Symposium sponsored by:

Johns Hopkins Center for Civilian Biodefense Studies

Department of Health and Human Services

Infectious Diseases Society of America

Advances in Biotechnology: Promise and Peril
George Poste, PhD

DR. HENDERSON: Our next speaker is Dr. George Poste, who's Chief Executive Officer of Health Technology Networks, a health care consulting group now based in Arizona, and he serves as well on the board of directors of a number of biotechnology firms. For the past 20 years Dr. Poste has been with SmithKline Beecham where most recently he served as President of Research and Development and Chief Science and Technology Officer. He holds a doctoral degree in veterinary medicine and a Ph.D. degree in experimental pathology from the University of Bristol in England. He's a Fellow of the Royal Society, the Royal College of Veterinary Surgeons and the Royal College of Pathologists. He has served on numerous advisory boards to governments both in this country and the United Kingdom, and most recently, he chaired the Defense Science Board's study entitled "Technologies for Biodefense." His paper is entitled "Advances in Biotechnology: Promise and Peril." Dr. Poste.

(Applause.)

DR. POSTE: Good morning. I'd like to thank the organizers for the invitation to participate in clearly a stellar assembly of speakers. The topic which I'm going to address, assuming that -- yes, there it is -- is this issue of biotechnology in context both as a classical dual use technology -- we've gone backwards. So let's -- if we can go forward. There we are.

I think if one looks at the technological foundations of military doctrine historically and, indeed, still dominant today is this issue of what I've paraphrased as "big bang, big metal," but in short, the technological underpinnings are primarily based upon the conceptual advances in physics and engineering, and the type of weaponry that is produced has the advantage for the intelligence community of creating high profile signatures.

But as we've just heard from Dr. Bracken, the framework of the political constituencies that may not necessarily look with less friendly attitude toward the United States and its allies, there is a change towards the prospect of asymmetric warfare utilizing two technologies: the first, undermining the increasing dependence of all of us upon information technology through assaults in the cyber warfare arena, and our topic today in terms of bio. because biotechnology undoubtedly changes the rules, as we will hear throughout this meeting, and I think it's probably fair to paraphrase it as the fact that biology for the first time is losing its innocence.

If you speak to many in the biomedical community where quite appropriately their principal modus operandi is the advancement of human health and quality of life, they're quite shocked to think that some of the things that they're working on could, in fact, have malignant application. A simple example would be the much publicized dimension of gene therapy, a well intentioned effort to restore bodily function by inserting genes into the human body, and as we've seen in well publicized tragic consequences of a recent death at the University of Pennsylvania, the issue of using infectious agents to introduce genes into the body, the issue is not whether or not that was an intellectually sound exercise. It clearly is, but with the recognition, surprise, surprise, it should hardly be a surprise that the body actually recognized the vector that was being used to deliver this gene into the body. So what is now the principal aim in gene therapy for beneficent application is to create stealth viral vectors, namely, viral vectors which will escape detection by the immune system of the host. And if you point this out to many of the denizens of the gene therapy community that they might actually be very much help in the military doctrine of Baghdad and others, they're quite shocked that such a prospect could even be considered.

So the issue of biology losing its innocence is something we have to seriously consider, and I think it will become an increasingly problematic issue for the academic research community where in physics, high energy physics, people have got you not to forbid them knowledge, but constraint knowledge. Biology has yet to make that transition. But what we're dealing with here clearly is an issue of increasingly complex dual use technologies. If we look at the beneficent phase of biotechnology, and this is the only slide on the beneficent domain, there are really four principal areas of application. The top box there on the left mapping the molecular basis of disease i the primary emphasis here, namely, the ability to elucidate biological mechanisms in health and diseases, providing a very rich vein of the pharmaceutical and biotech. industries to tap to identify new molecular targets for drugs, vaccines and diagnostics.

Moving down still on the left-hand side it's also revealing that diseases are far more complex than we thought in terms of their underlying molecular pathology, and therefore, diseases that may have similar clinical symptomatology, in fact, turn out to have distinct molecular pathologies, either the genetic or the proteomic level, leading to the issue that we have to think about the right drug for the right disease, and switching to the right-hand column is how does your unique genetic profile and my genetic profile influence in the top box how we respond to drugs and vaccines, particularly in terms of their efficacy and safety, and then longer term, the issue of how does my genetic composition and ours predispose us to major diseases. And all of these hold the promise of enormous gains in health care in the coming decades and, indeed, elements of that have already become reality.

