Cover Story

Gut Dwellers

CALS scientists delve into the microbial communities in our digestive tracts — and their implications for our health

New Clues to Healthy Bones for People with PKU

Posted on October 16, 2017 by gldavison

Individuals with the metabolic disorder phenylketonuria, or PKU, cannot metabolize the amino acid phenylalanine. Without careful dietary management, it can accumulate at high levels in their blood, leading to cognitive impairment, seizures, and other serious health problems.

There is no cure for PKU, and patients must adhere to a lifelong diet of medical foods that contain protein but are low in phenylalanine. Traditionally, these medical foods have been made using synthetic protein substitutes derived from mixtures of amino acids. But these amino acid- based medical foods could be contributing to the skeletal fragility seen in many PKU patients, according to a new study led by nutritional sciences professor Denise Ney and Bridget Stroup PhD’17.

The researchers also discovered that an alternative medical food, developed by Ney from a protein called glycomacropeptide (GMP) — a natural byproduct found in the whey extracted during cheese production — could allow PKU patients to manage their diets without compromising their bone health. This study represents the first human clinical trial comparing how different PKU-specific diets affect the bone health of people living with the disease.

Ney helped develop GMP-based foods for PKU patients just over a decade ago. In subsequent studies, she has shown that mice fed GMP-based diets have larger and stronger bones than mice on amino acid based diets. “It was a vital clue that there could be a link between amino acid medical foods and the skeletal fragility seen in many PKU patients,” says Ney, a researcher at UW–Madison’s Waisman Center.

For the current study, Ney and her research team assigned eight individuals with PKU to a diet of amino acid-based medical foods before switching them to GMP-based foods with a low dietary acid load. The researchers found that PKU patients had higher amounts of calcium and magnesium in their urine while on the amino acid based diet, a sign of bone breakdown, which can impair bone health.

“The amino acid medical foods have high acid loads, which can change the overall acid-base balance within the body,” Stroup says. Bones are able to buffer high acid loads in the body, but over time this leads to a breakdown and release of minerals. On the other hand, Glytactin (the trademarked brand name for the formulation used in the study) GMP medical foods do not have high acid loads.

Although the researchers did not directly measure bone breakdown and density in this study, other studies have found that reducing the acid content of diets leads to lower urine-calcium excretion and increased bone density.

These findings, Ney says, could also help patients with other kinds of metabolic disorders, like maple syrup urine disease. And although the sample size of the study was relatively small, it is typical of investigations into rare diseases; Ney hopes to secure additional funding for further study.

Ney is working on a larger clinical trial to study the metabolism of calcium and other minerals in PKU patients consuming amino acid or GMP medical foods. “We will be looking at bone health and also other physiological aspects, such as the gut microbiota,” she says.

Beyond Antibiotics

Posted on October 16, 2017 by gldavison

Since the beginning of their widespread adoption in the 1940s, antibiotics — the antimicrobial drugs we use to treat bacterial infections — have saved millions of lives. In recent years, however, misuse and overuse of these drugs in human medicine have helped put us on the path to a worldwide crisis. In this environment, harmful bacteria can evolve more rapidly, developing higher and higher levels of resistance. As a result, our “wonder drugs” are losing their effectiveness. This leads to longer and more complicated illnesses; greater risks for spreading infections; more hospital visits; the use of stronger, costlier, and more toxic drugs; and, ultimately, more deaths. Fortunately, scientists at CALS are facing this challenge head-on. From alternative forms of treatment to better methods of infection detection, here are some of the solutions they are working to bring to the world of modern medicine.

Friendly Microbes

Microbiologist Jan Peter van Pijkeren looks at probiotics — those microbes thought to provide health benefits in our bodies — as more than just friendly bugs. He sees them as a way to sneak in antibiotic-free treatment for disease-causing bacteria like Clostridium difficile.

Jan Peter van Pijkeren works with Laura Alexander, a doctoral student of microbiology, in his lab. (Photo by Tim Fitch)

Known as C. diff, this resilient gastrointestinal pathogen causes stomach pain, diarrhea, and potentially life-threatening inflammation of the colon. But by loading the probiotic bacterium Lactobacillus reuteri with viruses targeted at C. diff, van Pijkeren aims to deliver genetic instructions that cause the pathogen to self-destruct.

In an ironic twist of fate, C. diff often colonizes the gut after antibiotics wipe out the microbial communities that normally keep it at bay. Infections often happen in hospitals, where antibiotics are becoming more common. Additional antibiotic treatments targeting C. diff don’t always work, and the infection recurs in as many as 20 percent of patients.

“The downside of antibiotics is they are a sledgehammer that depletes and destroys the gut microbial community,” says van Pijkeren, an assistant professor of food science. “You want to instead use a scalpel to specifically eradicate the microbe of interest.”

Van Pijkeren thinks that L. reuteri, a probiotic bacterium found in many foods and the intestines of most animals, could be that scalpel. His team was able to amplify by 100-fold the natural ability of their strain of the bacterium to survive its trip through the harsh environment of the gut, making it a good candidate to deliver antibiotic-free treatments to the intestines where C. diff resides.

Van Pijkeren’s idea, in collaboration with Rodolphe Barrangou of North Carolina State University, is to use one of C. diff’s own defense mechanisms, called CRISPR, against it. CRISPR is a genetic surveillance system that bacteria use to protect themselves from invading viruses, which inject DNA into bacterial cells to attempt to replicate. If a bacterium has the right sequence of DNA to match an invading virus, it can use the CRISPR system to cut the viral DNA, thereby inactivating it and preventing infection.

Scientists have used this ability to cut specific sequences of DNA to genetically engineer a wide range of organisms for research aimed at developing new therapeutics. The van Pijkeren lab, which has been developing CRISPR to genetically engineer L. reuteri, now wants to co-opt the system by delivering DNA that targets C. diff’s own chromosome. That DNA will be injected by C. diffspecific viruses, which will hitch a ride with L. reuteri into the intestines.

If it works, C. diff will unwittingly cut and degrade its own DNA, preventing the pathogen from multiplying and doing more damage. Because both the viruses and the genetic instructions are targeted at C. diff, Pijkeren believes no helpful bacteria should be harmed.

Working with Barrangou and funding from the National Institutes of Health, van Pijkeren has engineered L. reuteri to produce viruses that target lactic acid bacteria, an initial step toward getting the probiotic to produce C. diff-specific viruses. They are also developing ways to induce the probiotic to release these viruses at the right time inside the gut. If these lab tests go well, van Pijkeren’s goal is to start testing the system in a mouse model of C. diff infection soon.

“I think it’s pretty fascinating that an organism like Lactobacillus in such low numbers and small amounts can actually have a health benefit,” van Pijkeren says. “To then exploit these microbes to deliver therapeutics is very appealing because we know humans have been safely consuming them for thousands of years.”

“Grazing” Amoeba

Bacteria have developed an uncountable number of chemistries, lifestyles, attacks, and defenses through 2.5 billion years of evolution. One of the most impressive defenses is biofilm — a community of bacteria enmeshed in a matrix that protects against single-celled predators and antibiotics. But there’s a way through every suit of armor, and professor of bacteriology Marcin Filutowicz has found one.

Along with Dean Sanders, presently at the Wisconsin Institute for Discovery, and patent co-inventor Katarzyna Borys, Filutowicz has shown the first proof that a certain group of amoeba called dictyostelids (“dicty”) can penetrate biofilms and eat the bacteria within. In a recent study, the researchers pitted four types of dicty against biofilm-forming bacteria that harm humans or plants. For example, they targeted Pseudomonas aeruginosa, a common, multidrug-resistant bacteria that afflicts people with burn wounds or cystic fibrosis, and Erwinia amylovora, the cause of a devastating disease known as fire blight in apple and pear trees.

As expected, the results depended on the strain of dicty and the bacterial species. In several cases, the dicty completely obliterated thriving biofilms containing millions of bacteria, all of it captured in time-lapse, microscopic movies, the first of their kind. In addition to the cinematic evidence (see video above), other indicators of successful attacks against all four species of bacteria include spore germination and the subsequent union of single-celled dicty into a multicellular “slug” (a striking trait that has earned dicty the label “social amoeba”).

Filutowicz became interested in dictyostelids after discovering a neglected archive of about 1,800 strains amassed by Kenneth Raper, a UW–Madison bacteriology professor who discovered the soil-dwelling microbes and started collecting them in the 1930s. He found that Raper and his team were feeding and growing dictys in the lab using bacterial prey, but nobody had pursued their commercial potential as microbe hunters.

