Class Act: Timothy Guthrie

Biochemistry senior Timothy Guthrie knows that science and success are about small steps. It’s those tiny strides that drive him to excel both in the lab and in the pole-vaulting pit.

Last summer Guthrie, a student athlete, earned a summer Biochemistry Undergraduate Summer Research Scholarship and spent lots of time in the lab of biochemistry professor Judith Kimble. There he worked, and continues to work, on making different mutations in a protein important for stem cell renewal.

“When I finally get something right in the lab that I’ve been working on for a month or two, it’s a really satisfying feeling,” says Guthrie, who plans to apply to medical school this summer.

Guthrie’s work allows the lab to better understand the molecular mechanism behind stem cell renewal in a tiny roundworm species called Caenorhabditis elegans, used as a model because their stem cells are easier to study than those in humans. Stem cell renewal is essential for the organism to keep producing cells it needs to develop and reproduce. By making different mutations to a protein important to this process, researchers can work to determine the role of the protein.

“The ultimate goal of stem cells is for therapeutic use, but we’ve got to work to understand the stem cells first—and the only way to do that is piece by piece,” says Guthrie. “That’s what Professor Kimble’s lab is doing.”

Getting involved in undergraduate research has helped Guthrie gain critical lab experience and also helped build connections between what he learns about in class and the experiments he performs in the lab.

“Along with knowledge of lab techniques and research, I’ve gained a better appreciation for the scientific discoveries we’ve already made,” he says. “All of those big successes and drugs we’ve discovered were made up of small steps like the ones I get to be a part of in the lab.”

Timothy Guthrie, Biochemistry senior, works with data on stem cells research.
Photo by: Robin Davies/UW–Madison MediaLab at Biochemistry

A New Weapon Against Bacterial Disease

Bacteria that are resistant to antibiotics are one of the biggest problems facing public health today. About 800,000 children worldwide die before their fifth birthday from diarrheal diseases that evade treatment. The concentration of those diseases is highest in parts of Africa and Asia.

To address the problem, CALS biochemist Srivatsan (“Vatsan”) Raman hopes to harness the power of phages—viruses that infect bacteria but leave humans unscathed. With help from a grant from the Bill and Melinda Gates Foundation, Raman’s team is designing phages to specifically target bacteria that are causing diseases in infants.

Raman describes antibiotics—how doctors usually fight infections—as hammers that take out many bacteria, both harmful and beneficial. This means they can affect the entire human microbiome, which is the community of microbes on, inside and around the human body.

“We do not yet have the tools to selectively edit the composition of a microbiome,” Raman explains. But that is one of the goals of his lab’s work with phages. Unlike antibiotics, phages are very specific. A phage only infects one type of bacterial host. It is this specificity that presents Raman and his researchers with opportunities—but also some challenges.

Phages, which resemble lunar landers, locate bacterial hosts by attaching to specific receptors on the cell’s surface. Once they have found their host, some phages, called obligate lytic phages, quickly infect the cell and replicate. Once replication is complete, the new phage progeny burst out of the cell, ready to infect and kill the next available host.

Raman’s goal is to be able to control many steps in this process. He is investigating a way to engineer a phage that can be programmed to target specific bacteria. By changing just the “legs” of the lunar lander, the designer phage can target and eliminate any bacteria the researchers wish.

However, while destruction of bacteria is the ultimate goal, the process also creates problems. Many bacteria contain toxins that are released if the bacteria die in large numbers. So Raman’s team is also trying to control the rate at which phages infect and kill cells inside the body. “We can keep the phage on a leash and determine when and where it can infect,” describes Kelly Schwartz, a postdoctoral fellow in Raman’s laboratory.

Raman believes “designer phages” have great promise for human health.

“I was drawn to this research because designer phages can provide a potential solution to the antibiotic resistance problem,” notes Raman. “These bacteria are resistant to anything you throw at them and are killers in developing countries.

“And the next question, if we are successful, is ‘How can we turn these phages into actual medications that can be delivered to these areas?’ That challenge awaits us further down the road,” Raman says.

Vatsan Raman in his lab: The biochemist is engineering viruses that can vanquish harmful bacteria. Photo by Robin Davies/UW–Madison MediaLab at Biochemistry

The Mysteries of Mitochondria

Imagine having your car towed to the shop for unknown repairs, and watching a trusted local mechanic pop the hood and take a ponderous look inside. Minutes pass as he runs a gauntlet of software and fluid checks, and pokes around the hoses, belts and cords. He finally emerges with a strange-looking broken part in his hand.

“This might be the culprit,” he says. “But honestly, I’ve never seen a part like this before.”

Dave Pagliarini can relate to this feeling. As an associate professor of biochemistry, Pagliarini studies engines of an entirely different stripe—engines called mitochondria, which power biological life. These tiny, grain-shaped organelles reside inside virtually every plant and animal cell type, and perform the critical task of breaking down nutritional elements and converting them into energy for basic cellular function.

