Appendix A

Contributed Manuscripts

A1

EHEC O104:H4 IN GERMANY 2011: LARGE OUTBREAK
OF BLOODY DIARRHEA AND HAEMOLYTIC
URAEMIC SYNDROME BY SHIGA TOXIN—PRODUCING
E. COLI VIA CONTAMINATED FOOD

Reinhard Burger1,2

In the summer of 2011 Germany experienced one of the largest outbreaks of a food-borne infection caused by enterohaemorrhagic Escherichia coli (EHEC) with the serotype O104:H4. A large number of cases with bloody diarrhea and haemolytic uraemic syndrome (HUS) occurred. Never before was such a high rate of HUS cases observed in an outbreak caused by a food-borne pathogen. The events in Germany caused by EHEC O104:H4 in the summer of 2011 show dramatically how rapidly an infectious agent is able to develop into a major health threat for a whole country. The outbreak caused widespread concern among the population, turning soon into fear. People expecting safe and healthy food felt threatened. It changed the eating habits of the majority of the population, and it had enormous economic consequences, particularly for farmers producing salad ingredients. It resulted in a large number of seriously ill patients and in a substantial number of deaths. The burden of disease and the economic consequences

images

1 For the HUS investigation team of the Robert Koch Institute.

2 Robert Koch Institute, Nordufer 20, 13353 Berlin, Germany (BurgerR@rki.de).



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Appendix A Contributed Manuscripts A1 EHEC O104:H4 IN GERMANY 2011: LARGE OUTBREAK OF BLOODY DIARRHEA AND HAEMOLYTIC URAEMIC SYNDROME BY SHIGA TOXIN–PRODUCING E. COLI VIA CONTAMINATED FOOD Reinhard Burger1,2 In the summer of 2011 Germany experienced one of the largest outbreaks of a food-borne infection caused by enterohaemorrhagic Escherichia coli (EHEC) with the serotype O104:H4. A large number of cases with bloody diarrhea and haemolytic uraemic syndrome (HUS) occurred. Never before was such a high rate of HUS cases observed in an outbreak caused by a food-borne pathogen. The events in Germany caused by EHEC O104:H4 in the summer of 2011 show dramatically how rapidly an infectious agent is able to develop into a major health threat for a whole country. The outbreak caused widespread concern among the population, turning soon into fear. People expecting safe and healthy food felt threatened. It changed the eating habits of the majority of the population, and it had enormous economic consequences, particularly for farmers producing salad ingredients. It resulted in a large number of seriously ill patients and in a sub- stantial number of deaths. The burden of disease and the economic consequences 1 For the HUS investigation team of the Robert Koch Institute. 2 Robert Koch Institute, Nordufer 20, 13353 Berlin, Germany (BurgerR@rki.de). 115

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116 IMPROVING FOOD SAFETY THROUGH A ONE HEALTH APPROACH have made it a tragedy for many. It is important to analyse this outbreak scientifi- cally in order to learn from this unique event and to be prepared for comparable infections in the future. In particular, all the steps regarding detection of cases, diagnostic procedures, identification of vehicle and origin, and infection control measures, all the way to therapy, should be reflected carefully. Usually, even ex- perienced physicians encounter only a few cases of EHEC-induced HUS in adults in their whole career. Therefore, the large number of cases in Germany represents a valuable source of information for future epidemics. This manuscript summarises the work of the HUS investigation team of the Robert Koch Institute (RKI) and gives an overview of the work done by the colleagues in the Department of Infectious Disease Epidemiology at the RKI (G. Krause, C. Frank, D. Werber, K. Stark, and U. Buchholz), the Department for Infectious Diseases (M. Mielke and A. Fruth), and the RKI-Consultant Labora- tory for HUS/EHEC at the University of Münster (H. Karch). Many additional colleagues were involved. Epidemic Profile and Development of the Outbreak The extent of the outbreak becomes apparent by comparison with the aver- age annual numbers of EHEC cases or HUS in Germany. In previous years about 1,000 patients per year were identified, with a median age of about 5 years. Of these patients about 70 per year developed HUS, with a median age of about 2 years (Frank et al., 2011a). In the outbreak from May to September 2011, ap- proximately 3,000 EHEC cases were observed with a median age of 46 years, 58 percent of those patients were female, and 18 deaths were observed among the EHEC patients (0.6 percent). An additional 855 EHEC patients who developed HUS were identified (Frank et al., 2011b). This represents more than 20 percent of the total number of patients (3,842). The large majority of these patients were adults, the average age was 42 years, 68 percent of the HUS cases were female, and 35 deaths were observed among the HUS patients (4.1 percent). The total death toll was 53 patients (Figure A1-1). Analysis of the incidence of HUS by the likely county of infection re- vealed that northern Germany was mainly affected. The same is true for cases with travel history; also for these patients the county of residence at the time of infection was northern Germany. Most cases were observed in the states of Schleswig-Holstein, Mecklenburg-Western Pomerania, Hamburg, Bremen, and Lower Saxony. Later in the epidemic, cases were found in all of the 16 German states. The incidence in the five northern German states varied from 1.8 to 10 cases per 100,000 persons. All other states had incidence rates with less than 1 case per 100,000 persons (Frank et al., 2011b; Wadl et al., 2011). A substantial number of EHEC or HUS cases occurred also internationally during this time, particularly in the European Union, but also a few cases in the United States and Canada. Particularly affected was Sweden with 35 EHEC

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117 APPENDIX A FIGURE A1-1 Total number of EHEC and HUS cases and associated deaths during the outbreak of EHEC O104:H4 inFigure 2011 in Germany and comparison to an average summer A1-1.eps bitmap year. and 18 HUS cases including one fatality, Denmark with 15 EHEC and 10 HUS cases, and France with 10 EHEC and 8 HUS cases. Single cases were found in 12 additional European countries. In the United States 2 EHEC and 4 HUS cases were identified with one fatality, and Canada had a single EHEC case. An epidemiological analysis revealed that—with two exceptions—all cases in this outbreak of EHEC or HUS found internationally were directly or indirectly as- sociated with a visit to Germany during the weeks of the outbreak. Most of these patients visited northern Germany for a shorter or longer period of time during the peak of the outbreak. The RKI was notified about the outbreak by a phone call from the local health authority of the state of Hamburg on May 19, 2011. Immediately (i.e., the next day), the RKI sent a substantial team of experts to Hamburg in support of the local colleagues. The subsequent epidemiological analysis revealed in retro- spect that the outbreak had in fact started at the beginning of May and reached the peak of cases on May 22, 2011 (Figure A1-2). Thus, there was an obvious and substantial notification delay (Altmann et al., 2011). Up to the moment of notifying the RKI, a large proportion of the infections had already occurred. After May 22 both the reported number of EHEC gastroenteritis and the number of HUS cases decreased (Wadl et al., 2011). The team of epidemiological specialists sent to Hamburg started right away with initial explorative interviews. The team size was enlarged in the next days