“They grow on E. coli [a common resident of the human intestine], and I quickly realized that, because dicty are not pathogenic, we might use them as a biological weapon against bacteria.”

Marcin Filutowicz (Photo by Allan Attie)

Since 2010, Filutowicz has learned a good deal about how dicty “graze” upon bacteria, and which ones they prefer. “We looked at how these cells dismantle biofilms, trying to understand what physical, chemical, and mechanical forces deconstruct the biofilms, and how the dicty move in 3-D space,” he says. “These are phagocytes, and they behave much like our own immune cells, except our immune cells do not break down biofilms.”

His collaborator, Curtis Brandt, a professor of ophthalmology and visual science at UW–Madison, has produced promising results suggesting that the organisms are harmless to rodents. Now, the National Institutes of Health have given them and AmebaGone a $1.5 million grant to support their research on using dictys to fight bacterial keratitis, an eye infection, first in rodents and then in rabbits and humans.

“This medical application has a lot of promise,” Filutowicz says.

More near-term use for dicty are found in agriculture. In 2010, Filutowicz formed AmebaGone. With funding from the National Science Foundation, the firm has been advancing dicty products toward commercializations, including treatments for fire blight and other bacterial infections of crops.

“Our 2017 external field trials for fire blight treatments were very promising,” says Chad Hall, a senior scientist and director of AmebaGone’s fire blight project. “Several of our dicty-based products reduced fire blight disease without harming either trees or fruit. In fact, one of our treatments was as effective as the antibiotic streptomycin, which is the gold standard treatment for fire blight control in conventional apple orchards but is now banned in organic apple production.”

Infection Detection

One way to prevent the overuse of antibiotics, and the drug resistance it creates, is to determine when treatment is not needed. And that’s one of the benefits of a new system developed by Isomark, a UW–Madison spin-off company, and its founder, Mark Cook.

Isomark’s system measures carbon isotopes in exhaled breath. Without even touching the patient, it can offer the earliest warning of severe bacterial infection, says Cook, a professor of animal sciences. He founded the company in 2005 along with Warren Porter, a professor of zoology; nutritionist Dan Butz; and others.

Their novel detection device can often spot a bacterial infection before the patient feels symptoms, increasing the potential for faster, better treatment for severe infections. The company is focused on intensive care units (ICUs), which treat about 5 million people in the United States each year.

Antibiotic-resistant bacteria like MRSA (methicillin-resistant staph aureus) are an accelerating problem in hospitals, says Isomark CEO Joe Kremer. “The average hospital stay is five days, but it’s 20 days with a hospital-acquired, resistant infection. The healthcare industry puts the cost of diagnosis, treatment, and the extended stay at $35 billion to $88 billion.”

Isomark’s analytical instrument offers earlier detection of bacterial infection by measuring the ratio of carbon isotopes in patients’ breath samples. (Photo by Ben Vincent)

These figures do not account for the pain, worry, and deaths associated with these severe infections. About 100,000 Americans die of a hospital-acquired infection each year, Kremer says, and ever-more stringent controls have not brought the problem to heel. But earlier detection may help.

When the immune system responds to an infection, subtle changes in the ratio of the common carbon 12 isotope and the rare carbon 13 can be detected long before a doctor, a blood test, or even the patient knows that an infection is present. (Isotopes are chemically identical versions of an element that can be distinguished by their differing masses.)

After gathering breath samples and medical records from 100 ICU patients, Isomark scientists saw a telltale change in the isotope ratio for each patient who became ill. “Our studies show that we are 18 to 48 hours ahead of when clinicians suspect an infection,” Cook says.

Rapid detection offers multiple benefits, he adds. This includes earlier treatment, which can reduce the ill effects that come with a severe infection, and earlier guidance for physicians about the need for tests to determine the location and cause of an infection. It can also lead to less antibiotic use.

Because bacterial infections are a major hazard in ICUs and operating rooms, “Antibiotics may be thrown at every patient after surgery as a preventive, but that is actually breeding resistance,” Cook says. “If a breath test comes back negative, antibiotics may be unnecessary.”

Since the test measures nonradioactive isotopes in exhaled breath, the procedure is noninvasive and safe. And the testing process could hardly be simpler. The patient breathes into a bag, or a sample is grabbed from a ventilator. The bag is connected to the tester, the patient ID is punched in, and results appear in 10 minutes.

Isomark is seeking FDA approval as a medical device and is gearing up for a final “regulatory trial” that will look at 300 patients in up to six hospitals nationwide. “We can’t be sure about the FDA’s decision, but the agency has been very positive,” Kremer says. A decision could arrive in January 2018.

EDITOR’S NOTE

We are sad to report that Professor Mark Cook passed away in early September due to complications of cancer. He will be deeply missed by the CALS community and beyond. Read more about his life and distinguished career as a teacher, mentor, entrepreneur, and groundbreaking researcher in the realms of food production and animal health.

To Market, to Market

Posted on July 1, 2016 by intern

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.

Safer Nanotech

Posted on July 1, 2016 by intern

Although so tiny they are invisible, it’s easy to see that nanomaterials are becoming a big thing. There are odor-fighting socks and antibacterial dishrags impregnated with silver nanoparticles. Nano-sized titanium dioxide can be found in a long list of food and consumer products, including salad dressing, cake frosting, toothpaste and sunscreen. The vibrantly colored screen of the Kindle Fire can be attributed to quantum dots, a.k.a. nano-scale crystals of semiconductors such as cadmium selenide. And the list goes on.

Nanomaterials are tiny by definition, measuring between 1 and 100 nanometers along one or more dimension. (By comparison, a human hair is approximately 100,000 nanometers in width.) At this scale, they possess unique physical and chemical properties that make them useful for a wide array of applications, including consumer products, environmental remediation and medicine. Yet there are many unanswered questions about their safety.

“We don’t know a lot about the toxicity of nanomaterials, and we have much to learn about the potential risks associated with the release of these materials into the environment,” says Joel Pedersen, Rothermel Bascom Professor of Soil Science at CALS.

Pedersen is part of a collaborative, multidisciplinary research team exploring these unknowns as part of the UW–Madison-based Center for Sustainable Nanotechnology, which was founded in 2012 with support from the National Science Foundation. Center scientists are working to understand how nanomaterials interact with living systems and the environment, with the practical goal of developing the insights needed to start creating nanomaterials that are designed to be more environmentally benign. This includes re-engineering them to make them safer, if needed.

With expertise in chemistry, biology and engineering, Pedersen is in charge of the Center’s efforts to develop laboratory models to assess the biological impacts of nanomaterials. While he has done some experiments in zebrafish, Pedersen’s work for the Center focuses on innovative, non-biological approaches, including creating “artificial cell surfaces” in the lab.

“Our intent is to get down to the molecular level,” Pedersen explains. “What are the rules that govern how these materials interact with biological systems? In particular, how do these particles interact with cell membranes?”

One way Pedersen’s group makes artificial cell surfaces is by depositing lipid vesicles on a special quartz crystal sensor until the vesicles spontaneously rupture and then fuse to form a lipid bilayer—the basic structure of a cell membrane—on the sensor’s surface.

When electricity is applied to the sensor, it causes the system to vibrate at a particular frequency. Next, Pedersen’s team applies nanomaterials to the artificial cell surface. The sensor can detect subtle changes in the frequency of the vibration, yielding clues about the interaction between the material and the membrane.

By combining the results of this approach with others, Pedersen is finding that some nanoparticles, by virtue of their unique physical and chemical properties, seem to be able to extract lipids from the cell surface.

“Our results are consistent with the idea that these nanoparticles are grabbing lipids out of the membrane and acquiring a lipid coating when they come in contact with a cell,” explains Pedersen.

This cell membrane-disrupting behavior is a concern for the health of humans and animals. And while Pedersen’s team hasn’t observed this behavior in models of bacterial cell surfaces, there are other, broader concerns about the impacts of nanomaterials on microbial communities in the environment.

“Eukaryotes are our main focus, but there is some concern that nanomaterials in the environment can alter microbial community compositions. At present, we don’t know to what extent such changes could be problematic,” says Pedersen.

The information gained from Pedersen’s research will help inform the work of other scientists in the Center for Sustainable Nanotechnology who focus on tweaking nanoparticles to make them safer.

“Ultimately, the goal is to redesign nanomaterials to minimize their adverse effects, or find better ways to embed them in materials so they aren’t released into the environment,” Pedersen says.