Pagliarini says that only two decades ago, science had all but closed the book on mitochondria, assuming all the important pathways and processes had been worked out. But lately, the field of mitochondrial research is being defined more by how little we know about their complex role in maintaining health—and their connection to literally hundreds of diseases when things go haywire.

As one measure of this great unknown, Pagliarini points to “orphan proteins”—more than 300 proteins associated with mitochondria that still have no defined function. In a mechanical sense, they are parts without a defined purpose. A big focus of Pagliarini’s research today is linking these orphan proteins to their rightful homes and understanding how their dysfunction affects disease.

But as a University of California, San Diego graduate student in the early 2000s, Pagliarini didn’t have mitochondria anywhere on his radar. He was studying a group of proteins involved in cell signaling when he made an entirely unexpected discovery: One of those proteins traced directly back to mitochondria. Later, as a postdoctoral researcher at Harvard Medical School, he produced a seminal work on identifying all mitochondrial proteins, published in the journal Cell in 2008, which has been cited more than 1,000 times.

“That set off a whole new direction for me,” Pagliarini says. “To find something that no one expected to be there made me fascinated about what else we didn’t know. And as we began to realize there was a lot we didn’t know, I just saw a lot of opportunity.

“That’s when I became a ‘mitochondriac,’” he says with a laugh.

Mitochondria consume about 95 percent of the oxygen we breathe to make a chemical substance called ATP—or adenosine triphosphate—that is the “chemical energy currency” our bodies use to power cellular processes.

But “cellular powerhouse” is only one important function of mitochondria. For example, mitochondria are recognized as key players in cellular signaling and cellular apoptosis, or programmed cell death. They also appear to play a significant but not fully understood role in certain cancers, Parkinson’s, Alzheimer’s, diabetes and autism. And their composition varies markedly across tissue types—meaning there are many places where things can go awry.

“There are many different ways to break machines like mitochondria,” he says.

The Pagliarini lab focuses on establishing a fundamental understanding of mitochondria, with the recognition that we can’t cure what we don’t understand. There is a dire need to develop therapies for people who suffer from mitochondrial disease, which occur in 1 in 4,000 people and can be fatal or have devastating health consequences.

“There are so many diseases that are rare individually, but collectively affect lots of people,” Pagliarini says. “These are heartbreaking diseases for which we can only offer palliative care. I believe that in the long term, a fundamental understanding of how the mitochon-dria work will give us an opportunity for real cures.”

Dr. Philip Yeske, the science and alliance officer of the United Mitochondrial Disease Foundation (UMDF), agrees that mitochondrial diseases pose unique medical challenges. There are about 250 mutations on both the nuclear and mitochondrial DNA that can lead to disease. And any given mutation can manifest itself in entirely different symptoms—heart-related problems for one patient and neurological disorders for another.

“The standard of care for patients affected by mitochondrial disease right now is treatment with vitamins and supplements,” Yeske says. “There are no licensed therapies available. And with the vitamin and supplement care, we don’t know enough about them to even say they are effective.”

But thanks to a rapidly growing body of research, prospects are looking more positive. A decade ago, therapeutics would have been a “pipe dream,” Yeske says, but in 2016, four companies are in active clinical trials for mitochondrial disease therapeutics, and many more are in preclinical planning.

“We’re at the beginning of an era of mitochondrial medicine, and that’s really exciting,” Yeske says.

At UW-Madison, Pagliarini’s young career has been on overdrive. Only months after arriving at CALS in 2009, his lab was jump-started by major research support from the federal economic stimulus program, which funded only the top 2 percent of proposals that year. Shortly after, he was named a Searle scholar and helped craft a major grant related to the NIH National Protein Structure Initiative, which further put his work on mitochondrial proteins in the national spotlight.

The past academic year could arguably be Pagliarini’s most exciting yet. In fall 2015, Pagliarini was named director of the Morgridge Institute for Research Metabolism Theme, which aims to establish a vibrant group of researchers focused on the basic underpinnings of metabolism. The Morgridge Institute is poised to make strategic hires and investments under Pagliarini’s direction that will help UW–Madison grow and thrive in this field.

This year, Pagliarini experienced a pinnacle of recognition as the recipient of a Presidential Early Career Award, given to top scientists and engineers in an array of fields. He and 100 national honorees visited the White House in May, touring its opulent historical meeting rooms and chatting with President Barack Obama and special guest Jeff Bezos, the CEO of Amazon.

“It was pretty special,” Pagliarini says. “What really stood out about it was how optimistic and forward-looking it was. You hear so much in science now about problems with funding or rising competition from other countries. This was very much about celebrating what we can do with U.S.-driven scientific research.”

Brad Schwartz, CEO of the Morgridge Institute, started getting indications early that Pagliarini was the right person to lead the campus-wide initiative. While meeting with potential recruits in 2014 from leading research universities, Schwartz was struck by how frequently Pagliarini’s name came up in conversations.

“After a very thorough national search, it only reinforced that Dave had the innovative thinking and creativity we were looking for,” Schwartz says. “He has all the personal characteristics needed to help build stronger community around as many as 500 scientists working on some aspect of metabolism in Madison.”

