Antibiotics Off the Beaten Path

As more antibiotic-resistant “superbugs” emerge, it’s clear that we desperately need new antimicrobial drugs. Yet, over the past couple of decades, antibiotic discovery has largely been stagnant.

“The reality is there’s almost no new antibiotics that are developed. And that’s because pharmaceutical companies have decreased their investment—in part because of the rediscovery issue,” explains bacteriology professor Cameron Currie.

The “rediscovery issue” refers to the fact that soil has historically been the prime source of new antibiotics—but it seems to be tapped out. When scientists screen soil microbes for new antibiotics, they keep finding the same compounds over and over again.

Currie is part of a team that is looking elsewhere.

Currie and his colleagues have been focusing their efforts on microbes that are associated with insects, plants and marine life from all around the United States, funded by a $16 million grant from the National Institutes of Health that was awarded in 2014.

“One of the major hurdles is finding new compounds, and that’s where we’re really excelling,” says Currie, a co-principal investigator on the grant. His partner is David Andes in the UW–Madison School of Medicine and Public Health.

At the front end, the work involves some good old-fashioned bioprospecting. Currie’s group, which is in charge of the terrestrial sphere, has gathered more than 2,000 flies, aphids, caterpillars, bees, ants and other insects, as well as mushrooms and plants, from locales near and far, including Alaska, Hawaii and Wisconsin’s Devil’s Lake.

Back at the lab, things get high-tech pretty quickly. Microbes are isolated from the samples and tested for antimicrobial activity. Promising strains undergo genetic sequencing that allows Currie’s group to determine how likely they are to produce novel antibiotic compounds. From there, other scientists involved in the grant go on to test the most promising compounds in a mouse model of infection. This approach has already yielded some exciting drug candidates.

“We have 9,000 strains to screen, and we have already found some new compounds that are effective at combating infections in mice and have low toxicity,” says Currie.

With so many samples to process, Currie’s group adopted bar code technology to help them keep track. They have a bar code reader—like you’d find in a grocery store— connected to a lab computer that they use to scan petri dishes, look up samples and add new data. For each microbial strain they’ve isolated, the database has photos of the “host” insect or plant, GPS coordinates for the collection site, assay results, genetic sequence and much more.

At this point, Currie feels confident that the project will pay off, and he’s eager to see one of the group’s compounds go into human clinical trials.

“If you find one new antibiotic that gets used in treatment, it’s a major success. You’re saving people’s lives,” Currie says.

To Market, to Market

If you’re familiar with the College of Agricultural and Life Sciences (CALS), you no doubt know all about Stephen Babcock and his test that more than 100 years ago revolutionized the dairy industry by providing an inexpensive, easy way to determine the fat content of milk (thus preventing dishonest farmers from watering it down). What you might not know is that his great discovery went unpatented. The only money Babcock received for his invention was $5,000 as part of a Capper Award—given for distinguished service to agriculture—in 1930.

Just years before Babcock received that award, another entrepreneur was hard at work in his lab—and his discovery would break ground not only in science, but also in direct remuneration for the university.

In 1923, Harry Steenbock discovered that irradiating food increased its vitamin D content, thus treating rickets, a disease caused by vitamin D deficiency. After using $300 of his own money to patent his irradiation technique, Steenbock recognized the value of such patents to the university. He became influential in the formation in 1925 of the Wisconsin Alumni Research Foundation (WARF), a technology transfer office that patents UW–Madison innovations and returns the proceeds back to the university.

Discoveries have continued flowing from CALS, and WARF plays a vital role for researchers wanting to patent and license their ideas. But today’s innovators and entrepreneurs have some added help: a new program called Discovery to Product, or D2P for short.

Established in 2013, and co-funded by UW–Madison and WARF, D2P has two main goals: to bring ideas to market through the formation of startup companies, and to serve as an on-campus portal for entrepreneurs looking for help. Together, WARF and D2P form a solid support for researchers looking to move their ideas to market. That was the intent of then-UW provost Paul DeLuca and WARF managing director Carl Gulbrandsen in conceiving of the program.

“The idea of D2P is to make available a set of skills and expertise that was previously unavailable to coach people with entrepreneurial interests,” explains Leigh Cagan, WARF’s chief technology commercialization officer and a D2P board member. “There needed to be a function like that inside the university, and it would be hard for WARF to do that from the outside as a separate entity, which it is.”

D2P gained steam after its initial conception under former UW–Madison chancellor David Ward, and the arrival of Rebecca Blank as chancellor sealed the deal.

“Chancellor Blank, former secretary of the U.S. Department of Commerce, was interested in business and entrepreneurship. D2P really started to move forward when she was hired,” says Mark Cook, a CALS professor of animal sciences. Cook, who holds more than 40 patented technologies, launched the D2P plan and served as interim D2P director and board chair.