CRISPR: The Promise and the Peril

Posted on July 1, 2016 by intern

DIETRAM SCHEUFELE, a CALS professor of life sciences communication, serves on a national panel examining the implications of human genome editing.

The committee, appointed late last year by the National Academies of Sciences, Engineering and Medicine, is examining the clinical, ethical, legal and social implications of the emerging technology. Genome editing holds great medical promise but also poses risks of off-target genetic alterations and raises fears it could irrevocably alter the human germline.

Led by UW–Madison law professor Alta Charo and MIT biologist Richard Hynes, the committee will specifically advise on questions about how risks should be quantified and whether some aspects of the technology should or should not go forward.

The ability to “edit” genes to target genetic defects became a much more plausible process with the advent of a technology called CRISPR (an acronym for Clustered Regularly Interspaced Short Palindromic Repeats), which can be used to precisely target and cut portions of a DNA sequence.

Controversy arose last year when a Chinese scientific team used CRISPR genome editing on non-viable human embryos. The experiment produced a number of “off-target events” that altered unintended parts of the genome.

Scheufele has published extensively in the areas of public opinion, political communication and public attitudes toward emerging technologies, including nanotechnology, synthetic biology, stem cell research, nuclear energy, and genetically modified organisms. Web of Science lists Scheufele’s publications among the 1 percent most-cited articles in the fields of general social science and plant and animal science. Scheufele also serves on two other committees for the National Academies of Sciences, Engineering and Medicine: a committee on “The Science of Science Communication: A Research Agenda,” and the Division on Earth and Life Studies (DELS) Advisory Committee.

What’s the focus of your panel?

The committee that I serve on deals with human gene editing research and its potential applications. That includes potential future uses that could alter the human germline, which means that edited genes would be passed on to subsequent generations as part of the human gene pool.

But of course there are a lot of applications of gene editing techniques in agriculture and the life sciences, with the attempts to use genetically modified male mosquitoes to combat the spread of the Zika virus being just one recent example.

What are the potential dangers?

Identifying potential problems or concerns is part of the committee’s charge, and our report will work very carefully through both the scientific complexities of the technology as well as ethical, regulatory or political challenges that might emerge. Many of these challenges are focused on specific applications, such as germline editing. Once germline alterations are introduced into the human population, some have argued, they might be difficult to reverse and to contain within a single community or even country.

In many ways, the benefits are much more clear-cut, especially when it comes to helping parents whose genome puts their biological children at risk of inheriting certain diseases. Many patient advocacy groups are especially excited about the potential for medical breakthroughs in this arena.

What is the charge of your study committee? Are there specific deliverables, and what is the timeline?

The National Academies gave the committee a fairly detailed Statement of Task that can be found on our committee’s web page [link provided below]. In short, we will examine the state of the science of human gene editing as well as the ethical, legal and social implications of its applications in biomedical research and medicine.

Our work actually follows a pretty tight timeline that includes a number of additional meetings and informationgathering sessions. Most of the committee deliberations are open to the public and webcast by the National Academies. Once complete, the draft report will be vetted in a very stringent review procedure. There also have been and will continue to be numerous opportunities for formal public input, including on the draft report. If everything goes according to plan, the report will be released in fall 2016.

What role will you play on it as a communication scientist? What expertise do you bring to the table?

Human gene editing shares a number of characteristics with other recent scientific breakthroughs. One of them is an extremely fast bench-to-bedside transition. In other words, the time it takes to translate basic research into clinical or even market applications is shorter than it has been in the past. New gene editing technologies such as CRISPR provide us with faster, cheaper and more accurate tools for gene editing. But that also means that we as a society must have many of the ethical, legal and social debates surrounding gene editing at the same time that we are developing potential applications.

That is why more and more scientists are calling for what Alan Leshner, former CEO of the American Association for the Advancement of Science, has described as an “honest, bidirectional dialogue” between the scientific community and the public. Interestingly, the 21st Century Nanotechnology Research and Development Act of 2003 legislatively mandated public engagement through “regular and ongoing public discussions.” So the idea is not new, and researchers in the Department of Life Science Communication (LSC) at CALS were in fact involved in two long-term NSF center grants examining the societal impacts of nanotechnology and ways of building a better public dialogue. As a result, much of the research teaching we are doing here in the department focuses on how to best facilitate communication about emerging science among all relevant stakeholders in society.

What experiences from past science communication efforts inform your thinking about how best to communicate about gene editing?

Much of our work in LSC over the last few years has examined emerging areas of science that are surrounded by public opinion dynamics similar to what we might see for gene editing. This research has included work on public opinion on embryonic stem cell research, and also research on how non-expert audiences make sense of the risks and benefits of genetically modified organisms. Our research program has also led to regular engagements with policy communities in Wisconsin and in Washington, DC. When I co-chaired the National Academies’ Roundtable on Public Interfaces of the Life Sciences, for instance, I worked with bench scientists, social scientists and practitioners to build a better dialogue about emerging technologies between scientists and the public. g What aspects of gene editing seem to confuse or frighten people the most? We just collected two representative national surveys, tapping people’s views on synthetic biology, gene editing and other scientific breakthroughs. And our findings show that concerns about overstepping moral boundaries with potential applications of gene editing in humans and “blurring lines between God and man,” as the question was phrased, are definitely on people’s minds when thinking about this new technology. In LSC, we will continue to track public attitudes, especially surrounding the societal, ethical and regulatory questions that arise from applications of gene editing.

Obviously people are already reporting, writing, thinking and talking about CRISPR. Do you have any immediate recommendations for how to communicate about this subject?

It will be particularly important to keep two things in mind. First, this is an exciting area for science, but many of the questions and debates surrounding human gene editing will focus on ethical, moral or political rather than scientific questions. And we as scientists should be prepared to engage in those discussions, making sure that they are based on the best available science.

Second, having an honest dialogue among different stakeholders will require a conversation that is—at least in part—about values. And scientists will have to resist the intuitive urge to try and convince others by offering more scientific facts. Our own research and that of many colleagues has shown that the same scientific information will be interpreted very differently by audiences with different value systems. The same science, in other words, means different things to different people. And public reactions to many potential applications of gene editing will be no exception. g

PHOTO – Dietram Scheufele, professor of life sciences communication.

Photo by Sevie Kenyon

Training to Make a Difference

Posted on July 1, 2016 by intern

People have around 40 productive years during adulthood to make a positive impact on the world, according to Howard G. Buffett in his book, 40 Chances: Finding Hope in a Hungry World.

It’s a concept that Kate Griswold BS’16, who graduated in May with a degree in life sciences communication, is keenly aware of.

Griswold was among 40 college students nationwide selected in 2012 to participate in the nonprofit Agriculture Future of America’s 40 Chances Fellows program. The goal of the four-year program, funded by the Howard G. Buffett Foundation’s 40 Chances awareness campaign, is to prepare young people to address global agriculture- and food-related challenges.

“I’m passionate about international food security and transparency in the American agricultural system,” says Griswold. “Thanks to my experiences, I feel excited and ready to go out into the workforce and help contribute to the conversations—and solutions—related to these important topics.”

Griswold and her cohort participated in leadership conferences, agricultural institutes, career mentoring sessions and professional development workshops. The program culminated in a two-and-a-half-week international experience—which, for Griswold and eight other students, meant going to Bolivia.

Guided by native Bolivians, the students visited processing plants and production facilities as well as farmers in various regions. Two of the country’s main crops are soybeans and quinoa, a small, gluten-free grain that is highly nutritious and growing in popularity worldwide. But according to Griswold, “Bolivia, which is one of the biggest producers of quinoa, is still one of the poorest countries in South America.”

A key lesson, Griswold says, is that education alone is not enough to change the standard of living and way of life in other cultures.

“The fact that there isn’t an easy fix to get people out of poverty is something I’ve learned to appreciate a lot more,” says Griswold. “I now have a much better understanding of the time it takes to implement change and the trust that needs to be built with the local people in order to do so.”

As a fresh graduate, Griswold is using the first of her 40 chances by joining John Deere as a marketing representative.

Photo Credit – Kate Griswold

Catch up with Andrea Garber

Posted on July 1, 2016 by intern

Andrea Garber, PhD,

As a professor of pediatrics at the University of California, San Francisco, Andrea Garber BS’92 PhD’99 conducted a groundbreaking study concerning a very vulnerable group: patients hospitalized with anorexia nervosa, an eating disorder that often proves fatal. It is most prevalent among teenage girls and young women.

