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Article

Emerging and Reemerging InfectiousDiseases: The Perpetual ChallengeAnthony S. Fauci, MD

Abstract

Public health officials once suggested

that it might someday be possible toclose the book on the study and

treatment of infectious diseases.

However, it is now clear that endemicdiseases as well as newly emerging ones

(e.g., severe acute respiratory syndrome

[SARS]), reemerging ones (e.g., West Nile

virus), and even deliberately disseminated

infectious diseases (e.g., anthrax frombioterrorism) continue to pose a

substantial threat throughout the world.

Over the past several decades, the global

effort to identify and characterize

infectious agents, decipher the underlyingpathways by which they cause disease, and

develop preventive measures and

treatments for many of the worlds most

dangerous pathogens has helped control

many endemic diseases.

But despite considerable progress,

infectious diseases continue to present

significant challenges as new microbial

threats emerge and reemerge. HIV/AIDS,

malaria, tuberculosis, influenza, SARS,

West Nile virus, Marburg virus, and

bioterrorism are examples of some of the

emerging and reemerging threats. In

responding to these ongoing challenges,

a new paradigm in countermeasuredevelopment is needed. In the past, U.S.

government-sponsored biomedical

researchers have focused on basic

research and concept development,

leaving product development to the

pharmaceutical industry. Increasingly,

however, the government has become

involved in more targeted

countermeasure development efforts. In

this regard, partnerships between

government, industry, and academia are

necessary as we struggle to maintain and

update our armamentarium in the

struggle to outwit the microbes that

pose a never-ending threat to mankind.

Acad Med. 2005; 80:10791085.

In 1963, the respected physician andanthropologist T. Aidan Cockburn, in abook called The Evolution and Eradicationof Infectious Diseases, made thisstatement:

We can look forward with confidence to aconsiderable degree of freedom frominfectious diseases at a time not too far in

the future. Indeed . . . it seems reasonableto anticipate that within some measurabletime . . . all the major infections will havedisappeared.1

Five years later, the U.S. Surgeon Generalnoted that it might be possible withinterventions such as antimicrobials andvaccines to close the book on infectiousdiseases and shift public health resourcesto chronic diseases.2

At the time, I was just finishing mymedical residency at the New York

HospitalCornell Medical Center andwas on my way to the National Institutesof Health to begin, of all things, afellowship in infectious diseases. You canimagine how I felt after several years ofinternal medicine residency preparingmyself for a subspecialty in which publichealth leaders were telling me indirectly

that I was wasting my time because therewas little left to do.

However, even public health leaders canmake mistakes. At about that time therewere scattered reports about a veryinteresting wasting disease amongAfricans that was noticed by missionaries.We now realize that these were theearliest cases of a newly emerginginfectious disease: HIV/AIDS. Today,HIV/AIDS and other infectious diseasescontinue to pose a substantial threatthroughout the world.

According to the World HealthOrganizations 2004 World Health Report,infectious diseases accounted for about26% of the 57 million deaths worldwidein 2002.3 Collectively, infectious diseasesare the second leading cause of deathglobally (following cardiovasculardisease), but among young people (thoseunder the age of 50) infections areoverwhelmingly the leading cause ofdeath. In addition, infectious diseasesaccount for nearly 30% of all disability-

adjusted life years (DALYs), which reflectthe number of healthy years lost toillness.3

Among the infectious diseasesthroughout the world, the baselinematrix of infectious diseases constitutesan ongoing threat. Other diseases that

occur intermittently, some as little blipson the radar screen and some as majorpublic health issues. At some point intime, the matrix diseases have all beenemerging diseases. But after a while theybecome so entrenched that they areconsidered part of the background matrixand not emerging or reemerging diseases.So as we eradicate diseases such as polioand smallpox, something else emergesand takes their place. This is the nature ofthe perpetual challenge of infectiousdiseases, as stated in this articles title.

I now would like to discuss some of thelessons we have learned as we combatinfectious diseases and how the nextgeneration of physicians and researchersmight build on our experience as theyface the challenge of outwitting themicrobes that will continue to plaguemankind.

