Early Infectious Disease Diagnosis Using Genomics
A key pillar and unmet need in the defense against threats to health is the ability to recognize the etiological factor(s) and predict the course of disease, at early points in the timeline of the process. This ability would enable early intervention in the disease process when there is the greatest likelihood of benefit, as well as triaging of hosts, based on individual need. Genomic tools and approaches have enabled a more detailed description of host-microbe encounters, and shed light on fundamentally important processes, including the cellular responses associated with infection. Genome-wide transcript-abundance profiles, like other comprehensive molecular readouts of host physiological state, provide a detailed blueprint of the host-pathogen dialogue during microbial disease. Studies of cancer based on genome-wide transcript-abundance profiles have led to novel signatures that predict disease outcome and serve as useful clinical classifiers. The highly dynamic and compartmentalized aspects of the host response to pathogens complicate efforts to identify predictive signatures for infectious diseases. Yet, studies of systemic infectious diseases so far suggest the possibility of successfully discriminating between different types (classes) of infection and predicting clinical outcome. In addition, host gene expression analysis could lead to the identification of early signatures associated with a protective immune response, both to natural infection and to vaccination. Early explorations in some of these areas indicate the potential feasibility of this approach but also point to important unmet challenges.
David Relman is associate professor of medicine, and of microbiology and immunology at Stanford University. He is also chief, infectious diseases section, at the VA Palo Alto Health Care System in Palo Alto, California.
A native of Boston, Massachusetts, Relman holds an SB degree from the Massachusetts Institute of Technology and received his MD degree, magna cum laude, from Harvard Medical School in 1982. Following postdoctoral clinical training at Massachusetts General Hospital in internal medicine and in infectious diseases, Relman served as a postdoctoral research fellow in microbiology at Stanford University in the laboratory of Stanley Falkow from 1986 until 1992. He joined the Stanford University faculty in 1992 and was appointed associate professor (with tenure) in 2001. His research is directed towards the characterization of the human indigenous microbial communities of the mouth and gut, with emphasis on understanding variation in diversity, succession, the effects of disturbance, and the role of these communities in oral and intestinal disease.
Experimental approaches include molecular phylogenetics, ecological statistics, single cell genomics, and community-wide metagenomics. A second area of research concerns the classification structure of humans and non-human primates with systemic infectious diseases, based on patterns of genome-wide gene transcript abundance in blood and other tissues. The goals of this work are to recognize classes of pathogen and predict clinical outcome at early time points in the disease process, as well as gain further insights into virulence (e.g., of variola and monkeypox viruses). Past achievements include the description of a novel approach for identifying previously-unknown pathogens (selected as one of the 50 most important papers of the last century by the American Society for Microbiology), the identification of a number of new human microbial pathogens, including the agent of Whipple's disease, and the most extensive descriptions to date of the human indigenous microbial community. See http://relman.stanford.edu. Relman received the Squibb Award from the Infectious Diseases Society of America (2001), the Senior Scholar Award in Global Infectious Diseases from the Ellison Medical Foundation (2002), and is a recipient of an NIH Director's Pioneer Award (2006). He is a member of the American Society for Clinical Investigation and was named a Fellow of the American Academy of Microbiology in 2003.
Relman currently serves on the Board of Scientific Counselors of the National Institute of Dental and Craniofacial Research and was a member of the Board of Directors of the Infectious Diseases Society of America (2003-2006), and co-chair of the National Academy of Sciences' Committee on Advances in Technology and the Prevention of Their Application to Next Generation Biowarfare (2004-2006). He is a member of the National Science Advisory Board for Biosecurity, the Institute of Medicine's Forum on Microbial Threats, and advises several U.S. Government departments and agencies on matters related to microbial pathogen detection and future biological threats.
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Roundtable Forum - Anxious Times: Seeing Beyond a World of Perpetual Threats
Timely reunion panel hosted by Stanford president John Hennessy, moderated by Stanford alum Ted Koppel, and featuring Bill Perry and George Shultz.
The final decade of the 20th century was a time of great optimism. The fall of the Iron Curtain ushered in a new era of democracy and freedom for millions. The expansion of the European Union promised to open borders to trade and opportunity. The technology revolutions of the 1990s promised to bridge cultural gaps and unite diverse people.
Yet, in the first decade of the 21st century, this optimism has faded in the face of myriad threats: the menace of terrorism and nuclear proliferation, the danger of virulent pandemics, the global dependence on oil from volatile regions, and the far-reaching and often unsettling implications of an interconnected planet.