Garber and her team discovered that the standard “refeeding” protocol used in hospitals nationwide—that is, the necessarily careful reintroduction of food to patients who have been starving themselves—was too low in calories and was in fact causing patients to continue losing weight even during longer hospital stays. The phenomenon had been long observed, but Garber’s study, published in 2012 and based on the largest cohort of its kind, was the first to actually prove it.

• What makes this work so critical?

Anorexia nervosa is the most deadly psychiatric illness. It has a mortality rate of 5 to 6 percent, which is the highest among all psychiatric diagnoses, and the recovery rates are really low. Studies that are using the absolute best forms of treatment and psychotherapy still show that maybe only 30 percent at the lowest— but at the highest, half—of patients are recovered at one year. So we absolutely need to develop better treatments.

• What protocols do you think will be more effective?

In a new five-year study, we are testing a higher-calorie refeeding protocol, starting at 2,000 calories per day and advancing quickly by 200 calories per day. We’ll compare this to a group receiving a lower-calorie protocol, starting at 1,400 calories per day and advancing slowly by 200 calories every other day. This lower-calorie diet is in fact a little higher than the traditional recommendation to start at 1,200 calories.

• Why have such low-calorie diets been used with anorexia patients?

For safety. “Low and slow” refeeding is believed to minimize risk for the refeeding syndrome, which was first documented around the time of World War II. It’s characterized by life-threatening shifts in fluids and electrolytes that can occur when nutrition is reintroduced in starved patients. At UCSF and our collaborating site at Stanford, we are set up for a high degree of medical management and we can carefully monitor for any signs of refeeding syndrome. The main one is electrolyte shifts, which our physicians check every day and correct as needed with supplements. A key question is, how much medical intervention is needed to keep higher-calorie refeeding safe? That’s important to know before disseminating these protocols to other settings, such as residential treatment facilities.

• Do these protocols have implications for patients after hospital discharge?

We’re looking very closely at relapse rates. Forty percent of these young people relapse within one year of their first hospitalization. If higher-calorie refeeding gives us shorter hospital stays, but these kids end up coming right back, then we’ve undone any potential benefit of that shorter stay. While the higher-calorie refeeding seems promising in terms of faster weight gain and shorter hospital stay, there are many unanswered questions about potential long-term benefits, long-term risks and the overall effect on recovery.

PHOTO – Andrea Garber BS’92 PhD’99 Nutritional Science

A Jolt to the System

Posted on March 4, 2016 by jfischer

As a linebacker for the UW–Madison Badgers, Chris Borland made a name for himself as a hard-hitting tackler. His senior year, he was selected as a first-team All-American as well as the top linebacker and defensive player in the Big Ten Conference.

A third-round draft pick, Borland seemed destined for a headline career in the National Football League. But during a full-contact practice at the San Francisco 49ers summer training camp in August 2014, Borland got his “bell rung” by a 290-pound fullback during a routine exercise. Though Borland felt dazed, he played through—as he’d done dozens of times before.

Like many football players, Borland had endured his share of hard hits, including two diagnosed concussions. This particular hit, however, got him thinking seriously about the future, and about the negative effects that repeated collisions could have on his long-term physical and cognitive health. Even so, he went on to play a dynamite rookie year.

Then, after the season was over, Borland quit.

The announcement shocked the sports world. Borland was 24 years old and healthy, yet chose to walk away from a $2.3 million, four-year contract.

“I just honestly want to do what’s best for my health,” Borland explained on ESPN’s Outside the Lines. “From what I’ve researched and what I’ve experienced, I don’t think it’s worth the risk.”

With their repeated hits, football players—along with boxers—are at increased risk of developing chronic traumatic encephalopathy (CTE), a degenerative brain disease marked by memory loss, depression, suicidal thoughts, aggression and dementia. Of 91 brains donated to science by former NFL players, 87 have tested positive for CTE. It’s seen as a likely contributing factor to nine suicides by current and retired football players over the past decade.

Borland didn’t want to share that fate.

“To me, Chris Borland is a hero. He walked away before he made the big bucks and he was very explicit about why he quit—that it was not worth it to him,” says CALS genetics professor Barry Ganetzky, whose findings about the central nervous system in fruit flies are shedding light on what hard hits do to humans.

Ganetzky isn’t a sports guy, but he started paying attention to football-related brain injuries after the 2012 suicide of New England Patriots linebacker Junior Seau, intrigued by the biological processes driving this tragic phenomenon.

“I started wondering, what’s the link between a blow to the head and neurodegeneration 10 or 20 years down the line? When I started digging into the scientific literature, it became clear that we know very little,” says Ganetzky, who held the Steenbock Chair for Biological Sciences for 20 years. “And my usual response is, well, if we don’t understand something about the brain, then we should be studying it in flies.”

Fruit flies, officially known as Drosophila melanogaster, are a widely studied model organism, with a vast arsenal of genetic and molecular tools available to support that work. Flies reproduce rapidly and are easy to work with, enabling swift research progress. They are well suited for brain research because they have nerve cells, neural circuitry and a hard skull-like cuticle remarkably similar to our own, allowing scientists to conduct probing experiments that would be difficult in rodent models—and impossible in human subjects.

Fly models already exist to study Alzheimer’s, Parkinson’s and a number of other neurological diseases. Why not concussion? But there wasn’t a model available.

Then Ganetzky remembered work he’d done decades earlier.

“It occurred to me that I knew how to make flies have a concussion, and I had done it 40 years ago as a post-doc,” says Ganetzky. “I thought, ‘That’s it!’”

It was a simple thing: As a post-doctoral researcher at the California Institute of Technology, Ganetzky decided to see if any of his flies happened to be bang-sensitive mutants, flies that display seizures and paralysis after given a high-powered swirl on a vortex machine. But he didn’t have a vortex nearby, so he decided to just bang the vials against his hand.

“After a couple of sharp whacks, some of the flies were hanging out at the bottom of the vial, stunned. Others were on their backs, obviously knocked out. And after a few minutes, they all got up and started walking around again,” recalls Ganetzky.

He immediately knew the flies weren’t bang-sensitive—it’s an extremely rare mutation—but Seau’s death helped Ganetzky realize they had displayed symptoms “very similar in many respects to the empirical definition of a concussion.”

After developing and validating the new fly model, Ganetzky and UW genetics professor David Wassarman have been able to charge forward with brain injury research. The model has already been used to reveal key genes involved in the body’s response to brain injury. It’s also poised to help unlock medical applications, including a genetic test for high-risk individuals and an assortment of promising drugs and treatments.

In addition to helping athletes in contact sports, these advances will benefit the millions of Americans each year who experience traumatic brain injury due to falls, car accidents and violent assaults.

“At the most fundamental level, we just want to understand how traumatic brain injury works,” explains Ganetzky. “However, this is a major medical problem for which there are not many good—or any good—treatments or therapies or preventives, and so that is part of our motivation. If we can learn the genes and the molecules and the pathways, can we come up with interventions?”

Ganetzky was raised in a working-class neighborhood in Chicago by a candy salesman father and a homemaker mother. Growing up, he had an abundance of natural curiosity and asked a lot of tough questions—and often questioned the answers he received. While this trait caused him some problems as a youth, it came to serve him well in science.

At the University of Illinois in Chicago, he figured he’d become a chemist for the good career prospects. He ended up switching to the biological sciences, however, after a 10-week honors biology research experience in a Drosophila lab that expanded into a two-year project. From that point forward he stuck with flies, earning his doctoral degree at the University of Washington and then doing his post-doc work at Caltech.

In 1979, Ganetzky joined the University of Wisconsin–Madison, where he chose to focus his research program on exploring temperature-sensitive paralytic mutants, flies that behave normally at room temperature, but then start to tremble and twitch—or pass out—when things heat up. For each mutant he identified, he sought to uncover the faulty gene involved, and thus better understand how brain cells work.

Over the decades, this approach enabled Ganetzky’s team to discover a number of critical genes and molecular pathways involved in brain cell signaling, including those required for the release of neurotransmitters. That body of work established Ganetzky as one of the foremost leaders in neurogenetics. Some of his findings shed light on human genetic diseases and led to a test that’s now routinely used to assess the safety of new pharmaceutical drugs. For his contributions, Ganetzky was elected in 2006 to the National Academy of Sciences, the nation’s preeminent scientific society.

After Ganetzky’s “eureka moment” about fly concussions in spring 2012, he immediately reached out to colleague David Wassarman, a genetics professor in the UW–Madison School of Medicine and Public Health. Wassarman, who studies human neuronal disorders using fruit flies, had already been attending Ganetzky’s lab meetings for a few years after some of their research findings linking the innate immune response and neurodegeneration dovetailed.

