It's been said that World War I was the chemists' war and World War II the physicists' war, but that World War III is destined to be the mathematicians' war.

With the gravest threat to U.S. security now posed by rogue terrorists who simultaneously hold a grudge and have access to weapons of mass destruction, some of this country's prime human calculators are on the case.

Combatting terrorism not with mortars and missiles but with mathematical models, they intend to prove this theorem: There literally is safety in numbers.

In their vanguard is an amiable Stanford University professor who, by devoting himself to the application of math principles to doomsday scenarios, is beginning to acquire the nickname "Dr. Doom." The attacks of Sept. 11 inspired mathematician Lawrence Wein to channel his expertise into some of the most compelling questions of our time.

He has ciphered the risks of our "woefully inadequate" inspection of container ships, assessed the effectiveness of border-control fingerprint checks to spot terrorists, and performed what may well be the first math analyses of hypothetical botulism, anthrax and smallpox contaminations.

Recall the agitation last year over warnings that the nation's milk supply was vulnerable, based on the calculation that one terrorist with a few grams of botulinum could contaminate a tanker and potentially poison 100,000 gallons of milk? That's just one of many tidings of comfort and joy brought to you by Wein.

Another such upper is that just about 6 percent of containers shipped into U.S. ports will be categorized as suspicious and subjected to tests for a nuclear device, based on a system that relies largely on reporting by the shipper. The rest, Wein noted, "just waltz right into the country without an inspector laying an eye on them."

At Stanford's Graduate School of Business, he teaches a core course in operations, and he says the parallels are strikingly similar: Just as McDonald's needs a well-designed distribution system to get its hamburgers out quickly, so the government needs a well-designed distribution system to get vaccines and antibiotics to citizens who might sicken or die from a bioterror attack. In math lingo, some of these computations rest on "queueing theory" -- the notion that a lot of needy people must line up behind a limited number of distributors.

And what do we do after crunching millions of numbers to arrive at specific prescriptions? Wein has taken on the role of necessary nag to a torpid federal bureaucracy and recalcitrant industries.

In fact, the feds scrambled to try to suppress publication of his damning milk study as a threat to national security -- an argument the journal Proceedings of the National Academy of Sciences rejected before publishing the work.

These days, Wein regularly testifies at congressional hearings, addresses scientific forums and pens op-ed pieces in national newspapers about precisely what the government should be doing -- and where it is falling short.

"I believe my work demonstrates that numbers really matter, and we need to pay attention to what they tell us," said Wein, a critic of the federal government's homeland security failures in key areas, particularly at the ports. "I really don't bring my own personal political views into this -- I would be just as critical of the federal bureaucracy if a Democrat were in the White House.

"Bureaucracy just isn't designed to respond nimbly."

On the other hand, politicians are eager to do something, anything, that might thwart a terror attack or save lives. But in an information vacuum, that makes them easy prey for entrepreneurs hawking all kinds of safety gadgets.

So, much of Wein's math analysis goes beyond documenting threats to assess the most effective, cost-efficient remedies.

Take the milk scare, for example. Wein urged the government to mandate that milk tanks and trucks be locked, that two people be present when it is transferred along each part of the supply chain, and that milk truck drivers use a 15 minute test to detect any toxins. The estimated cost of all this: 2 cents per gallon.

Some other experts disputed Wein's assumptions, and dairy industry groups insisted they already had taken extra steps such as raising pasteurization temperatures to secure the milk supply. They dismissed the scenarios Wein described as "highly unlikely or impossible."

To avoid being victimized by a radioactive device aboard a tanker -- otherwise known as a "poor man's missile" -- he and colleague Stephen Flynn of the Council on Foreign Relations advocate using techniques such as gamma-ray imaging to screen 100 percent of containers. They calculate the cost at $7 per container.

Some of Wein's calculations have translated into real reform.

In 2004, he presented to the White House his findings that the system of collecting only two fingerprints from incoming foreign visitors ran a high risk of missing terrorists because so many prints turned out to be of poor quality. His solution was simple: Take prints from all 10 digits. The government adopted it.

His 2003 research into the most effective response to an anthrax attack prompted pilot programs that are now testing his finding that the best way to widely distribute antibiotics would be by mail carriers, who already go door to door.

Albert Einstein once observed: "As far as the laws of mathematics refer to reality, they are not certain; and as far as they are certain, they do not refer to reality."

And sure enough, one of the impediments to fighting terrorists with mathematics is the paucity of hard data.

