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

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

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

Deltanoid

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

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

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

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

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

TRAC Microbiology

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

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

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

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

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

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

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

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

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

As a dietitian at Children’s Hospital in Milwaukee, Zupec-Kania and her team had been using the ketogenic diet, a high-fat, low-carb diet—think Atkins—shown to greatly reduce or eliminate seizures. And writer/producer Abrahams (Airplane!, The Naked Gun), whose young son Charlie had been saved by the diet, wanted to partner with her to spread the word.

Charlie had begun having seizures at 12 months, and after going through a half-dozen medications and brain surgery still was having up to 200 seizures a day. “He lived in a car seat,” says Zupec-Kania. “It was the only safe place they could put him because he would have a seizure and just collapse.”

Through his own research Abrahams learned about the diet and took Charlie for treatment at Johns Hopkins, one of relatively few hospitals that offered it. Almost immediately the boy stopped seizing and after a few years was weaned off the diet.

Abrahams formed The Charlie Foundation to promote access to the diet and soon heard that Children’s Hospital in his native Milwaukee had been another early adopter. Abrahams reached out to Zupec-Kania and her team to help them scale up use and start training physicians, nurses and dietitians at other hospitals.

Zupec-Kania found that work so rewarding that eventually she joined The Charlie Foundation full-time, where she writes journal articles and develops online support materials about the diet along with training healthcare professionals. Her work takes her all around the United States and much of the world, including Saudi Arabia (see photo), the Dominican Republic and Germany.

No one knows why this diet works or why it has permanent effects, right?

That’s right, no one knows why the diet affects seizures. But many scientists are trying to solve this mystery—they believe that a healing occurs in the brain. At UW–Madison, physician Carl Stafstrom has done research on this and he’s also treating patients with the diet.

Is the ketogenic diet just for kids?

No. We are finding it works in adults as well. The problem with adults is that compliance with any type of diet is
difficult.

Why is the diet still not a treatment of first resort?

It’s much easier to prescribe a medication, and if clinicians are going to use the diet, they need to have a team in place—a neurologist, a nurse and a dietitian—to initiate and manage it. The diet is not started at home, it’s started in the hospital under medical supervision. Also, there isn’t a treatment code for the diet, so insurance reimbursement is really poor. That’s been a barrier as well.

When you first met Jim, did you feel at all starstruck?

I did! I remember sitting there when he called, thinking “Is this Hollywood producer really talking to me?” But the more I talked to him, the more he seemed like just a regular guy from Milwaukee because he has that familiar accent. He is the nicest man—the most warm, kind, caring person.

More information at charliefoundation.org.

“It was my impression that this was just going to be a pilot project, but we’re actually going to publish the results,” says Kennedy, an animal sciences major.

Kennedy was one of seven undergraduates who interned at the internationally respected Food Research Institute (FRI), which is housed in CALS and focuses on microbial food safety. The internship program, which debuted this summer, had students investigating everything from Salmonella and E. coli to Clostridium and Aspergillus.

“Training is an important part of the FRI mission,” says Chuck Czuprynski, the institute’s director. “So we decided to create an opportunity where young people can learn about—and deal with—real food safety problems.”

In Kennedy’s case, she worked with FRI mentors and scientists at Oscar Mayer Foods in Madison to tackle a challenge faced by many large meat processing facilities: keeping the growth of the foodborne pathogen Clostridium perfringens in check as large volumes of uncured, processed meats are cooled after cooking. Cooling is energy-intensive, and Kennedy’s project showed that plants can cool their deli-style turkey more slowly—but still safely—if they add some potassium lactate, a commonly used antimicrobial, to the meat.

“Oscar Mayer waited eagerly for Katie’s results,” says FRI assistant director Kathy Glass, who co-mentored Kennedy. “They provide Oscar Mayer, as well as other FRI sponsors in the meat industry, with the safety data they need to show inspectors that the cooling system they’d like to implement is indeed safe.”

Another goal of the internship program is to raise awareness about academic and professional career opportunities in the food safety field. To that end, the interns met weekly to hear from scientists in the field and also toured a handful of food processing plants.