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118 IMPROVING FOOD SAFETY THROUGH A ONE HEALTH APPROACH Evidence for sprouts as the 7th cohort study only risk factor 6th cohort study 5th cohort study cases Fälle (n) 4th cohort study 3rd cohort study = 2174) EHEC (n 250 2nd cohort study (n = 749) HUS 1st cohort study 200 2nd Online-questionnaire 1st Online-questionnaire 3rd Explorative questionnaire 150 2nd Explorative questionnaire 6th Case-control study Explorative questionnaire 100 5th Case-control study 4th Case-control study Call from local health department 3rd Case-control study Invitation from Hamburg 50 2nd Case-control study 1st Case-control study 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 May June FIGURE A1-2 Epidemiological curve of EHEC (gray) and HUS cases (dark) and over- view of epidemiological studies performed by the Robert Koch Institute for identification of sprouts as the vehicle of transmission. SOURCE: Robert Koch Institute. (up to 15 members), and a substantial number of case-control studies, additional explorative interviews, and cohort studies were started. As early as May 21 (i.e., 2 days after the RKI was notified), the first qualitative evidence for the role of vegetables was obtained. Raw milk products or products from raw meat, which frequently represent a source of infections with EHEC, had already been ruled out as the origin of infection in this outbreak. On May 22 the corresponding infor- mation was submitted to the European Early Warning and Response System and to the World Health Organization. Local public health authorities were warned, and initial interviews were given to the German press. During the next few days, information was provided on the website and in a series of press conferences and interviews. On May 25 (i.e., 5 days after the outbreak), the pathogen was identi- fied from patient samples as EHEC O104:H4 by the RKI-Consulting Laboratory for HUS in Münster and the National Reference Centre laboratory for bacterial enteric pathogens at the RKI (Buchholz et al., 2011). After a number of telephone conferences, the RKI together with the Federal Institute for Risk Assessment and the Federal Office of Consumer Protection

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119 APPENDIX A and Food Safety conducted a press conference advising on food consumption. Advice was given not to consume raw tomatoes, cucumbers, and salad in northern Germany. This recommendation was based on the increased risk of illness after consumption of these raw salads in northern Germany. Unfortunately, the majority of the press reported this advice as warning against salad from northern Germany. Once the magnitude of the outbreak became apparent, the RKI immediately established a website providing all details about the infectious agent, updated as they developed, both for the medical specialists and microbiological laboratories in Germany and abroad and for the general public. Data sheets on the infectious agent and frequently asked questions, sometimes updated several times a day, proved to be an important source of information. After mid-June 2011 only single cases of HUS occurred. On July 26 the RKI declared in a press conference the end of the outbreak because no new cases clearly associated with the outbreak had been reported for 3 consecutive weeks since the last newly reported illness on July 4. Identification of the Infection Vehicle In addition to the explorative interviews and case-control studies, cohort studies in disease clusters proved to be particularly helpful. Beginning on June 1, more than 30 cohorts were investigated in order to identify the vehicle of infec- tions and to identify further cases. Particularly useful were cohort studies of travel groups that included international visitors or tourist groups from abroad. Here a close cooperation with foreign health authorities was instrumental. For a number of travel groups the length of stay, the particular location, and food consumption could be reconstructed in detail. Also, cluster analysis of patients associated with food consumption in different restaurant-associated outbreaks provided information. An analysis of billing data of guests at an affected canteen provided further data. In these studies a detailed investigation was performed using ordering information and additional details documenting the consumption as revealed by the corresponding bills. The most substantial evidence regarding the vehicle of infection was obtained by a so-called recipe-based restaurant cohort study (Buchholz et al., 2011). Sprouts as the Responsible Vehicle of Infection In the course of the epidemiological analysis it became obvious that patient memory is not a reliable source of information. This proved to be particularly true because in these EHEC/HUS patients not only symptoms of gastrointestinal infection and impaired kidney function were observed but also major neurological symptoms, preventing reliable interviews. Therefore, the recipe-based restaurant cohort study was designed to obtain information independent of a functioning patient memory (Figure A1-3).

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120 IMPROVING FOOD SAFETY THROUGH A ONE HEALTH APPROACH FIGURE A1-3 Recipe-based restaurant cohort study of the Robert Koch Institute reveals risk for infection associated with the consumption of sprouts. Figure A1-3.eps SOURCE: Taken from Buchholz et al., NEJM, 365, 1763 (2011). bitmap Ten cohorts with a total of 168 guests of a given restaurant in the city of Lübeck in Schleswig-Holstein were identified. All persons had dinner at the same restaurant between May 12 and 16. Eighteen percent of the guests consuming food at this restaurant showed bloody diarrhea or EHEC/HUS within 14 days (31 persons). All persons were questioned about which meals they ordered, using photos of the dishes as a reminder. Booking details and billing documents were utilized. Using these consumption data from the individual guests, the chef of the restaurant was interviewed about the detailed ingredients of each dish ordered by the guests. This included not only the major ingredients of each dish itself but also elements used for decoration of the dish or of the salad served separately. This approach provided reliable information about which food ingredients each guest had actually ordered and eaten. This interview technique and analysis had the major advantage that it was no longer necessary to depend on the memory of the guests to find out what they had eaten. Additional verification was obtained through photos taken at the table by a number of groups. These photos confirmed the details given for the nature of the ordered dish and its contents. In univariate analysis the relative risk of disease was 14.2 times higher for persons eating sprouts compared to that of persons not eating sprouts (Buchholz et al., 2011). All 31 patients with EHEC/HUS had consumed sprouts. None of the guests who did not consume sprouts became ill. Based on these cohort studies, in a joint press conference of the RKI with the food safety authorities on June 10 the public announcement was made that sprouts were the vehicle of infection. The

