets from academic laboratories.

That model has been shattered. It lies in ruins, and a new model has emerged. Through our efforts, we have provided other biotechnology companies and large pharmaceutical companies with a systematic understanding of human gene anatomy. We now have basically all human genes available in a form in which they can be used. This form is the cDNA, which is a stable product of the messenger RNA that the cell uses to make proteins. We have about 140,000 different genes in our freezers. We know where each is expressed in the body, and we have tools that allow us to assess that with much greater precision if we want. We can associate these genes with health and disease. This capability has launched a series of new discoveries, the like of which the industry has never seen. There are now literally hundreds, probably over a thousand, new targets that can link chemical discovery with a disease.

Let me just give an example. Take a problem: osteoporosis. There are two ways to look at it: build more bone, or stop the destruction of bone. As you know, bone is dynamic, not static. It is being built and destroyed all the time. So one approach was to sort through this large collection of genes for anything that looks like a growth factor, and test it to see if it makes an osteoblast grow. That worked, and we found a new osteoblast growth factor, which is currently in human clinical trials. It actually doesn't work by making osteoblasts grow directly - it antagonizes an inhibitor of osteoblast growth. (Our bodies are a little complicated. This is like an anti-missile-missile). So, that is a drug.

In another approach, we took apart the osteoclast, that cell that destroys bone. We took an inventory of its gene parts. The most abundant part we found, accounting for 5% of its total output, was a gene product that our computers told us looked very much like an enzyme, found in rats, that chews up cartilage. What is bone but mineralized cartilage? We found that this protein was secreted by osteoclasts and that it would chop up cartilage. When we prevented it from doing so (by genetically knocking it out in mice or by inhibiting it with chemicals), the animals developed thicker bones.

Neither of these two approaches came from genetics. We did not look at different human beings or different mouse strains. We looked at what normal cells do when they build bone and when they destroy bone. We used anatomical principles: Where are the genes being used? What do they look like? This is the principle that has transformed modern pharmaceutical discovery, and it is basically unstated. It is not familiar to the public at large, because it has not been described in the media. The media, for whatever reasons, have focused on the genome revolution as being a way to understand our differences. But when you look at genes as an anatomist does, you focus more on similarities. In any group of people there are more similarities than differences. We all have one head; most of us have two eyes, two ears, a nose, and two hands; our organs are in the same place; we have the same cells, the same organelles, and, in fact, largely the same genes. At the level of our genes, we are surprisingly similar.

Think, for example, what insulin is. Insulin is a product made by a human being. It is as much a part of a human being as is the heart or a finger. It may not look like much as a drug in a bottle-a little white powder-but it is a human part. It is also a powerful drug to treat a dreadful disease.

We are treating diseases by sharing our parts. What we are really doing is a micro-transplant: that insulin was made from one unique person. One gene was cloned and used to manufacture that human part in bulk, and in a pure form. And that one insulin molecule, from one unique individual, is used to treat everybody with diabetes. At the level of our genes and proteins, we are made of interchangeable parts. If we were not, how could we ever be created from two different sets of genes - one from our mothers and one from our fathers? It must be that our genes are interchangeable.

Therein, I think, lies a principle for a new and better form of medicine. We may not be reaching the end of discovery of new chemical drugs, but we are certainly running into difficulties. Those difficulties are manifest in a productivity crisis in the pharmaceutical industry. More and more dollars are going into producing fewer and fewer drugs. That means the industry itself is in a crisis. The biggest problem is not in deciding what to work on. We now know what to work on. We have new technologies that reveal the crystal structures of our targets, and extremely powerful chemical tools. Rather, the problem is: how many foreign chemicals can the human body tolerate at the same time?

Think of somebody 75 years old. That person may be taking a sleeping pill, an anti-depressant, medication for high blood pressure, and perhaps two or three other drugs, for example pain medication. A woman may have osteoporosis and be taking an estrogen supplement. That is a lot for the poor liver to handle! It is like stuffing people into a phone booth: you get the first one in, you get the second one in, you get the third one in - but every success leads to a future problem. Our metabolic pathways are being blocked. This is why in the last two years we have seen seven major failures because of drug-drug interactions. Drugs that had been approved had to be pulled off the market.