“I was surprised that every place we visited had microbiologists and food scientists. I don’t think people realize those types of jobs are available at food processing plants,” says Brad Gietman, a medical microbiology and immunology major who spent the summer studying how long, filamentous Salmonella cells—which are found on certain foods—sometimes break apart into scores of daughter cells, increasing the risk of foodborne illness.

Both Gietman and Kennedy are continuing their lab work this fall, and Kennedy is now leaning toward doing a yearlong internship at a food company before going to veterinary school.

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

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

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

How did you start working with these organisms?

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

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

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

That’s surprising.

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

How do you picture amoebas being used in medicine?

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

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

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

As a childhood obesity expert, Adams knows another fact about today’s kids of summer: Many of them are at serious risk of packing on pounds. The children she treats at her practice in the UW Pediatric Fitness Clinic already struggle with weight gain and low fitness levels, and now 90 percent of them are coming back 5 to 10 pounds heavier after the three-month summer break, she says, without an associated increase in height. For young kids and teens, it’s a devastating amount to gain, especially since statistics say those excess pounds may never come off again. And her patients are hardly alone. According to the American Heart Association, one in three American children are now overweight or obese, putting them squarely on the path to adult obesity and at risk for adult diseases, including diabetes, heart disease, arthritis and kidney stones.

“We have kids in our clinic who are type 2 diabetics and hypertensive and on cholesterol medication in their early teens. They look like mini-adults,” Adams says. “They’re physiologically much older in their bodies than they should be. And that’s tragic.”

These troubling trends have led doctors, nutritionists and health advocates to introduce a multitude of anti-obesity programs, including the national “Let’s Move!” campaign started by First Lady Michelle Obama last year. Educational initiatives, healthier school lunch programs, and kid-tailored fitness regimens are all being tried. But amid these carefully orchestrated interventions, a team of CALS and SMPH researchers is now wondering if we’ve missed an obvious part of the prescription, especially for children in summer.

With kids staying indoors in record numbers, what if we just got them to go outside?  This doesn’t mean shuttling them to weekly soccer games or other activities by car; kids today get plenty of that, says Sam Dennis, a CALS landscape architect who specializes in children’s environments and collaborates frequently with Adams. What Dennis has in mind are the outdoor experiences children used to have in the past—the type that 50- and 60-something adults describe when asked to explain how they played as children.

“They’ll say, ‘We didn’t have any equipment and we didn’t have organized teams. We would just go out into the woods and build forts or make mud pies,’” says Dennis, who collects these accounts to inform his design of children’s play spaces. “And they get very caught up and animated in telling stories of how they played in nature as kids.”

These children of 40 and 50 years ago not only played outside more; they were also only one-third as likely to be overweight as their counterparts today. Being outside obviously removes kids from the indoor temptations of snacking and screen time. Plus, research shows that kids who spend more time outdoors are also more likely to be physically active, Dennis says.

Yet like many seemingly simple solutions, this one, too, has a catch. Earlier generations of kids played outdoors and were slimmer for it not because they were somehow healthier or more capable of making good choices than children are today—even though some grownups like to think so.

“It’s not that we were so much smarter,” says SMPH physician and pediatrics professor Aaron Carrel, with a smile. Kids have always been kids. The difference was the environment.

“Obesogenic” is what the  Centers for Disease Control and Prevention calls the American landscape today, meaning it promotes unhealthy eating, a sedentary lifestyle, too many calories—and extra pounds. The more fattening aspects of our surroundings are easy to spot: a fast food hamburger and super-sized fries, for example. But what makes obesity so hard to prevent nowadays is that many things that foster weight gain have become part of our everyday lives, says Carrel. We take elevators instead of stairs, we drive instead of walk, we lift our garage doors with the press of a button. As a result, we probably expend 100 to 300 fewer calories each day than people did 30 years ago, while also taking in 100 to 300 more. And those added calories … well, they add up.

2. You won’t like their relatives, either
Bedbugs are a family of true bugs (Cimicidae) and are related to stink bugs, assassin bugs and other insects in the order Hemiptera. There are 15 species of these wingless, blood-feeding parasites in North America, with a majority associated with specific species of birds or bats. There are two species that feed and breed on humans—the human bedbug Cimex lectularis and the tropical bedbug Cimex hemipterus. Biologically, bedbugs can be thought of as indoor mosquitoes without the disease issues.