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121 APPENDIX A earlier warning against the consumption of salad was now focused on a warning against consumption of the salad ingredient sprouts. Origin of Bacterial Contamination of the Sprouts The more than 40 clusters within this outbreak were analyzed for a common denominator. The federal authorities responsible for food safety in Germany (the Federal Institute for Risk Assessment and the Federal Office of Consumer Protec- tion and Food Safety) performed an intensive forward-backward tracing of the food supply chain of the various cluster locations (Figure A1-4). Through one or several distributors and intermediates, all clusters turned out to be connected to a specific food enterprise producing sprouts commercially. All infections within this outbreak in the state of Lower Saxony had in common that originally the supply of sprouts came from this single food enterprise. Two clusters of infection independent of the outbreak in Lower Saxony pro- vided information on the origin of the sprout contamination (Appel et al., 2011). Both clusters had definitely no connection to the sprout producer in Lower Saxony. One cluster consisted of so-called self-sprouters (i.e., consumers who grow their FIGURE A1-4 Trading network reveals linkage of 41 identified outbreak clusters. Supply chain of contaminated sprouts leads to one single sprout producer farm in Lower Saxony. SOURCE: Modified from Buchholz et al., NEJM, 365, 1763 (2011). Figure A1-4.eps bitmap

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122 IMPROVING FOOD SAFETY THROUGH A ONE HEALTH APPROACH own sprouts at home from seeds provided by commercial suppliers). The second source of information was a small outbreak comprising 15 cases in the area of Bordeaux in France in mid-June. Detailed and labor-intensive tracing of the deliv- ery channels revealed that the only common feature of the seeds used for growing sprouts in the food enterprises in Lower Saxony, in Bordeaux, and in the private households with the home-grown sprouts was a given lot of fenugreek seeds origi- nating from Egypt. Fenugreek seeds (Trigonella foenum-graecum) are frequently used for the production of sprouts. The seeds are also used in many other food products (e.g., spices, cheese, and even tea) because of their very aromatic taste and intensive smell. The seeds are small (4-5 mm) and have a peanut-like colour. Through a number of intermediates located in different countries this seed lot had been delivered to these three outbreak locations. No other common ingredient used for the production of sprouts was identified. This was clear evidence that contaminated seeds used for sprout growing were responsible for the outbreak (Appel et al., 2011). By nature, the epidemiological evidence is indirect or cir- cumstantial but it explained the distribution of infections. The corresponding lot of fenugreek seeds was removed from the market. It is difficult to verify how complete this removal was. “Stealth Food” When the affected patients were interviewed initially during the first weeks of the outbreak, it became obvious that people do not remember in detail what they ate 1 or 2 weeks ago. Only in retrospect, after the second or third interview together with reports in the press, did they realize and remember that their dishes had in fact contained sprouts. Similar phenomena had been observed internation- ally in other outbreaks. In 2008, jalapeno chili peppers were contaminated with Salmonella Saintpaul in the United States. Chili peppers are used as an ingredient in tomato sauce-like salsa. The consumers were not aware that one of the spicy ingredients was chili peppers and, when interviewed, denied consumption of this food item, thereby delaying the identification of the vehicle. The identification of sprouts as a source in Germany within less than 3 weeks was quite rapid. The identification of the chili peppers took about 7 weeks. In another outbreak in 1996 with radish sprouts causing an outbreak of EHEC O157 in Japan, 7 weeks were required for the detection of the outbreak and 4 weeks to identify its source. Microbiological Characterization of EHEC O104:H4 Once the outbreak had been recognized, EHEC O104:H4 was rapidly iso- lated from stool specimens of affected patients within a few days (Figure A1-5) (Askar et al., 2011, Bielaszewska et al., 2011). This is a rare serotype that had not been described previously in animals. As a rule, faecal contamination by ruminants is responsible for EHEC infections through vegetables or through

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123 APPENDIX A FIGURE A1-5 Electron micrograph of EHEC O104:H4. SOURCE: Laue, Robert Koch Institute. Figure A1-5.eps food products derived from animals (milk, meat). The usual EHEC strains (e.g., bitmap EHEC O157) are found in faeces of ruminants. EHEC O104:H4 has only rarely been identified previously in human beings (in a total of seven patients). A closely related EHEC strain, HUSEC041, was identified in 2001 by the laboratory of Karch at the University of Münster, Germany. Later, a few cases were identified in Korea in 2006, in Georgia in 2009, and in Finland in 2010. A detailed microbiological characterization of EHEC O104:H4 was performed at the National Reference Centre for Gastrointestinal Bacteria at the RKI and the RKI-Consultant Laboratory of Karch in Münster (Bielaszewska et al., 2011; Brzuskiewicz et al., 2011). From the virulence markers, the outbreak strain was negative for Shiga toxin 1 and positive for Shiga toxin 2 (variant vtx2a of Shiga toxin 2). It was negative for Intimin (eae) and also negative for enterohaemolysin (hly). Macrorestriction analysis (pulsed-field gel electrophoresis) with a number of selected isolates obtained from various areas of Germany showed the same pattern, indicating early that the corresponding patients were all affected by one and the same outbreak event.