What do I mean by a newly emergingdisease? A newly emerging disease is adisease that has never been recognizedbefore. HIV/AIDS is a newly emerging

Dr. Fauci is director, National Institute of Allergyand Infectious Diseases, National Institutes of Health,Department of Health and Human Services,Bethesda, Maryland.

This article is based on the 2005 Robert H. EbertMemorial Lecture, delivered by the author on April 9,2005, at the spring meeting of the Association ofAmerican Medical Colleges Council of Deans, SantaFe, New Mexico.

Correspondence should be addressed to Dr. Fauci,NIAID/National Institutes of Health, Bldg 31, Room7A03, MSC 2520, 9000 Rockville Pike, Bethesda,MD 20892-2520; e-mail: [email protected].

Academic Medicine, Vol. 80, No. 12 / December 2005 1079


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disease, as is severe acute respiratorysyndrome (SARS), Nipah virusencephalitis, and variant Creutzfeld-Jakob disease (see Figure 1). Reemerging,or resurging, diseases are those that havebeen around for decades or centuries, buthave come back in a different form or adifferent location. Examples are WestNile virus in the Western hemisphere,

monkeypox in the United States, anddengue rebounding in Brazil and otherparts of South America and working itsway into the Caribbean. Deliberatelyemerging diseases are those that areintentionally introduced. These areagents of bioterror, the most recent andimportant example of which is anthrax.Newly emerging, reemerging, anddeliberately emerging diseases are alltreated much the same way from a publichealth and scientific standpoint.4

Multiple factors, including economicdevelopment and land use, humandemographics and behavior, andinternational travel and commerce,contribute to the emergence andreemergence of infectious diseases.5

Almost all of these factors reflect in somemeasure the encroachment of humancivilization on the environment and onthe microbial species that inhabit ourenvironment. The human species lives ina delicate balance with microbial species;there is an ever-present tension betweenthe two. If we perturb this balance,

microbes almost always figure out a wayto counterbalance the effect. Lymedisease emerged as we developed landnear forests; changes in social structureand human behavior contributed to the

emergence of HIV/AIDS; andmonkeypox emerged in the United Stateswhen people started adopting exotic petssuch as Gambian rats.

Approximately 75% of emergingpathogens are zoonotic,6 that is,communicated by animals to humans.When humans encroach upon a

rainforest they become exposed to virusesand other microbes that they otherwisewould not have encountered. HIV/AIDS,avian influenza, monkeypox, Nipah,SARS, and Ebola are all the result, to agreater or lesser extent, of interactionswith animals that led to the emergenceand reemergence of deadly diseases.

Two fundamental characteristics ofmicrobes allow them to circumvent ourattempts to control them. Whereashuman generations occur approximatelyevery two decades, those of microbes can

occur in minutes, allowing them torapidly replicate. Microbes also canmutate with each replication cycle. Theirability to replicate and mutate gives themthe ability to circumvent humaninterventions, be they antimicrobials,vaccines, or public health measures.

In our battle with microbes, we have anumber of weapons in ourarmamentarium. First of all, we have anintellect and a will. We use these toimplement public health measures,biomedical research, and technological

advances. In essence, the human speciesuses its intellect and will to contain, or atleast strike a balance with, microbialspecies that rely on genes, replication,and mutation.

Basic Research

Fundamental research underlies almosteverything we do in studying andresponding to infectious diseases. Fromunderstanding pathogenesis, virulencefactors, patterns of transmission, andhost susceptibility, to developing newtechnologies and countermeasures suchas vaccines, therapeutics, and diagnostics,

basic research is an essential componentof the enterprise.

In particular, advances in genomics andproteomics have helped us betterunderstand mechanisms of pathogenesis,host immunity, and drug resistance andare helping us identify new drug targetsand develop new vaccines anddiagnostics. Progress in syntheticchemistry, robotics, and computermodeling are leading to advances in drugdesign, high-throughput screening,

and predictive models of diseasetransmission. Developments in molecularand genetic epidemiology are helpingus understand pathogen virulence,transmission patterns, and hostsusceptibility. This is particularlyimportant in HIV/AIDS and avianinfluenza, because we can trace theevolution of different viral subtypesacross continents. Finally, informationtechnology makes an importantcontribution to all aspects of basic andapplied research.7

Genomics and proteomics have played apivotal role in basic research in infectiousdiseases. Today, an unknown microbecan often be identified and sequencedwithin days.8 This rapid sequencingcapability helps to illuminate virulencefactors and pathogenic mechanisms, aswell as immune-evasion factors,receptors, and the immunodominantantigens to develop vaccines. The abilityto sequence and annotate microbes nowhas taken its place at the forefront of howwe deal with emerging and reemerginginfections. I would like to now examine afew of these diseases.