3. They travel because we do
Widespread travel has allowed bedbugs to “hitchhike” and become reestablished throughout the world. Bedbugs first started to appear in motels, hotels and youth hostels. Infestations then appeared in multifamily dwellings. Now we hear about infestations in subway benches, hospitals, movie theaters, libraries and retail stores. Bedbugs must be brought into homes by people. The two most common sources are infested items such as used furniture, or they are brought into a home on baggage that has become infested.

4. And now for the good news
Bedbugs are the only blood-feeding insect that has not been associated with any human diseases. More than 30 percent of people bitten do not show reactions to the bites. Bites often look like mosquito bites or hives and are clustered in areas on the arms, neck or back. They can be very itchy, but there can be a delayed reaction of 12 to 24 hours or more before you see a reaction.

5. You’ll still want to get rid of them
Bedbug control requires experience and it is strongly suggested that you seek professional help. Early treatment before populations become high is important. Bedbugs can be killed by heating them above ca. 112 degrees Fahrenheit. Putting clothes into a drier for 15 minutes under medium heat will kill bedbugs. Cold is effective, but requires hours of exposure around 0 degrees. Drying dusts have been used in void spaces to desiccate these insects. Pesticides often require multiple and very thorough treatments to be successful. Treatments are very expensive, which leads to people delaying starting them.

Phillip Pellitteri is a distinguished faculty associate in the CALS Department of Entomology. He runs the Insect Diagnostic Lab, which was established to identify insects and insect-damaged plant material from around the state and recommend controls to both county extension offices and commercial concerns. He also teaches in the Master Gardener program.

But a team of researchers led by Laura Kiessling, a UW professor of biochemistry and chemistry, has developed a culture system that promises a more uniform and, for cells destined for therapy, safer product. The system is inexpensive and takes much of the guesswork out of culturing the all-purpose cells. “It’s a technology that anyone can use,” says Kiessling. “It’s very simple.”

At present, human embryonic stem cells are cultured mostly for use in research settings. And while culture systems have improved over time, scientists still use lab dishes coated with mouse cells or mouse proteins to grow batches of human cells. Doing so, however, increases the chances of contamination by animal pathogens such as viruses, a serious concern for cells that might be used
in therapy.

“The disadvantages of the culture systems commonly used now are that they are undefined—you don’t really know what your cells are in contact with—and there is no uniformity, which means there is batch-to-batch variability,” Kiessling explains. “The system we’ve developed is fully defined and inexpensive.”

Instead of mouse cells or proteins, Kiessling’s new culture system utilizes synthetic, chemically made protein fragments. The system can culture cells in their undifferentiated states for up to three months and possibly longer. It also works for induced pluripotent stem cells, the adult cells genetically reprogrammed to behave like embryonic stem cells.

Cells maintained in the system were subsequently tested to see if they could differentiate into desired cell types, and performed just as well as cells grown in commercially available cell culture systems, Kiessling says.

The first clinical trials involving human embryonic stem cells are underway. As more tests in human patients are initiated, confidence in the safety of those cells will be a top concern, notes Kiessling.

1. Collect a sample and extract its DNA. Scientists only need a tiny amount of DNA—around 100 micrograms—to construct a DNA profile from a crime scene sample. That’s so little, a few cells from saliva on a straw will do.

2. Amplify the telltale regions. Scientists use a powerful technique called Polymerase Chain Reaction (PCR) to make millions of copies of the sample’s telltale DNA regions. In particular, they home in on regions known as Short Tandem Repeats, or STRs, which are composed of short units of DNA—just four or five bases long—that are repeated numerous times in a row. What makes these regions telltale is that the number of repeats they contain varies widely from person to person. In criminal investigations, 13 such STR regions, all located in the non-coding DNA between our genes, are analyzed for the number of repeated units they contain.

3. Count the repeats. During PCR, fluorescent dyes are attached to all the STR copies that get made—one type of dye for each STR region—so that all of the DNA copies from a given region can be distinguished from the others in the mix. Scientists run the mixture through a capillary electophoresis machine, which separates the various DNA fragments by size. From there, it’s a fairly easy thing to calculate the length of each STR region, and, therefore, the number of repetitive units at each site.