With the light green and operational funds from WARF and the University secured, D2P was on its way. But for the program to delve into one of its goals— helping entrepreneurs bring their ideas to market—additional funding was needed.

For that money, Cook and DeLuca put together a proposal for an economic development grant from the University of Wisconsin System. They were awarded $2.4 million, and the Igniter Fund was born. Because the grant was good only for two years, the search for projects to support with the new funds started right away.

By mid-2014, veteran entrepreneur John Biondi was on board as director, project proposals were coming in and D2P was in business. To date, 25 projects have gone through the Igniter program, which provides funding and guidance for projects at what Biondi calls the technical proof of concept stage. Much of the guidance comes from mentors-in-residence, experienced entrepreneurs that walk new innovators down the path to commercialization.

“For Igniter projects, they need to demonstrate that their innovation works, that they’re not just at an early idea stage,” explains Biondi. “Our commitment to those projects is to stay with them from initial engagement until one of three things happen: they become a startup company; they get licensed or we hand them over to WARF for licensing; or we determine this project might not be commercial after all.”

For projects that may not be destined for startup or that need some additional development before going to market, the collaboration between WARF and D2P becomes invaluable. WARF can patent and license discoveries that may not be a good fit for a startup company. They also provide money, called Accelerator funding, for projects that need some more proof of concept. Innovations that may not be ready for Igniter funds, but that are of potential interest to WARF, can apply for these funds to help them move through the earlier stages toward market.

“Some projects receive both Accelerator and Igniter funding,” says Cagan. “Some get funding from one and not the other. But we work together closely and the programs are being administered with a similar set of goals. We’re delighted by anything that helps grow entrepreneurial skills, companies and employment in this area.”

With support and funding from both WARF and D2P, entrepreneurship on campus is flourishing. While the first batch of Igniter funding has been allocated, Biondi is currently working to secure more funds for the future. In the meantime, he and others involved in the program make it clear that the other aspect of D2P—its mission to become a portal and resource for entrepreneurs on campus—is going strong.

“We want to be the go-to place where entrepreneurs come to ask questions on campus, the starting point for their quest down the entrepreneurial path,” says Biondi.

It’s a tall order, but it’s a goal that all those associated with D2P feel strongly about. Brian Fox, professor and chair of biochemistry at CALS and a D2P advisory board member, echoes Biondi’s thoughts.

“D2P was created to fill an important role on campus,” Fox says. “That is to serve as a hub, a knowledge base for all the types of entrepreneurship that might occur on campus and to provide expertise to help people think about moving from the lab to the market. That’s a key value of D2P.”

Over the past two years, D2P, in collaboration with WARF, has served as precisely that for the 25 Igniter projects and numerous other entrepreneurs looking for help, expertise and inspiration on their paths from innovation to market. The stories of these four CALS researchers serve to illustrate the program’s value.

Reducing Antibiotics in Food Animals

Animal sciences professor Mark Cook, in addition to helping establish D2P, has a long record of innovation and entrepreneurship. His latest endeavor, a product that has the potential to do away with antibiotics in animals used for food, could have huge implications for the animal industry. And as he explains it, the entire innovation was unintentional.

“It was kind of a mistake,” he says with a laugh. “We were trying to make an antibody”—a protein used by the immune system to neutralize pathogens—“that would cause gut inflammation in chickens and be a model for Crohn’s disease or inflammatory bowel disease.”

To do this, Cook’s team vaccinated hens so they would produce a particular antibody that could then be sprayed on feed of other chickens. That antibody is supposed to cause inflammation in the chickens that eat the food. The researchers’ model didn’t appear to work. Maybe they had to spark inflammation, give it a little push, they thought. So they infected the birds with a common protozoan disease called coccidia.

“Jordan Sand, who was doing this work, came to me with the results of that experiment and again said, ‘It didn’t work,’” explains Cook. “When I looked at the data, I saw it was just the opposite of what we expected. The antibody had protected the animals against coccidia, the main reason we feed antibiotics to poultry. We knew right away this was big.”

The possibilities of such an innovation—an antibiotic-free method for controlling disease—are huge as consumers demand antibiotic-free food and companies look for ways to accommodate those demands. With that potential in hand, things moved quickly for Cook and Sand. They filed patents through WARF, collaborated with faculty colleagues and conducted experiments to test other animals and determine the best treatment methods. More research was funded through the WARF Accelerator program, and it became clear that this technology could provide the basis for a startup company.

While Cook didn’t receive funds from D2P to bring the product to market, he and Sand used D2P’s consulting services throughout their work—and continue to do so. Between WARF funding and help from D2P, Cook says starting the current company, Ab E Discovery, has been dramatically different from his previous startup experiences.