The Pagliarini lab is focused on a grand question: How do we define the unknown parts that contribute to the fully functioning engine of mitochondria? Pagliarini teamed with chemistry professor Josh Coon to win an award from a UW–Madison and Wisconsin Alumni Research Foundation (WARF) initiative called UW 2020—supporting projects that could change the direction of a field.

The goal will be to develop a “genetic knockout” strategy for a wide range of human cell lines. By analyzing all of the cellular changes that occur in each “knockout”—cells with a single gene removed—the researchers will be able to define molecular signatures that show an association between orphan proteins and established ones.

The team already has demonstrated great success by applying the same process to yeast, a model organism that is simple and fast growing, and employs cellular processes similar to those in humans. The yeast project, recently published in Nature Biotechnology, completed 174 individual gene deletions that helped predict the function of many orphan proteins. Replicating this process with human cells will require CRISPR gene editing technology as well as a private sector partner to create these knockout cell lines in an industrial process, so that the scientists can focus on growing and analyzing the lines.

Another research theme focuses on an important component of the energy chemical ATP production process called coenzyme Q. This lipid was discovered at the UW–Madison Enzyme Institute in the 1950s and was recognized as a key missing piece in the electron transport chain that mitochondria use for ATP synthesis. It is a complex molecule that needs to be made by mitochondria and is not supplied in the human diet.

Coenzyme Q deficiency causes a wide array of problems, from minor muscle disorders to severe disabilities and death. The research challenge is a familiar one: several steps in the coenzyme Q pathway are accomplished by proteins that have yet to be identified and defined. If the lab can identify the different steps of biosynthesis the body uses to make this important molecule, Pagliarini says, it could lead to breakthrough therapeutics to replace its loss. Some of the precursors for making coenzyme Q follow the same pathways as cholesterol, and statin-based drugs that block cholesterol may provide important insights.

Pagliarini and his 18-member research team now make their home on the second floor of the Discovery Building, which is dedicated to collaborative science that cuts across disciplines. The team includes postdoctorates, graduate students, senior staff researchers and a healthy mix of undergraduates.

They can even claim a bit of celebrity: PhD student Zachary Kemmerer is a former college wrestler and premier athlete who competes on the hit TV competition “American Ninja Warrior,” and is known as the “Science Ninja.” Kemmerer contributes to Discovery science outreach programs, helping kids get pumped up about the possibilities of science. His motto: “Powered by Mitochondria.”

Assistant scientist Jarred Rensvold PhD’15 first joined the Pagliarini lab as a graduate student at its inception in 2009 and has been there ever since. In one afternoon just before graduate school began, a parade of biochemistry professors offered “elevator pitches” of their work to new graduate students, hoping to generate recruits. “Dave gave a really energetic talk and I could see he was really excited about starting up his lab,” Rensvold says. “He seemed like he would be an excellent mentor. Even with all of his expanded responsibilities today, he makes time to give to each individual and each project in his lab, which is remarkable, I think.”

Postdoctoral research associate Natalie Niemi’s introduction to mitochondria was remarkably similar to Pagliarini’s, having “stumbled” on a connection in graduate school while doing unrelated protein studies. Today she studies an important process called phosphorylation, which is the turning on or off of enzymes that control energy metabolism. She has funding from the UMDF on this topic, and she gives back by helping organize a Wisconsin “Energy for Life” fundraiser to support UMDF causes.

“I think the potential to have an impact on the future matters,” Niemi says. “We’re working quite a few steps back from clinical trials, but trying to project how your research could have an impact on human health is rewarding. It’s also rewarding to make discoveries and be the first person to know something.”

The future for Pagliarini is brimming with opportunity. If you think of metabolism research as a living cell within UW–Madison, the Morgridge Metabolism Initiative provides a nucleus—or, perhaps, a mitochondrion!—for the first time. The effort already has produced a monthly symposia series and a major investment in mass spectrometry tools—a gold standard technology for conducting metabolism research.

Part of the challenge is building a sense of community within a very diverse group of researchers, where one finds pockets of metabolism-related work in the medical school, in countless bioscience labs, in chemical engineering, computer science and bioinformatics. The potential for new ideas and collaborations is only beginning.

“We’re in the era of collaborative science, so as our interactions build and gain success, they are bound to attract more people,” says Brian Fox, professor and chair of biochemistry. “Dave’s got a great eye for a problem, he’s very articulate in describing that problem, and he’s an excellent collaborator. That’s the kind of style that will help drive a campus-level project like the metabolism initiative.”

A New Tool to Fight Cancer?

A New Tool to Fight Cancer?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

Stealth Entry

Many human diseases—including cancer—are caused by protein malfunctions. Those malfunctions, in turn, are caused by damaged DNA that gets translated into the damaged proteins. While many clinicians and scientists are trying to treat those diseases by fixing the DNA, Ron Raines is taking a different approach—he’s looking to replace the proteins directly.

“Our strategy is to do gene therapy without the genes,” explains Raines, a professor of biochemistry. “We want to skip the genes and go right to the proteins.”