Important Emerging andReemerging Diseases

HIV/AIDS

HIV/AIDS was first described in thescientific literature in June 1981.9,10

Because the AIDS pandemic is now morethan 20 years old, it will soon beconsidered one of the fundamental

Figure 1 Examples of emerging and reemerging infectious diseases throughout the world.

Adapted from Morens DM et al.4

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matrix diseases. However, in 1981, it wastruly an emerging disease. As illustratedin Figure 2, nearly 40 million peoplethroughout the world are currentlyinfected with HIV, two thirds of whomlive in sub-Saharan Africa.11 In 2004,three million people died from AIDS andnearly five million adults and childrenbecame infected with HIV; 90% of new

infections occur in the developingworld.11

When HIV/AIDS first emerged, therewere many misunderstandings. Initiallywe measured the time from infection todisease manifestations in months or veryfew years. It now appears that withouttherapy there is a median ten-year timeperiod before advanced HIV disease orAIDS develops. So those patients whowere first identified in 1981 had likelybeen infected with HIV for many years

before developing symptoms of theadvanced disease.

Despite the current concentration ofdisease burden in sub-Saharan Africa,Asia likely will be the next epicenter ofthis disease. Currently about five millionpeople in India are infected with HIV,but that is less than 1% of the adultpopulation. In Botswana, 37% of theadult population is infected, but thepopulation is only 1.6 million.12,13 If theprevalence rate in India, which has a totalpopulation of more than one billion,

were to approach what we are seeing inAfrica, the impact would be enormous.

In our own country, we have becomesomewhat numbed to the HIV/AIDS

pandemic. I gave a lecture recently tosome students at a college in Washington,DC, and realized that almost no one elsein the room had been born when HIVemerged. To them, HIV/AIDS has justbecome part of the landscape. In theUnited States, cumulatively, we have hadalmost one million AIDS diagnoses and525,000 deaths. About one million people

living with HIV infection, half of whomare untested, untreated, or both.14 Thereally sobering issue about HIV/AIDS inthe United States is the 40,000 newinfections that occur each year. In themid-1980s, the number of new infectionseach year peaked at 150,000, thenthrough prevention efforts fell to aplateau of about 40,000, which is still anunacceptable level.15 The demographicsof new HIV infections have changed. Onepercent of new infections occurred inwomen in the early 1980s, but today

more than a quarter of new infections areamong women. Half of all new infectionstoday occur in people under the age of25, and the rates of infection aresignificantly higher among minorities,particularly African Americans andHispanics.14

Despite these challenges, much has beenaccomplished in the fight against HIV/AIDS. One of the great triumphs of ourinvestment in basic biomedical researchis the development of potentantiretroviral drugs that have prolonged

and improved the lives of HIV-infectedindividuals. The AIDS research modelserves as a valid paradigm forapproaching other diseases of globalimportance. When adequate resources

are invested in attacking a problem, youget results, as evidenced by the list ofmore than 20 drugs that have beenapproved by the Food and DrugAdministration for the treatment of HIV/AIDS. As shown in Figure 3, we have seena dramatic decline in AIDS deaths in theUnited States since the mid 1990s, whencombination antiretroviral therapy

(ART) was introduced. However, asfewer people die and a consistent 40,000people become infected each year, thenumber of people living with AIDScontinues to increase.