The other side of it, of course, though also focuses on microbiology, and that is the question of the analysis of microbial genomes certainly has many important applications in the beneficent arena, but the other element of it is this, namely, that by mapping the molecular basis of microbial disease, we also identify new ways of using that information to, in fact, attack human populations and moving into the other side of the slide, so-called exploring biospace. It's very clear that the evolution, even though it's quite magnificent in its products, has only explored a very small fraction of the potential building blocks that sort of essentially nature is a molecular lego whether you're working at the gene or the protein level. The ability to create total novel genes and novel proteins and, therefore, novel organisms opens up a quite fascinating domain both in the beneficent, but equally the malignant level. And as systems biology gains momentum over the next two decades, namely, the ability to build up from gene to protein, to understand the complex genetic circuitry that pertains to engineering the specificity of different cell types in the body or the profiles of different microorganisms, computer programs become increasingly accurate in predicting the behavior of biological systems.

And so that issue of biology en silico will also become an important tool, but if we focus now on the overtly malignant aspect of this, it is the identification of new molecular targets for bioagents, and with their understandable anthropocentric focus, we tend to forget that there is a devastating range even if only at the economic level, a devastating range of targets in terms of animal and plant populations, and irrespective of whether the target is man, animals, or plants, there are number of increasingly powerful and interesting technologies which can be applied here.

The first is to expand the tissue or host range, the recent paper that was published, for example, in Nature Biotechnology showing that through recombination you could completely change the host range and tissue range of retroviruses simply by doing molecular shuffling techniques. New modes of spread, the ability to take an agent which from the standpoint of the bioweaponeer has an inconvenient mode of spread and convert that to an aerosol spread, becomes obviously an area of appeal, well established elements from both the U.S., but certainly the Soviet strategy circumventing the ability to create organisms that either lack an antigen to escape the diagnostic test, the acronym Dx, or the ability to circumvent therapy with antibiotics, Rx, or to have altered antigens that permit you to escape from immune protection from the vaccines which are available.

Hypermutable agents. You could almost argue that HIV in its own right is a hypermutable agent, but it's very clear from looking at antibiotic resistance issues in bacteria that there is a subset of bacterial populations which actually have hypermutable status that relates to alterations in their nucleic acid repair enzymes, and these, therefore become obvious targets to create agents that are hypermutable both in terms of driving patterns of pleiotropic antibiotic resistance, but also the ability to escape from immune assault by the body. And the dimension which I'll come back to is actually using the body's own defense mechanisms against itself in this case engineering organisms that actually produce an over reaction on the part of the body in terms of lymphokine and cytokine response to induce shock syndromes.

Hybrid agents. We've heard about small pox ebola hybrids. Recombination agents, which will be the equivalent of binary chemical agents whereby the two agents that go in a nominally avirulent in their own right, but in fact are capable of recombining within the body to create a virulent agent or, as we have recently seen some aspects of the Soviet program, the equivalent of using a bacterium to carry in a virus, but the virus is only activated when the patient is treated with antibiotics so, in fact, providing a rather nice twist to the issue of protective defense.

And then presumably the most sinister element of all would be the question of latent integrated agents where you would use something like a retroviral vector to integrate an agent into the genome of a host with a controller gene, and you can, of course, activate the controller gene to activate the agent after it has already been in place when you presume that the political ideology of your enemy has become sufficiently offensive. The other element, of course, is moving beyond bugs, and this is what I've called here the brain bomb. In short, the other dimension of this is expanding the definition of bioagent beyond bugs. In short, as we begin to understand the exquisite molecular mechanisms that regulate this remarkable structure called the human body or, indeed, plant and animal function as well, the ability to understand those circuits means that simultaneously we gain the capacity to scramble them.

So that means that you can engineer a series, a complete spectrum of activity from transient immobilization, so in terms of crowd control or, indeed, troop control to catastrophic effects which can be acute or chronic, and the two most obvious areas where that applies are what we already know, the activation of inflammatory cascades. I referred earlier to bugs specifically engineered to elicit massive production of cytokines or lymphokines in the body. But I think some of the other more interesting dimensions to this are how do you actually scramble or trigger near a pathway. Think about the implication of wide induction of the ability to activate violence, induction of widespread lethargy. Some may argue it's already here, but --

(Laughter.)