In such uneasy times, is it safe to feel safe? What is the way forward in the midst of these challenges? What will it take? What is Stanford doing to help address these issues?
Panelists
John L. Hennessy, Stanford President and Bing Presidential Professor
Jean-Pierre Garnier, MBA '74, CEO, GlaxoSmithKline
The Hon. Anthony M. Kennedy, '58, Supreme Court Justice
William J. Perry, '49, MS '50, former Secretary of Defense, Berberian Professor in the School of Engineering
Dr. Lucy Shapiro, Ludwig Professor of developmental biology and cancer researcher
George P. Shultz, former Secretary of State, Ford Distinguished Fellow, Hoover Institution
Jerry Yang, '90, MS '90, co-founder, Yahoo!
Cancer Risk Following Exposure to Low Level Radiation
For the past five years, the Committee on the Biological Effects of Ionizing Radiation (BEIR VII) of the National Academy of Science has reviewed and analyzed the health risks from exposure to low levels of radiation (X-rays and gamma rays.) This re-assessment followed a period of rich accumulation of biologic and epidemiologic data from 1990 on, the year of the last previous study (BEIR V.)
The scientific evidence showed that even low doses of radiation may pose a risk of cancer, and that there was no threshold below which exposure may be viewed as harmless. Lifetime excess risks were determined for 12 relatively common cancers. While the over-all risk of cancer at low radiation levels is small, the mortality in women is higher than in men, and infants are at greater risk than adults. The presentation will review the conclusions of the 700-page report.
Herbert L. Abrams, M.D., Professor Emeritus of Radiology at Stanford, was formerly Philip H. Cook Professor and Chairman of Radiology at Harvard, and has been a CISAC Member-in-Residence since 1985. He served as one of the two physicians on the BEIR VII committee, the other members, representing radiation biology, cancer biology, physics, epidemiology and genetics. The 1st edition of his three volume work, Abrams Angiography: Vascular and Interventional Radiology, was published in 1961, the fifth edition in 2005. He is the author or co-author of six other books on Congenital Heart Disease, Coronary Arteriography, Diagnostic Decision Making, Diagnostic Technology Assessment, and Presidential Disability and of over 200 refereed papers on cardiovascular disease, health policy, disabled leadership, human instability in the nuclear forces, and inadvertent nuclear war. A member of the Institute of Medicine of the National Academy of Sciences, he was also the founding Vice-President of International Physicians for the Prevention of Nuclear War (IPPNW), recipient of the 1985 Nobel Peace Prize.
Reuben W. Hills Conference Room
Censoring Science Won't Make Us Any Safer
In 1920, the Irish Republican Army reportedly considered a terrifying new weapon: typhoid-contaminated milk. Reading from an IRA memo he claimed had been captured in a recent raid, Sir Hamar Greenwood described to Parliament the ease with which "fresh and virulent cultures" could be obtained and introduced into milk served to British soldiers. Although the plot would only target the military, the memo expressed concern that the disease might spread to the general population.
Although the IRA never used this weapon, the incident illustrates that poisoning a nation's milk supply with biological agents hardly ranks as a new concept. Yet just two weeks ago, the National Academy of Sciences' journal suspended publication of an article analyzing the vulnerability of the U.S. milk supply to botulinum toxin, because the Department of Health and Human Services warned that information in the article provided a "road map for terrorists."
That approach may sound reasonable, but the effort to suppress scientific information reflects a dangerously outdated attitude. Today, information relating to microbiology is widely and instantly available, from the Internet to high school textbooks to doctoral theses. Our best defense against those who would use it as a weapon is to ensure that our own scientists have better information. That means encouraging publication.
The article in question, written by Stanford University professor Lawrence Wein and graduate student Yifan Liu, describes a theoretical terrorist who obtains a few grams of botulinum toxin on the black market and pours it into an unlocked milk tank. Transferred to giant dairy silos, the toxin contaminates a much larger supply. Because even a millionth of a gram may be enough to kill an adult, hundreds of thousands of people die. (Wein summarized the article in an op-ed he wrote for the New York Times.) The scenario is frightening, and it is meant to be -- the authors want the dairy industry and its federal regulators to take defensive action.
The national academy's suspension of the article reflects an increasing concern that publication of sensitive data can provide terrorists with a how-to manual, but it also brings to the fore an increasing anxiety in the scientific community that curbing the dissemination of research may impair our ability to counter biological threats. This dilemma reached national prominence in fall 2001, when 9/11 and the anthrax mailings drew attention to another controversial article. This one came from a team of Australian scientists.