4. Look for a match. To convict a suspect, his or her STR repeats must match those in the crime scene sample—at all 13 STR regions. According to the FBI, when all 13 STR sites match perfectly, it’s virtually guaranteed you’ve got your culprit; the odds of fingering the wrong person are about one in 1 billion. A single STR mismatch, however, is enough to exonerate a suspect and spur investigators to search CODIS, the nation’s database of DNA profiles, in hopes of solving the crime.

What is a centromere?

Humans have about 30,000 genes carried by our 46 chromosomes. Each chromosome has one centromere, a stretch of DNA that ensures the accurate transmission of the chromosomes—our genetic material—into daughter cells during cell division.

You can actually see the centromere under the microscope—it looks like a constriction on the chromosome. It’s an extremely complex structure. There’s a lot of protein involved, and the centromere’s DNA—how to describe it? It’s junk DNA, basically. It doesn’t have genes, just a lot of repetitive junk DNA.

When did scientists discover the centromere is full of junk DNA? When they sequenced the human genome?

Scientists say that the human genome has been sequenced, that the mouse genome has been sequenced, but people don’t realize that none of the centromeres have been sequenced. They just don’t count it. And most scientists don’t care because there are no genes [in those regions]. Plus, it’s almost impossible to sequence centromeres with current technology—they are too long and contain too much repetitive DNA.

But rice is a different story. The centromere on rice chromosome 8 is not particularly repetitive, so my team was able to sequence it back in 2004. We were the first team to sequence a centromere from a multicellular species, and, surprisingly, we found genes in it!

How did this rice centromere end up with genes in it?

Let me try to explain what we think is going on in this strange case. In the scientific community, people are starting to believe that centromeres originate somewhere. They don’t just exist, right? And when a new centromere emerges—a neo-centromere—it may look like a regular piece of DNA, with genes in it. Over time, however, as it evolves, the centromere accumulates junk DNA for whatever reason.

So, the rice centromere that we sequenced, we believe, is somewhere in the middle of this evolutionary process. It’s like a caveman. It is starting to accumulate some repetitive, junk DNA, but it still has some genes in it.

It’s interesting to consider that centromeres can evolve.

With funding from the NSF, we are now trying to understand the evolution of this rice centromere over the past 10 million years. To get at this question, we’re sequen-cing this centromere in five different species of wild rice, which diverged from cultivated rice between 1 million and 10 million years ago. We’ll be able to see what kinds of changes happened over that time—how the genes moved away, how the junk DNA accumulated.

This work will help us figure out the minimum requirements needed to make a centromere. There are a lot of things we don’t know right now, but if we can figure out the answers, this work will ultimately help us design artificial chromosomes. That’s the long-term goal.

A farm safety specialist at the UW-Madison Center for Agricultural Safety and Health, Skjolaas knows all too well the multitude of dangers that exist on the state’s farms. Each year in Wisconsin, around 30 people die in farm-related accidents, with causes ranging from tractor rollovers to inhalation of toxic gases inside silos. But Skjolaas says few first responders have experience with modern farms and farm equipment, complicating rescue efforts and costing valuable time.

To compensate, Skjolaas began offering workshops on farm rescue training to firefighters around the state. Her first attempt, in 2007, was little more than a Powerpoint presentation, but now the workshops have evolved into orchestrated, hands-on exercises that teach participants how to respond to farm accidents without putting their own lives in jeopardy. At the Nehls farm, for instance, CALS machinery expert Jeff Nelson, who also serves as a volunteer firefighter, demonstrated how to deploy rescue equipment on heavy-duty farm equipment.

“We’re used to grabbing the Jaws of Life and chopping off the door (of a wrecked car) or using what we call the spreaders and just pulling the door right off,” says Nelson. “But because of the strength of the metal (on tractors), that’s not possible. You’ve got to disassemble more. You’ve got to bend more than cut.”

With requests for farm rescue trainings on the rise, Skjolaas is gearing up to start offering annual workshops in each region of the state so that representatives from all of the state’s fire departments can afford to attend.

“We train regularly on ladders, on driving the fire truck, and on farm accidents so we will be ready for when we need that one skill,” says Juneau Fire Chief Curtis Ninmann, who attended the exercise at the Nehls farm. “You never know what’s going to happen.”