“I did a demonstration of fruit fly concussion for David, and I remember his response very well,” says Ganetzky. “His jaw kind of dropped, and he said, ‘If you’re not going to study that, then I want to.’”

It was exactly the response that Ganetzky had been hoping for. With retirement looming on the horizon, Ganetzky needed a trusted and enthusiastic collaborator to help pursue the work—someone who would be willing to take on more and more as time went on. Wassarman was game.

“I wanted to put both feet in,” says Wassarman. “I said, ‘If we’re going to do it, let’s do it.’”

As a first order of business, Wassarman developed a tool capable of delivering a consistent “dose” of brain injury to flies. The result, known as the High-Impact Trauma (HIT) device, utilizes a metal spring to slam a vial of flies against a firm foam surface. In this setup, it’s important to note, the brain injury the flies experience is caused by the rapid acceleration and deacceleration of their bodies; it’s not necessarily about a direct hit to the head.

“Quite often, as with football players, it can happen because they are running fast and then meet an immovable object. The concussion is caused by a kind of whiplash, where the brain is ricocheting off the inside the skull, and that’s what’s causing the damage,” says Ganetzky. “That’s what we’re doing here with the flies.”

Ganetzky and Wassarman found that flies injured using the HIT device exhibit many of the classic symptoms of traumatic brain injury (TBI) seen in humans. As they reported in the Proceedings of the National Academies of Science in 2013, flies show temporary incapacitation and loss of coordination immediately after injury. Those that survive severe injury go on to develop long-term symptoms: activation of the innate immune response, neurodegeneration and early death.

These TBI flies have the potential to reveal much-needed insights—and medical interventions—for the millions of Americans who experience traumatic brain injury each year. According to the U.S. Centers for Disease Control and Prevention, TBIs cause around 2.5 million emergency room visits, 283,600 hospitalizations and 52,800 deaths each year. Top causes are falls, motor vehicle accidents, and blows or jolts to the head or body, including sports-related concussions. Bomb blasts can cause brain trauma in soldiers in combat zones. Across the country, as many as 6.5 million people are believed to be struggling with the consequences of TBI, and the total economic cost of this health issue is estimated to be $76 billion per year.

In a demonstration of the power of the TBI model, Rebeccah Katzenberger, a senior research specialist in Wassarman’s lab, subjected 179 genetically unique strains of flies to four strikes of the HIT device—meant to simulate a series of severe brain injuries—and then monitored them for death at 24 hours post-injury, a data point that serves as an easy-to-measure proxy for the various negative events unfolding inside the body.

The results revealed a huge diversity of responses, underscoring the fact that genotypes matter when it comes to TBI response. Some strains were particularly susceptible to death, losing as many as 57 percent of the flies in those first 24 hours, while others were much more resilient, losing just 7 percent. The team then identified the genes that possibly made a difference, publishing their findings in eLife in March 2015.

“Now we have these 100 genes, and scientists can start looking at them in more detail,” says Wassarman. “A lot of them are genes that had never really been implicated in traumatic brain injury before. I think this is going to be one of our big contributions.”

These findings, the researchers note, may help explain why people respond so differently to similar brain injury events, and may help lead to a genetic test to identify high-risk individuals.
“Once we understand those genetic links, we’ll be able to test people and tell them, ‘Look, you probably shouldn’t play football. You should play non-contact sports,’” explains Ganetzky.

After identifying the TBI genes, Ganetzky and Wassarman immediately noticed a handful of genes involved in tissue barrier regulation. Tissue barriers—such as the intestinal barrier and the blood-brain barrier—function as biological blockades keeping “bad” things out while allowing “good” things to pass through.

To explore the connection between brain injury and tissue barriers, the duo had Katzenberger conduct a simple, colorful experiment that involves adding bright blue dye to the flies’ food. Under normal conditions, when flies eat the blue-colored food, it stays in the gut, something that is readily observable through the fly exoskeleton. However, after exposure to brain injury—via the HIT device or by having their heads pinched with a forceps—they found that the dye leaks out of the gut and turns the entire body blue, a phenomenon called “smurfing” (after the blue Smurf cartoon characters).

Leaky tissue barriers have previously been observed in rodent models of brain injury as well as in human medical cases. “Somehow this injury to the brain is triggering a series of events that leads to the breakdown of the intestinal barrier,” notes Ganetzky. “So there’s some sort of cross-talk going on between the brain and the intestine, but we don’t fully understand it yet.”

Upon further exploration, Ganetzky and Wassarman were able to confirm that—along with the blue dye—glucose and bacteria were also crossing the intestinal barrier into the fly’s circulatory system, or hemolymph, after brain injury. Homing in on glucose, they found that it plays a causative role in fly death after TBI. “By simply withholding sugar, we were able to keep some of these flies alive, and by a substantial margin,” says Wassarman.

If the findings hold up in rodent models and in human trials, he notes, athletes may one day find themselves advised to avoid certain foods after experiencing concussion.

The bacteria that cross the intestinal barrier appear to be playing more of a long game. Ganetzky and Wassarman believe they are the culprits triggering the innate immune response observed in TBI flies. The innate immune response, also known as the inflammatory response, is the body’s natural reaction to microbial invasion and other stressors. If properly controlled—turned on and off at the right time—it protects the body. If left on, however, it can cause collateral damage throughout the body, including damaging brain cells.

“Here’s what we think is happening: Traumatic brain injury is causing increased intestinal permeability. That causes the bacteria to leak out, which turns on the innate immune response, and that is possibly leading to neurodegeneration down the line,” explains Wassarman.

Ganetzky and Wassarman are intrigued by a concept that is emerging from their work and related studies: that TBI accelerates aging. Some of the key physical outcomes of brain injury—problems with tissue barriers and increased inflammation—are also hallmarks of the natural aging process. More support for this idea came in summer 2015, with the release of a report describing signs of early aging in the brains of war veterans exposed to bomb blasts in Iraq and Afghanistan.

“Somehow a blow to the head is activating all of these pathways related to aging and speeding them all up. Biologically, I think that this is maybe one of the most fascinating things about the whole project,” says Ganetzky, noting that TBI flies are a great model for further exploration.

Even at this early stage, without fully understanding the basic scientific mechanisms involved, the model is already revealing some promising medical applications. As soon as Ganetzky and Wassarman realized that the inflammatory response might lead to neurodegeneration, a treatment suggested itself: Could a simple anti-inflammatory help? They tried giving TBI-injured flies some aspirin mixed in their food. It helped.

“Our studies show that there appears to be a window of time after brain injury when the flies are particularly susceptible to dying. And if we can prevent certain events from happening during this time, then we can prevent death,” says Wassarman. “That’s what we think aspirin is doing—by lowering the innate immune response.”

The next step is to look for drug candidates that work even better than aspirin. Ganetzky and Wassarman are in the process of screening a set of 2,400 compounds, and they’ve already found a handful of very promising ones that can now be tested in rodent models and, ultimately, in human clinical trials.

“It would be wonderful if someday it were possible to offer a simple intervention beyond surgery to help individuals who have suffered a severe traumatic brain injury,” says Wassarman.

There’s a lot left to learn, and Ganetzky and Wassarman are eager to pursue all that the model can tell them. With Ganetzky’s retirement set for early 2016, the work of securing the project’s first federal grant and conducting experiments will largely fall to Wassarman.

But Ganetzky won’t be out of the picture. He continues to keep up on brain injury medical cases and scientific discoveries, and is encouraged by the national conversation about sports and brain injuries that’s starting to gain traction—and by the NFL’s commitment to scientific research in this area.

Some of these advances can be attributed, in part, to Chris Borland, whose post-NFL journey has led him deeper into the world of sports-related brain injury. Borland has submitted to numerous brain scans to support research, and has also become a sought-after speaker, touring the country to raise awareness about the risks of concussion.

It’s that kind of dedication to public service on the part of Borland and many other athletes, along with the excitement of discovery, that’s keeping Ganetzky in the game. Despite his retirement, Ganetzky plans to keep a scaled-back version of his lab running for at least a few more years.

Keeping Us Safe

Posted on March 4, 2016 by jfischer

It’s hard to believe now, but when the Food Research Institute (FRI) was established in 1946—two years prior to the founding of the World Health Organization—botulism and salmonellosis were poorly understood, and staphylococcal food poisoning was just beginning to be elucidated. Many otherwise well-known diseases were only alleged to be food-borne, and the causes of many known foodborne illnesses had yet to be established.