“D2P is a game changer,” says Cook. “In other cases, there was no structure on campus to help. When you had a technology that wasn’t going to be licensed, you had to figure out where to get the money to start a company. There were no resources available, so you did what you could, through trial and error, and hoped. Now with WARF and D2P working together, there’s both technical de-risking and market de-risking.”

The combination of WARF and D2P has certainly paid off for Cook and Sand. They have a team and a CEO, and are now producing product. Interest in the product is immense, Cook says. He’d like to see the company grow and expand—and stay in Wisconsin.

“It’s been a dream of mine to make Wisconsin a centerpiece in this technology,” Cook says. “I’d like to see the structure strong here in Wisconsin, so that even when it’s taken over, it’ll be a Wisconsin company. That’s my hope.”

Better Corn for Biofuel

Corn is a common sight in Wisconsin and the upper Midwest, but it’s actually more of a tropical species. As the growing regions for corn move farther north, a corn hybrid has to flower and mature more quickly to produce crop within a shorter growing season. That flowering time is determined by the genetics of the corn hybrid.

Conversely, delayed flowering is beneficial for other uses of corn. For example, when flowering is delayed, corn can produce more biomass instead of food, and that biomass can then be used as raw material to make biofuel.

The genetics of different hybrids controls their flowering time and, therefore, how useful they are for given purposes or growing regions. Shawn Kaeppler, a professor of agronomy, is working to better understand those genes and how various hybrids can best fit a desired function. Much of his work is done in collaboration with fellow agronomy professor Natalia de Leon.

“We look across different populations and cross plants to produce progeny with different flowering times,” Kaeppler explains. “Then we use genetic mapping strategies to understand which genes are important for those traits.”

Throughout his work with plant genetics, Kaeppler has taken full advantage of resources for entreprenuers on campus. He has patents filed or pending, and he has also received Accelerator funds through WARF. For his project looking at the genetics behind flowering time, Kaeppler and graduate student Brett Burdo received Igniter funds from D2P as well. The Igniter program has proven invaluable for Kaeppler and Burdo as they try to place their innovation in the best position for success.

“I found the Igniter program very useful, to go through the process of understanding what it takes to get a product to market,” says Kaeppler. “It also includes funding for some of the steps in the research and for some of the time that’s spent. I can’t fund my graduate student off a federal grant to participate in something like this, so the Igniter funding allowed for correct portioning of funding.”

The end goal of Kaeppler’s project is to develop a transgenic plant as a research model and license the technology, not develop a startup company. His team is currently testing transgenic plants to work up a full package of information that interested companies would use to decide if they should license the technology. For Kaeppler, licensing is the best option since they can avoid trying to compete with big agricultural companies, and the technology will still get out to the market where it’s needed to create change.

“In this area of technology transfer, it is important not only to bring resources back to UW but also to participate in meeting the challenges the world is facing with increasing populations,” says Kaeppler. “Programs like D2P and WARF are critical at this point in time to see the potential of these discoveries realized.”

A Diet to Treat Disease

Around the world, about 60,000 people are estimated to have phenylketonuria, or PKU. Those with the inherited disorder are unable to process phenylalanine, a compound found in most foods. Treatment used to consist of a limited diet difficult to stomach. Then, about 13 years ago, nutritional sciences professor Denise Ney was approached to help improve that course of treatment.

Dietitians at UW–Madison’s Waisman Center wanted someone to research use of a protein isolated from cheese whey—called glycomacropeptide, or GMP—as a dietary option for people living with PKU. Ney took on the challenge, and with the help of a multidisciplinary team, a new diet composition for PKU patients was patented and licensed.

“Mine is not a typical story,” says Ney, who also serves as a D2P advisory board member. “Things happened quickly and I can’t tell you why, other than hard work, a good idea and the right group of people. We’ve had help from many people—including our statistician Murray Clayton, a professor of plant pathology and statistics, and the Center for Dairy Research—which helped with development of the foods and with sensory analysis.”

Being at the right place at the right time had a lot to do with her success thus far, Ney notes. “I’m not sure this could have happened many places in the world other than on this campus because we have all the needed components—the Waisman Center for care of patients with PKU, the Wisconsin Center for Dairy Research, the clinical research unit at University of Wisconsin Hospitals and Clinics, and faculty with expertise in nutritional sciences and food science,” she says.

Ney is currently wrapping up a major clinical trial of the food formulations, referred to as GMP medical foods, that she and her team developed. In addition to those efforts, the new diet has also shown surprising promise in two other, seemingly unrelated, areas: weight loss and osteoporosis prevention.