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124 IMPROVING FOOD SAFETY THROUGH A ONE HEALTH APPROACH Surprisingly, the outbreak strain showed virulence characteristics of entero- aggregative E. coli (EAEC). It had the typical EAEC virulence plasmid with adhesion fimbriae type AAF/I. This virulence plasmid has not been described pre- viously in EHEC isolates. All other previously identified EAEC or Shiga toxin– producing E. coli (STEC)/EAEC O104:H4 had AAF/III fimbriae. Subsequent sequencing revealed strong homology to an enteroaggregative E. coli (EAEC 55989). Obviously, the outbreak strain EHEC O104:H4 represents a virulence combination of two different pathogens. The origin of this outbreak strain with the characteristics of two different pathogens remains unclear for the time being. It is unclear whether the new EHEC O104:H4 pathotype had developed from two separate ancestors by horizontal gene transfer, leading to the observed acquisi- tion of virulence factors (Figure A1-6) (Brzuskiewicz et al., 2011; Mellmann et al., 2011; Rasko et al., 2011). A number of mobile genetic elements can transfer traits in E. coli like the Stx-bacteriophage found in EHEC strains. Alternatively, an evolutionary model is discussed, postulating a common progenitor of EAEC FIGURE A1-6 Putative origin of the EHEC outbreak strain as a combination of virulence traits derived from two different Figure A1-6.eps ancestors. SOURCE: Brzuszkiewicz et al. (2011).bitmap

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125 APPENDIX A 55989 and EHEC O104:H5 developing into two lines, each losing or acquiring virulence factors. The second explanation is favoured by the group from Karch, University of Münster. The continuously updated EHEC datasheet on the RKI website summa- rized all known characteristics of the pathogen and suggested the proper micro - biological diagnostic procedures. ESBL Resistance Phenotype The microbiological characterization revealed a resistance unusual for intes- tinal E. coli. The outbreak strain had an extended-spectrum β-lactamase (ESBL). This is an unusual property of intestinal E. coli. This resistance phenotype allowed efficient diagnostics of the outbreak strain. It permitted the use of the corresponding selective media for a targeted search in clinical samples, facilitat- ing a rapid diagnosis. Colonies on an ESBL-agar plate were further characterized with multiplex polymerase chain reaction screening for genes of Shiga toxin 1 and 2 and Intimin. Absence of Direct Microbiological Evidence for Contamination of Seeds with EHEC O104:H4 The identification of seeds as the source and sprouts as the vehicle of infec- tion relied on sophisticated and elegant epidemiological analysis (i.e., indirect evidence). Direct microbiological evidence has not been obtained so far (Aurass et al., 2011). Intensive bacteriological screening of the fenugreek sprouts and seeds was performed. A large number of samples were also taken at the produc- tion site of the sprouts, including the water supply or waste water. All attempts to identify the outbreak strain on seeds or sprouts or in the samples obtained at the production site failed. Sampling sprouts in households with EHEC cases was suc- cessful in one or two cases. However, these results were more than questionable. One positive result was obtained from a single box of sprouts originating from the incriminated producer. However, it had already been opened in a household with EHEC cases and might simply have been contaminated by the handling. In another example the outbreak strain was identified in salad samples found in a trashcan days after disposal. Also here, the causal connection is unclear. One reason for the failure to identify the outbreak strain through bacterio- logical screening may be the enormous size of the incriminated fenugreek seed lot. The lot size was around 15,000 kg. If only a minor part of this lot had indeed been contaminated, searching for contaminated seeds would resemble the search for a needle in a haystack. In addition, on the same day, the sprout-producing enterprise received another lot of seeds from the same seed distributor. The incriminated lot had been distributed to 70 different companies, 54 of them in Germany and 16 of them in 11 European countries (Appel et al., 2011). How-

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358 IMPROVING FOOD SAFETY THROUGH A ONE HEALTH APPROACH (the Americas). Far more Native Americans resisting European colonists died of newly introduced Old World diseases than of sword and bullet wounds. Those invisible agents of New World conquest were Old World microbes to which Euro- peans had both some acquired immunity based on individual exposure and some genetic resistance based on population exposure over time, but to which previ- ously unexposed Native American populations had no immunity or resistance (Crosby, 1986; Diamond, 1997; McNeill, 1976; Ramenofsky, 1987). In contrast, no comparably devastating diseases awaited Europeans in the New World, which proved to be a relatively healthy environment for Europeans until yellow fever and malaria of Old World origins arrived (McNeill, 2006). Why was pathogen exchange between Old and New Worlds so unequal? Of the 25 major human diseases analysed, Chagas’ disease is the only one that clearly originated in the New World. For two others, syphilis and tuberculosis, the debate is unresolved: it remains uncertain in which hemisphere syphilis origi- nated, and whether tuberculosis originated independently in both hemispheres or was brought to the Americas by Europeans. Nothing is known about the geo- graphic origins of rotavirus, rubella, tetanus and typhus. For all of the other 18 major pathogens, Old World origins are certain or probable. Our preceding discussion of the animal origins of human pathogens may help explain this asymmetry. More temperate diseases arose in the Old World than New World because far more animals that could furnish ancestral pathogens were domesticated in the Old World. Of the world’s 14 major species of domestic mammalian livestock, 13, including the five most abundant species with which we come into closest contact (cow, sheep, goat, pig and horse), originated in the Old World (Diamond, 1997). The sole livestock species domesticated in the New World was the llama, but it is not known to have infected us with any pathogens (Diamond, 1997; Dobson, 1996)—perhaps because its traditional geographic range was confined to the Andes, it was not milked or ridden or hitched to ploughs, and it was not cuddled or kept indoors (as are some calves, lambs and piglets). Among the reasons why far more tropical diseases (nine versus one) arose in the Old World than the New World are that the genetic distance between humans and New World monkeys is almost double that between humans and Old World mon- keys, and is many times that between humans and Old World apes; and that much more evolutionary time was available for transfers from animals to humans in the Old World (about 5 million years) than in the New World (about 14,000 years). Outlook and Future Research Directions Many research directions on infectious disease origins merit more effort. We conclude by calling attention to two such directions: clarifying the origins of existing major diseases, and surveillance for early detection of new potentially major diseases.

