FDA has released new regulatory processes for intentional genomic alterations (IGAs) in animals, citing the need to update due to evolving science and innovations in animal biotechnology. “These updated guidance documents demonstrate our commitment to facilitating innovation while ensuring product safety,” Tracey Forfa, director of FDA’s Center for Veterinary Medicine, said in a prepared statement. “These technologies hold great promise for many uses and public and animal health benefits, such as animal disease resistance, control of zoonotic disease transmission, improved animal husbandry, and increased food production and quality.”

Elizabeth Presnell, an attorney with Food Industry Counsel, tells Food Quality & Safety that IGAs in animals refer to modifications made to an animal’s genomic DNA using advanced molecular technologies, and FDA has established a risk categorization that splits IGAs into three categories based on risk to both animals and the food supply. “Category 1 is alterations not subject to approval; category 2 is going through a partial approval process where FDA will evaluate the risk and then determine whether or not the alteration needs to go through full approval; and then category 3 is where there is a risk to the food supply where a full approval will be undertaken.”

She explains that this will look a lot like what drug approvals currently undergo.

Mike Schmidt, an attorney from Schmidt and Clark who focuses on food safety and regulatory compliance, calls this a significant development that could have profound impacts on food safety in the years ahead. “This modernization could result in greater regulatory flexibility, pre­dictability, and efficiency,” he tells FQ&S. “For example, the FDA may not require developers of specific types of IGAs in animals to file an application or obtain FDA approval before marketing their product. This could speed up the introduction of these products to the market.”

Some experts believe that the expedited process may raise food safety concerns. While genomic changes can provide advantages such as disease resistance, heat tolerance, faster growth, and feed efficiency, they may also introduce new risks. “For example, changes that result in faster growth may have an impact on the nutritional value of the food produced by these animals,” Schmidt says. “Therefore, it’s crucial that these products are thoroughly evaluated for their potential impacts on food safety before they are introduced into the market.”

In this regard, FDA has established a memorandum of understanding with USDA to clarify roles and responsibilities for regulating IGAs in animals. “It’s an interesting action by FDA as there are critics on both sides,” Presnell says. “With animal agriculture geneticists saying this isn’t going far enough, and then people opposing it because some of the processes are easier to achieve.”

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Listeria monocytogenes soon may become easier to track down in food recalls and other investigations, thanks to a new genomic and geological mapping tool created by Cornell University food scientists. The national atlas will tell scientists where Listeria and other related species reside within the contiguous United States. This could help trace and pinpoint sources of the pathogen found in ingredients, food processing facilities, and finished products, according to research published in Nature Microbiology.

Knowing that the pathogen occurs naturally in soil, the researchers asked hundreds of scientists across the country to collect soil samples from generally undisturbed places in the natural world, such as the off-trail areas of state and national parks. From these samples, the group developed a nationwide atlas of 1,854 listeria isolates, representing 594 strains, and 12 families of the bacteria, called phylogroups.

“As we’re trying to figure out the risk of getting Listeria from soil and different locations, our group created a more systematic way of assessing how frequently different Listeria are found in different locations,” says senior author Martin Wiedmann, PhD, a food safety and food science professor in the Cornell University College of Agriculture and Life Sciences in Ithaca, N.Y. “We’ve studied Listeria in places as diverse as New York, Colorado, and California, but before this atlas, [it] was difficult to make comparisons and assess Listeria diversity in different locations.”

Lead author Jingqiu Liao, PhD, who worked in Dr. Wiedmann’s laboratory as a graduate student, is now a post-doctoral researcher at Columbia University. She found Listeria present across a wide range of environmental circumstances. This bacterium is controlled mainly by soil moisture, salinity concentrations and molybdenum—a trace mineral found in milk, cheese, grains, legumes, leafy vegetables, and organ meats.

“The goal of this work was to systematically collect soil samples across the United States,” says Dr. Liao, “and to capture the true large-scale spatial distribution, genomic diversity, and population structure of Listeria species in the natural environment.

“With whole genome sequencing and comprehensive population genomics analyses,” Dr. Liao says, “we provided answers to the ecological and evolutionary drivers of bacterial genome flexibility—an important open question in the field of microbiology.”

Dr. Liao says that this work can serve as a reference for future population genomics studies and will likely benefit the food industry by locating Listeria contaminations that may have a natural origin.

If the pathogen is found in a processing facility in the western U.S., for example, and that facility had used ingredients from a distant state, Dr. Wiedmann says, “Knowing the genomic information of Listeria isolates and their possible locations across the U.S., we can better narrow the origins to a specific region. You can use this information almost like a traceback; it’s not always proof, but it leads you to evidence.”