“My hypothesis, which has been borne out with the research, is that GMP will improve bone strength and help prevent fractures, which are complications of PKU,” explains Ney. “I have a comprehensive study where I do analysis of bone structure and biomechanical performance, and I also get information about body fat. I observed that all of the mice that were fed GMP, whether they had PKU or not, had less body fat and the bones were bigger and stronger.” Interestingly, the response was greater in female compared with male mice.

To support further research on this new aspect of the project, Ney received Accelerator funds from WARF for a second patent issued in 2015 titled “Use of GMP to Improve Women’s Health.” Ney and her team, including nutritional sciences professor Eric Yen, are excited about the possibilities of food products made with GMP that may help combat obesity and also promote bone health in women.

“There is a huge market for such products,” says Ney. “We go from a considerably small group of PKU patients who can benefit from this to a huge market of women if this pans out. It’s interesting, because I think I’m kind of an unexpected success, an illustration of the untapped potential we have here on campus.”

Fewer Antibiotics in Ethanol Plants

Bacteria and the antibiotics used to kill them can cause significant problems in everything from food sources to biofuel. In biofuel production plants, bacteria that produce lactic acid compete with the wanted microbes producing ethanol. At low levels, these bacteria decrease ethanol production. At high levels, they can produce so much lactic acid that it stops fermentation and ethanol production altogether.

The most obvious solution for stopping these lactic acid bacteria would be antibiotics. But as in other industries, antibiotics can cause problems. First, they can be expensive for ethanol producers to purchase and add to their workflow. The second issue is even more problematic.

“A by-product of the ethanol industry is feed,” explains James Steele, a professor of food science. “Most of the corn kernel goes toward ethanol and what remains goes to feed. And it’s excellent animal feed.”

But if antibiotics are introduced into the ethanol plant, that animal feed byproduct can’t truly be called antibioticfree. That’s a problem as more and more consumers demand antibiotic-free food sources. But Steele and his colleagues have a solution—a way to block the negative effects of lactic acid bacteria without adding antibiotics.

“We’ve taken the bacteria that produce lactic acid and re-engineered it to produce ethanol,” says Steele. “These new bacteria, then, compete with the lactic acid bacteria and increase ethanol production. Ethanol plants can avoid the use of antibiotics, eliminating that cost and increasing the value of their animal feed by-product.”

The bacteria that Steele and his team have genetically engineered can play an enormous role in reducing antibiotic use. But that benefit of their innovation didn’t immediately become their selling point. Rather, their marketing message was developed through help from D2P and the Igniter program.

“Learning through D2P completely changed how we position our product and how we interact with the industry,” says Steele. And through that work with D2P, Steele plans to later this year incorporate a company called Lactic Solutions. “D2P has helped us with the finance, the organization, the science, everything. Every aspect of starting a business has been dealt with.”

Steele and his collaborators are now working to refine their innovation and ideas for commercialization using Accelerator funds from WARF. Steele’s work, supported by both WARF and D2P, is a perfect example of how the entities are working together to successfully bring lab work to the market.

“There is no doubt in my mind that we would not be where we are today without D2P,” says Steele. “On top of that you add WARF, and the two together is what really makes it so special. There’s nothing else like it at other campuses.”

With such a strong partnership campaigning for and supporting entrepreneurship at UW–Madison, CALS’ strong history of innovation is poised to endure far into the future, continuing to bring innovations from campus to the world. And that is the embodiment of the Wisconsin Idea.

 

To Eat It—Or Not

Food engineer Sundaram Gunasekaran, a professor of biological systems engineering, works with gold. But you won’t find the shiny yellow stuff in his lab; instead, the vials on his bench are mostly purple and red. Gunasekaran works with tiny pieces of gold—nanoparticles—that come in almost every color except gold. And those colors can tell a story.

Gunasekaran’s research focuses on food safety concerns, such as whether a food product was transported and stored properly or whether it has become contaminated. But how can a producer or consumer easily know a product’s history and whether it is
safe to eat? That’s where gold nanoparticles come in handy.

“The color of gold nanoparticles will change depending on the size and shape of the particle,” explains Gunasekaran. “At different temperatures, depending on how long you let the particles grow, they acquire different sizes and shapes. And that changes their colors.”

Gunasekaran’s lab is using those color changes for a difficult task—tracking the time and temperature history of a food product as it is packaged, transported and stored. Up to now similar sensors have given consumers some of this information, but they can miss such critical events as, for example, a short temperature spike that could be enough to kick-start the growth of a dangerous microorganism.

The sensors that Gunasekaran and his team are developing provide a more complete and accurate story. The new sensor can differentiate between food stored at high temperatures first and low temperatures second versus a product stored first at low temperatures and then at high temperatures. And that’s thanks to the properties of the gold nano-particles. The color of the first sample would be different than that of the second because of how and when the particles changed size and shape.

“We’re able to do this because the nanoparticle synthesis is affected by how the particles grow initially versus later,” explains Gunasekaran. “We call this the thermal history indicator, or THI.”