Now the oldest U.S. academic program focused on food safety, FRI moved from the University of Chicago to the University of Wisconsin–Madison in 1966 under the leadership of bacteriology professor Edwin “Mike” Foster.

And ever since, FRI has served as a portal to UW–Madison’s food safety expertise for food companies in Wisconsin, in the U.S. and around the world. Housed within CALS, the institute is an interdepartmental entity with faculty from bacteriology, animal sciences, food science, plant pathology, medical microbiology and immunology, and pathobiological sciences, drawing not only from CALS but also from the School of Medicine and Public Health and the School of Veterinary Medicine.

FRI offers a wealth of educational opportunities to both undergraduate and graduate students. Since 2011, FRI has coordinated its Undergraduate Research Program in Food Safety, which provides students with hands-on experience in basic science and applied investigations of food safety issues. FRI faculty and staff have trained hundreds of undergraduate and graduate students, post-docs, visiting scientists and research specialists throughout the years, and FRI alumni have gone on to hold positions in industry, government and academia across the country and abroad.

In keeping with the Wisconsin Idea, FRI’s reach extends well beyond campus boundaries through industry partnerships, especially with its 40 sponsor companies. The Applied Food Safety Lab and laboratories of FRI faculty collaborate with food processors to identify safe food formulations and processing techniques. The institute also provides outreach and training to both food companies and the greater scientific community through meetings, short courses, conferences and symposia.

“FRI is an outstanding example of how a public-private partnership can benefit the academic mission of UW–Madison and the needs of the Wisconsin food industry,” says FRI director Charles Czuprynski.

During the past 70 years, FRI has made many insights into the causes and transmission of foodborne diseases. Early on, FRI research established methods to identify and detect staphylococcal enterotoxins. Work conducted by FRI scientists pioneered understanding of the molecular mechanisms of botulinum toxin production and led to the harness of the toxin for biomedical uses. FRI faculty are leaders in mycotoxin research and have made important contributions to understanding the shedding of E. coli O157 by cattle, survival of Salmonella in stressful conditions and the role of Listeria in foodborne disease. FRI research also identified the health benefits of conjugated linoleic acid in foods of animal origin and conditions that might result in formation of undesirable components in processed foods.

Looking to the future, FRI research is investigating novel mechanisms to prevent food-borne pathogen growth in meat and dairy products, interaction of plant pathogens and pests with human food-borne pathogens, food-animal antibiotic alternatives, and the role of the microbiome in health and disease.

FRI will celebrate its 70th anniversary at its 2016 Spring Meeting May 18–19 at the Fluno Center on the UW–Madison campus. There’s also a reception on May 17 at Dejope Hall, near the grounds of the original FRI building. For more information about FRI and anniversary events, visit fri.wisc.edu.

Ecuador: Better Health through Messaging

Posted on March 4, 2016 by jfischer

Some communities in Ecuador face high incidences of water-borne illness because of contaminated water or poor hygiene and sanitation. It’s a multipronged problem calling for an interdisciplinary approach combining natural, medical and social sciences. Bret Shaw, a CALS professor of life sciences communication, last year helped implement a social science approach with funding from the UW–Madison Global Health Institute.

“I used a social marketing perspective, which utilizes psychological and communication tools, to try to help villagers make lasting behavior changes in how they interact with water and sanitation,” explains Shaw.

Shaw worked with two undergraduates, Lauren Feierstein and Brenna O’Halloran, to create health behavioral prompts—small signs in Spanish left in important areas where a reminder to wash hands is vital, such as in bathrooms, near sinks and on bottles of water. Since many people in the community have limited literacy, it was important for the prompts to use images and very few words.

While the concept can seem intuitive, years of research show that the most effective prompts focus on self-efficacy—showing individuals how easy a behavior is—and making sure that the people in the graphic are relatable to the target population. The images and words Shaw’s team used were as specific as possible, showing an individual washing his or her hands with just a simple phrase underneath.

“Understanding the perspectives on why someone wouldn’t do something such as boil their water or wash their hands was very important,” says Feierstein, who also worked with residents on making and distributing organic soap. “Knowing those barriers was crucial to addressing the issue from all angles.”

The project was an extension of a course called “Water for Life Sustainability and Health,” a partnership between the Madison-based Ceiba Foundation for Tropical Conservation and the Global Health Institute. The course is led by Catherine Woodward, a faculty associate with UW–Madison’s Institute for Biology Education and president of the Ceiba Foundation. Shaw was brought in to offer guidance about how social marketing strategies can encourage healthy behavior.

“I’m a biologist and most of the people we work with are biologists, so having a communications person on board was a critical part of getting the message out,” says Woodward. “And not just about the message and having people understand why it’s a good idea to conserve natural resources—but also to actually get them to change their behavior.”

A New Tool to Fight Cancer?

Posted on March 4, 2016 by jfischer

A study involving CALS researchers has linked two seemingly unrelated cancer treatments that are both being tested in clinical trials. One treatment is a vaccine that targets a structure on the outside of cancer cells. The other is a slightly altered human enzyme that breaks apart RNA and causes the cell to self-destruct.

The new understanding could help both approaches, says biochemistry professor Ronald Raines, who has long studied ribonucleases—enzymes that break apart RNA, a messenger with multiple roles inside the cell. In 1998, he discovered how to alter one ribonuclease to avoid its deactivation in the body. Soon thereafter, he found that the engineered ribonuclease was more toxic to cancer cells than to others.

Raines patented the advance through the Wisconsin Alumni Research Foundation (WARF) and, with fellow CALS biochemist Laura Kiessling, co-founded Quintessence Biosciences in Madison. They remain shareholders in the firm, which has licensed the patent from WARF and begun early-phase human trials with the ribonuclease at the UW Carbone Cancer Center and MD Anderson Cancer Center in Houston.

The current study began as an effort to figure out why the ribonuclease was selective for cancer cells. To identify which structure on the cell surface helped it enter the cell, Raines screened 264 structures using a specially designed chip. The winner was a carbohydrate called Globo H.

“We were surprised—delighted!—to see that, because we already knew that Globo H is an antigen that is abundant in many tumors,” says Raines. Antigens are molecules with structures that are recognizable to proteins called antibodies. “Globo H is under development as the basis for a vaccine that will teach the immune system to recognize and kill cancer cells,” he says.

Working with Samuel Danishefsky, who solved the difficult problem of synthesizing Globo H at the Memorial Sloan-Kettering Cancer Center in New York, Raines found that reducing the Globo H display on their surface made breast cancer cells less vulnerable to ribonucleases like those that Quintessence is testing. “This was exciting, as we now have a much clearer idea of how our drug candidate is working,” says Raines.

CALS biochemistry professor John Markley aided the research with studies of the structure of the molecules in question.

The picture that emerges from their work is of ribonucleases patrolling our bodies, looking for signs of cancer cells, Raines says: “We are working to demonstrate this surveillance more clearly in mice.”

As other scientists test whether using a vaccine will start an immune attack on Globo H, Raines says, “We are probing a different type of immunity. This innate immunity does not involve the immune system. It’s a way for our bodies to fight cancer without using white blood cells or antibodies—just an enzyme and a carbohydrate.”

PHOTO—Biochemistry professor Ron Raines is devising new ways to destroy cancer cells.

Photo by Sevie Kenyon BS’80 MS’06

Bitten

Posted on November 3, 2015 by jfischer

There’s no ignoring it. Some of the students enrolled in this medical entomology class are far more attractive than others. They know it, their classmates know it, and so does Susan Paskewitz, professor and chair of the Department of Entomology.

Paskewitz describes herself as “relatively unattractive,” and she proceeds to prove it using the same test her students have just performed. She fills a small vial with warm water, rubs it between her palms to coat it with volatile compounds from her skin, then places the vial on top of a thin membrane stretched over the top of a plastic container akin to an economy-sized ice cream tub. She invites a visitor to do the same.

Waiting on the other side of that membrane are 20 blood-starved specimens of Aedes aegypti, commonly known as the yellow fever mosquito. Hungry as they are, the insects don’t show a lot of interest in Paskewitz’s vial. They hover near where it touches the membrane, but only two or three land. The visitor’s vial, on the other hand, is a busy spot. At least a dozen have landed and are testing the surface with their needle-like proboscises.

“Wow,” says Paskewitz. “You’re really attractive!”