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On February 1, the CDC officially declared that the E. coli outbreak linked to Chipotle restaurants late last year was over, but not before the disease had sickened 58 people across 12 states. That was after hundreds of Chipotle customers had fallen victim to two norovirus outbreaks in California and Massachusetts. Not surprisingly, the chain’s stock price took a dive of 40 percent in early January and Chipotle announced it expected to lose 15 percent of its profits this year.

While the outbreak was winding down, the Consortium for Sequencing the Food Supply Chain (CSFSC) announced that chromogenic- and molecular-testing firm BioRad had joined their team. Formed out of a meeting between industry, government, and academic experts on food safety, the CSFSC is anchored in a collaboration between IBM Research and Mars Inc. and is working toward large-scale sequencing of the DNA and RNA of major food ingredients in order to help reduce outbreaks like those at Chipotle.

“As the food supply chain becomes more global and complex,” says Jeff Welser, vice president and lab director of IBM Research-Almaden in San Jose, “new, innovative approaches that use genetic data to better understand and improve food safety are emerging, holding the promise of unparalleled insight and understanding of the total supply chain.”

The goal of the CSFSC, he says, is to conduct the largest-ever metagenomics study to categorize and understand the growth and behaviour of microorganisms in a factory environment and help identify, interpret, and promote healthy and protective microbial management systems.

“Often, as in the case with Chipotle,” Welser says, “we don’t know there’s an outbreak until someone gets sick. By monitoring the microbiome, we hope it will be possible to identify changes earlier in the food supply chain, giving us a chance to react sooner. In other words, it’s possible the data could enable us to prevent pathogen contamination and spread before anyone succumbs to illness.”

The CSFSC’s scientists are beginning with a close investigation of the genetic fingerprints of organisms like bacteria, fungi, and viruses, and exploring the way they grow across a variety of environments. Subsequently, they will use big data analysis to investigate bacterial interactions.

BioRad is a supplier of rapid food-testing methods, software, and reagents, with which the CSFSC hopes to speed the progress of its testing. Welser adds that the consortium is also in talks with other prospective partners at the moment, and invites interested parties to contact them as well.

Norman Schwartz, president and CEO at BioRad, says that his company has made its name providing innovative approaches to life-science research and clinical diagnostics, as well as an expertise in applied microbiology.

“These two capabilities are very complementary to those of our partners of the consortium,” says Schwartz. “Bio-Rad hopes that the consortium will validate new food-testing approaches that could enlarge Bio-Rad’s product offering in this area and leverage a targeted NGS technology that Bio-Rad recently acquired.”  Welser, meanwhile, says the CSFSC’s findings will be published in public journals and shared globally with the food-safety community. “We will also be building tools and analytics the industry can implement in their normal operations,” he says.

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FDA has created and applied in real time public health use, a U.S.-based open-source whole genome sequencing (WGS) integrated network of state, federal, and commercial partners. The network, known as “GenomeTrakr,” represents the first distributed genomic food shield for identifying and tracing foodborne outbreak pathogens back to their source. In only its third year, GenomeTrakr is already enhancing investigations of outbreaks of foodborne illnesses and compliance actions, enabling more accurate and rapid recalls of contaminated foods, and monitoring of preventive controls effectively in the food manufacturing environment. The resulting public genomic database of foodborne pathogens can support dramatically investigators ability to link specific food products, processing sites, and farms, providing valuable insight into the origin of the contaminated food. GenomeTrakr essentially creates a searchable, digital high-resolution fingerprint of the complete genetic make-up of individual pathogens, permitting otherwise indistinguishable bacteria to be easily separated and identified.

“This [database] is clearly the most powerful approach yet developed for tracking and tracing pathogens, and we expect it to have a very significant positive impact on food safety,” says Steven Musser, PhD, deputy director for scientific operations at FDA’s Center for Food Safety and Applied Nutrition (CFSAN). Considering the limited number of FDA food inspectors and the global nature of the food supply, the development and continual building (adding sequences and metadata) of GenomeTrakr is essential.

The food safety impacts of this network are impressive. Its current membership includes 30 public health, food safety, and academic laboratories from federal, state, and international stakeholders. The network has already shown great promise in enhancing the traceability of food and feed supply contamination events at the national level including Salmonella and Listeria monocytogenes. Moreover, WGS of microbial pathogens is now supplanting traditional microbiological analytics with rapid single data output summaries for antimicrobial resistance profiling, detection of high risk virulence profiles, and general identification strategies that supersede serological, phenotypic, and classical culture testing making the technology critical for an effective public health response to bacterial outbreaks.