These gold nanoparticle sensors are being patented through the Wisconsin Alumni Research Foundation (WARF), and students in Gunasekaran’s lab won a UW–Madison Discovery to Product award. The student team also won a People’s Choice
award in the 2014 Agricultural Innovation Prize competition.

They are now working to further develop and optimize the system. Since different food products travel through different channels, some sensors will be best used to track long-distance travel over the course of a month, while others will track history for only a matter of hours. Some sensors will work best in frozen storage and others will be optimized for various room temperatures.

The goal of optimization is a simple-to-use biosensor customized for any given food product. Gunasekaran envisions the sensors—now being developed as self-adhesive dots or stickers—being used anywhere along the food production channel. Producers, packagers, transporters and even consumers could easily use the biosensors to understand the thermal history of their product, saving time and money and avoiding recalls and health issues.

“There are a number of ways to use this technology, and making a food product’s history easy to see is the key,” says Gunasekaran. “Food is being wasted because people are throwing it out according to an expiration date, or people are getting sick because they eat food that’s gone bad. Those things can be avoided by having a better product safety indicator.”

Give: Supporting Food Safety

When Kikkoman wanted to establish a naturally brewed soy sauce plant in Walworth, Wisconsin—an operation that was to become the world’s largest—the company had a top-notch consultant at CALS to help them out.

That expert was professor Edwin “Mike” Foster, a noted bacteriologist who was the first director of the Food Research Institute (FRI) and the person responsible for FRI moving to UW–Madison from the University of Chicago in 1966.

“Mike was invaluable in offering guidance on how to address and validate regulatory issues related to the safety of soy sauce as Kikkoman went through the process of gaining FDA approval,” says FRI director Charles Czuprynski. Over the years UW–Madison has continued to play a role in testing potential new uses of sauce and products derived in the fermentation process, he notes.

Out of long-standing gratitude, the Kikkoman Foods Foundation has named a new scholarship fund in Foster’s honor. The “Kikkoman Scholarship in Honor of Dr. Edwin (Mike) Foster,” as it is called, will be awarded by the FRI each year “to a deserving undergraduate student with a demonstrated interest in food microbiology and food safety,” says Czuprynski. The award amount will be in the range of $1,000 to $1,200.

Czuprynski regards the Kikkoman plant as a remarkable Wisconsin success story—and a tribute to Kikkoman’s long-range leadership vision, supportive relationship with their workers and cooperation with local businesses and communities. “This scholarship is just one example of their generous support of UW–Madison and the UW System,” Czuprynski says.

The UW Foundation maintains more than 6,000 gift funds that provide critical resources for the educational and research activities of CALS.

Contributions to the Kikkoman Scholarship in Honor of Dr. Edwin (Mike) Foster fund are welcome at http://go.wisc.edu/08c3m5.

If you wish to establish your own scholarship fund, contact Sara Anderson at the University of Wisconsin Foundation, sara.anderson@supportuw.org, (608) 263-9537.

To make a more general contribution to scholarships at CALS, visit the Agricultural and Life Sciences Scholarship Fund at http://go.wisc.edu/3q63sr.

Microbes & Human Health

Jim Steele used to be one of the skeptics. He’d be at a conference, listening to early research on the health benefits of probiotics. Steele scoffed at the small experiments. “We would literally try not to laugh in the audience, but we’d laugh pretty hard when we went out that night,” he admits.

But slowly the punch lines gave way to revelation. Steele, a professor in CALS’ Department of Food Science, conducts research on lactic acid bacteria, with a focus on Lactobacillus species. They’re important for human gut health, critical for the production of cheese and yogurts, and are the most common probiotic genus. He knew how incredibly useful they were, but still watched with a humbling disbelief as the data on the health potential of these microbes kept getting broader, deeper and more intriguing.

Our microbiota—what we call the totality of our bacterial companions—is ridiculously complex. Each human harbors a wildly diverse ecosystem of bacteria, both in the gut and elsewhere on the body. They have us completely outnumbered: where the typical body may contain a trillion human cells, your microbial complement is 10 trillion. They have 100 times more genes than you, a catalog of life potential called the microbiome. (The terms “microbiome” and “microbiota” are often used interchangeably in the popular press.)

While our initial, germaphobic impulse may be to freak out, most of these bacterial companions are friendly, even essential. On the most basic level they aid digestion. But they also train our immune system, regulate metabolism, and manufacture vital substances such as neurotransmitters. All of these things happen primarily in the gut. “In many ways the gut microbiota functions like an organ,” says Steele. “It’s extraordinarily important for human health,” with as much as 30 percent of the small molecules in the blood being of microbial origin.