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359 APPENDIX A Origins of established diseases. This review illustrates big gaps in our under- standing of the origins of even the established major infectious diseases. Almost all the studies that we have reviewed were based on specimens collected oppor- tunistically from domestic animals and a few easily sampled wild animal spe- cies, rather than on systematic surveys for particular classes of agents over the spectrum of domestic and wild animals. A case in point is our ignorance even about smallpox virus, the virus that has had perhaps the greatest impact on human history in the past 4,000 years. Despite some knowledge of poxviruses infecting our domestic mammals, we know little about poxvirus diversity among African rodents, from which those poxviruses of domestic mammals are thought to have evolved. We do not even know whether ‘camelpox’, the closest known relative of smallpox virus, is truly confined to camels as its name implies or is instead a rodent virus with a broad host range. There could be still-unknown poxviruses more similar to smallpox virus in yet unstudied animal reservoirs, and those unknown poxviruses could be important not only as disease threats but also as reagents for drug and vaccine development. Equally basic questions arise for other major pathogens. While falciparum malaria, an infection imposing one of the heaviest global burdens today, seems to have originated from a bird parasite whose descendants include both the Plasmodium falciparum infecting humans and the P. reichenowii infecting chim- panzees, malaria researchers still debate whether the bird parasite was introduced to both humans and chimpanzees (Waters et al., 1991) a few thousand years ago in association with human agriculture, or instead more than five million years ago before the split of humans and chimpanzees from each other (Ayala et al., 1999). Although resolving this debate will not help us eradicate malaria, it is fascinating in its own right and could contribute to our broader understanding of disease emergence. In the case of rubella, a human crowd disease that must have emerged only in the past 11,000 years and for which some close relative may thus still exist among animals, no even remotely related virus is known; one or more may be lurking undiscovered somewhere. Does the recent identification of porcine rubulavirus and the Mapuera virus in bats as the closest known relatives of mumps virus mean that pigs infected humans, or that human mumps infected pigs, or that bats independently infected both humans and pigs? Is human tuber- culosis descended from a ruminant mycobacterium that recently infected humans from domestic animals (a formerly prevalent view), or from an ancient human mycobacterium that has come to infect domestic and wild ruminants (a currently popular view)? To fill these and other yawning gaps in our understanding of disease origins, we propose an ‘origins initiative’ aimed at identifying the origins of a dozen of the most important human infectious diseases: for example, AIDS, cholera, dengue fever, falciparum malaria, hepatitis B, influenza A, measles, plague, rotavirus, smallpox, tuberculosis and typhoid. Although more is already known about the origins of some of these agents (AIDS, influenza A and measles) than about

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360 IMPROVING FOOD SAFETY THROUGH A ONE HEALTH APPROACH others (rotavirus, smallpox and tuberculosis), more comprehensive screening is still likely to yield significant new information about even the most studied agents, as illustrated by the recent demonstration that gorillas rather than chim- panzees were probably the donor species for the O-group of human immunodefi- ciency virus (HIV)-1 (Van Heuverswyn et al., 2006). The proposed effort would involve systematic sampling and phylogeographic analysis of related pathogens in diverse animal species: not just pigs and other species chosen for their ready availability, but a wider range of wild and domestic species whose direct contact (for example, as bushmeat) or indirect contact (for example, vector-mediated) with humans could plausibly have led to human infections. In addition to the historical and evolutionary significance of knowledge gained through such an origins initiative, it could yield other benefits such as: identifying the closest rela- tives of human pathogens; a better understanding of how diseases have emerged; new laboratory models for studying public health threats; and perhaps clues that could aid in predictions of future disease threats. A global early warning system. Most major human infectious diseases have animal origins, and we continue to be bombarded by novel animal pathogens. Yet there is no ongoing systematic global effort to monitor for pathogens emerging from animals to humans. Such an effort could help us to describe the diversity of microbial agents to which our species is exposed; to characterize animal patho- gens that might threaten us in the future; and perhaps to detect and control a local human emergence before it has a chance to spread globally. In our view, monitoring should focus on people with high levels of exposure to wild animals, such as hunters, butchers of wild game, wildlife veterinarians, workers in the wildlife trade, and zoo workers. Such people regularly become infected with animal viruses, and their infections can be monitored over time and traced to other people in contact with them. One of us (N.D.W.) has been working in Cameroon to monitor microbes in people who hunt wild game, in other people in their community, and in their animal prey (Wolfe et al., 2004). The study is now expanding to other continents and to monitor domestic animals (such as dogs) that live in close proximity to humans but are exposed to wild animals through hunting and scavenging. Monitoring of people, animals, and animal die-offs (Kuiken et al., 2003) will serve as an early warning system for disease emergence, while also providing a unique archive of pathogens infecting humans and the animals to which we are exposed. Specimens from such highly exposed human populations could be screened specifically for agents known to be present in the animals they hunt (for example, retroviruses among hunters of non- human primates), as well as generically using broad screening tools such as viral microarrays (Wang et al., 2003) and random amplification polymerase chain reac- tion (PCR) (Jones et al., 2005). Such monitoring efforts also provide potentially invaluable repositories, which would be available for study after future outbreaks in order to reconstruct an outbreak’s origin, and as a source of relevant reagents.