I think there is a better way to think about medicine. Now that we have a complete "parts list" of human beings, we can begin to use those parts themselves as medicine, just as we use insulin as a drug. I believe that we are on the brink of ushering in a new medicine based on the cellular communications network that distinguishes us from amoeba. The differences between a human and an amoeba do not lie chiefly in what happens inside your cells. Rather, the differences lie in what happens between your cells-the communications that take place through the outer surfaces of cells. Cells can be seen as relatively simple transduction devices. They can either grow or not grow; remain as they are or differentiate; continue to live or die; stay put or move. That is about all they can do. All of those decisions are determined, to a first approximation, by unitary steps: a signal and a response. That is somewhat simplified, but not excessively. Our concept is to isolate and characterize that subset of genes - about 10%, we think - that controls those signals, and to focus on that as the new medicine

Where can you get with that? I believe that it will allow us to rebuild, repair, and control most aspects of our anatomy and physiology, and to control pathology. Let me give you a few examples:

To grow. We have a drug working its way through clinical trials - it has just been successful in its first Phase Two controlled trial - to treat large, unhealing wounds in elderly patients. Any of you who have elderly relatives know that this is a serious problem. We looked for, and found, the protein signal that the body makes to heal skin. I am happy to say that we can grow skin at a much faster rate than normal by applying this purified protein to large open wounds. For other purposes, for example military ones, it should work to repair smoke inhalation damage, large burns, chemical burns to the mucosae, and other wounds such as radiation damage. We are using it internally to heal chemically-induced burns, ones that chemotherapy causes in the mouth and intestines. We are also using it to treat ulcerative colitis. I think there will be a wide range of applications for this one signal to grow new skin, or new mucosa. This signal happens to work only on injured tissues, so it is a special repair factor.

To change. We have looked for, and found, a substance that does not cause blood vessel cells or lymph vessel cells to grow, but does cause them to assemble into tubes. So if you have a sheet of cells, and you apply this substance, when you come back the next day you have tubes. We inject it into cardiac muscle that is deprived of oxygen as a result of coronary artery blockage, and we find new blood and lymph vessels assembled, and patients doing better. We hope it will be an alternative to coronary bypass surgery. Again, you can imagine some military applications for help to heal wounded tissues.

Not to grow. One of the major types of damage suffered by people undergoing radiation and chemotherapy is to their immune system. It is always growing, and therefore is killed along with the cancer, because cancer drugs and radiation kill growing cells. We reasoned that the body must make an "off-switch." When you are full up with blood, you must be able to turn off its production. And we guessed that you might be able to turn it off at the source, the stem cells. We looked for, and found, that "off-switch." We are now treating cancer patients with it. We give it to them just before chemotherapy, and it seems as though it is going to protect their entire hematopoietic system from the serious damage caused by chemo- and radiation therapy. Military applications include protecting people who may be in hazardous radiation or chemical environments.

A differentiation switch. What happens when your body sees a foreign substance? It begins to make an immune reaction. This is a complicated process. In one of the arms of the immune system, the B-cells that produce antibodies are educated. They go on to produce plasma cells, which produce lots of antibodies. As in many parts of the body, we overdo it. When you start to make B-cells and plasma cells, you would make a huge amount of antibodies unless a countervailing force acted to prune back that tendency. One activity stimulates it, and a negative force keeps it in check. We have now found the substance that counteracts the negative force that keeps antibody production in check. The net result is that you can stimulate antibody production at will. We call that substance B Lymphocyte Stimulator. We are now using it as a drug. We recently received approval to test it for people who do not make enough antibodies because they have inherited incapacities. Many older people do not make enough antibodies, nor do AIDS patients and patients recovering from chemotherapy or radiation insult. People who are fighting antibiotic-resistant infections could surely use more antibodies. So there are many uses of this factor.

Think, for example, about rabies vaccine. It works because rabies is slow - it does not cause damage in a day or two, but rather takes days or weeks to work its way up through your nerves to your brain , if you are bitten in an extremity. You have enough time to introduce a vaccine to protect yourself from this progression. Most viruses work much more quickly, in a week or 10 days, so our immune systems cannot gear up. It would be great if we had something that could allow our immune system to out-run most pathogens, so that they would be treated as if we had already been vaccinated. Vaccines do not throw up a "Guard-All" shield that prevents a virus from ever getting to you. They work by eliciting a rapid immune response - a memory response. We are now, I think, on the brink of being able to elicit a memory response, or a response as good as a memory response, fast enough to treat people who might be infected with exotic agents or antibiotic-resistant agents.