An Important Role for WGS

Recent devastating outbreaks associated with consumption of fresh-cut produce have reinforced the notion that foodborne disease remains a substantial global challenge to public health. Mitigating foodborne illness, at times, seems an intractable challenge. One longstanding problem is the ability to rapidly identify the food associated with the outbreak being investigated. Despite the best efforts of food safety experts, the tools available for tracking foodborne outbreaks were sometimes too slow or uninformative to effectively pinpoint the source of the outbreaks. With the limitations of traditional subtyping methods, federal public health and food safety laboratories are exploiting WGS to delimit outbreak scope, traceback to point source, and make early predictions about important traits that a pathogen may harbor such as antimicrobial resistance. Highly parallel robotic genomic sequencers can sequence the DNA of a bacterial pathogen in a matter of hours. When coupled with validated, analytical bioinformatic pipelines such as the one established by FDA’s CFSAN, accurate and stable genetic changes can be identified that can distinguish foodborne outbreak strains down to the source level including specific farms, food types, and geographic regions.

Eric Brown, PhD, director of the division of microbiology at CFSAN, compared the application of WGS for delimiting foodborne outbreaks to the impact that the Hubble Space Telescope had on our understanding of galaxies. “Can you imagine how astronomers felt the day the Hubble sent back its first pictures of the universe? This is exactly how we felt in 2009 when we applied WGS for the first time to a Salmonella-induced foodborne outbreak.”

Numerous recent published examples illustrate the ability of WGS to discern high-resolution genetic relatedness of otherwise indistinguishable isolates. Proof of principle studies have been undertaken using the technology at numerous public health institutes both nationally and internationally. So much so, the success of WGS for rapid source tracking of pathogens is now well documented. In 2012, 425 individuals in the U.S. became sick from ingesting food that contained either Salmonella Bareilly or Salmonella Nchanga. Through traditional epidemiology methods, the illnesses were ultimately linked to a frozen raw yellowfin tuna product known as Nakaochi Scrape, which had been imported from India. (Nakaochi Scrape is tuna backmeat that is scraped from the bones of tuna and may be used in sushi, sashimi, ceviche, and other similar dishes.)

As part of the outbreak investigation FDA performed WGS on Salmonella isolated from product samples and from clinical samples to determine their DNA makeup. This data helped to more accurately determine which illnesses were part of the outbreak and which illnesses were similar but unrelated. However, FDA also did something else—a retrospective analysis. It performed WGS on about a dozen Salmonella Bareilly isolates stored in freezers from previous Salmonella Bareilly food contamination events. What FDA found was that the Salmonella Bareilly DNA for the samples tied to the 2012 outbreak was very similar to the Salmonella Bareilly DNA isolated from shrimp that came from a processing plant in southwest India several years earlier. In fact, the plant that processed the Nakaochi Scrape was only about five miles away from the plant that processed the shrimp. This observation was significant as it indicated that the paring of genomic information with geographic information might have the potential to be a powerful tool for traceback investigations. This event provided the impetus for creating the GenomeTrakr network and the increased use of genomic information in foodborne outbreak investigations.

As noted by Marc Allard, PhD, the genomics-area coordinator for CFSAN’s microbiology program, “Our freezers are virtually full of Salmonella, Listeria, and other enteric pathogens collected as part of FDA’s own inspection and sampling work. These collections represent a virtual treasure trove of genomic diversity and are invaluable as reference strains in an ever-expanding whole genome sequencing database.”

GenomeTrakr: The Basics

In late 2012, FDA launched its GenomeTrakr network, the first distributed WGS network focused on the development of a highly informative, metadata rich, and fully transparent WGS database of environmental and food-associated enteric pathogens. In short, this database was launched to enhance our ability to use WGS to track foodborne pathogens. The network has created a publicly accessible global database containing the genetic makeup of thousands of foodborne disease-causing bacteria. CFSAN and the National Center for Biotechnology Information (NCBI) at the National Institutes of Health (NIH) collaboratively developed the necessary database and associated software tools. Much of this development continues to make genomic analysis more fully accessible to end-users from federal, state, academic, and industry sectors. Many of the state labs also are members of the Food Emergency Response Network putting them directly into many investigations of food contamination events. Our goal is to further enhance the network by growing the database while also adding more partners from public health, clinical, and regulatory agencies around the country as well as internationally.