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361 APPENDIX A References Anderson, R. M. & May, R. M. Infectious Diseases of Humans: Dynamics and Control (Oxford Univ. Press, Oxford, UK, 1991). Antia, R., Regoes, R. H., Koella, J. C. & Bergstrom, C. T. The role of evolution in the emergence of infectious diseases. Nature 426, 658–661 (2003). Ayala, F. J., Escalante, A. A. & Rich, S. M. Evolution of Plasmodium and the recent origin of the world populations of Plasmodium falciparum. Parassitologia 41, 55–68 (1999). Bellwood, P. First Farmers: the Origins of Agriculture Societies (Blackwell, Oxford, 2005). Crosby, A. W. Ecological Imperialism: the Biological Expansion of Europe 900–1900 (Cambridge Univ. Press, Cambridge, UK, 1986). Diamond, J. & Panosian, C. in When Disease Makes History: Epidemics and Great Historical Turning Points (ed. Hämäläinen, P.) 17–44 (Helsinki Univ. Press, 2006). Diamond, J. Evolution, consequences, and future of plant and animal domestication. Nature 418, 34–41 (2002). Diamond, J. Guns, Germs, and Steel: the Fates of Human Societies (Norton, New York, 1997). Dobson, A. P. & Carper, E. R. Infectious diseases and human population history. Bioscience 46, 115–126 (1996). Jones, M. S. et al. New DNA viruses identified in patients with acute viral infection syndrome. J. Virol. 79, 8230–8236 (2005). Kuiken, T. et al. Pathogen surveillance in animals. Science 309, 1680–1681 (2005). Lopez, A. D., Mathers, C. D., Ezzati, N., Jamison, D. T. & Murray, C. J. L. (eds) Global Burden of Disease and Risk Factors (Oxford Univ. Press, New York, 2006). May, R. M., Gupta, S. & McLean, A. R. Infectious disease dynamics: what characterizes a successful invader? Phil. Trans. R. Soc. Lond. B 356, 901–910 (2001). McNeill, J. R. in When Disease Makes History: Epidemics and Great Historical Turning Points (ed. Hämäläinen, P.) 81–111 (Helsinki Univ. Press, Helsinki, 2006). McNeill, W. H. Plagues and Peoples (Anchor, Garden City, 1976). Morens, D. M., Folkers, G. K. & Fauci, A. S. The challenge of emerging and re-emerging infectious diseases. Nature 430, 242–249 (2004). Morse, S. S. Factors in the emergence of infectious diseases. Emerg. Infect. Dis. 1, 7–15 (1995). Moya, A., Holmes, E. C. & Gonzalez-Candelas, F. The population genetics and evolutionary epide- miology of RNA viruses. Nature Rev. Microbiol. 2, 279–288 (2004). Ramenofsky, A. Vectors of Death: the Archaeology of European Contact (New Mexico Press, Albuquerque, 1987). Switzer, W. M. et al. Ancient co-speciation of simian foamy viruses and primates. Nature 434, 376–380 (2005). Taylor, L. H., Latham, S. M. & Woolhouse, M. E. Risk factors for human disease emergence. Phil. Trans. R. Soc. Lond. B 356, 983–989 (2001). Van Heuverswyn, F. et al. Human immunodeficiency viruses: SIV infection in wild gorillas. Nature 444, 164 (2006). Wang, D. et al. Viral discovery and sequence recovery using DNA microarrays. PLoS Biol. 1, E2 (2003). Waters, A. P., Higgins, D. G. & McCutchan, T. F. Plasmodium falciparum appears to have arisen as a result of lateral transfer between avian and human hosts. Proc. Natl Acad. Sci. USA 88, 3140–3144 (1991). Weiss, R. A. & McMichael, A. J. Social and environmental risk factors in the emergence of infectious diseases. Nature Med. 10, S70–S76 (2004). Wilson, M. E. Travel and the emergence of infectious diseases. Emerg. Infect. Dis. 1, 39–46 (1995). Wolfe, N. D. et al. Naturally acquired simian retrovirus infections in central African hunters. Lancet 363, 932–937 (2004).

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362 IMPROVING FOOD SAFETY THROUGH A ONE HEALTH APPROACH Supplementary Information is linked to the online version of the paper at www. nature.com/nature. Acknowledgements We thank L. Krain for assistance with Supplementary Note S10; M. Antolin, D. Burke, L. Fleisher, E. Holmes, L. Real, A. Rimoin, R. Weiss and M. Woolhouse for comments; and many other colleagues for provid- ing information. This work was supported by an NIH Director’s Pioneer Award and Fogarty International Center IRSDA Award (to N.D.W.), a W. W. Smith Foundation award (to N.D.W.), and National Geographic Society awards (to J.D. and N.D.W.). Author Information Reprints and permissions information is available at www. nature.com/reprints. The authors declare no competing financial interests. Corre- spondence should be addressed to N.W. (nwolfe@ucla.edu) or J.D. (jdiamond@ geog.ucla.edu). A17 THE OUTLOOK FOR PUBLIC FOOD SAFETY RESEARCH AND USDA SCIENCE Catherine Woteki37, 38 Thank you and good afternoon. I’d like to take this opportunity to speak with you today to talk about food safety research at the U.S. Department of Agriculture (USDA) and One Health. As some of you might know, I served as the first Under Secretary for Food Safety at USDA from 1997 to 2001, where I oversaw U.S. government food safety policy development and USDA’s continuity of operations planning. I’m now USDA’s Chief Scientist and Under Secretary for Research, Educa- tion and Economics, where I play a role in managing USDA’s food and agricul- ture research portfolio. My own academic background is in human nutrition—so I’ve been lucky to have been able to focus on different aspects of our food and agricultural system. But in reality, all three of these fields—food safety, nutrition, and production agriculture research—are intimately connected. At USDA these three fields converge, and in order to ensure our food and feed systems are safe, health promoting, productive, and sustainable, we need to 37 USDA Chief Scientist and Under Secretary, Research, Education, and Economics. 38 Remarks delivered at “Improving Food Safety Through One Health—Institute of Medicine/ Forum on Microbial Threats,” December 14, 2011.

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363 APPENDIX A make sure that our research programs are planned with these goals in mind. As we used to say in Food Safety—no food is nutritious unless it is safe. As you are well aware, 65 percent of the emerging infectious diseases of the past 60 years have come from pathogens that have jumped from animals to humans. Many of the pathogens that cause food-borne illness for thousands of Americans every year reside in animals without causing severe illness but can cause life-threatening illness in people. Greater coordination between human and animal health professionals is be- coming a prominent theme among many infectious disease professionals and is becoming the new norm for addressing emerging pathogens. USDA is the premier organization with veterinary, food safety, nutrition, wildlife, plant, economics, and biotechnology expertise to meet the challenges of this growing coordination and communication among human, animal, and environmental infectious disease professionals. Given this diversity of expertise, USDA identified a need for a comprehensive national strategy for One Health based upon pandemic planning for both highly pathogenic H5N1 avian influenza and 2009 pandemic H1N1 influenza viruses. USDA formed two new department-wide interdisciplinary groups to support interdepartmental initiatives at both the policy and technical levels that enhance human, animal, and environmental health. In a world where disease knows no boundaries, the One Health concept has evolved as the most practical and common-sense means for coordinating between the public health and animal health sectors as well as acknowledging the impact of the environment in the incubation and transfer of infectious diseases. This comprehensive approach will improve global capabilities to detect, prevent, prepare for, and respond to emerging diseases, pandemic threats, and other issues at the human animal and ecosystem interface. USDA is developing a greater clarity, understanding, and definition of its One Health approach. The many cross-cutting organizational structures being created around One Health will help USDA meet the complex challenges of world hunger, food security, environmental stewardship, climate change, and emerging diseases in an ever-changing world. USDA is using the One Health working group to coordinate efforts addressing the use of antibiotics in farm animals and its impact on anti- biotic resistance. USDA is also working with the Food and Drug Administration (FDA) in addressing this important societal issue. By applying One Health principles, it is USDA’s hope to encourage a syn- ergy of ideas, reduce program redundancy, and apply this holistic approach— ultimately—to improving global (human, animal, and environmental) health. As many of you know, USDA, through its Food Safety and Inspection Ser- vice (FSIS), ensures the safety of meat, poultry, and processed egg products both domestically and from countries approved to export to the United States. Prevention is the guiding principle of USDA’s food safety efforts.