The strategy is intriguing, but there’s a problem. Proteins have a hard time getting into cells where they would do their work. The lipid bilayer of a cell membrane serves as a barrier that keeps the inside of the cell in and the outside out. That membrane stops potential intruders—including uninvited proteins—from entering.

Raines and his team have found a way around this in what amounts to a kind of biochemical calling card. They can attach “decorations,” using what is called an ester bond, to the protein to change its characteristics. The ester bonds link the protein to a “moiety,” a molecule that gives the protein a desired attribute or function.

“Moieties could encourage cell entry, which is one of our major goals,” says Raines. “But moieties could also enhance the movement of the protein in an animal body. Or they could be agents that target the protein, for example, to cancer cells specifically.”

Modifying proteins to give them these attributes has been done using other approaches, but those changes are permanent and can cause problems. The modified protein might not function normally, or the immune system might see the protein as foreign and mount an attack.

Raines’ strategy avoids these problems by using reversible modifications. Because the moieties are added using ester bonds, they are removed once inside a target cell. Naturally occurring enzymes in the cell—called esterases—sever the ester bonds and break off the moieties. What’s left is the normal protein without any decorations. That protein can then do its job.

“We don’t have the problem of damaging the function of the protein or of an immune response because what we ultimately deliver will be the wild-type protein, the protein as it’s naturally found in cells,” explains Raines.

The strategy is promising, and the Wisconsin Alumni Research Foundation (WARF) already has patent applications for it on file. Raines’ lab is now working to make adding the decorations as straightforward and user-friendly as possible. That way, scientists and clinicians could add a moiety of their choosing and get the protein to perform its desired function.

Raines sees innumerable possibilities.

“We’re very excited about this because it has a lot of potential,” he says. “We can now decorate proteins reversibly with pretty much any molecule you can imagine. We are exploring the possibilities to try to bring something closer to the clinic.”

Turning them on

CALS biochemistry professor Hazel Holden is excited about science. So when she witnessed science becoming “boring” in her daughter’s classroom—a feeling several classmates shared—she decided to take matters into her own hands.

Some five years ago she created Project CRYSTAL—Colleagues Researching with Young Scientists, Teaching and Learning—a program designed to challenge middle schoolers who show an aptitude for science. The program is funded by the National Science Foundation.

Each school year, Holden takes four eighthgrade students under her wing for weekly hands-on sessions. “We’re trying to de-stigmatize science by exposing kids to material they otherwise would never have been exposed to,” she says.

And it’s impressive stuff. The students start by extracting DNA from yeast cells they have grown themselves. They then use the extracted DNA to practice the art of polymerase chain reaction (PCR for short), the process by which a piece of DNA is replicated to produce thousands to millions of copies of a targeted DNA sequence.

Switching between 10-minute lecture and lab segments keeps the kids motivated, and with clever anecdotes sprinkled throughout the lecture material, the young students are never bored.

This class format is used to progress to more advanced skills such as protein purification—the isolation of proteins from, in this case, E. coli cells— and X-ray crystallography, a tool used by the students to identify the molecular structure of a crystalline protein. The year ends with a group poster presentation— a rite of passage that most students don’t experience until much later.

“I was able to work in a real lab and gain lab experience. I do not think many 12-year-olds are able to have an experience like that,” says Project CRYSTAL alumna Manpreet Kaur, now a high school senior. “Before the program I did not have any knowledge of X-ray crystallography, and now I am able to explain the process in science classes.”

The program inspired Kaur to take several AP Science classes and affirmed her plans to become a doctor.

Holden has published her curriculum as an 80-page book, and Project CRYSTAL was introduced at Indiana University–Purdue University Indianapolis during the current school year.

The program has benefited graduate students almost as much as the youngsters, giving them experience teaching complex science at the most basic level.

“This class puts our own graduate work in perspective. You get more excited about your own research by watching them get excited about the small things, like pipetting,” reflects biochemistry doctoral student Ari Salinger.

Looking ahead, Holden hopes that what she has created will inspire other universities to implement similar programs.

“The students want to learn more—and they are ready for it,” Holden says.

Unpuzzling Diabetes

The body makes it seem so simple.

You take a bite of supper, and the black-box machinery of metabolism hums into life, transforming food into fuel and building materials. It’s the most primal biology: Every living thing must find energy, and must regulate its consumption.

But for an alarming and ever-increasing number of people, the machinery breaks down. The diagnosis? Diabetes.

Alan Attie, a CALS professor of biochemistry, has been peering into the black box for two decades now, trying to identify the pathways in our bodies by which the disease is formed. “You can’t find a better excuse to study metabolic processes than diabetes,” he says. “It’s very, very rich.”

Type 2 diabetes, caused by an inability to produce enough insulin to keep the body’s blood glucose at normal levels, is a global health crisis that has accelerated at a frightening speed over the last 20 years—roughly the same time Attie has been studying it.

It’s an enormously complex disease driven by both genetics and the environment. A DNA glitch here, an external variable there, and the body slides irretrievably out of balance. But only sometimes. Most people who develop type 2 diabetes are obese, yet most people who are obese don’t actually wind up diabetic.