In another context, those three words could make your day. But not here. Nobody wants this kind of animal magnetism. Nobody wants to be the person who’s cursing and slapping and reaching for the DEET while others are calmly eating their brats and potato salad.

If you’re that person, take heart. Paskewitz can tell you a little bit about why you might have more than your share of interspecies charisma and offer some suggestions on how to scale it back. But first, let’s talk about why this matters.

An average American adult outweighs an average-size mosquito by about 30 million to one. Ounce for ounce, that’s like the USS Nimitz vis-a-vis a good-size duck. But while it’s a safe bet that a 100,000-ton aircraft carrier won’t change course to avoid a six-pound mallard, it’s almost certain that, on a regular basis, you change your behavior to avoid being bitten by a 2.5-milligram mosquito.

Mosquitoes cause us to do things we’d rather not, like dosing ourselves with a repellent that’s sticky and smelly and comes with a sobering warning label (you can apply it to your kids’ skin, but keep the bottle out of their reach), or pulling on long pants, long sleeves, a hat and maybe a head net on a sweltering midsummer day.

Mosquitoes keep us inside when we’d much prefer to go out. In the summer of 2009, Paskewitz and environmental economist Katherine Dickinson, of the Colorado-based National Center for Atmospheric Research, asked a sample of Madison residents how they coped when mosquitoes got fierce.

The second-most-common answer (right after applying repellent) was to stay indoors. About two-thirds of the respondents said they had curtailed outdoor household activities—gardening, yard work, sitting on the deck—in the past month because of mosquitoes, especially in the evening hours, which, for working people, may be the only time available to get a little fresh air. About a third said they had avoided outings, and a similar share said they had avoided outdoor exercise.

Nobody wants to be outside more than John Bates, of Manitowish. An author of seven books about Wisconsin’s north woods and a naturalist by trade, Bates leads interpretive hikes year-round—except in June: “We just kind of throw the month out. The mosquitoes cause too much discomfort for people to listen to interpretation. All we can do is keep walking. People hire me because they want to learn more about the place than they knew before they came. If they can’t stop to listen, what’s the point?”

If we do venture out when mosquitoes are massing, we may not get the experience we were hoping for. Andrew Teichmiller, an outfitter of bikes and paddling gear in Minoqua, recalls mountain biking in 2014, arguably the area’s worst mosquito year ever. “You had to ride the complete trail without stopping, all the way back to the parking lot, and jump in the car, quick, because if you stopped there were 15 or 20 mosquitoes on you immediately.” As for camping: “It’s a different type of experience when you can’t sit by the fire at night and tell stories. You’re forced to run for your tent. It definitely affects the feel of the trip.”

But let’s be clear: A ruined camping trip is far from the worst possible consequence of a mosquito bite.

Mosquitoes transmit diseases that kill nearly a million people every year and sicken hundreds of millions. Tropical and subtropical areas bear the brunt of this, but no place is immune, including Wisconsin. Malaria plagued the immigrants who settled in Wisconsin in the 1800s, and various types of encephalitis are diagnosed on a regular basis.

But today the biggest concern is West Nile virus (WNV). Wisconsin has been relatively lucky since the first case arrived here in 2002, with a total of 230 cases reported through 2014. But all four adjacent states have had bigger outbreaks—notably Illinois, with 2,093 cases total and 884 in its worst year, most of them just across the border in the Chicago area. Wisconsin’s worst year brought 57 cases.

Most cases of WNV bring no symptoms, according to the Centers for Disease Control, but about one in five can involve a fever, headache, body aches, vomiting and a fatigue that can last for weeks or months. Fewer than 1 percent of WNV victims display severe neurologic symptoms, including disorientation, coma, tremors, seizures or paralysis, and of those, about 1 percent die.

Nevertheless, Wisconsin residents are bothered much more by the nuisance of biting mosquitoes than they are worried about West Nile virus. The Madison residents responding to Katherine Dickinson’s 2009 survey said they’d be willing to pay an average of $149 for a hypothetical program to control nuisance mosquitoes, but wouldn’t pay anything for one targeted at mosquitoes carrying WNV when risks were as low as they were at the time (about one case per year in Madison with a population of 250,000).

It’s not surprising to find that attitude in Wisconsin, where mosquito-borne disease is relatively rare, but Dickinson says that people tend to think the same way in places where mosquito bites are often fatal. She observes that in Tanzania, biting mosquitoes were a major factor motivating people to use bed nets. “It was a similar situation to ours,” she says. “Some mosquitoes are more noticeable and more of a nuisance, but those that transmit malaria are kind of sneaky; people don’t feel them biting as much. In areas where mosquitoes were more of a nuisance, people used the bed nets more.”

Biting-wise, there’s an important distinction between nuisance mosquitoes and the ones that transmit WNV. The former come at us aggressively, in such staggering numbers that they’re impossible to ignore. They remind us to protect ourselves. Culex pipiens, the WNV vectors, are more subtle and harder to notice.

Nuisance mosquitoes and the WNV carriers also show up at different times. The most annoying biters—Aedes vexans in particular—are floodwater species that breed after a stretch of wet weather. Culex breed in water that stagnates during a dry spell.

“When it’s been really dry, the water just sits in the stormwater catch basins that are the biggest sources of the WNV vectors,” says Paskewitz. “There’s not enough rain to flush them. Things get more fetid, stinkier. That’s the year when we see a ton of Culex.”

The take-home message: If you only grab the DEET when the biting is so bad that you can’t stand to be without it, you’re not protecting yourself against West Nile virus.
“You need to protect yourself against bites even if you’re not getting a lot of them,” says John Hausbeck, director of environmental health services for Dane County and the City of Madison. “We’ll see summers where it’s really dry and the floodwater mosquitoes are very limited, but we still have plenty of small pools that the Culex can breed in.”

That “biting pressure” is something that Hausbeck needs to stay on top of, and Paskewitz helps with that. She and former grad student Patrick Irwin PhD’10 were able to characterize the types of sites where Culex are most likely to breed and identified alternatives for treating them—for example, introducing fathead minnows to feed on Culex larvae. She and her students analyze the mosquitoes trapped in the area to see how many are Culex and whether they’re carrying WNV. Their data tell Hausbeck whether he needs to issue a public alert.

It’s important to remain vigilant. “When West Nile first came into the country, people doubted it would make it through the first winter,” Paskewitz says. “Well, it did persist, and in a very short period of time it whipped across the whole country. We’ve had a lot of cases in new places. First it was really bad in North and South Dakota. Then Colorado and Arizona. Then Texas, Illinois. It’s really hard to predict. And given the vagaries of climate, we just don’t know whether the next year it might be Wisconsin.”

Maybe WNV hasn’t changed Wisconsin residents’ ideas about why to guard against mosquito bites, but it certainly has spurred a lot of questions about how. There is a seemingly endless list of products and strategies, that, according to somebody, will eliminate mosquitoes or repel them—and since WNV arrived, Paskewitz has been getting questions about pretty much all of them.

“They call me to ask, ‘Would this work or wouldn’t it?’ There is a lot of misinformation out there and not many good sources of information, so I realized I needed to get a better idea of what the science was behind these things,” Paskewitz says.

As she comes up with answers, she posts summaries online. Her website, http://go.wisc.edu/mosquitoes, gets plenty of visits (55,000 last year) and triggers a lot of calls from media from across the nation.

A few of her findings:

• Repellents can be very effective, but comparing them is tricky. There are lots of products with varying active ingredients offered in different concentrations and combinations. Generally speaking, DEET, Picaridin, IR3535, and oil of lemon eucalyptus have good track records. There are also a number of other plant-based compounds—garlic, catnip oil, vanilla and oil of cloves, for example—for which there’s less research and conflicting results. The website sums all this up and gives links to more information.
Yard traps get a thumbs-down. “We tested those and didn’t get any positive outcome,” Paskewitz says. Yard traps lure mosquitoes by releasing C02, light or octenol, a compound contained in our breath and sweat. Sure, they can catch mosquitoes by the hundreds, Paskewitz says. But does this significantly reduce the numbers that bite you? Properly controlled studies say “no.”

• “Sonic” devices—wristbands, smartphone apps, etc.—do better at extracting your money than keeping mosquitoes off your deck. “You can test them yourself,” Paskewitz says. “Sit at the picnic table and count how many mosquitoes land on you, then turn on the device and count again. Or you can trust the research and save your money.”