AIDS patients in other countries have notfared as well. Of the estimated 6.5 millionlow- and middle-income people in othercountries who need treatment, most ofwhom live in sub-Saharan Africa, only15% are receiving antiretroviral drugs.16

However, we are making some progress.Two or three years ago, only 1% of thosein need in developing countries weretreated. We progressed from treating5,000 to 10,000 patients to treating970,000 globally as a result of a veryaggressive effort by the Global Fund toFight AIDS, Tuberculosis and Malariaand the Presidents Emergency Plan forAIDS Relief (PEPFAR).16 The presidentsprogram, which aims to prevent sevenmillion infections, treat two millionpeople, and care for ten million patients,is on target. As of March 31, 2005,235,000 people in 15 countries, more

than half of them women, were receivingART through PEPFAR. However, it isimportant to realize that these peopleneed to be treated for life. Unless we slowthe rate of new HIV infections, continuedtreatment of significant numbers of AIDSpatients throughout the world will not befeasible, neither logisitically norfinancially. This brings us to the issue ofHIV prevention.

We often lose sight of the fact that HIV/AIDS is a totally preventable disease.There are multiple modalities ofprevention, and some of them work verywell. The various strategies, includingeducation, behavior modification,treatment of drug users, distribution ofcondoms, clean syringes, needle exchangeprograms, topical microbicides,antiretroviral therapy, and abstinence canprevent HIV/AIDS, but all of theseapproaches must be pursuedconcomitantly.

In a perfect world, we would not need anHIV/AIDS vaccine, but we do not live in

Figure 2 Global geographic distribution of people living with HIV/AIDS, December 2004. Source:

UNAIDS 2004 AIDS Epidemic Update, December 2004.11

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a perfect world and people continue toput themselves and others at risk. Hence,a vaccine is needed. The scientificchallenge of developing an effective HIV

vaccine is formidable. For every othermajor infectious diseaseeven the greatkillers and maimers such as smallpox,polio, and measlesthe body handles theinvading microbes the vast majority ofthe time without a vaccine. Historically,only 25% to 30% of people infected withthe smallpox virus died; 70% to 75% ofthose infected recover spontaneously.17,18

Similarly, more than 98% of peopleinfected with poliovirus never experienceserious complications.19,20 The reason isthat the body has the capability of

ultimately mounting an effective immuneresponse, generally an antibody response,to eliminate the microbe.

No such luck with HIV. Of the more than60 million people who have been infectedwith HIV since the beginning of theepidemic, there is not a single well-documented case of someone who hascompletely cleared the virus after havinghad an established infection.15

Lymphocyte cultures from people whoare doing very well clinically still yield thevirus. Even for people on drug therapy

for eight to nine years with undetectableviral loads, the virus can be cultured fromtheir lymphocytes.15

To address the many hurdles in HIVvaccine development, the Global HIV/AIDS Vaccine Enterprise was proposed in2003 and endorsed by the G8 summitin June 2004. The Enterprise, aninternational consortium of independentparties, is part of an effort to encouragethe global scientific community to pursuecommon goals using complementary

strategies and to avoid doing overlappingor repetitive experiments. Theinternational group has met regularlysince the summer of 2003 and has

developed a strategic plan that is freelyaccessible on the Internet.21

Malaria and tuberculosis

Malaria is one of those diseases that mostpeople in the developed world just do notthink about. Yet more than one millionpeople with malaria die each year. Every30 seconds, a child dies of malaria.22 Overthe past few years, we have madeconsiderable progress in malaria research.Scientists now have completed thegenomic sequence of the most virulent

malaria-causing parasite, Plasmodiumfalciparum, as well as that ofAnophelesgambiae, one of the important mosquitospecies that carries the parasite.23,24 Withthe human genome sequence alsoavailable, we have the genomes of thehost, the vector, and the microbecompletely sequenced. This informationcan now be helpful in the design ofeffective drugs and vaccines as well as inother areas of malaria control. Morerecently, a trial of a malaria vaccineconducted among children inMozambique showed 30% efficacy inpreventing infection and nearly 60%efficacy in preventing severe disease.25

Although the vaccine is not as efficaciousas most commonly used childhoodvaccines, it has the potential for savingmillions of lives.