Early research has suggested possible microbiota links to protecting against gastric cancers, asthma, numerous GI disorders, autoimmune disease, metabolic syndrome, depression and anxiety. And the pace of discovery seems to be accelerating; these headlines broke in just a few months last spring:
• Mouse studies suggested that the microbe Akkersmania muciniphila may be a critical factor in obesity;
• Kwashiorkor, a form of severe malnutrition that causes distended bellies in children, was linked to a stagnant microbiota;
• Risk of developing Type 2 diabetes was linked to an altered gut microbiota.

The catch: For all the alluring promise of microbes for human health—and it’s now clear they’re critically important—we have almost no idea how this complex system works.

The human gastrointestinal (GI) tract is a classic black box containing hundreds or thousands of species of bacteria (how many depends on how you define a species). There are viruses, fungi and protozoans. Add to that each person’s distinct DNA and their unique geographic, dietary and medical history—each of which can have short- and long-term effects on microbiota. This on-board ecosystem is as unique as your DNA.

Beyond these singularities, the action is microscopic and often molecular, and even depends on location in the GI tract. Most microbiota studies are done with fecal material. “Is that very informative of what’s going on in the ileum?” asks Steele, referring to the final section of the small intestine, which is thought to be the primary site where immunomodulation occurs. “From an ecosystem perspective, fecal material is many miles away from the ileum. Is it really reflective of the ileum community?”

Protecting our Pollinators

People and bees have a long shared history. Honeybees, natives of Europe, were carried to the United States by early settlers to provide honey and wax for candles. As agriculture spread, bees became increasingly important to farmers as pollinators, inadvertently fertilizing plants by moving pollen from male to female plant parts as they collected nectar and pollen for food. Today, more than two-thirds of the world’s crop plants—including many nuts, fruits and vegetables—depend on animal pollination, with bees carrying the bulk of that load.

It’s no surprise that beekeeping has become a big business in the farm-rich Midwest. Wisconsin is one of the top honey-producing states in the country, with more than 60,000 commercial hives. The 2012 state honey crop was valued at $8.87 million, a 31 percent increase over the previous year, likely due in part to the mild winter of 2011–2012.

But other numbers are more troubling. Nationwide, honeybee populations have dropped precipitously in the past decade even as demand for pollination-dependent crops has risen. The unexplained deaths have been attributed to colony collapse disorder (CCD), a mysterious condition in which bees abandon their hives and simply disappear, leaving behind queens, broods and untouched stores of honey and pollen. Annual overwintering losses now average around 30 percent of managed colonies, hitting 31.1 percent this past winter; a decade ago losses were around 15 percent. Native bee species are more challenging to document, but there is some evidence that they are declining as well.

Despite extensive research, CCD has not been linked to any specific trigger. Parasitic mites, fungal infections and other diseases, poor nutrition, pesticide exposure and even climate change all have been implicated, but attempts to elucidate the roles of individual factors have failed to yield conclusive or satisfying answers. Even less is known about native bees and the factors that influence their health.

Poised at the interface of ecology and economy, bees highlight the complexity of human interactions with natural systems. As reports of disappearing pollinators fill the news, researchers at CALS are investigating the many factors at play—biological, environmental, social—to figure out what is happening to our bees, the impacts of our choices as farmers and consumers, and where we can go from here.

Ann Berres-Olivotti

Ann Berres-Olivotti is a senior manager on the technical service team at Foremost Farms USA, where she primarily works in pharmaceutical lactose operations in the areas of quality assurance, process improvement and product functionality. “My favorite parts of the job are process improvements and educating end users regarding product capabilities,” she says. “Designing a practical process for a new product is one of the more exciting aspects of the job.”

Donald H. Burr

Keeping the public safe from emergencies or outbreaks involving biological, chemical or radiological contamination of food is all in a day’s work for Donald Burr, who is a captain in the U.S. Public Health Service assigned to the FDA’s Center for Food Safety and Applied Nutrition. Burr helped design the FDA’s Food Emergency Response Network (FERN), which coordinates the response of food-testing laboratories at the local, state and federal levels following an emergency or outbreak. FERN was formed following the highly publicized anthrax attacks of 2001, and since then Burr has remained involved in the agency’s food defense and counter-terrorism activities. “It’s been gratifying to see the effectiveness of this program when there have been threats to our food supply,” Burr says.

While earning his doctorate at CALS, Burr worked at the UW–Madison Food Research Institute, where he helped develop animal models for infant botulism. After graduating he decided to pursue careers in both the U.S. Navy and the U.S. Public Health Service. “That allowed me to continue in the field of public health microbiology while at the same time serving my country,” he says.

Kurt Fenster

As a manager in bioprocess development with Dupont Nutrition and Health, Kurt Fenster examines the effects of various strains of bacteria—lactic acid bacteria, bifidobacteria and propionibacteria—in manufacturing cultures for such products as probiotic dietary supplements, dairy cultures and silage inoculants.