Approximately every four years, Australia suffers a mouse infestation. In 1998, scientists in Canberra began examining the feasibility of using a highly contagious disease, mousepox, to alter the rodents' ability to reproduce. Their experiments yielded surprising results. Researchers working with mice naturally resistant to the disease found that combining a gene from the rodent's immune system (interleukin-4) with the pox virus and inserting the pathogen into the animals killed them -- all of them. Plus 60 percent of the mice not naturally resistant who had been vaccinated against mousepox.
In February 2001 the American SocietyforMicrobiologists' (ASM) Journal of Virology reported the findings. Alarm ensued. The mousepox virus is closely related to smallpox -- one of the most dangerous pathogens known to humans. And the rudimentary nature of the experiment demonstrated how even basic, inexpensive microbiology can yield devastating results.
When the anthrax attacks burst into the news seven months later, the mousepox case became a lightning rod for deep-seated fears about biological weapons. The Economist reported rumors about the White House pressuring American microbiology journals to restrict publication of similar pieces. Samuel Kaplan, chair of the ASM publications board, convened a meeting of the editors in chief of the ASM's nine primary journals and two review journals. Hoping to head off government censorship, the organization -- while affirming its earlier decision -- ordered its peer reviewers to take national security and the society's code of ethics into account.
Not only publications came under pressure, but research itself. In spring 2002 the newly formed Department of Homeland Security developed an information-security policy to prevent certain foreign nationals from gaining access to a range of experimental data. New federal regulations required that particular universities and laboratories submit to unannounced inspections, register their supplies and obtain security clearances. Legislation required that all genetic engineering experiments be cleared by the government.
On the mousepox front, however, important developments were transpiring. Because the Australian research had entered the public domain, scientists around the world began working on the problem. In November 2003, St. Louis University announced an effective medical defense against a pathogen similar to -- but even more deadly than -- the one created in Australia. This result would undoubtedly not have been achieved, or at least not as quickly, without the attention drawn by the ASM article.
The dissemination of nuclear technology presents an obvious comparison. The 1946 Atomic Energy Act classifies nuclear information "from birth." Strong arguments can be made in favor of such restrictions: The science involved in the construction of the bomb was complex and its application primarily limited to weapons. A short-term monopoly was possible. Secrecy bought the United States time to establish an international nonproliferation regime. And little public good would have been achieved by making the information widely available.
Biological information and the issues surrounding it are different. It is not possible to establish even a limited monopoly over microbiology. The field is too fundamental to the improvement of global public health, and too central to the development of important industries such as pharmaceuticals and plastics, to be isolated. Moreover, the list of diseases that pose a threat ranges from high-end bugs, like smallpox, to common viruses, such as influenza. Where does one draw the line for national security?
Experience suggests that the government errs on the side of caution. In 1951, the Invention Secrecy Act gave the government the authority to suppress any design it deemed detrimental to national defense. Certain areas of research-- atomic energy and cryptography -- consistently fell within its purview. But the state also placed secrecy orders on aspects of cold fusion, space technology, radar missile systems, citizens band radio voice scramblers, optical engineering and vacuum technology. Such caution, in the microbiology realm, may yield devastating results. It is not in the national interest to stunt research into biological threats.
In fact, the more likely menace comes from naturally occurring diseases. In 1918 a natural outbreak of the flu infected one-fifth of the world's population and 25 percent of the United States'. Within two years it killed more than 650,000 Americans, resulting in a 10-year drop in average lifespan. Despite constant research into emerging strains, the American Lung Association estimates that the flu and related complications kill 36,000 Americans each year. Another 5,000 die annually from food-borne pathogens -- an extraordinarily large number of which have no known cure. The science involved in responding to these diseases is incremental, meaning that small steps taken by individual laboratories around the world need to be shared for larger progress to be made.
The idea that scientific freedom strengthens national security is not new. In the early 1980s, a joint Panel on Scientific Communication and National Security concluded security by secrecywasuntenable. Its report called instead for security by accomplishment -- ensuring strength through advancing research. Ironically, one of the three major institutions participating was the National Academy of Sciences -- the body that suspended publication of the milk article earlier this month.
The government has a vested interest in creating a public conversation about ways in which our society is vulnerable to attack. Citizens are entitled to know when their milk, their water, their bridges, their hospitals lack security precautions. If discussion of these issues is censored, the state and private industry come under less pressure to alter behavior; indeed, powerful private interests may actively lobby against having to install expensive protections. And failure to act may be deadly.