Tuberculosis is another major killer,causing the deaths of about two millionpeople each year.26 About one third of theworlds population is infected with themycobacterium that causes tuberculosis,and almost four million have the active

disease at any time, including the 300,000new cases of multiple-drug-resistanttuberculosis that develop each year.26

Tuberculosis is especially prevalentamong patients with HIV/AIDS: about46% of people in the developing worldwith HIV are co-infected withtuberculosis and 13% of the deathsamong HIV-infected individuals are from

disseminated tuberculosis.26

Influenza

Influenza, as common as it is, is a greatlymisunderstood disease. Each year weconfront seasonal, or interpandemic,influenza. Seasonal influenza kills about250,000 to 500,000 people each yearthroughout the world.27 In the UnitedStates, 36,000 people with influenza dieeach year, more than 90% of whom are65 years or older.28 Superimposed on thisyearly cycle is the ever-present threat of

an influenza pandemic. A pandemicoccurs through exposure to a microbe forwhich there is no baseline immunity inthe population.

The worst influenza pandemic in historyoccurred in 19181919.29 There were 40million deaths throughout the world anda half-million deaths in the United States.Unlike the seasonal flu that typically killsthe elderly, the 1918 pandemic killedyoung people as well. Even though theywere fundamentally healthy, 20-, 30-, and

40-year-old people were dying becausethey had no background immunity to avirus that was particularly virulent.

Influenza virus strains are designated bythe composition of their hemagglutininand neuraminidase proteins. The majorinfluenza strain circulating in 2005 is anH3N2 strain. Virtually every year, thesequence of the prevalent strain mutatesslightly in a process known as drift. Adrift from an H3N2 Panama strain to anH3N2 Fujian strain (as occurred in the20032004 influenza season) represents a

relatively minor mutation; if you werevaccinated or are immune to a Panamastrain, you would also harbor somedegree of crossreacting, baselineimmunity to a Fujian strain.

However, an antigenic shift occurs whenan influenza strain emerges that issubstantially different from anything towhich the population has been previouslyexposed. Figure 4 illustrates thetimetables of the three influenzapandemics that occurred in the 20th

Figure 3 AIDS in the United States. Estimated number of cases, deaths, and people living with

AIDS in the United States, 19812003. Source: Centers for Disease Control and Prevention,

2004.14

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century. In 1918, H1N1 first appeared; in1957 H2N2 emerged, and in 1968, wefirst saw H3N2.29

Over the past few years, many moreinfluenza strains have emerged with thecapability of infecting humans. TheH5N1 strain likely evolved from a few

flocks of chickens in Hong Kong (whereit was first noticed in 1996 and infected asmall number of humans in 1997) to thesituation today where it has infectednumerous flocks, as well as wild birdsthroughout Southeast Asia.30 Hundredsof millions of birds have been infected;more than 100 million chickens have diedor have been culled to slow the spread ofthe H5N1 virus.

We are now faced with what I call anescalating scale of compounding

probabilities. If a few birds are infected,there is a problem, but not a big problem.When more birds are infected, theproblem is getting bigger. When the virusjumps to humans, the problem is gettingeven more serious. If it jumps tosignificant numbers of humans, thethreat becomes more serious still.

Between December 2003 and June 28,2005, 108 laboratory-confirmed cases ofhuman infection with the H5N1 avianinfluenza virus and 54 deaths werereported to the World Health

Organization.30 Not long ago, the firstdocumented cases of human-to-humantransmission were reported in a Thaifamily.31 Clearly, the virus is percolatingamong avian populations in SoutheastAsia. If the virus develops the capabilityof efficiently transmitting from human tohuman, then we have the makings of aninfluenza pandemic. Is it likely that willhappen? No, it is not likely, but it is quitepossible and significantly more probablethan it was ten years ago. In response, weare doing what we should be doing: basic

research to understand virulence factors,the factors that allow transmission fromone animal species to another animalspecies, and the mechanisms oftransmissibility.