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364 IMPROVING FOOD SAFETY THROUGH A ONE HEALTH APPROACH USDA, FDA, and Centers for Disease Control and Prevention (CDC), along with help from consumers and the industry, have made great strides in reducing E. coli O157 illnesses. O157 illnesses have declined by nearly half over the past 14 years, and in the past 2 years, the nation’s public health objective in this area has been met. This success is due, in large part, to the Pathogen Reduction and Hazard Analysis Critical Control Point (PR_HACCP) introduced to enhance meat safety practices and is followed up with other preventive measures within USDA and the industry. HACCP by its nature is a holistic approach to an environment where food is processed. But prevention and inspections are most effective when they are based on good scientific principles. USDA’s primary research agencies—through intramural and extramural programs—provide the science-based knowledge to inform food safety policies and regulatory decisions. As USDA’s Chief Scientist, I believe we need to reinforce the role that science is playing in our food safety efforts. Food safety research really is a prerequisite for food safety intelligence, and our ability to keep our food system safe is circumscribed by our knowledge of threats to the health of that system. Research is often a silent partner in food safety, working behind the scenes, before the inspections. We often speak of taking a “farm-to-table” approach to food safety—food and agricultural research is a vital third factor in this equation. Only occasionally is the value of food and agricultural science brought into the limelight—an unfortunate outbreak of food-borne illness, for example, or recent movies like Contagion, raise awareness of ongoing research—but are quickly forgotten when the crisis passes or movie ends. Outbreaks draw the public into the conversation. But we need to raise aware- ness of the food safety research that outlasts the news cycle surrounding out- breaks. For food safety, we can’t afford to take our eyes off the ball. Our research programs are our best weapon for identifying new threats. We monitor the latest food-borne illness epidemiological data to identify emerging threats. We work closely with our research partners to develop tests and new technological approaches that work in a regulatory setting, as well as to develop intervention strategies to reduce risk throughout the food chain. USDA’s Agricultural Research Service (ARS) conducts research on the highest priority national and international food-borne pathogens and contaminants. ARS also conducts research for its stakeholders, including its regulatory clients, FSIS and FDA. Because of its infrastructure, ARS is able to conduct long-term research as well as to quickly respond to newly identified threats. ARS remains flexible to emerging needs, and can and does redirect programs to respond to requests from FSIS, FDA, and CDC. The ARS food safety program has several centers across the United States dedicated to research covering important food-borne pathogens and contami- nants. ARS research focuses on identifying ways to assess, control, or eliminate potentially harmful food contaminants, including those that are accidentally or

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365 APPENDIX A intentionally introduced and naturally occurring pathogenic bacteria, viruses, parasites, and chemical contaminants to ensure the food supply is safe and secure and that foreign and domestic regulatory requirements are met. Based on stakeholders’ needs, ARS research focuses on several major areas, including pathogen sources and reservoirs, detection methods, and postharvest processing. Scientists around the world recognize that the emerging human diseases of this century will continue to arise from the animal kingdom. This past decade has seen an unprecedented epizootic, or animal epidemic, of highly pathogenic avian influenza viruses, mainly affecting poultry, but also infecting several other animal species and humans. Human infections have been associated with direct or indirect contact with live or dead poultry, and animals have been infected through the consumption of infected birds or their products, so there continues to be great concern with these viruses. USDA-funded scientists have been researching this disease since 1963 and have developed and evaluated avian influenza vaccines, helped assess public health threats, evaluated virus virulence, and helped develop protocols for inac- tivating flu viruses in food. When the 2009 pandemic H1N1 influenza A virus emerged in April that year, scientists at first concluded that the virus came from pigs. Pigs can serve as one of the vessels for the “mixing” of avian influenza and human influenza that could set the stage for pandemic avian influenza. We now know that H1N1 is a “triple reassortant virus,” which means it contains genetic material from swine, avian, and human influenza viruses—a mix that may help the virus spread quickly and pass between humans and pigs and, importantly, become more virulent. As early as 2007, USDA-funded scientists had been monitoring for strains of influenza that could spread between pig and human populations. When, in August 2007, several people exhibiting their pigs at a county fair in Ohio developed flu- like symptoms, ARS scientists quickly characterized the virus and found that in pigs it was more virulent than average, instigating immediate close monitoring of the virus in swine, birds, and other species. The following year USDA and CDC launched a collaborative effort to de- velop a national swine influenza virus (SIV) surveillance pilot program to better understand the epidemiology of SIV infections and to improve diagnostic tests, preventive management, and vaccines for swine and humans. This program was instrumental in implementing surveillance for the 2009 outbreak. USDA-funded research contributes to public health by identifying emerging disease strains, assessing current vaccines against emerging strains, and develop- ing standards for inactivating food-borne elements. These research programs are vital as emerging strains continue to evolve, including the nonseasonal H3N2 virus that has just been reported in children in the United States in 2011. Recognizing that food safety and food security are global issues, the ARS