I’ve always loved science, animals and the environment. I’ve also always been really active and enjoyed sports. When I entered UW, zoology seemed the obvious choice, and during that time I studied marine biology on a semester abroad in Australia. But after graduation I felt that marine biology was a better hobby than a career. During a lunch with my sister she casually said, “You’ve always loved cooking and food—why don’t you go into nutrition?” After giving it some thought I realized she was right—I had always been experimenting with food, cooking and nutrition.

How did you hit upon the nexus of fitness and healthy food? Most businesses seem to do one or the other.

An all-inclusive approach to health makes sense. My husband, Ryan, is a master-level personal trainer. Clients get expert advice from him on their exercise and learn cutting-edge techniques to improve their fitness. As a registered dietician, I provide reputable individualized nutrition information. The meal plan service takes it a step further by making healthy eating convenient. We’re a one-stop shop for expert fitness and health enhancement. As entrepreneurs, we saw an opportunity to combine our skills to offer something unique.

What’s the most rewarding thing about your work?

Helping people make positive changes toward their health. It fuels me to work harder as more people I work with make changes and are so grateful for my help. I also value that I can be creative daily through exercise, cooking and motivational techniques.

What’s your best advice for people who want to lead more healthful lives?

Define what “healthy” is to you and create a plan to make changes weekly. Also, when it comes to weight loss there is a science to work with, so seek professional advice and help where necessary so your efforts pay off.

Does being an entrepreneur have its scary moments?

Yes, but that fear becomes a fuel, a drive to work harder and smarter.

The diagnosis had surprised Lan. Malaria seemed like a far-off threat, the scourge of rural areas dotted with rice paddies and infested with mosquitoes. But even in the metropolitan climes of central China’s biggest city, where government trucks rolled down the avenues dousing neighborhoods with DDT, the threat of the disease was never too distant. As everywhere in the tropical and subtropical regions of Earth—where nearly 50 percent of the world’s population now lives—malaria lurks just one fateful bite away.

Lan’s illness was one of roughly one-half billion cases of malaria around the world in 1973. Because her family had easy access to medications, she avoided a far more somber statistic: More than a million people die from malaria every year, most of them children. Instead, Lan endured two weeks of shivering, fevers and aches and then recovered, well enough to return to school. Malaria was finished with her.

But Que Lan was not finished with malaria.

Now, nearly four decades after the bell first rung in her bout with the disease, Lan is halfway across the world, preparing to land her first solid blow. Malaria has not gone away and is as menacing as ever. While the disease has been pushed out of more temperate (and more prosperous) areas like Europe and the United States, malaria is still present in 108 of the world’s 195 countries. In most years, more than 250 million people will get sick with malaria and one million—most of them children—will die. Those statistics have led groups such as the Bill and Melinda Gates Foundation to declare all-out war on malaria, making eradication of the disease its number one medical goal. The World Health Organization and National Institutes of Health are equally engaged in the fight. But while these scientists and public-health officials struggle to control the disease and its devastating effects, Lan, a CALS associate professor of entomology, is attacking the source—the six-legged pest that malaria uses to get around. .

Entomology has come a long way from the days of peering through magnifying glasses at anthills. Today, entomologists like Lan peer at bugs from the inside out, scouring their genes for the drivers of their behavior. In her office on the 8^th floor of Russell Labs, Lan hunches over her office computer and motions for a colleague to take a look at the bright bands of color on the screen. The bands are genetic code and, from that code, Lan has teased out a single gene essential to mosquito survival. A weakness. A genetic chink in the armor. In a multi-year study funded partly by the U.S. Department of Defense—which hopes to find better mosquito-control methods to protect troops in tropical regions—she’s also found a way to prevent that gene from doing its job. This is the target her lab is aiming for in a promising new approach in the fight against malaria.A target that, Lan hopes, can  debug the bug.