We have developed an H5N1 vaccinebased on the virus that is currently

circulating in Asia; a clinical trial of thisvaccine was initiated in April 2005. Initialresults show that the vaccine is safe andimmunogenic. The U.S. government haspurchased two million doses of thisH5N1 vaccine for the strategic nationalstockpile and has also begun to stockpilethe antiviral compound known asTamiflu, which is effective against theH5N1 virus. These efforts are part of theHHS Pandemic Influenza Response andPreparedness Plan.32

SARS

Two years ago, the world experiencedanother newly emerging microbeapreviously unknown coronavirusthatcaused SARS. Fortunately, the morbidityand mortality associated with the SARSoutbreak were not as great as what weobserve every year with influenza. TheSARS outbreak turned out to be a classicstudy in epidemiology with regard totracking the point source, the spread, andthe containment of the virus. SARS firstappeared in Guangdong Province in

China. It was not reported to authoritiesuntil it emerged in Hong Kong, when anindex case who traveled from Guangdongto Hong Kong stayed at the Metropolehotel and infected at least 14 people.33

Those individuals did some travelingthroughout the world. Within months wehad an epidemic that temporarilytransfixed the world and didextraordinary economic damage inCanada, China, Hong Kong, and othercountries. There were 8,098 reportedcases and 774 deaths.33

SARS taught us an important lesson.Academic scientists, public healthofficials, and pharmaceutical companiesacted together in a way that wasunprecedented, leading to thedevelopment of promising vaccinecandidates in record time. The newmicrobe was identified in March 2003and was rapidly sequenced; a vaccine was

developed by the following March. InDecember 2004, a clinical trial of theSARS vaccine began.34 This likely was thefastest time frame in the history ofbiomedical research from theidentification of a previously unknownmicrobe to the beginning of a clinicaltrial. Such rapid progress could not haveoccurred 30 to 40 years ago. Thus, asmicrobes continue to emerge, wecontinue to develop technologicaladvances that will, hopefully, keep us onestep ahead of our microbial foes.

West Nile virus

Whereas SARS is an emerging infection,West Nile virus is a reemerging infection.It has existed in Africa and the MiddleEast for decades, if not centuries. In 1999,it landed in Queens, New York, via anunknown route. The infection thenproceeded to move across the country,with different hot spots each year.35,36 In1999, the hotspot was Long Island andNew York City. In the year 2000, itspread a little bit and many people were

not terribly worried. However, all themakings for an epidemic were in place:the right mosquito, the right microbe,and suitable hosts. In 2001, the hotspotsexpanded throughout New York Stateand to Connecticut, Maryland, andFlorida. In 2002, hotspots appeared in theMidwest, and further west in 2003. By2004, the epidemic crossed the RockyMountains and emerged in California,Arizona, and Colorado. In 2004, 2,470cases and 88 deaths were reported.36 WestNile is likely to follow the path of otherinfectious encephalopathies such as St.

Louis encephalitis and eastern equineencephalitis, becoming part of thebackground matrix of infectious diseases.

The research enterprise also has movedrapidly to respond to West Nile virus. Inparticular, scientists have created achimeric vaccine against West Nile virus.Genes coding for the immunodominantantigens of the West Nile virus (aflavivirus) were spliced into the genomeof an attenuated yellow fever virus(another flavivirus) vaccine to yield a

Figure 4 Influenza virus timeline. Appearance of influenza viruses infecting humans, 19182005.

Source: World Health Organization, 2005.29

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chimeric yellow fever/West Nile virusvaccine. This vaccine is now in clinicaltrials with promising early results. Asimilar chimeric vaccine has also beencreated with an attenuated dengue virusvector. Other West Nile vaccineapproaches also are being pursued,including a DNA vaccine andrecombinant subunit vaccines, as well as

new approaches to therapy.37

Marburg virus

We recently experienced an outbreak ofMarburg virus in Angola. This virus,related to Ebola virus, was first detectedin 1967 in Marburg, Germany whenpeople working with monkeys fromUganda became infected, resulting inseven deaths. Throughout the years inKenya, South Africa, the DemocraticRepublic of the Congo, and mostrecently, Angola, the virus has reemerged.