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366 IMPROVING FOOD SAFETY THROUGH A ONE HEALTH APPROACH Food Safety and Animal Health national programs participate in both national and international collaborations through formal and informal partnerships. Currently, ARS has numerous federal research relationships, including with FSIS, APHIS, FDA, CDC, EPA, DHS, and NIFA. ARS, APHIS, NIFA, FSIS, and FDA have annual and quarterly meetings with leadership to discuss ongoing and upcoming research needs and set priorities. ARS has many research relationships with academia, especially where the food safety program is collocated with or near a university. ARS is also a member of the National Alliance for Food Safety and Security (NAFSS), a consortium of more than 20 State Agricultural Universities. ARS is co-chair of the Joint Com- mittee on Research (JCR) to address food security research (under Homeland Security Presidential Directive-9) with industry and government. Our extramural program is the National Institute of Food and Agriculture (NIFA). NIFA provides grants that support important research, education, and extension needs and can be used to conduct large population-based studies and other types of basic and applied food safety research. USDA’s extramural grant programs at NIFA reach out annually to FDA and FSIS to share research priorities and to identify areas where joint research can benefit each agency, as well as our shared publics. In 2011, a series of joint meet- ings were held to determine priorities, to identify areas of potential collaboration, and to identify gaps in the current research. In 2009, FDA and NIFA collaborated to solicit research focused on integrat- ing food system signals with geospatial or other innovative technologies used to detect produce contamination. Food system signals are clusters of illnesses re- ported by government authorities, or problems identified through routine testing. Geospatial technologies include a range of tools for mapping and analyzing data derived from natural resource information, such as climate and environmental monitoring, to predict a future event. Recently, NIFA awarded two Coordinated Agricultural Project (CAP) grants. One of the CAP grants will help to facilitate research on norovirus, which is a little-understood but difficult virus that causes food-borne and environmentally transferred illness. The other CAP grant will focus on developing intervention and risk management strategies for reducing Shiga toxin–producing E. coli con- tamination in pre- and postharvest environments for beef and beef products. Both CAP grants were awarded through the Agriculture and Food Research Initiative (AFRI), the flagship competitive grant program administered by NIFA. The National Integrated Food Safety Initiative (NIFSI), another competi- tive grant program administered by NIFA, has awarded more than $15 million annually to support a variety of food safety priorities in applied research, edu- cation, and extension. For the past several years, the NIFSI program identified produce safety as a special emphasis area in its annual Request for Applications. Special emphasis areas are selected based on current food safety trends (illness

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367 APPENDIX A outbreaks), stakeholder input, and collaboration with other federal food safety agencies. Other NIFA competitive grant programs that provide extramural grant fund- ing for food safety include the Expanded Food and Nutrition Education Program, the Specialty Crop Research Initiative, and the Water Quality Program. Food safety program priorities for all NIFA grant programs are developed with stake- holder input from USDA’s sister federal food safety agencies, university, and industry partners and stakeholders. The major advantage here is that when it comes to food safety there is great deal of consensus that cuts across institutional and international borders as well as public–private interests. Collectively, USDA agencies, such as FSIS, APHIS Veterinary Services, ARS, and NIFA, are working with industry partners to ensure that hazards are identified and controlled throughout various stages of food production. But despite the value our research brings to food safety, the continued suc- cess and growth of that system is currently being challenged on two fronts. In 2006, the total domestic food and agriculture R&D performed was just over $11 billion, with $5 billion from the public sector and $6 billion from the private sector. The public sector tends to do the more fundamental, precompeti- tive, public good research that does not provide an immediate “return on invest- ment,” while the private sector picks up the public-sector research and does the development that leads to new products and new technologies. We know that other countries, most notably China, are ramping up their investments in agriculture research just as the United States is cutting back. Historically, over much of the life of our 150-year-old public research system, the United States has been the leader in agriculture research, which has driven the evolution of science and technology. Recently that dedication has fallen off. This trend doesn’t bode well for our country, its health, the health of our economy, or our food safety research leadership. There is no country other than ours that holds the leadership position or the trust of the rest of the world to do this crucial research. Our research has a proven track record of success—now more than ever, policy needs to be as scientific as our science: evidence and performance based. Part of the issue here is that the USDA science agencies are suffering from a funding gap when compared to other U.S. government science agencies. As many of you know, much of USDA’s capacity for doing cutting-edge research depends on both the authorizing and appropriating cycles, and in the past several weeks we’ve seen a lot of activity on both fronts. On November 17, Congress approved the annual spending bill for USDA and it was signed into law the next day. While the final version emerging from Congress was not as damag- ing as the House Agriculture Appropriations Committee’s proposal earlier this year, this 2012 agriculture appropriations legislation continues the steady stream of cuts to agricultural science that started with the 2011 spending bill.

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368 IMPROVING FOOD SAFETY THROUGH A ONE HEALTH APPROACH On the authorizing front, with the demise of the “Supercommittee” process, it is expected now that the House and Senate Agriculture Committees will consider a reauthorization of the 2008 Farm Bill next year. As many of you may know, the Farm Bill process comes around every 5 years when existing authorities for the Department expire. Not every Farm Bill is expected to be as transformational for agricultural science as the 2008 Farm Bill, which created NIFA to be the foremost extramural agricultural research granting agency in the nation, as well as NIFA’s flagship granting program, the Agriculture and Food Research Initiative (AFRI). But every Farm Bill has a significant impact on research. More fundamentally than funding (and this is the second primary challenge), our country simply isn’t doing enough to educate a sufficient number of students in the STEM (science, technology, engineering, and mathematics) disciplines, and particularly in the food, agriculture, and natural resource sciences, to meet future demand. Over the past 30 years, the total number of Ph.D. recipients in agricultural fields has only remained constant, while the numbers of Ph.D.s awarded in other life science fields has grown. Because of the tight correspondence of grant fund- ing to graduate student training, it’s not surprising that flat funding of research leads to flat education of graduate students. Within agricultural disciplines, there has actually been a decline in the num- ber of Ph.D.s awarded in plant, animal, and forestry sciences while the number in environmental science has risen. So our education isn’t keeping up with our scientific needs. The private sector often highlights that it does not have the workforce needed for agricultural research—meaning that, at a time where jobs are in short supply for most of the population, there are jobs going unfilled in these crucial sciences. Training the scientists today to solve the food and agricultural challenges of tomorrow is one of the smartest investments we can make—must make—if we are serious about leading the world to a food secure future. At every turn, in every partnership, USDA science agencies are delivering on their mission to help ensure a healthy, productive, safe, and sustainable food and agricultural system, while protecting our precious natural and human resources. Now more than ever we cannot relent in our support for food and agricultural science, nor neglect to educate and train the future scientists who will take the advances made today to new heights. So we need to continue to stress the vital importance of this research and emphasize the benefits it brings to society. As awareness grows, sustained support for food and agricultural research will follow. I look forward to continue working with many of you here today to strengthen the ability of food and agricultural science to keep our food system safe and secure. Thank you.