Humans have been swatting at mosquitoes for millennia. And mosquitoes have returned the favor, injecting us with all sorts of diseases, from dengue fever to lymphatic filariasis to West Nile virus. But malaria is king of them all, a harbinger of death and disease throughout the ages. Descriptions of malaria symptoms can be found in ancient Chinese medical writings dating back to 2700 B.C. and are scattered throughout Greek and Roman texts. The disease has claimed millions upon millions of lives, including those of several popes, the Italian poet, Dante, and, some scholars believe, Alexander the Great. Outbreaks of malaria have sent famous explorers far off course and swung the outcomes of wars by incapacitating entire armies.

As is to be expected with such a devastating disease, we’ve spent centuries battling back. In ancient China, a remedy for malaria’s intense fevers was made from dried wormwood leaves. In the 17^th century, it was bark from the Cinchona calisaya tree that grew high in the Peruvian Andes. The active ingredients from both remedies are still used today in some malaria drugs. Other anti-malarial drugs were developed during both World War II and the Vietnam War as prosperous nations searched for ways to minimize the effects of malaria on their forces. Today, travelers to malaria-afflicted regions can take any of a half-dozen drugs to prevent infection and treat symptoms. But the development of new drugs has slowed dramatically, and the old ones are growing less effective as the disease gains resistance to them.

When a mosquito infects a person with malaria, they are actually injecting the plasmodium parasite into the bloodstream. Plasmodium heads for the liver where it begins to reproduce. It eventually builds an army of parasites that swarm into the bloodstream where they kill red blood cells and, sometimes, their host. During this stage of the disease, a single person can have millions upon millions of plasmodium parasites reproducing in their body. Multiply that single infection with hundreds of millions of people also carrying hundreds of millions of plasmodium parasites, and resistance to commonly used drugs is an inescapable result. To stay ahead of malaria means keeping it on its toes. Researchers know that the war will not be won with World War II-era weapons. It will take a modern, multifaceted arsenal to keep pace.

This is a lesson that the World Health Organization learned the hard way. In 1955, the WHO announced its Global Malaria Eradication Programme, aiming to rid the world of the disease with the help of newly developed weapons—including anti-malarial drugs developed during World War II and the insecticide DDT—and some it hoped were on the way. Medical science believed a vaccine to ward off malarial infection was close at hand, and buoyed by that optimism, the WHO boldly predicted the tropics could be soon free from the grip of the disease. But while the campaign did push malaria out of temperate regions of the United States and Europe, the disease proved intractable in other areas. A vaccine did not emerge, and the parasite quickly evolved resistance to many of the new drugs. But the WHO’s biggest shortcoming was underestimating the complexity of eradicating such a disease. That kind of bold aim necessitates more than good medicine.

“With malaria, we have pretty good drugs,” says Bruce Christensen, a parasitologist in the UW School of Veterinary Medicine.. “The problem is you don’t have very good infrastructure for health facilities (in developing nations). So it’s really hard for people to even get medical care. So even if you have good drugs, you probably don’t have them in the areas where you need them.”

At every turn, the WHO’s efforts were thwarted by the realities of human nature. People didn’t use the bed nets that were handed out in villages to prevent mosquito bites because the nets were stifling to sleep under and were handy as fishing nets. A campaign to spray the walls of houses with DDT met with a similarly unexpected failure. “One of the big problems they had with their workers was they would leave one wall unsprayed,” says Christensen. “And the reason they did that is because if they sprayed all the walls and killed all the mosquitoes, then they were out of a job and this was the best job they’d ever had.”

DDT presented other problems, as well. The insecticide had been the go-to weapon for mosquito control since 1948, when Paul Mueller won a Nobel Prize for demonstrating its lethal power over insects. By the 1960s, however, the pesticide once hailed as a miracle was looking more like an environmental monster, laying waste to birds, frogs and other animals. Facing mounting criticism from conservationists, the U.S. Environmental Protection Agency banned its use in 1972. With no U.S. market to serve, many companies stopped manufacturing DDT, making it scarcer and more expensive for widespread applications in the tropics. Plus, after three decades of near-exclusive use, it, too, was losing its potency.

In 1973—the same year that Que Lan was shivering under her blankets and unknowingly preparing for a career doing battle with malaria—the WHO threw in the towel. Malaria, the organization admitted, was hopelessly entrenched in certain parts of the globe.