Tracking this riddle has led Attie and his lab to several major discoveries, chief among them identifying two genes associated with diabetes: Sorcs1 and Tomosyn-2. Through years of elaborate experimentation, Attie and his team teased them from the genetic haystack and then relentlessly deciphered their role in metabolic malfunction.

Science has uncovered more than 140 genes that play a role in diabetes, yet genetic screening still has little value for patients. As with any part of a large and complicated puzzle, it’s hard to see precisely how Sorcs1 and Tomosyn-2 fit in until we have more pieces. The biology of diabetes is so complex that we can’t be certain what the discoveries may ultimately mean. But both genes have shed light on critical stages in metabolism and offer intriguing targets for potential drugs.

Attie need not look far to replenish his motivation. His own mother suffers from diabetes, and she used to quiz him weekly about when he would cure her. “The painful answer is that translation of basic research into cures takes a long time,” Attie once told the American Diabetes Association. “The most important clues that can lead to cures do not necessarily come from targeted research or research initially thought to be relevant to the disease.”

Alan Attie grew up an expatriate in Venezuela, where his father, Solomon, originally from Brooklyn, New York, ran a textile factory (Attie’s mother had family in South America). Poverty and then World War II had kept Solomon from traditional schooling, but he managed to put himself through high school at night, and he nurtured a deep passion for literature, poetry, history and politics. At home he ran the family dinner table like a college seminar. “Our evening meal was like a 20-year course,” recalls Attie. “It was the most stimulating part of our day growing up. I was reading Shakespeare with my father and my siblings when I was 10 years old.”

Still, Attie wasn’t quite prepared for the academic rigor of UW–Madison when he arrived in 1972. He’d never had to work particularly hard in high school and was shocked by how much time and effort college required. His grades were poor and his introduction to chemistry lackluster.

But the BioCore curriculum—an intercollege program focusing on doing science, not memorizing facts—turned Attie’s natural inquisitiveness and enthusiasm toward science. During a cell biology course where his lab reports had to be written like journal articles, Attie decided he really wanted to be a biologist. Following graduate school at the University of California, San Diego, he found himself back at UW– Madison as a young assistant professor. Ten years had passed since his freshman matriculation.

Attie’s first research focus was cholesterol metabolism, but his curiosity led him elsewhere. Until 2001 he held a joint appointment with the School of Veterinary Medicine, where he taught an introductory class in biochemistry. While preparing for the class he read broadly in metabolism and found himself continually drawn toward the quandary of diabetes.

Increasingly he found himself suffering from “discovery envy,” he says. “And then I finally decided one day I do want it to be me.” Midcareer course changes are never easy, but Attie plotted a careful transition that gained momentum with hard work and good fortune.

In 1992 Dennis McGarry, a prominent diabetes scholar, published a provocative thought experiment in Science. It had been observed for centuries that diabetics had sweet urine, and one of the earliest researchers in the disease, Oskar Minkowski, had surmised that diabetes was therefore a dysfunction of sugar metabolism. McGarry speculated that if Minkowski had had no sense of taste and had relied instead on the smell of a diabetic’s urine, he would have smelled ketone bodies, a hallmark of lipid metabolism. Might he have concluded instead that diabetes was a defect in lipid metabolism?

Soon afterward, McGarry and Attie wound up at the same research symposium in Edmonton and shared breakfast every morning. “I’m really interested in diabetes,” said Attie. “Is there room for someone like me who has been working on lipid metabolism for 20 years?” McGarry encouraged Attie, a pep talk that gave him confidence that maybe he wasn’t committing career suicide.

Gradually Attie’s new focus gathered steam. When another UW diabetes researcher left for Washington state, Attie was able to bring on researcher Mary Rabaglia from that lab. She was highly skilled in the lab manipulation of pancreatic islets, the home of the beta cells that produce insulin. Her arrival jump-started Attie’s efforts. “It was an unbelievable stroke of luck because she brought all that expertise,” says Attie.

Attie also felt he needed a new analytical toolbox, and he saw real potential in using mouse genetics to study diabetes. With one small problem: He didn’t know any genetics. So he went to the Jackson Laboratory in Bar Harbor, Maine—a global center of mouse research—and took a mouse genetics course (which he now teaches there).

The learning soon paid off. Gene chip technology was just becoming available, and industry pioneer Affymetrix was looking to commercialize the expensive technology. The company was interested in funding labs to demonstrate that the power was worth the price. Attie proposed looking at how genes were turned on and off in the fat-storing cells of diabetic mice, and Affymetrix approved the project.

Exploring gene expression—which genes get turned on and off—was an important first clue in figuring out which genes might contribute to diabetes. With thousands of proteins and a still unknown quantity of genes in play, diabetes is vexingly elaborate. Gene chip technology brought previously unimaginable power to the equation. “The reason for doing genetics is we can’t imagine the complexity of these processes,” Attie explains. “We really do need the serendipity of genetics to find our way.”