“Scientifically, it is exciting to unlock the secrets of these strains,” says Fenster. “We’re creating superior products for our business units to bring to market—and, ultimately, our customers get the benefit.”

Virginia N. “Jenny” Scott

The Food Safety Modernization Act signed into law by President Barack Obama in January 2011 called for all kinds of new food safety regulations and guidelines—and Jenny Scott, as a senior advisor in the FDA’s Center for Food Safety and Applied Nutrition, serves as the technical point person for questions and consultation needs related to preventing hazards in food. In her position she develops and implements policies, regulations and guidelines related to food safety and provides technical expertise in a variety of food safety areas. She also leads the U.S. delegation at the Codex Alimentarius Committee on Food Hygiene. Codex is an international body whose food standards are recognized by the World Trade Organization in the resolution of trade disputes.

Tech Transfer Showcase

When CALS biochemistry professor Harry Steenbock experimented with vitamin D in the early 1920s, his work proved groundbreaking in more ways than one.

Steenbock’s discovery that he could increase the vitamin D content of foods through irradiation with ultraviolet light eventually eliminated rickets, a then-common and often deadly disease characterized by softening of the bone due to vitamin D deficiency.

With his own $300, Steenbock patented his discovery and offered it to the University of Wisconsin. When the university declined, Steenbock conceived of the idea to form a foundation to collect, invest and distribute money earned through research-based discovery—
a pivotal step in establishing the Wisconsin Alumni Research Foundation (WARF), the nation’s first university technology transfer office. WARF’s first licensing agreement with Quaker Oats in 1927 led to the fortification of breakfast cereals with vitamin D.

Since then WARF has patented nearly 2,000 university inventions. And—in the grand tradition of Steenbock—many of them stem from the labs of CALS scientists and alumni. Here we present some highlights from recent years.

Deltanoid

Though the term biotechnology was little known in his time, Steenbock was one of the world’s first biotechnologists—and he passed on that torch to his gifted graduate student, Hector DeLuca.

The path was not always smooth, and DeLuca hit some obstacles when his own seminal work on vitamin D in the 1960s led him to WARF. When he discovered the active form of vitamin D and chemically identified its structure, he was unable to file a patent due to unwieldy government restrictions. DeLuca eventually obtained a patent with the help of WARF patent attorney Howard Bremer and some influential people in Washington. That same group worked with federal legislators on the 1980 Bayh-Dole Act, which allowed nonprofit organizations to obtain patents spurred by federally funded research. As a result, WARF now holds more than 200 active patents from the DeLuca lab.

DeLuca is the founder of three spin-off companies, each stemming from his vitamin D work. Bone Care International, a maker of drugs to treat dialysis patients, was sold in 2005 to the biotech firm Genzyme for nearly $600 million. A second company, Tetrionics (now SAFC Pharma), was acquired by Sigma Aldrich Fine Chemicals in 2004 for close to $60 million.

Now DeLuca’s main focus is Deltanoid Pharmaceuticals, which he founded nearly 10 years ago with his fellow biochemistry professor (and wife) Margaret Clagett-Dame. The company is testing various vitamin D derivatives against osteoporosis, psoriasis, and kidney and autoimmune diseases, as well as other types of compounds to treat kidney failure. In clinical trials one vitamin D derivative seems to be highly effective in stimulating bone growth, and a number of other Deltanoid products are nearing the human testing phase.

With a business office located on Madison’s Monroe Street and about 10 employees, DeLuca describes Deltanoid as small but tenacious. “Our plan is to keep the company lean and mean until it has an income of its own,” he says.

TRAC Microbiology

Food contamination outbreaks generate headlines, especially when they result in illness or death. Virginia Deibel, while still a graduate student in food science and bacteriology at CALS, combined her interest in both subjects by forming TRAC Microbiology, a company that helps keep our food supply safe.

Deibel describes how it felt when TRAC played a pivotal role in identifying the type and location of bacteria that forced a shutdown in a large meat processing plant. The culprit turned out to be Listeria monocytogenes, the same bacteria that recently killed several dozen people who ate contaminated cantaloupes.

“We went in and found where the bacteria were harboring, removed it and tested that it was effectively gone. We then rewrote the client’s food safety programs, retrained all their employees and presented our corrective actions to the USDA,” Deibel recounts. “During the retraining phase I had employees coming up to me and thanking me for reopening the plant, which impacted entire families. That made me realize what we could do for a community.”

Deibel founded TRAC (for Testing, Research, Auditing and Consulting) 12 years ago. She was less than 18 months away from completing her Ph.D. when she began redirecting her energy toward writing a business plan and securing a start-up loan of $400,000.