The failure of eradication triggered a shift in thinking about malaria control. Many scientists and public-health officials realized that malaria and mosquitoes went hand in hand. You could never kill the disease, without also going after its carrier. In his 2010 letter to Gates Foundation supporters, Bill Gates even acknowledges that modern medicine isn’t ready to eliminate malaria. A vaccine, he says, is at least ten years away. We have to get better at killing mosquitoes.

The approach, called vector control, sounds hopeless at first. Places where malaria is endemic are home to multiple millions of mosquitoes that thrive year-round.No method of insect control could possibly eliminate that kind of population.Papua New Guinea is a perfect example, says Bruce Christensen. Mosquitoes there often lay their eggs in puddles of rainwater that collect in cattle hoof prints. Multiply a hundred eggs by a million hoofprints and the numbers quickly become incomprehensible. “What do you do?” Christensen asks. “Do you try to put [pesticide] everywhere? Because there are breeding sites everywhere.” The best that can be hoped for is to knock mosquito populations back, especially around areas more densely populated with people.

The authors of a new report on malaria control say such modest efforts may actually produce major results. . Published in the August issue of PLoS Medicine, the article points out that in parts of sub-Saharan Africa, a person can receive up to one thousand infectious bites from a malaria-carrying mosquito each year. Those mosquitoes aren’t just injecting that person with the disease, they are often also picking up a new batch of the parasite to carry to someone else. That means that, even if a massive campaign of drug delivery pushed the malaria to the brink of regional extinction, a single infected person moving in to the area could give rise to thousands of new infections and quickly re-establish the disease.

Controlling mosquitoes, on the other hand, makes it more difficult for the disease to rebound from successful anti-malaria campaigns. Reduce the number of mosquitoes in a malaria-infected environment by just half, and the instances of multiple infections and transmissions can drop by entire orders of magnitude. You simply can’t overestimate the role mosquitoes play the authors conclude. And that means that, to wage a truly effective campaign against malaria you need more than a doctor. You need an exterminator.

After her bout with malaria, Que Lan went on to study the sciences. She studied  microbiology at Wuhan University in China and earning a master’s degree at Brock College in St. Catharine’s, Ontario. But it took one intriguing offer—an invitation to complete her doctoral work at the University of Minnesota in noted entomologist Ann Fallon’s mosquito lab – for Lan to realize that the mosquito that bit her in 1973 was still buzzing around in the back of her head. It seemed like a crazy idea, the bravado of young ambition, but Que Lan wanted to bite back “I thought maybe someday I can do something about this,” says Lan, laughing at the audacity of her younger self. “It was just this kind of remote idea (that) maybe someday I can do something (to help).”

Under Fallon’s tutelage, Lan learned molecular biology, which she says “was really nothing to do with killing mosquitoes,” Her research had more to do with what makes them thrive. But after joining the UW-Madison faculty in 2000, she set out to turn that knowledge into better weapons for mosquito control.

“The key,” she says, “is to really understand the biology of your target insect and develop specific components that just target that.”

Lan knew from her Ph.D. work that mosquitoes, like all arthropods, don’t make their own steroids or cholesterols. Both substances are essential for survival, and insects must get them from their food sources. So when Lan discovered that a gene called sterol carrier protein-2 was activated in proteins in the gut during feeding, she knew she had found an essential link in a mosquito’s ability to live. “That’s the Achilles’ heel,” she says. “(I thought) if I can destroy this pathway, they may not survive.”

Her lab turned their focus exclusively on the gene. They mapped its proteins to decipher the chemical transactions that took place around the gene and studied when and where it was switched on. They studied the function of the gene during the mosquito’s various development stages, which led to a critical discovery: If the gene was not allowed to activate inside a mosquito egg, the developing larva would not get the cholesterol it needed and the egg would not hatch. In other words, silence the gene and you silence the bug.

The finding was a career-defining achievement in itself. Researchers often only get this far—learning something new that hasn’t been known before. But Lan wanted more. She knew the finding represented an exploitable weakness, one that could be developed into a method of control. Imagine, for example, dropping a pellet into a pool of standing water, where mosquitoes lay their eggs, that would deliver a knock-out blow to the eggs’ cholesterol-uptake capacity. Although her focus had been on mosquitoes of the species aedes egypti, which carry yellow fever, Lan was confident it would work for malaria- and West Nile-transmitting mosquitoes, as well. The idea of those little pellets preventing a disease-carrying swarm from hatching, Lan says, “is really satisfying.”