Terrorists will obtain knowledge. Our best option is to blunt their efforts to exploit it. That means developing, producing and stockpiling effective vaccines. It means funding research into biosensors -- devices that detect the presence of toxic substances in the environment -- and creating more effective reporting requirements for early identification of disease outbreaks. And it means strengthening our public health system.
For better or worse, the cat is out of the bag -- something brought home to me last weekend when I visited the Tech Museum of Innovation in San Jose. One hands-on exhibit allowed children to transfer genetic material from one species to another. I watched a 4-year-old girl take a red test tube whose contents included a gene that makes certain jellyfish glow green. Using a pipette, she transferred the material to a blue test tube containing bacteria. She cooled the solution, then heated it, allowing the gene to enter the bacteria. Following instructions on a touch-screen computer, she transferred the contents to a petri dish, wrote her name on the bottom, and placed the dish in an incubator. The next day, she could log on to a Web site to view her experiment, and see her bacteria glowing a genetically modified green.
In other words, the pre-kindergartener (with a great deal of help from the museum) had conducted an experiment that echoed the Australian mousepox study. Obviously, this is not something the child could do in her basement. But just as obviously, the state of public knowledge is long past anyone's ability to censor it.
Allowing potentially harmful information to enter the public domain flies in the face of our traditional way of thinking about national security threats. But we have entered a new world. Keeping scientists from sharing information damages our ability to respond to terrorism and to natural disease, which is more likely and just as devastating. Our best hope to head off both threats may well be to stay one step ahead.
Effective Policies to Control BSE (Mad Cow Disease)
Cellular prion protein (PrPC) is present in the healthy adult brain. It is a presumably essential membrane protein but its cellular function is unclear. Like Ice-9 - the fictitious water allotrope in Kurt Vonnegut's Cat's Cradle, which "taught the atoms a novel way in which to stack, lock and crystallize until the oceans turned to ice" - cellular prion protein can, in a rare event, adopt a pathogenic and 'contagious' shape, PrPSc, which causes mad cow disease or Bovine Spongiform Encephalopathy (BSE). New variant Creutzfeldt Jakob Disease (vCJD) is the human malady attributed to eating beef tainted with BSE. In comparison to the UK epidemic (at the peak of which 37,280 cases of BSE were reported in the single year 1992), the emergence of four North American mad cows since May 2003 is minor yet still alarming. This work examines the USDA's response to indigenous BSE as manifested in "The Final Rule" (9 CFR 93-96, Jan 4, 2005) and questions whether current regulations are stringent enough to keep PrPSc out of cattle feed and human food.
Sheila Healy is a CISAC Science Fellow. She is currently analyzing USDA policy addressing Bovine Spongiform Encephalopathy (BSE) or mad cow disease. She recently finished a postdoctoral appointment in Stanley Prusiner's laboratory in the Department of Neurology at the University of California, San Francisco. There she studied the molecular and structural requirements for the conversion of cellular prion protein to its pathogenic form, the agent that causes BSE. She holds a doctoral degree in biochemistry and molecular and cellular biology from the University of Arizona.
Reuben W. Hills Conference Room, East 207, Encina Hall
More Secure World: Our Shared Responsibility, A
United Nations Secretary-General Kofi Annan created the High-Level Panel on Threats, Challenges, and Change in September 2003 with SIIS and CISAC senior fellow Stephen J. Stedman as its research director to identify the major global threats and generate new ideas about policies and institutions to enable the U.N. to be effective in the 21st century.
The panel issued a four-part report, A More Secure World: Our Shared Responsibility, in December 2004.
PART ONE: The panel identifies six types of threats of greatest global concern: war between states; violence within states; poverty, infectious disease, and environmental degradation; nuclear, chemical, biological, and radiological weapons; terrorism; and transnational crime. A collective security system must take all member states' threats seriously and deal with them equitably.
PART TWO: In prescribing policies to prevent threats from spreading or worsening, the report emphasizes development as the first line of defense. Combating poverty and infectious disease, the panel argues, will save millions of lives and strengthen states' capacity to deter terrorism, crime, and proliferation of nuclear and biological weapons. The report also urges the U.N. to improve its capacity for preventive diplomacy and mediation and to forge a counterterrorism strategy.
PART THREE: The report reiterates the U.N.'s recognition of states' right to self-defense, but also suggests that the Security Council should consider stepping in more often to exercise its preventive authority. Peacekeeping, peace enforcement, and peace building are vital to global security, and developed nations should do more to transform their armies into units suitable for peace operations. Post-conflict peace building should be a core function of the U.N.