-- but the overall issue is the fact that think about assault against an advanced economic power where you're capable of inducing significant behavioral shifts in an economically productive population. This also creates another conundrum to the extent that this is not so much bioagents in their own right, but by understanding the underlying biological design principles that regulate critical metabolic pathways within the body, you actually shift back to chemical agents to cause the disregulation. So, in fact, it would be unlikely that you would use an infectious agent to induce widespread shifts in behavioral profile, but by understanding the specific mechanisms that regulate major cognitive functions and mood, you would then, in fact, use a chemical assault to induce that approach.

The other dimension which has already been referred to this morning is the increasing ubiquity of biotechnological capabilities. It would be interesting to reflect if Ted Kazinski (phonetic) had been trained in the 1990s whether he would have chosen to use bombs or would have walked along and dropped something into a hamburger plant as an alternative, as the ubiquity of Biotechnology 101 becomes increasing commonplace in the university curriculum around the world.

But the other issue, of course, and what this slide is meant to illustrate is scale and scalability. You can produce agents on a very small scale, as shown on the right, or migrate it through to very large scale production capabilities, as we know that the Soviet Union had committed itself to.

But the real issue is the fact that these technologies, in addition to changing the threat spectrum by definition, will also escalate the complexities of surveillancing inspection requirements under the biological and toxin weapons convention because not only do we have a dramatic expansion in the number of theoretical dual use facilities under the convention because of the proliferation of biotechnology as an industrial enterprise. We're going to require an entirely new repertoire of analytical methods with which we must equip our inspectors if they're actually to sniff out what is really going on, and much of it -- there's a third hyphen there, cyber-forensics -- becomes very important because you can hide a lot of black activities in white databases simply by fragmenting those data sets. And at the same time, the nature and identification of bioagents under the general purpose criterion has to become increasingly broadened, and some of the examples are shown there on the slide, and as has been reflected in discussions with the farmer and biotech. industries, there is substantial resistance to arbitrary and capricious inspection, particularly from countries that might very well be interested in usurping intellectual property, circumventing intellectual property by gaining insight into what those companies are doing on a legitimate basis.

So it's a complex brew, but coming back to the principal issue, and that is the fact that you can write any scenario you want, if you want to hire a group of biomercenaries to put on an island somewhere, you can write your own scenario. Do you want to kill millions or do you actually just want to sustain a pattern of psychological operations against the great Satan? Do you actually want to declare a priori that will strike a U.S. city every third Friday in the month, not to kill people, but merely show that I can render your society vulnerable and erode confidence in government?

So we all know that the whole symposia and volumes are published on every type of scenario ranging from the catastrophic to the amusing that come forward, but the real issue is the fact that we have multiple agents, multiple agents in terms of bacteria, viruses, fungi; multiple targets within humans, plants, and animals; multiple environments in which that can occur.

So we've got multiple scenarios. That demands a wide spectrum of defense postures. This is far more complex than anything in the nuclear arena, far more complex than anything in the chemical arena. So we've got two choices. Is it paralysis or purposeful threat reduction? It is, indeed, complex, but it is not impossible.

Where do we actually find some of the more generic solutions that will be applicable to a variety of activities? And certainly something now I'm going to essentially focus on, some of the recent deliberations of the Defense Science Board, and that is working under the principle of one key element, and that is that faster identification saves lives, and in that I'm focusing primarily on the diagnosis of infection in people because, as this audience well understands, the distinction between bio versus chemical and nuclear is the fact that no matter how grotesque chemical and nuclear may be, once the incident occurs, it is over. You know the extent of the carnage. You know the extent of the mop-up operation.

But in bio, the first time you will probably find that you've actually got a problem on your hand is when it's imbedded in the health care system. So when the emergency rooms of this nation were filling up with people with influenza-like symptoms in February of this year, how did we not know that that was not actually one of the major threat agents being used against us?

A lot of emphasis is being put into sensor technology, and we'll hear more about that from Dr. Alving a little later in this meeting, but this is an extraordinarily complex area to be working in, and I think that although she'll be talking about it, the Defense Science Board has now made a more focused effort to look at this issue of how do we improve the speed, breadth, and accuracy of clinical diagnosis, recognizing that the first time we'll probably see this is when it's actually in the health care system.