The GenomeTrakr was originally comprised of labs in FDA/CFSAN, nine FDA Office of Regulatory Affairs field labs, and public health or agricultural labs from four states including New York, Florida, Washington, and Arizona. Data curation and bioinformatics support was provided by NCBI at NIH. In 2013, GenomeTrakr added labs from Minnesota and Virginia, and in 2014, brought onboard labs in New Mexico, Maryland, and Texas, and another New York lab. In addition, the CDC, USDA’s Food Safety and Inspection Service, academic departments of veterinary science and agriculture, public health laboratories, and several other state-related groups have now acquired WGS technology and are actively collaborating with FDA in the sequencing of food and environmental isolates of Salmonella, Listeria monocytogenes, and Shiga toxin-producing E. coli. Most of these laboratories are equipped with Miseq desktop sequencers, and CFSAN provides technical support for wet-lab and bioinformatic methods and a web-based communication tool for real time data sharing. Currently, sequences are streamed from individual state laboratory Miseqs to a CFSAN computer where they are quality checked and formatted for upload to the GenomeTrakr database. CFSAN is working with NCBI and commercial software vendors to develop simpler tools that will allow individual laboratories to add sequences to the public database directly.

A Paradigm Shift on Two Fronts

Everyone who has seen the potential of WGS applied to food safety microbiology realizes that the technology brings huge paradigm shifts for how enteric pathogens will be tested and how they are tracked back to their source. The first paradigm shift includes using the increased resolution from WGS to intervene earlier in investigations. The second paradigm shift involves the new ability to link isolates across multiple years, whereby low-level contamination events can be linked across geographic time and space. However, there is a third paradigm shift and it relates to how information is shared. The GenomeTrakr database is public, meaning that anyone in the world can freely contribute and obtain information from it.

“People like to focus on the technology as the paradigm shift but, in my opinion, a really important advance is the open data-sharing model,” exclaims Ruth Timme, PhD, FDA senior scientist and GenomeTrakr network principal coordinator. Of course, this approach would not prevent some aspects of the metadata to be held by individual organizations because of concerns about public release of proprietary information. The open database also allows FDA to go beyond the development of a source-tracking scheme. Several additional applications and benefits of the technology include: readily available antimicrobial resistance profiling to 98 percent accuracy; serological characterization without a need for classical antibody testing; virulence pathogenicity assessment for emerging bacterial pathogens; and, of course, high resolution subtyping, which has been its most widespread application to date.

“WGS is good because it can dig down deeper and identify the specific isolate and tell investigators what area or producer it could have come from,” says Capt. Palmer Orlandi, PhD, senior science advisor in FDA’s Office of Foods and Veterinary Medicine and member of the Commissioned Corps of the U.S. Public Health Service. Sample collection and sequence cataloging from food production sites can help monitor compliance with FDA’s rules on safe food handling practices and enhance preventive controls for food safety.

Ultimately, sequencing capability should be distributed to as many sites as possible so that public health laboratories can move sequences from their collections and current surveillance and inspection activities into the database as quickly as possible. Dr. Allard emphasizes that “this public approach provides useful data to industry and academic partners, as well as to any federal or international agency that wishes to add value to the collected data.” The current GenomeTrakr database contains sequences from roughly 14,000 Salmonella isolates and more than 3,300 Listeria isolates, and is growing by more than 700 new draft genomes per month. New phylogenetic trees showing emerging linkages and relatedness are produced daily by NCBI and are publicly accessible.

Casting a Broad Net

The GenomeTrakr has already expanded and benefitted from other important WGS projects being carried out by public health experts in the U.S. and abroad. The CDC’s Real-Time Listeria monocytogenes WGS pilot, which is sequencing all clinical cases of L. monocytogenes reported by the states since the fall of 2013 to enhance surveillance, is an example. FDA and other GenomeTrakr sites are working with CDC by contributing genomes of all food and environmental L. monocytogenes to the database. The work is making great strides in public health officials’ efforts to delimit illness clusters and sources of contamination caused by this dangerous pathogen.

Errol Strain, PhD, CFSAN’s lead bioinformaticist, puts a finer point on the importance of the collaboration with CDC. “To be able to go beyond what we once thought was a typical Listeria outbreak and now detect the outlying and more subtle contamination events caused by this pathogen is hugely impactful to food safety and public health.” This real time collaboration has increased the number of Listeria outbreaks discovered and characterized, and has reduced the time to detection and increased regulatory activity for this pathogen in a significant way.