An anthrax scenario illustrates the point. Estimates of fatalities per kilogram of poisonous agent released vary from a low of zero to a high of 660,000. That's because of variables: the dose required to cause infection, the percentage of people who survive infection, the degree of aerosol dispersion, the density of the population, the environmental stability of the agent and the effectiveness of a public health system response.

As Wein acknowledges, "It's not like we can do massive clinical trials on this."

The trail of what-ifs is so convoluted that in 2002 the National Academy of Sciences cited "an irreducible uncertainly of several orders of magnitude in the number of people who will be infected in an open-air release."

This makes some experts suspicious of anybody's calculations, even from a researcher with a pedigree like Wein's.

"With so much uncertainly surrounding the outcome of a bioweapons attack, it does not make sense to plan extensive biodefense programs when more-certain public threats, particularly those involving nuclear weapons, require attention," argued Allison Macfarlane, research associate in the Science, Technology and Global Security Working Group at MIT.

But Wein is undeterred, and is busy on new assessments. Yet he insists his work has not impaired his ability to sleep soundly.

"People really are much more likely to suffer from cancer than a terrorist attack, but that doesn't merit the same attention," he said. "We should do what makes sense to protect ourselves from both."

The European Forum at the Freeman Spogli Institute for International Studies at Stanford University had an eventful and exciting 2005-06 academic year. We organized almost thirty seminars, workshops and other events on cultural, economic and political issues affecting Europe, its relations with the United States and its role in the world.

We hosted several prominent politicians and diplomats during the academic year. In October John Bruton, European Union Ambassador to the United States and former Prime Minister of Ireland (1994-97), presented his views on Europe and the United States as global partners. Earlier during the Fall we were honored to welcome Latvian Foreign Affairs Minister Artis Pabriks. He gave a lecture on Latvia's current challenges in foreign policy and homeland security.

During the Winter term Estonian President Arnold Rüütel visited Stanford. In his talk he addressed such issues as Estonia's relations with the United States, the European Union and Russia. Andras Simonyi, Hungarian Ambassador to the United States, also visited the European Forum. He presented a fascinating lecture on the political and economic situation in Hungary two years into its EU membership. Three more diplomats gave talks during the Winter Quarter. Kurt Volker, Principal Deputy Assistant Secretary of State for European and Eurasian Affairs, spoke about the United States, Europe and the broader Middle East. Dominic Martin, Counsellor at the British Embassy in Washington, talked about the United Kingdom and its current challenges and opportunities in world politics. Richard Morningstar, former United States Ambassador to the European Union, Lecturer at the Stanford Law School and European Forum Research Affiliate, presented his insights into the cooperation between the United States and the European Union in counter-terrorism. This last seminar was part of a series of events the European Forum organized on the manners in which European countries and institutions are dealing with the threat of terrorism, following the attacks in Madrid and London.

The War on Terror was also among the issues addressed by Joschka Fischer, former German Foreign Minister (1998-2005). He visited the Freeman Spogli Institute for International Studies in April and gave a 2006 Frank E. and Arthur W. Payne Distinguished Lecture for a standing room only crowd at the Bechtel Conference Center at Encina Hall. He talked about Europe's prospects in a globalized world and the future of transatlantic relations. British Ambassador Sir David Manning gave an equally well-attended and equally impressive 2006 Frank E. and Arthur W. Payne Distinguished Lecture on energy as a burning issue in foreign policy.

Other events organized on the topic of counter-terrorism included a round-table discussion on anti-terrorism finance, by Jacob Shapiro, Laura Donohue and Khalid Medani, all affiliated to Stanford University, and a lecture on the French experience of counter-terrorism by Jeremy Shapiro from the Brookings Institution. The series of events culminated with a lecture and a seminar by prolific author and columnist Christopher Hitchens. During a visit to the European Forum in May he presented his fascinating and thought-provoking views on the war on terror, and the situation in Iraq and Iran. The series of events on terrorism is to continue during the next academic year and will culminate with a Thinking Terrorism conference in late 2007.

Furthermore, we organized a number of events on other political issues. German sociologist Heinz Bude, from the University of Kassel, presented his views on the most recent German elections from a broad, societal and historical perspective, paying attention to the 1968 student uprisings and their long-term impact on German society. Christian Deubner, from the CEPII research center in Paris, shared his opinions on current developments in French politics, with a focus on the French rejection of the EU Constitution earlier this year and its impact on France's position in the EU. German author Peter Schneider offered his reflections on the cultural differences between Europe and the United States. He compared the relationship between the two continents to a marriage that has its ups and downs, but endures. Josef Joffe, Editor of the German newspaper Die Zeit, pointed at cultural, demographic, political and economic reasons to argue that the European Union is not about to become a new superpower.