• Bats are busted. The idea that a colony of bats can consume millions of mosquitoes per night came from a study in which someone put a bat in a room full of mosquitoes and estimated how many it ate. The question is, given the choice, is that what bats eat in the wild? Researchers who examined the stomach contents and fecal pellets of bats have found bigger insects, like butterflies, moths and beetles, but very few mosquitoes. “Bat houses are great for conserving bats,” Paskewitz says, “but not for mosquito control.”

• Avoiding bananas—When she first heard the idea that eating bananas makes you more attractive to mosquitoes, Paskewitz raised her eyebrows. “I thought, okay, we’ll debunk that,” she says. She was teaching medical entomology at the time with 24 students—enough for a robust sample—so she made it a class project. For several weeks, each student ate a banana and then performed an attractiveness assay at prescribed intervals. “We were really intrigued. It did look like we were getting an increase a couple hours after eating the bananas.”

Paskewitz repeated the trial the next two times the course was offered, with a few tweaks to the methodology: Half the students ate bananas, the other half grapes. “The third trial was the best of all—the strongest statistical evidence and the most repeatable,” Paskewitz says. “We did it three times and saw a strong difference between the groups. Grapes didn’t matter, bananas did. At that point I was convinced. I think it’s real,” she says. Does that mean you if you leave bananas out of your picnic fruit salad, you can skip the bug spray? Probably not, Paskewitz says.

Because “less attractive” is not the same as mosquito-proof, Paskewitz gets plenty of mosquito bites, probably more than her share, because she spends a lot of time around mosquitoes—in the woods doing field research, in her garden, and in her lab. When you’re a mosquito researcher, getting bitten comes with the job.

What Makes You Attractive?

It sounds like the topic of an article in Seventeen magazine—and, interestingly, some of the same general categories apply whether you’re talking about your appeal to a mosquito or to a certain someone of your own species.

Your breath. If you breathe, you’re mosquito bait. Every breath adds to a plume of carbon dioxide (CO2 levels in your breath are 100 times that of the atmosphere) emanating from where you stand. “That’s the big signal,” says entomology professor Susan Paskewitz. “Insects are very sensitive to chemical cues. They’ll zigzag to pick up the chemical as it gets stronger and stronger, circling to narrow in on you.”

Your aroma. Once they find you, mosquitoes use chemical cues to decide whether to land and dig in. They have a lot to sort through: You emit roughly 400 different compounds from your skin and 200 in your breath. Many mosquito species won’t land on humans, even if they’re starved for blood. Others will bite us in a pinch but prefer other hosts, Paskewitz says.

Your genes. Perhaps you were born to be bitten. A pilot study at the London School of Hygiene & Tropical Medicine found that identical twin sisters were significantly more alike in their attractiveness to mosquitoes than were non-identical twins. Since identical twins are closely matched genetically, this suggests that some of your Culicidae charisma is inherited. Some volatile compounds on our skin are produced by skin cells (others are produced by bacteria), which would be gene-regulated, the study’s authors note.

Your jeans. What color you wear matters. This is based on a series of studies in which researchers draped different colors of cloth on human volunteers or on robots heated to simulate human body temperatures, then counted mosquito landings. For the most part, darker colors were more attractive. White was least attractive, followed by yellow, blue, red and black.

Your smelly feet. “The malaria mosquito is really attracted to the smell of funky feet,” Paskewitz says. “It’s a classic story in medical entomology. The compound that makes feet smell funky and attractive to mosquitoes is the same one that causes Limburger cheese to smell the way it does.” That compound is produced by bacteria that can accumulate in the moist spots between your toes, and are kin to those used to culture Limburger.

Your drinking habits. A number of researchers speculate that drinking alcohol makes you more attractive to mosquitoes. A team in Japan put this to the test. They asked some volunteers to drink 350 ml of beer while a control subject did not. The percentage of mosquito landings after alcohol consumption increased substantially. Why this happens is unresolved, although some have speculated that people who have been drinking are easier targets because they move more slowly.

Getting Under Your Skin

Maybe you don’t get more mosquito bites than other people. Maybe your body just makes a bigger deal of it. The swelling, redness and itching are signs of your immune system kicking into gear, explains Apple Bodemer, an assistant professor of dermatology at the UW–Madison School of Medicine and Public Health. And some people’s immune systems kick harder than others.

A mosquito bite involves give and take. Before drawing out up to .001 milliliters of your blood, the mosquito injects a bit of its saliva, which contains anticoagulants to prevent clotting. You can spare the blood, but the saliva is a problem. That’s how disease gets transmitted. And the saliva contains foreign proteins, or antigens, that spur your immune system to create antibodies, Bodemer explains. “When antibodies bind to the antigens, it initiates an inflammatory response, which includes the release of histamine, which causes the blood vessels to dilate, which brings the swelling and redness and the inflammatory mediators that are responsible for the itching.”

This doesn’t happen the first time you’re bitten. It’s the second time, when your body has built up the antibodies, that your immune system engages. If you get bitten enough times by the same strain of mosquito, you may become desensitized and have either a very mild reaction or no reaction at all to the bites. “People often have more vigorous immune responses early in the season and then, as the summer goes on, they don’t have as much swelling and redness and itching,” Bodemer says. “But when you go a winter without any exposure, you often become resensitized.”

For the same reason, younger kids tend to have more aggressive reactions. Once they’ve had several years of mosquito exposure, their response tends to die down, Bodemer says.
As for scratching? Doctor’s orders: Don’t! “Scratching really promotes the full inflammatory reaction. It causes more irritation, causing the blood vessels to be more dilated and further dispersing the inflammatory mediators. It initiates a cycle of swelling, redness and itching. If you can avoid scratching, a lot of times the bumps will disappear.”

Antihistamines can ease the itching, she says, or you can try a home remedy: “I paint a little clear nail polish on the mosquito bite. That will stop the itching to some degree and allow the inflammation to clear up more quickly,” Bodemer says. “Some people cover the bite with Scotch tape for two to four hours. The tape stops you from scratching and when you peel it off, it removes some of the mosquito saliva.”

Wisconsin’s Pestilent Past

Wisconsin’s 19th-century settlers knew that mosquitoes were biting them, and they knew that something was making them sick—but they didn’t put the two together.

Their doctors blamed the ailment on “malarial vapors” emitted by decaying vegetation in the swamps, according to Peter T. Harstad, a UW–Madison educated historian who authored several articles on the health of Midwestern settlers. Harstad used reports by military and civilian doctors as well as immigrants’ diaries and letters to chronicle the devastation caused by what was sometimes called “intermittent fever” because the symptoms—chills, aches and a general fatigue—often recurred over a period of months or years.

“I became sick as soon as I came here and have been sick for eighteen months with malarial fever, which is very severe and painful and sometimes fatal,” reads one letter excerpted by Harstad, written in 1941 by a resident of Muskego. “My wife and I are now somewhat better, but far from being well. This year seventy or eighty Norwegians died here … Many became widows and fatherless this year.” About 13 percent of Muskego’s population died that year, Harstad estimates. The town was hard hit because of an abundance of marshes, a relatively warm climate, and the fact that Norwegian immigrants had no resistance to the disease.

Soldiers also suffered. Harstad cites army reports of malaria outbreaks as far north as Ft. Snelling, near present-day St. Paul. Hardest hit was Ft. Crawford, located amid miles of Mississippi River wetlands at Prairie du Chien. In the fall of 1930, there were about 150 cases reported among the 190 soldiers stationed there. To treat the disease, army surgeons were directed to “extract from twelve to twenty ounces of blood, an operation which it is sometimes required to repeat once or twice.” Wisconsin was mostly malaria-free by the end of the 19th century, as farmers drained wetlands and better housing shut out mosquitoes.

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Grow – Wisconsin's Magazine for the Life Sciences

Wisconsin's Magazine for the Life Sciences

Gut Dwellers

Category Archives: Health and Wellness

New Clues to Healthy Bones for People with PKU

Beyond Antibiotics

Friendly Microbes

“Grazing” Amoeba

Infection Detection

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CRISPR: The Promise and the Peril

Training to Make a Difference

Catch up with Andrea Garber

A Jolt to the System

Keeping Us Safe

Ecuador: Better Health through Messaging

A New Tool to Fight Cancer?

Bitten

Spring 2018 Issue

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The Method Maker

A Precise Hope

New Resources for Discovery

Class Act: Kai Rasmussen — ‘Let’s Grow Plants in Space’

Fermentation Education

Corn Conundrum

Winter Awakens Spring Flowering

Mongoose Tracker

Catch up with … Anna Snider BS’98 Horticulture

Final Exam