PART FOUR: The report prescribes revitalization of the Security Council and the General Assembly, and creation of a new Peacebuilding Commission. On the Security Council, the report provides two options for achieving reforms: one would appoint new permanent members, and the other would establish new long-term, renewable seats. Neither option creates any new vetoes.
Biotechnology and Bioterrorism: An Unprecedented World
The web of measures that comprise the nuclear non-proliferation regime continues to hold at bay the "nuclear-armed crowd" that was part of President John F. Kennedy's alarming vision in 1963. The number of nuclear weapons states in 2004 stands at only eight or nine, and assertive steps may yet keep this number from growing. The proliferation of biological weapons, however, is quite another matter. Biotechnological capacity is increasing and spreading rapidly. This trend seems unstoppable, since the economic, medical, and food-security benefits of genetic manipulation appear so great. As a consequence, thresholds for the artificial enhancement or creation of dangerous pathogens--disease-causing organisms--will steadily drop. Neither Cold War bilateral arms control nor multilateral non-proliferation provide good models for how we are to manage this new challenge. Much more than in the nuclear case, civilization will have to cope with, rather than shape, its biological future.
Biological Security in a Changed World
The horrifying events of 11 September 2001 serve notice that civilization will confront severe challenges in the twenty-first century. As national security budgets expand in response, we should recognize that only a broad conception of security will be adequate to meet some of the threats that we may face. Biological security provides a powerful example. It must address both the challenge of biological weapons and that of infectious disease. The right approach should benefit public health even if major acts of biological terrorism never occur. Our thinking about biological security must transcend old misplaced analogies to nuclear and chemical security.
Nuclear security has been based on nonproliferation, deterrence, and defense, with intelligence woven throughout. Nonproliferation seeks to prevent the diversion of materials from civilian programs to military or terrorist weapons. Should nonproliferation fail, the United States relies on deterrence through the threat of retaliation. Defense, active or civil, has so far been less central.
Effective biological security requires a different mix. For all its challenges, nuclear nonproliferation is comparatively robust, in part because the production of weapons-usable uranium or plutonium provides a conspicuous bottleneck through which any nuclear program must pass, unless those materials are stolen. This is why preventing nuclear theft is such a high priority in the post-Cold War world. Biological agents
are easier to acquire. Most can be found in naturally occurring outbreaks. Weaponizing these agents has proved challenging for terrorist groups, but the Aum Shinrikyo's unsuccessful efforts to spray the anthrax organism throughout Tokyo in 1993 warned that attempted mass urban attacks were no longer in the realm of the fantastic.
The transfer of dangerous biological agents should be controlled where possible, and the spread of the technologies and personnel to weaponize them should be impeded. But any biological nonproliferation regime will necessarily be less robust than its nuclear counterpart, because the relevant materials, technologies, and knowledge are far more widespread.
Biological terrorism also challenges requirements for successful deterrence. Because some diseases incubate for a week or more, identifying the perpetrators of an attack may prove difficult. A terrorist group might even hope that its attack would go unrecognized; when followers of the Bhagwan Shree Rajneesh infected 750 Oregonians with salmonella in 1984, it took over a year before the infection was determined to have been intentional. Finally, as with any form of terrorism, some groups may simply be unconcerned about retaliation.
In the face of these difficulties, good intelligence is all the more important. Warning and prevention are preferable to coping with the consequences of an attack, but we must also be ready should an attack occur. This requires that greater emphasis be placed on improving public health, a kind of homeland defense that is applicable to both unintentional and intentional disease outbreaks.
Because of disease incubation times, the first responders to a biological attack may well be health-care workers at hospitals and clinics rather than specialized units. The speed and effectiveness of a response will depend on disease surveillance: the recognition by health-care workers that certain illnesses appear unusual and the rapid notification of the proper authorities. Because incubation times often exceed international travel times, both domestic and international components are required. But the domestic component of disease surveillance in most nations, including the United States, is too weak, and international networks are inadequate. Donor nations need to increase support for these efforts. And there are many other needs, such as developing and stockpiling sufficient vaccines, antibiotics, or antivirals and otherwise preparing to meet the enormous challenges that would be posed by a major outbreak. It is time to quicken the pace of these efforts, to which departments of health are as central as departments of defense.
Disease surveillance and response are not nonproliferation measures, so cannot substitute for an effective verification regime under the Biological Weapons Convention. But biological security requires the developed world, especially the United States, to see that its ongoing self-interest is closely allied with sustainable public-health improvements in the developing world. And the explosion of biotechnology, with the weapons implications that follow from it, requires the scientific community to discuss its responsibilities in earnest.