Ken Kollman, from the University of Michigan, presented a political-economic model of leadership in federations and applied it to the EU. Bert Martens, an economist at the EU Commission in Brussels, presented an analysis of the EU's export of political and economic institutions to its neighboring countries, and the incentives it provides for regime change. Markus Hadler, a sociologist at the University of Graz and visiting professor at the European Forum during the past academic year, offered an appraisal of democracy in Europe.

Simon Hug, from the University of Zürich, presented a political-economic model of the negotiations for an EU constitution. Yaron Deckel, from the European Broadcasting Service, talked about the most recent Israeli Elections. Cas Mudde, from the University of Antwerp, presented a talk on immigration and the success of populist parties in the Low Countries. Piet Jan Slot, from Leiden University, gave a seminar on the EU's plans for an internal market for services.

We also organized a number of seminars dealing with various aspects of World War II and its aftermath. There was a talk on the effects of the Europeanization of the holocaust on the attitudes toward Jews, by Werner Bergmann from the Technische Universität Berlin. Monica Siegel, from California State University, Sacramento, gave a presentation on memory and reconciliation in France and Germany. Richard Evans, from Cambridge University, talked about coercion and consent in Nazi Germany. Wolfgang Eichwede, from the University of Bremen, gave a seminar on the dissident movement and Samizdat culture in Eastern Europe. Holocaust survivor Leopold Engleitner and his biographer Bernhard Rammerstorfer talked about surviving Buchenwald as a Jehova's Witness. Martina Pottek, from Bonn University, gave a presentation about artistic concepts to commemorate the holocaust.

Andreas Dorschel, Professor at the University of Graz, and Visiting Austrian Chair Professor at the European Forum during the past academic year, presented a lecture on Bruckner and the 19th century fates of origin.

As the next academic year draws near, we anticipate many more prominent speakers to visit the European Forum. Included in our schedule is the Europe Now lecture featuring Daniel Cohn-Bendit in November 2006.

In 1979, anthrax was accidentally released in the city of Sverdlovsk (pop. 1,200,000) in the former Soviet Union, infecting about 80 to 100 people and killing at least 70. Russian officials claimed at the time that tainted meat sold on the black market was responsible; American officials argued that a nearby biological weapons facility released the killer spores. In the early 1990s, Harvard researchers visited the city to piece together the epidemiology of the outbreak. Their investigation, published in Science magazine in 1994, concluded that the Soviet cover story was false.

Now, physicist Dean A. Wilkening, director of the science program at Stanford's Center for International Security and Cooperation (CISAC), has revisited this Cold War tragedy and used its real-world data to improve our ability to model the medical effects of inhalational anthrax. This, in turn, allows him to model more accurately hypothetical scenarios such as the release of a kilogram of aerosolized anthrax in Washington, D.C., today.

The models researchers have used in such thought experiments "predict very different outcomes," says Wilkening, whose work to better understand the human effects of inhalational anthrax was supported by grants from the John D. and Catherine T. MacArthur Foundation and the Carnegie Corporation. Using real-world data from the Sverdlovsk outbreak and from limited nonhuman primate experiments, he was able to eliminate two of four theoretical models currently used in "what if?" scenarios that inform bioterrorism policies ranging from how much medicine we should have on hand in the Strategic National Stockpile to how rigorous post-attack decontamination efforts need to be. He reports his findings in the May 1 issue of Proceedings of the National Academy of Sciences.

"To date, researchers haven't paid enough attention to which model they use," Wilkening says. "Different models can give predictions that vary by a factor of 10 or more, so it matters which model one uses for predicting the human effects of inhalational anthrax." Wilkening aims to anchor models on the best available data and provide realistic models that the bioterrorism community can employ in policy studies.

The Sverdlovsk outbreak is "a sort of natural experiment," he says. "It's a tragic incident, but it also is a very valuable source of scientific data that one can use to distinguish between the four models currently in use." The upshot of his analysis is that two of the models currently in use are not accurate for predicting the human response to inhalational anthrax.

Insufficient data is available to resolve which of the remaining two models he examined is most accurate. That answer will have to await further data from costly nonhuman primate experiments, should they ever be performed (none are planned). "We have to use both [models] right now, or use them as bounding cases," he advises.

Wilkening explored four policy issues that illustrate the consequences of choosing different models: 1) calculating how many anthrax-exposed people would become infected and how many would die; 2) assessing if decontamination would be needed; 3) determining how soon exposed people would show symptoms and how soon doctors would recognize those symptoms as anthrax; and 4) calculating how soon exposed people need to receive antibiotics to avoid contracting the disease.