And what I really want to emphasize is the bottom box there. It's an integrated systems approach. You just can't have one element of this. You've got to be able to identify the agent. So we need better ways of identifying those agents. What are the fingerprints of those agents? How do we then actually build the diagnostic tests that exploit that knowledge to actually create the diagnostic tests themselves? That means nothing if you diagnose someone in Albuquerque if you can, in fact, mobilize that information into the network so that analysis and an automated computational network is key to faster mobilization of the medical response.

And one only has to look at the various reviews of the top-off exercise in Denver to see how you would overlay a grid of this kind. So how do we actually go about gaining this fingerprint of the various bioagents that may be used against us? And here is, in fact, where biotechnology can play an enormously important role whether it be at the level of the gene, genomic, or at the level of the proteins coded for by those genes, proteomic profiles. How do we go about profiling bioagents?

This does provide a capacity under Bullet 2 to simultaneously profile whether or not the bug has been engineered to make it resistant to drugs or vaccines. We need to archive samples from natural epidemics around the world. I think there is an extraordinary urgent priority as yet unrealized to profile this enormous inventory of agents that the former Soviet Union had assembled, and we also need to compare all of this against those organisms which are being used, but for legitimate intent by the pharma and biotech industries.

And what I'm now going to talk about has an undoubtedly parallel value in advance in public health, and it is essentially what I am referring to as the Zebra Project. If you think about the one thing which medics are taught around the world, it's the fact that the common diseases are, by definition, the most frequent. So if you hear hoof beats, it's more likely to be a horse than a zebra. The dilemma in the detection of bioagents, of course, is the fact that the bioagent is the zebra. So come back to February 2000 when the emergency rooms are filling up with influenza patients. It was much more likely to be influenza, but it could have been any one. Seven of the eight top bioagents that could be used against us would, in fact, present with similar symptomatology.

So how do you detect the occasional zebra amongst this thundering herd of horses is really the principle, and the focus here one suspects will be on something which we've called the zebra chip, which is really building on this enormous set of rapid advances which are occurring in miniaturization technology to immobilize oligonucleitides or genes onto chips to profile genes, and in this case you'd be profiling microbial genes. So already comprehensive chips capable of identifying up to a million distinct genetic signatures imbedded on a two centimeter by two centimeter chip beginning to become available. So the idea would be to build up a comprehensive genomic and proteomic profile of both conventional agents, as well as bioagents; put those onto chips.

The middle slide, for those of you not familiar with, you can just sense the technician's hand putting that biochip into the reader, which then scans it automatically to define whether or not it's a horse or a zebra, but again, coming back to the principle of integration, it means nothing if you generate information to say that a zebra is present if you can't mobilize that into the health care network at large. So, therefore, this has got to be automatically coupled into a computational reporting network. The advantage, coming back to the principle of the fact that faster identification and intervention saves lives, is the chips is more than just a diagnostic entity. It's a fundamental element in triage and infection control. It permits you to scrutinize and segment your at risk population. So if this room had been exposed, some might have symptoms. Fine, we know what we've got on our hands.

But for the rest of you who may be presymptomatic, how do we identify who is infected much earlier? That is relevant not only to the utilization of scarce resources, such as antibiotics and vaccines. It may be particularly pertinent in the context of the larger population as to how we impose quarantine because we as a public health community have lost any site of the implications of imposing quarantine,a nd dealing with the question of how the media would respond to the imposition of a quarantine in a large urban population barely bears consideration. But this issue is also critical in the context of disease management because if you can identify the bug earlier, particularly if it's got any unusual characteristics, then it's the right intervention for the right patient, and the longer term, this also leads to the ability after the incident for a much more robust opportunity for forensic attribution and for retribution, which would stand scrutiny in the court of public opinion.

So what you need then, of course, is the data collection through the zebra chip network and other indicators which are also equally important, but as I've emphasized, this means nothing unless you've got a parallel development of a complex computational system which is not in place at the present time to actually net work that information in real time to provide then the tools for improved incident management and command an control capabilities.

And a totally different topic, but the whole question of how you can use this information on bioagent signatures for the intelligence community and its capabilities is obviously a fertile area for expansion of skills in the intelligence community.

I'm not going to spend any time on medical responses to bioterrorism and biowarfare because there are others who are going to talk about the stark challenges in this arena, but I will talk about one aspect of it, which the Defense Science Board has been looking at, which is the drug and vaccine supply chain. If one takes the top 50 theoretical bioagents that could be used against us before you even more into the larger list of plants and animals, we really only have drugs and vaccines developed against 12 of those 50.