Fortunately, Marburg and Ebolaoutbreaks tend to appear in localizedregions and have not triggered epidemicsthroughout the world. Unlike influenza,which spreads even when people arerelatively asymptomatic, Ebola andMarburg are generally transmitted frompeople who are deathly ill. The people atgreatest risk of contracting disease arefamily members, physicians, and nursesin hospitals, undertakers, and otherpeople who come in close contact withinfected individuals. Unless the virus is

used as an agent of bioterrorism, it isunlikely that the world will experience anepidemic of Ebola or Marburg, merelybecause of the somewhat restrictedmanner of its transmission.38

Bioterrorism

One of those days in history that we willnever forget is September 11, 2001. Barelyhad the dust settled on Ground Zero inNew York City and the Pentagon whenan unknown bioterrorist sent anthraxspores through the mail, resulting in 22

anthrax cases and five deaths.39 Unlikeother infectious diseases, anthrax is notcommunicable, yet it virtuallyimmobilized Washington, DC. Peoplewere afraid to open their mail, andseveral mail facilities were closed down.Congressional office buildings wereclosed for months. A large infusion ofresources was invested in bioterrorismresearch, and the issue of how suchresearch should be conducted was thesubject of much debate. Should it bedone openly or covertly? I made the

argument that such research should bedone openly and transparently byresearchers who are already studyingemerging and reemerging diseases. Withan infusion of resources, we developed astrategic plan and research agenda, nowwidely transparent and available, whichcall for fundamental basic research asthe matrix for the development of

countermeasures against agents ofbioterror.40

A New Paradigm

One of the goals of infectious diseaseresearch is the development andproduction of countermeasures. Theacademic community has beenfundamentally concerned with basicresearch and concept development, andfor the most part has left thedevelopment of products to industry.

When industry has a product that theyknow will generate a major profit margin,they do not need much outside incentiveto pursue advanced productdevelopment. However, if faced with thechoice of putting $200 million into a newarea, will pharmaceutical companiesmake a product to combat an emergingmicrobe for which there is an uncertainmarket, or will they develop a new Viagraor a better Lipitor? The answer, at least interms of answering to shareholders, isobvious. So in developing products forpublic health issues, a new paradigm isneeded. In the present paradigm, thebiomedical research community providesthe push in the form of conceptdevelopment. The pull is generally themarketplace demand. However, there isnot a large marketplace demand forcountermeasures for emerging infections.Hence, we have to do things differently,and we are starting to observe a shift. Weare now seeing partnerships with industryfueled in part by programs thatdeveloped as a result of the ProjectBioshield bill that was signed last

summer. Through this project, $5.6billion has been put aside as a guaranteeto industry that if they make a productthat serves an important public healthneed, the government will buy it at a fairprice, even if it is never used. Thisprovides an important incentive forindustry to get involved.41

As a result of these efforts, several criticalcountermeasures have been developed.We started out with 18 million doses ofthe classic, proven smallpox vaccine, but

now have more than 300 million doses,enough for everyone in the country.Although it is a very effective vaccine,there are rare but serious side effects,which have prompted the biomedicalresearch community and the publichealth community to develop a second-generation vaccine that is much safer. Inaddition, new antiviral drugs are being

developed. For example, several monthsago, researchers found that a potentialanticancer drug that blocks a cellularsignal transduction cascade also interfereswith smallpox growth factor, essential tothe entry and replication of the smallpoxvirus.42 Thus, purely fundamental sciencehas opened up a new possible route fordeveloping countermeasures to smallpoxand other viruses that block cellularpathways. Other developments include anext-generation anthrax vaccine, Ebolavaccine, and monoclonal antibodies

against botulism toxin.

As we educate the next generation ofphysicians and researchers, it isimportant to keep this paradigm shift inmind. We need to help todays medicalstudents understand that they are part ofa global enterprise encompassingmultiple facets of patient care and drugdevelopment. As we struggle to keep astep ahead of the diseases that challengeus, it may not be sufficient to simply be agood doctor or a good scientist. We must

develop partnerships between clinicians,researchers, government, and industry todetect and diagnose disease, to conductbasic, applied, and clinical research, todevelop effective countermeasures, tomanufacture vaccines and drugs toprevent and treat disease, and to deliverthese therapies to the patients who needthem. Todays medical students will playan important role in all aspects of ourefforts to combat infectious diseases.

It is clear that we will rely heavily onfundamental science, its applications,intellectual capital, and research facilitiesin the ongoing struggle between microbesand humans, a challenge that isperpetual. I would like to close byquoting Dr. Joshua Lederberg,43 a personwhom I have admired for many years,who said it much better then I could:

The future of humanity and microbes

likely will unfold as episodes of a suspense

thriller that could be titled Our Wits

Versus Their Genes.

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