While tracking and tracing foodborne outbreaks is a primary application of the GenomeTrakr network, it is essential to note the broad important uses of such a database to food safety stakeholders. For instance, academic and environmental microbiology partners are using the database to accumulate broad amounts of genomic information on enteric pathogens that thrive in and around agricultural environments. Technology partners are mining these data for novel genetic targets to incorporate into assay design for improved pathogen detection systems, and industry partners are using the technology to mitigate safe food production and processing systems. Effective monitoring of supply chain ingredients means downstream cost and material savings for industry if they catch problems earlier and understand the root cause of the contamination event so that they can fix the problem and prevent it from happening in the future. Moreover, being able to distinguish between resident, facility contaminations versus a reintroduction of a pathogen strain from raw materials is a hugely beneficial application of the technology as the preventative solutions are different depending on where the contamination is coming from. Finally, the cost savings potential through monitoring with high certainty and with multi-analytes in one test cannot be overstated.

What’s Next

Through numerous earlier case studies gathered from 2009 to the present and now weekly regulatory decision making, it is clear that WGS is validated and reproducible. Moreover, WGS will be adopted globally as the new method for foodborne pathogen surveillance and characterization. To be universal and comprehensive, more states and countries need to be added to the database and there needs to be a harmonization of the different networks being built both nationally and internationally. More work still is needed for successful implementation of a global food shield including: increased funding for instrumentation and training; issues surrounding data and metadata release into the public domain; harmonization among different authorities with sometimes distinct mandates and conflicting missions; and finally issues regarding validating alternative informatics approaches to interpreting the data. None of these barriers are insurmountable, and many believe it is only a matter of time until we will see a global food shield.

In Closing

The years 2014 and 2015 are watershed years for the use of WGS for food safety and public health in that many firsts were encountered as WGS left the research arena and entered into regular production and use across many state, federal, and international food safety agencies. Numerous successful applications of pathogen surveillance and characterization among academic, industry, and government partners has made WGS more prominent than ever and it has never been more apparent that the future lies with this technology. One can expect additional applications and greater impact as more partners join these efforts. These initial investments into the GenomeTrakr network, the new WGS technologies, and the hard work of many public health professionals are truly transforming the public health paradigm and these improvements will have long lasting benefits for the public and food safety.

Dr. Allard is a research microbiologist in the molecular methods and subtyping branch within the division of microbiology at the FDA’s Office of Regulatory Science. To reach him or to get in contact with the other authors, email marc.allard@fda.hhs.gov.

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A collaboration between Mars Inc. and IBM will merge the skills of both companies to investigate the genetic fingerprints of bacteria, fungi, or viruses that are impacting the safety of the global food supply. This collaboration, called the Consortium for Sequencing the Food Supply Chain, was announced in January.

The collaboration, which will include partners from other companies and from academia, will use advances in genomics to sequence the DNA and RNA of food samples, helping to understand how contamination begins. The goals of the metagenomics research are to categorize and understand microorganisms and the factors that influence their activity in a normal, safe factory environment. Investigators involved in the consortium will study how the microorganisms proliferate and interact in different environments, such as on countertops and in raw materials. Applications of the research will eventually extend throughout the entire food supply chain, from the transport system to processing facilities and distribution channels, restaurants, and farmers. By applying the science of genomics with analytics techniques, the consortium hopes to identify methods that could curtail foodborne illness and risks in food management.

As collaborators, scientists at Mars Inc. will gather the first data samples and IBM’s genomics, healthcare, and analytics experts will provide the large-scale computational and data system needed for this type of research. Dave Crean, the vice president of corporate research and development at Mars Inc., says in a recent interview in IBM’s Dispatches from a Smarter Planet that the project aims to “understand all of the relationships among all the life forms in a factory environment and learn the conditions that enable pathogens to thrive.”

“We are thinking that maybe the factory has a microbiome just like your body has a microbiome. If we can understand the relationships, we can potentially start to influence the microbiome by shifting the conditions in the factory,” Crean says.

This is not the first collaboration related to genomics between Mars Inc. and IBM. In 2008, the two companies collaborated with the USDA-Agricultural Research Service (ARS) to sequence and analyze the cacao genome. The aim of that project was to create healthier and more sustainable cocoa crops that would be more disease resistant and would produce higher yields. The preliminary findings of the cacao genome were announced in 2010, three years ahead of schedule. Information about the cacao genome is now being tested in field research that makes use of the data, according to the USDA-ARS.

Holliman is a veteran journalist with extensive experience covering a variety of industries. Reach her at kathy.holliman@gmail.com.

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