“I knew from my work as a food scientist that there were many smaller companies that needed help with food safety,” says Deibel. “They simply did not have the necessary infrastructure to implement food safety systems.”

Initially TRAC services included helping food plants develop and update their food safety systems, train their quality assurance personnel and provide scientific justification for such practices as freezing, packaging and adding preservatives.

“Our original goals were to conduct research projects and provide food safety consultations,” says Deibel. But she soon discovered that many small food companies needed testing to meet customer requirements. That need inspired Deibel to expand its testing services, and TRAC, which eventually grew to 30 employees, soon succeeded in attracting larger clients from around the region.

Last fall Covance, one of the nation’s leading bioscience companies, announced the acquisition of TRAC Microbiology. Covance had paid close attention to TRAC and tapped Deibel to head development of its own food safety consulting division.

“Covance has excelled in so many different arenas—drug development, nutritional chemistry. I’m enjoying the challenge of helping such a respected company develop and grow a food microbiology arm,” says Deibel.

The Infection Eaters

Bacteriologist Marcin Filutowicz specializes in developing antimicrobial technologies that one day may help replace antibiotics—and save lives—as the power of our antibiotics arsenal wanes. But he doesn’t stop there. Filutowicz has founded or co-founded three biotech companies to help ensure that his technologies actually make it into the world’s hospitals. The idea for his newest venture, Amebagone, founded this year, sprung from his work investigating a collection of soil-borne amoebas assembled decades ago by UW bacteriologist Kenneth Raper, who is best known for helping ramp up penicillin production in time to save thousands of soldiers wounded during World War II.

Grow Magazine: Let’s start with the basics. What’s an amoeba?

Amoebas are unicellular organisms. They are not animals or plants or bacteria. They are protists, which is a whole separate group. And what they do, their sole purpose in life—as much as we can say—is to feed on bacteria. So this is their primary source of sustenance, and once they eat all of the bacteria in their environment they yell at each other—using chemical signals—and gather together.

On the Petri dish, you can see them swarming when they decide to aggregate. Initially, they form something that looks like a slug. It’s a community of a million or so amoebas that are packed together into a sack. The slug moves around looking for more food. If it can’t find anything to eat, the slug transforms into stalks and spores that get distributed by the wind. When the spores land on moist soil, they germinate and start eating the bacteria in the soil, and the process repeats itself.

How did you start working with these organisms?

For one of my companies, PlasmiGon, we needed access to libraries of small molecules to be successful. After screening a few libraries that were available to me, I started thinking about other potential sources of small molecules, and I realized that Ken Raper, who established the whole field of amoeba studies, had left a huge collection of amoebas in our department. This collection involves over 1,000 different amoebas gathered from five continents and several island nations. So it’s extremely diverse in terms of the geographical locations. It represents a huge resource of diversity of small molecules.

So my take was, why don’t we start reviving these amoebas and come up with techniques to look for useful small molecules produced by them? So we started opening those samples, some of them 70 years old. And then the issue was, well, how do you propagate them? Because, to be honest, I knew nothing about amoebas.

I went to a colleague and asked, “How do you grow these beasts? Do you grow them like bacteria?” And he said, “You feed them with bacteria.” The moment he said that—“You feed them with bacteria”—I went back to my office and I quickly computed all of the information I had learned over the past few days. I realized that this could be a new biotherapy because the particular amoeba we wanted to grow, Dictyostelium discoideum, is benign. There was no single report of it having adverse effects on humans, animals or plants. It’s an organism that you simply put alongside bacteria, and they do nothing else but eat it. I disclosed this to WARF in 2009, but they turned my disclosure down.

That’s surprising.

Not really. At the time, we didn’t have any proof-of-principle, no data, nothing. It was just an idea. But I decided that I could not let it die. I decided to form Amebagone and let that company patent the technology.

How do you picture amoebas being used in medicine?

Right now we’re focused on methicillin-resistant Staphylococcus aureus (MRSA). This MRSA is a major agent of nosocomial infections in hospitals. It kills a lot of people. And it happens that two billion people on this planet carry staph in their nostrils. It is part of our natural biota. They inhabit a very narrow area in our nostrils that has just the right temperature and salinity, so they are not all over. They are compartmentalized in a band or section of the nostrils.

And we all touch our noses. We can’t help it. As we touch, there’s moisture in there, and so we contaminate our fingertips. And after surgery, it’s natural to want to see the wound, and in many cases people accidentally self-contaminate the surgery site just by lifting up the dressing to look at it.

But if we can deliver amoebas to the nostrils pre-surgery, we can essentially decontaminate the nostrils of undesirable microbes. We did proof-of-principle experiments with MRSA, and amoebas eat MRSA like crazy. So even though antibiotics cannot kill MRSA, amoebas can.