This is an interesting concept. Let me extend it to other infectious diseases. Up to now, we have almost always regarded the treatment of infectious disease as fighting the organism that is infecting us - the parasite, the bacterium, the virus. But it is possible to look at infectious disease in a different way. It is a small set of genes and their products interacting with a much larger set of genes, which is us. In order for that pathogen to work, some meshing has to occur, an intricate dance between that organism's genes and our genes. Our efforts up to now-creating vaccines, using antibiotics-have been mostly focused on inhibiting the smaller set of genes.

I believe that we are poised to start a different kind of approach that focuses on the human susceptibility to disease. We now are in a position to understand those key elements with which the infectious disease organism must interact. I am thinking of some very specific examples: AIDS, some bacterial infections, and others in which we may begin to modify the human host. Not simply with a vaccine, but by some other means that may make us less susceptible to many infections. A whole new world of infectious disease research has now opened-understanding not just the microorganisms, which is important, but also the precise interactions between the two sets of genes and their products.

I think there is, finally, one other truly great and interesting challenge before us. We know, through many studies over the last 50 years, that the principles by which evolution has created living structures are principles of chemistry: putting atoms in aqueous or lipid solutions in precise, three-dimensional arrays. Thus has nature created structures as small and intricate as a virus, or as large as a redwood forest. Structures of incredible diversity are based on these principles. Up until now, it has been a hit-and-miss process. The slow process of evolution has led to the creation of those very intricate and most interesting structures. But we are now beginning to understand those principles of construction and organization.

We are still at a very early level of understanding. When, in a talk a few years ago, I described how we could reorganize blood vessels in a heart by putting in a single gene, one of our great computer scientists, Danny Hillis, said, "You know, I can't get a computer to do that. I wish I could write a new line of code and have the whole program readjust itself ... put in a new chip and have my computer readjust itself to a new and better form. I can't do that. How does the body do that?"

As I thought about the answer (and it took me a while to understand the question), we got into a good conversation, and I began to think about how much information is actually in our genes and in our proteins. I am a former chemist. There is an enormous amount of entropy, an enormous amount of information, in these structures - far more than we see just in the sequence of a gene or protein. What information is actually there? It has been selected over billions of years. Not only to work as a unit itself-for example, as an enzyme to crack apart a particular chemical, or to build a new structure-but to work with other proteins, organelles, cells, tissues, and organs. The information in a structure is the product of literally billions of years of interactions with a complex and changing environment. For as long as some animal precursor to human beings has had the capacity for thought and imagination, perhaps the past 2 million years, evolution has also worked through the process of thought and imagination.

So there are many layers of organization, including the level of thought and interaction with our environment, that go into crafting the details of a biological structure. They are marvelously information-rich. If we study biological organization in its diversity in other organisms and in our cells, we are studying how to build nanomachines-how to put information into the tiniest structures. This information allow these nanomachines to interact with the most complex of all environments: human society. Our proteins are crafted to work even at that level of complexity. They were not literally engineered, of course. The process just happened, but it produces results that look like engineering. And if we begin to understand how to do that engineering, we will be able to write genetic codes to make whatever proteins we want. Then we will at some point be able to create whatever structures we want. How much information we put into them will depend upon how fully we appreciate their articulation with their environment.

Therein, I think, lies a great opportunity for an organization like DARPA to change the industrial base, and indeed our relationship with the physical world. We know this type of engineering works. We are, if you will, living proof that it works, and that problems such as "stickiness" that people worry about can be overcome. They have been overcome. I think that form of study takes us not only in the direction of new and better medicines, but into a very interesting world of materials whose physical properties are engineered at the level of the atom. The major architectural element in that world is not anything like a silicon chip. It is an atom whose three-dimensional coordinates have been chosen with due consideration for all of the interactions it must have.

So the implications of this new revolution in biology go far beyond biology itself. They include a greatly enhanced understanding of our material world; the prospect of much better and longer health; even, specifically, new ways to defend ourselves against organisms that are either natural or man-made. Much more than this, the revolution I speak of is a transforming conception of what we are in relation to the physical and chemical world, and how we can use our knowledge to further our own ends.