Attie sent Sam Nadler, a new M.D./ Ph.D. candidate, off to Maryland and California for training. It was an ambitious project, and the old analytical tools broke under the mountain of new data. Enlisting the help of Brian Yandell, a CALS professor of horticulture with a joint appointment in statistics, they were able to interpret their data.

In late 2000 the team published the first paper on genome expression changes in diabetes using gene chip technology. It was premature to get too excited—they were, in effect, translating a book of unknown length, and had only finished the first of many chapters.

But it was an important demonstration of the power of their new tools. And Attie and his lab were now a known quantity in the world of diabetes research, and part of the conversation.

Attie’s team could now assess any DNA they got their hands on, but there was still too much static hiding the working genes. Only by basing his experiments on other, more tangible clues could Attie find anything useful.

He decided to tackle the obesity link. “Most people who have diabetes are obese, but most people who are obese don’t have diabetes,” he notes. To get at the problem, Attie’s team took two strains of lab mice: a standard control strain known as “black 6” (B6) and a diabetic strain (BTBR) that, when the mice became obese, were diabetic. The team intercrossed the two strains for two generations, testing the second generation of mice for diabetes. Offspring were strategically bred to enable the lab to pinpoint the genes responsible for diabetes susceptibility.

The collaboration that had begun with Brian Yandell now expanded to include Christina Kendziorski, a professor of biostatistics with the School of Medicine and Public Health. Teasing conclusions from large data sets was an exciting new field, and the team saw real potential for developing new techniques— and they had the statistics grad students to do it. Some even took up residence in Attie’s lab to be closer to the puzzles cascading from each successive experiment. It was like game after game of Clue, only with a half million possible rooms, a half million possible murder weapons, and a half million possible suspects. And as many homicides as you wanted to look for. Some computations took days.

Ultimately they were looking for genes, but what they found at first were just general target zones, located on chromosomes 16 and 19. That was a big first step, but chromosomes are constructed of many millions of base pairs—the building blocks of DNA . Considered relatively small, chromosome 19 still runs to about 61 million base pairs. The first round of sifting reduced the search zone to a neighborhood with only 7 million base pairs, an almost 90 percent narrowing of the field.

Pinpointing the gene required a constant shuffling of the genetic deck, counting on the random nature of sexual reproduction to winnow away the chaff, revealing the kernel of the gene. It’s a process that can take years, measured in mouse generations. Finally, in 2006, they were able to pinpoint the precise location of Sorcs1. It was a triumph, but it also set the stage for heartbreak.

Meanwhile, other projects kept rolling. Sushant Bhatnagar, a postdoctoral scholar in biochemistry, was working on the other target zone—chromosome 16. In 2011 he zeroed in on Tomosyn. “It was crazy,” he says of the work needed to sift through so many mouse generations.

But in the end they discovered that Tomosyn-2 played a critical role in diabetes. Tomosyn was also more willing to give up its secrets. Most of the myriad proteins in a beta cell are positive regulators, which means they facilitate flipping the insulin switch to “on.” Tomosyn is an off switch—one of very few known to exist.

Though mouse and human diabetes are different, the lab confirmed that the human version of Tomosyn plays a similar role. Now the challenge is using the clue to develop a targeted therapy. “Loss of insulin secretion leads directly to diabetes,” Bhatnagar explains. “If you can fix insulin secretion you can fix the majority of diabetes.”

Finding Sorcs1 had been difficult enough, but unlocking how it worked would prove devilishly complex. Two students tried and failed, and eventually left research altogether, demoralized by the dead ends. Attie felt terrible. “I always feel responsible for everything that goes on in the lab,” he says.

Then, in 2012, Attie welcomed a new postdoctoral scholar. The only problem was that Sorcs1 was a beta cell problem, and Melkam Kebede did not come to Madison to work on beta cells.

A child prodigy from Ethiopia by way of Australia, Kebede was through college by age 18 and had her Ph.D. at 23. After spending most of her career on beta cells, she was looking for something  different in her second postdoctoral position. Able to go almost anywhere, she chose Madison, and Attie.

“Of all the places I interviewed, Alan was the most passionate about teaching,” Kebede says. And she liked the way he encouraged people. She’d always been told that she was exceeding expectations, and nobody challenged her during interviews. Except for Attie. “I wanted someone to push me more, so I can do more than what I’ve been doing,” she says.

Pushing people, of course, is a delicate process, and easily fumbled. Attie instead seems to pull with a magnanimous curiosity. And with Kebede he was patient but persistent. Attie would keep asking: Why were the Sorcs mice diabetic? “You still have the parents of these mice waiting in the hallway at the hospital,” he would say. “They are buying so many coffees. You’ve got to come up with a reason why they are diabetic.”

Finally, Kebede couldn’t resist the puzzle—the opportunity to find the link between obesity and diabetes. While the lab hadn’t cracked Sorcs, they had narrowed the focus. And Angie Oler, an invaluable technician with 20 years of experience, would help her get the end game rolling.

In an obese person, cells do not respond completely to normal insulin levels—this is called insulin resistance. To compensate, the body typically produces more insulin. Type 2 diabetes develops when the insulin resistance outpaces the body’s attempt to make more. Sorcs seemed to play a role, but how?