"To figure out what happens in a bioterrorist event, you need to know two basic properties about the pathogen you're dealing with," Wilkening says. One is the dose-response curve, which determines the likelihood of becoming infected at different exposure levels--the higher the dose of anthrax you get, the higher the probability that you will become infected. The dose at which 50 percent of an exposed population becomes infected, called the ID50, is around 10,000 spores. The other basic property is the incubation-period distribution, or the time the pathogen takes to grow in the body before symptoms first appear.

Wilkening's study brought dose-dependence to a debate over how long the incubation period is for inhalational anthrax. Published data from vaccine efficacy tests in which nonhuman primates were challenged with high doses of anthrax--up to a million spores--indicate an incubation period of one to five days. Data from Sverdlovsk, which exposed people to low doses probably on the order of 1 to 10 spores, indicate a longer incubation period, about 10 days. Whereas previous authors have debated whether nonhuman primate experiments or the Sverdlovsk data should be used to determine the incubation period for inhalational anthrax in humans, Wilkening demonstrates that both estimates are correct, with the difference between them being due to the dose dependence of the incubation period and the very different doses received in each case.

"If you are exposed to a higher dose, there is a much higher chance that an anthrax spore will germinate quickly, thus leading to a shorter incubation period," he says. "Sverdlovsk was a low-dose exposure event and, consequently, one would expect anthrax spore germination to take a longer time, thus leading to a longer incubation period."

Truth and consequences

Russian officials confiscated the medical records of the Sverdlovsk victims and have so far refused to release details of what happened on April 2, 1979. "It would be nice to know exactly what happened, because that would allow us to model the event more accurately," Wilkening says.

Nevertheless, based on weather and other data from the day of the event, scientists think that around 2 p.m. spores, or dormant cells that revive under the right conditions, were released from a military facility, and the Bacillus anthracis spores spread up to 5 kilometers downwind. People breathed in the spores, which geminated and incubated in the body for between four to 40 days before people began to feel ill or show signs of illness such as sore throat, coughing, pains, aches and runny nose--the same symptoms as flu--that indicated they had entered what doctors call the prodromal phase. Within four days, people passed the point of no return, called the fulminant phase, in which toxins from the bacteria had built up to such an extent that people went into shock and died.

It's impossible to save those who've entered the fulminant phase and difficult to save those who've entered the prodromal phase. But if people can start treatment after exposure but before symptoms appear, there's a good chance that they will survive--a conclusion Wilkening draws from work by colleagues at Stanford's Center for Health Policy. Treatment primarily consists of antibiotics such as ciprofloxacin, doxycycline or penicillin. While a vaccine to prevent anthrax exists, it is not yet available for the general public but would be made available to people exposed to anthrax, according to the Centers for Disease Control and Prevention website.

In his study, Wilkening ruled out two of the four models because they either did not fit the Sverdlovsk data or the nonhuman primate data, or both. "There are two models that people have used that should no longer be used to predict fatalities, models B and C." (The four models used in his analysis are labeled A-D for convenience.)

Using the two remaining models A and D, he predicted that a hypothetical attack releasing 1 kilogram of anthrax spores in Washington, D.C., would infect between 4,000 and 50,000 people, most of whom would die if not treated quickly with antibiotics. The difference of a factor of 10, Wilkening points out, is "an uncertainty with which we must live for the time being until better data can resolve which of the models A or D is more accurate."

Regarding decontamination efforts, the higher the probability of becoming infected at low exposure levels, the greater the need for effective decontamination, especially for indoor environments. Spores "by nature are hardy," Wilkening says. In the soil, out of the way of sunlight, they can last for a decade. "Residual contamination can be a very serious problem in the wake of an attack," Wilkening says. "Unfortunately, both models A and D predict that residual surface contamination from anthrax spores will be a problem. Consequently, we need to come up with effective indoor decontamination strategies."

Analysts such as Professor Lawrence Wein of the Graduate School of Business are considering the issue. Last year, he assessed decontamination and concluded cleaning buildings to make them safe to reoccupy was a billion-dollar proposition.

In addition, the four models make very different predictions about when symptoms would occur. The day after exposure, they predict between 10 and 1,000 people feeling sick, with more people getting sick in the viable versus discredited models.

"In terms of detecting the outbreak rapidly, this is a good thing because it says that doctors could recognize it [sooner]," Wilkening says.

In terms of treating people before they reach the prodromal phase, however, this is a bad thing because people become sick quicker. Wilkening's analysis may help policymakers reassess how fast antibiotics need to reach people. His best model says administering antibiotics by day three saves 90 percent of exposed people. "Today we cannot meet the three-day requirement," he warns.