Thank you.

DISCUSSION

Question: I am a visiting Assistant Professor at the University of Pittsburgh. I am a computer scientist with a fascination for biology and trying to teach computational biology. We hear on the radio, and we heard today from you, also, that we will soon have a draft of the complete human genome. I've been given to understand that only 2% of the human DNA actually constitutes the coding region, and the rest, 98%, is labeled as "junk" or something else. So when we are talking about the complete human genome, are we talking about the 2%? Is that a valid assumption?

W Haseltine: Did I ask you to ask that question? Some of you may know that I am a skeptic when it comes to the importance of this recent announcement. Implicit in my remarks was that we focused on the genes. The way I think about it is that if the gene is the "present," then the chromosome, or genome, is the "package." We've extracted the "presents." What has been announced is a very accurate description of where all the "plastic peanuts" are in the box. So it's not exactly a great human achievement. However, it is emblematic and symbolic of a truly important transformation. And if you take it as that - and we are a symbolic species - it is a symbol of a new-found power.

The work itself actually is not yet done. It is a draft, and it is not available - there is no computer you can go to to find it yet. Try it sometime - I have! And even if it were done, it would not be particularly useful. Genes are scattered in little bits and fragments, "assembly is required," and there is no instruction manual. The first description of a human chromosome found no new genes and pointed out only where genes that had already been isolated by other methods were located.

So work on the genome itself is not what we pursued. We went to exactly the 3% that is useful and focused just on those parts. But whether it's the genomic work or the work with the genes that makes sense, we really are in revolutionary times. That's why I emphasize that the post-genomic era began five years ago.

The genome announcement is a marker for the general public that something new is afoot. It is an important and effective announcement, like landing a man on the moon. That could have been read as, "We're stronger than the Russians" (which we were and should have known anyway), or the beginning of a new use of space, which now allows global communications and satellite phones. The moon landing was a truly important event for mankind-not intrinsically, but because it was a marker for all to see of a transformation in the human relationship with the space beyond our own planet. I think something similar is true of the human genome announcement. We need our symbols. We need our flags. This is a flag for modern science.

Question: First of all, you got my hackles up a little bit - being a geneticist - by kind of dismissing the contribution of genetics to this.

WHaseltine: You must be a geneticist!

Question: I am a geneticist. I think, actually, that genetics has [contributed], and will continue to contribute to our understanding of a lot of these problems. But that's not the reason I'm up here.

There was a recent announcement - I believe it was in a report from the NIH - that the era of hypothesis-driven research may possibly be over, which I found especially bone-chilling. The idea that the inductive process in science may be over…that we actually know all the basic information we need to know, and now we just have to find out how to apply it. I got a little bit of the flavor of that from what you were saying, perhaps, as well. Would you comment on that?

WHaseltine: What has changed is the way we solve our problems. We will always start with a human problem that needs a solution. There are a lot of different starting points. You could start with a scientific question such as, "What is the composition of the surface of Mercury, as compared to the surface of Pluto?" That could be a question. The question that we always start with is, "How do you solve this major medical problem?" The tools that we have to do that are far more powerful and systematic than they were just a few years ago, but they are always hypothesis-driven. In the example of osteoporosis, the hypothesis is that you can cure osteoporosis by either making cells that produce bone grow faster, or by inhibiting those substances that destroy bone. That is hypothesis-driven research. But as powerful as our tools are, I think we should remind ourselves that we are still at a very primitive stage of understanding. I actually counted twelve different types of entropy involved in human life - twelve levels of organization. DNA sequence is one, protein sequence is a second, protein structure in three-dimensions is a third…Well, we have the DNA structure, or we are getting there. We have some protein structures, maybe one-tenth of them. We are still at an elementary level when it comes to understanding three-dimensional structures. And we are pretty much at sea with anything more complex than that. There is a huge amount to do, and a huge amount of hypothesis-driven research. The tools that genomics offers are powerful in their realm, but their realm is relatively confined. It is concerned with the more basic elements of the organization of life. Ultimately, we will move on to address the most interesting elements, that is to say the higher levels of organization of what in total we call "life".