“There are so many things in the body that contribute to controlling glucose levels in the blood,” Kebede explains. A beta cell has to sense an increase in glucose and secrete insulin, which then triggers other reactions that lead, ultimately, to glucose being removed from the blood and absorbed by the cells that need it. Sorcs1 could work anywhere in this great game of cellular call and response.

Despite all of the genetic and biochemical tools at Kebede’s disposal, it was ultimately a simple observation in a microscope that yielded the key. Insulin is manufactured in advance and stored by beta cells in the pancreas, then released as needed. Typically only 1 to 4 percent of the insulin is released at any one time, and a healthy beta cell would simply reload and release more insulin as needed. Examining hundreds upon thousands of cells, Kebede realized that the diabetic beta cells were partly emptied of insulin—but not enough to reveal an insulin secretory dysfunction.

The problem was that a standard lab testing for insulin production was a one-shot deal. The Sorcs1-deficient cells could handle that first test, but not a second test. Finally she understood: The diabetes was caused not by a lack of insulin, but by a failure to reload in a timely way.

The team had the answer—but after their first submission to the prestigious Journal of Clinical Investigations, they were asked to do 22 more experiments.

Kebede had been thinking along the same lines and had already begun the additional work. “We wanted to make sure we got the story right,” she says.

It took an extra eight months, but in August 2014 the paper was finally released. It was an exciting and novel find. In type 2 diabetes, it often seems as if the insulin-producing pancreatic beta cells are wearing down. The Sorcs1 discovery suggests a possible explanation for that, and also provides an important change in how to work with beta cells.

Around the same time, a related discovery came from, of all things, a single-celled organism called Tetrahymena thermophila being studied at the University of Chicago. Attie and Kebede went down to brainstorm with Aaron Turkewitz, a professor of molecular genetics and cell biology. It was an inside-baseball connection, the kind that might take pages to explain and doesn’t show up in grants or co-authored papers. But it personifies the role of a researcher like Attie in an endeavor as complex as decoding diabetes.

“His interests at the most basic scientific level have immense medical implications, and in that way, he connects to a large swath of investigators,” explains Peter Arvan, M.D., Ph.D., director of the University of Michigan Comprehensive Diabetes Center. “There are few like him, but he is a model investigator for the 21st century. As the science gets more complex, the field needs investigators like Alan to connect us.”

Once upon a time, Alan Attie had a bumper sticker that said, “Don’t believe everything you think.”

And Attie thinks about so many things. He makes very good wine and is an accomplished amateur photographer. As much as he loves research, he’s passionate about teaching. Conversations glide from the unification of Germany and money in politics, to Ebola and science funding, to income inequality and student debt.

Attie’s not the happiest of scientists right now. As the United States has reduced its lead in science funding, he’s become acutely aware that the kind of midcareer leap he made into diabetes would be impossible in today’s funding environment. He’s got fewer mice in inventory than at any time in recent memory—and to him that means discovery is languishing.

“We can’t pursue all of our good ideas. We can’t pursue all of our bad ideas, either. But we don’t know which ideas are good or bad until we try. The thing is, we’re not trying as much,” he concludes, frustrated. He worries that we’re losing our edge.

For example, he has a lead on a protein that appears to be involved in both Alzheimer’s and diabetes—perhaps the two greatest challenges to health care financing. “I won’t write the grant because it has zero chance of receiving funding,” Attie says. I

In an age where science seems so often a political pawn, it’s refreshing to hear it talked about as a human ideal.

In Attie’s vision, scientific thinking isn’t just running the numbers and picking the ones you like. It’s about “being self-critical, being introspective about how you think and what algorithm you’re using to arrive at a conclusion about anything in the world,” says Attie. “If that were a widespread value, I think our society would be different, better. We would have less hatred, less racism. We would be more nuanced in the way we judge other people.”

Meanwhile, there are mice to study and students to train. Attie’s been involved in the Collaborative Cross, a massive multi-institutional effort to refine mouse genetics to better allow the study of human disease. Using new mice strains, his team is beginning a major fishing expedition, a multiyear project focusing on insulin secretion and beta cell biology in general—utilizing brand new genetic techniques that already are being hailed as game-changing.

Attie knows there will likely be moments of eureka as well as dead-end heartbreak. The team that he loves so much will grow and change as members adapt to the shifting landscape of discovery. He’ll miss the old students and technicians as they move on, but he’ll gain new students and collaborators as he keeps asking the questions that come so naturally to him.

“Being in science is very humbling because I’ve been wrong about a lot of things over time,” says Attie. “That’s part of learning to be a scientist—and yet I think it’s also part of learning to become a better human being.”

Catch up with … Kartik Chandran

Kartik Chandran

Kartik Chandran

Kartik Chandran (PhD’01 Biochemistry) has spent years studying an organism that most of us hope never to experience: the Ebola virus. Last year the infectious agent not only spread within West Africa but also for the first time reached the United States. The ensuing panic prompted a number of national broadcast news media outlets to turn to Chandran for answers.