But even that still suffers enormous logistical shortcomings because one of the things of the friction free economy that's been achieved everywhere is the fact it's taken excess production capacity out of the hospital system. It has taken excess capacity out of the pharmaceutical production capacity.

So if top off had been real in Denver, we would have quickly run out of antibiotic to treat the population. If you look at even the recent approval of ciprofloxacin for the treatment of anthrax, we couldn't produce enough antibiotic at the present time to respond to short term needs. So there is an inadequacy of drug and vaccine stockpile. There is clearly, as we've seen in the debark with regard to vaccine development in the area of bioweapons, no incentives for the private sector to engage in this arena. We've concluded that DOD has underestimated the joint vaccine production requirements in this need, and there is a great ambiguity with regard to the ability to develop investigational trials and diagnostics under current FDA regulations.

So that means that not only have we certain current logistical shortcomings with regard to those drugs and vaccines which are already available. The other iceberg that sits out there under the water is the fact that we do not have drugs and vaccines for a significant category of agents who will be used against us, and in particular, major gaps against viruses. As many in this audience know, we really only have antiviral drugs against certain herpes viruses and the retroviruses, including HIV. Other than that, particularly for the hemorrhagic fevers, we have nothing. So we've got to really think about how we go forward over the coming decade in developing a much more focused R&D effort, again, with the engagement of the private sector.

But as Dr. Rodier emphasized at the beginning, all of this is also intimately linked to the premise of international public health surveillance. The ability of natural infectious disease to spread globally becomes a national security threat in its own right, and I don't want to emphasize any more on that other than to deal with one aspect of the biotechnological change.

If not now through bioterrorism, but an emerging infectious disease or even a traditional pathogen were to reemerge in our midst, how do we mobilize against an unexpected threat, whether it be natural or engineered? We have no surge on demand manufacturing capability, but a much more important and profound deficit in our knowledge is the fact that if Bug A appeared in our midst, we know little about how to rapidly identify the so-called epitopes, the immunizing component of those organisms. We not only do not have the tools to, even if we can sequence the entire genome of this bug when it arrives in our midst, we do not have computational tools that predict which are the most likely proteins which are going to be suitable for immunization. We have no logical tools to guide us as to whether we're going to activate the T helper one or T helper two pathway, which relates to the balance between antibodies and cytotoxic T cells in our body, but the most fundamental issue of all is time.

Vaccine production is biological. We either grow the bug or use recombinant technologies to isolate the gene for bits of that bug, and then produce those. But that takes a great deal of time. Typical vaccine production cycles, as many of you know, are anywhere between three and 18 months. That is a mobilization time that would not be suitable for dealing with an incident that occurred. So what we've really got to do, one of the great technical challenges for us is how do we actually create synthetic vaccines and convert a biological process to a chemical process.

Drugs, as you all know, are chemicals. Those are produced by chemical processes with shorter production times. Vaccines are biologicals. So how do we actually then convert a biological process to a chemical process and with it will come new regulatory complexities?

So in summary, ladies and gentlemen, what I've tried to emphasize here today is the fact that biotechnology has long been recognized as a dual use technology, but it is this dramatic quantal, disruptive dimension of biotech which is equally disruptive in the conventional civilian sector which is holding out great promise, but also raises a number of new challenges for national security. Part of that will be driven also not just by the ideological challenges that we will face from some of our enemies in terms of the attractions of biotech for asymmetric warfare, but the ubiquity of that technology will also facilitate that transition, and at the same time, we need to extend our dimension of understanding beyond bugs to understand that this will eventually over the coming decades also involve scrambling of intrinsic body circuits.

We are vulnerable, as is everyone in this regard. There's no particular uniqueness of the United States in this regard, but there are major shortcomings in any one of a number of sectors, and we nonetheless have the ability to utilize the potential of biotechnology, as I emphasized in the zebra chip dimension, to actually build a comprehensive surveillance network to better identify the threat when it comes. At the same time, we are vulnerable and must mount now a much more formidable effort to develop new drugs and vaccines, and I emphasize again that's equally important from the standpoint of emerging infectious diseases. New technology initiatives in diagnostics and therapeutics and vaccines will generate enormous parallel benefits for the civilian health care community, and I think that these are absolutely vital efforts which I can assure you the Defense Science Board is paying a great deal of attention to, and perhaps the best way to close is with that statement.

(Laughter.)

Thank you very much.
(Applause.)