But what would flip the switch? Lan needed a chemical that could knock the gene out of order. And that chemical needed to pose as little threat to humans, animals or the environment as possible. The last thing she wanted was to create another DDT. To avoid this, she took a trip to see a few robots on the west side of campus.

Housed in the Paul P. Carbone Comprehensive Cancer Center at the UW-Madison School of Medicine and Public Health, the Small-Molecule Screening Facility allows researchers to conduct thousands of experiments simultaneously. The facility boasts three robots that store tens of thousands of chemicals. Introduce those robots to a cell line or protein, and they’ll introduce it to a few molecules of every chemical at their disposal. Advanced and sensitive instruments monitor each experiment and alert researchers when there’s a “hit,” or, rather, when one chemical has achieved its desired results. And that’s what happened when Lan’s lab took sterol carrier protein-2 for run through the robot gauntlet: Out of tens of thousands of chemicals, they found a dozen that worked. And they all worked in much the same way. Like a game of molecular musical chairs, these synthetic chemicals competed with cholesterol for a seat on sterol carrier protein-2. For every molecule of the chemical that bound to the protein, a cholesterol molecule was out of luck. Lan left the facility with a plan—introduce enough molecules of the chemical to the game, and developing mosquitoes don’t get enough cholesterol to ever hatch from their eggs.

The trouble with synthetic chemicals, though, is that they hang around in the ecosystem long after they’ve been applied. If Lan’s chemical tool were going to see wide use, a better alternative would be to employ a natural chemical to muck with the bug’s genes. So Lan again turned to the library to find a natural chemical that mimicked the activity of the synthetics.

The source was unexpected—an Asian fruit called mangosteen, which contains a chemical that turns out to be a dead ringer for the best-performing of the synthetic chemicals Lan tested. Touted for the rejuvenating power of its juice, mangosteen is called “queen of the fruit” in parts of Southeast Asia, and Lan finds the fact that a malaria-infested country could harbor a promising new natural agent against the disease a delicious irony.

“We’re pretty sure this quality is one of (mangosteen’s) main evolutionary traits. It’s a naturally occurring defense compound,” she says. “We would never have imagined to use (mangosteen extract) on insects. Not in a million years if we didn’t get it from our library screening.”

Susan Paskewitz, a CALS entomology professor who also works on mosquito-borne disease, thinks there’s great promise in this new way of methodically developing insecticides. “In the old days we might have started with something that from lab experiments was known to kill agricultural pests and then tested it on mosquitoes,” she says. The power of genetics is to look at species-specific approaches, which could mean fewer unintended consequences.

And that seems true for Lan’s genetic attack strategy. Since the chemical approach employs a different mode of action than traditional pesticides, it promises to be effective against species that have grown resistant to those applications. There’s also little danger of the chemical affecting humans or other animals since chemicals bind differently in our DNA. And even if some of the chemicals bound and prevented uptake of cholesterol, it wouldn’t matter much since vertebrates make their own cholesterol.

Lan has taken this particular avenue of research as far as she can as a researcher. Her naturally derived cholesterol inhibitor has been submitted for a patent, and she’s now waiting to hear if industry will license the technology and develop a commercial product from it. She knows her find is not the “answer” to the malaria question. But she is convinced it will be a welcome addition to the fight.

“The toolbox is almost empty,” she says. “We’re just putting more tools into the toolbox.”

Of course, Lan knows her new tool won’t last forever. Someday the compound will grow obsolete as mosquitoes slowly evolve resistance. But she is confident science will uncover new weaknesses in mosquitoes’ makeup and reveal new routes of attack.

“You’re never going to win,” she says. “(Mosquitoes) have been around for millions of years, and they’re going to be around for another million years. We just try to avoid their contact (with humans) in high-density populations. That’s all we can do.” But, mosquitoes, beware. Just because she knows she can’t win, doesn’t mean Lan isn’t going to fight. As long as little girls  shiver under heavy blankets in the sweltering heat, she won’t give up. What that mosquito started back in 1973, Lan will never finish.