Ebola is a major focus of Chandran’s research as a professor of microbiology and immunology at the Albert Einstein College of Medicine in New York. His contributions include helping to identify both the chemical pathway Ebola uses to invade host cells and a specific mechanism inside of cells that acts as an Ebola receptor.

• What fascinates you about viruses?

So many things! They are just these incredible nanomachines, and are often so beautiful to look at. This is what got me into virology in the first place. My Ph.D. adviser at UW–Madison, Max Nibert, showed me some gorgeous image reconstructions of reovirus particles and I was hooked.

Viruses form such a crucial part of life on earth. Indeed, life as we know it wouldn’t exist without viruses. I’m fascinated by the perpetual war, ancient yet modern, that viruses and hosts wage against each other, and by how much that has shaped biology on this planet.

• In light of the recent Ebola outbreaks, do you have any words of comfort or hope? 

It has been horrifying to watch the Ebola epidemic take hold in West Africa. I am hopeful that the resources needed to control it are finally being brought to bear, with the U.S. leading the way. But it’s happening so slowly! We need to multiply our efforts by an order of magnitude and do it quickly— it still feels like the world is in denial about what is happening. I am optimistic also that we will be able to throw vaccines and therapeutics into the fight in the next few months.

But in the meantime, we need to find ways to short-circuit the delays involved in creating infrastructure like treatment centers and the challenge that staffing such centers entails. We have to do more to reduce the spread of the virus at the local level. This seems desperate, but I think we need to help people care for their own family members “in place” by providing the resources and information they need—personal protective gear, chlorine, food. And we have to do this in communities on a regular schedule, not just once by handing out a kit.

• What else would you like to tell the public about Ebola? 

We need a different approach to develop vaccines and therapeutics against emerging agents like Ebola that are not considered major public health threats (or were not, until a few months ago). This and other episodes illustrate the failure of our planet-spanning civilization to act with foresight and plan for the future. The model of letting the marketplace dictate which therapeutics get developed is clearly inadequate to this purpose, since it rewards only short-term thinking. Unfortunately, the government-driven model is not really optimal either—it takes too long to act and disburses funding too anemically.

I don’t pretend to know what the right models are, but I hope we will actively work on coming up with them in the coming months and years. Because this is definitely going to happen again—if not with Ebola, then with some other infectious agent.

Connecting Our Ways of Knowing

In any other classroom, mention of planting “Three Sisters” might cause confusion. But in Becky Nutt’s science class at Oneida Nation High School, located on a tribal reservation in northern Wisconsin, most students know that the Three Sisters are corn, beans and squash, crops that in Native American tradition are planted together in a single mound.

Guided by Nutt, their questions focus on photosynthesis, the process by which plants like the Three Sisters convert sunlight into the energy they need to grow and produce oxygen. The lesson culminates with each student pretending to be an atom of a particular element in that process— oxygen, carbon or hydrogen—and “form bonds” by holding hands or throwing an arm around a classmate’s shoulders. It’s a fun lesson that resonates, judging by both the enthusiastic participation and the thoughtful entries each student writes afterward in a logbook.

The students know the lesson as part of a “pilot curriculum from UW–Madison,” as Nutt tells them—perhaps the easiest way to explain POSOH (poh-SOH), which is both the Menominee word for “hello” and an acronym for “Place-based Opportunities for Sustainable Outcomes and High Hopes.” The program is being developed in partner- ship with both Oneida and Menominee communities.

But what POSOH really represents is a new way of teaching science. Funded by a $4.7 million grant awarded by the U.S. Department of Agriculture in 2011, the program has the mission of helping prepare Native American students for bioenergy and sustainability-related studies and careers. POSOH aims to achieve that by offering science education that is both place-based and culturally relevant, attributes that have been shown to improve learning.

“We’re hoping to help make science relevant to young people,” says CALS biochemistry professor and POSOH project director Rick Amasino. “Bioenergy and sustainability offer an entrée into broader science education.”

For Native American students, sustainability is an obvious fit for science discussion, Amasino notes. The Native American concept of thinking in “seven generations”—how the natural resource management decisions we make today could affect people far into the future—has sustainability at its foundation, and most Native American traditions reflect that value. The Three Sisters, for example, offer a way to discuss not only photosynthesis but also indigenous contributions to our knowledge of agronomy, including how mixed crops support long-term soil health and animal habitat.

An innovative program like POSOH is needed because current teaching methods are not proving effective with Native American students. Native American students score lower in reading and math than their white counter- parts in elementary and high school, and only a low percentage have ACT scores that indicate college readiness, according to “The State of Education for Native Students,” a 2013 report by The Education Trust. Other studies show higher dropout rates and unemployment among Native Americans—and, specifically, that Native Americans are vastly underrepresented in STEM fields as students, teachers and professionals.

Verna Fowler, president of the College of Menominee Nation, sees POSOH as offering a crucial connection. Her tribal community college, along with CESA 8, the state public education authority that includes the Menominee Indian School District, has been a key partner in developing and piloting POSOH. Other leading partners include Michigan State University and, within UW–Madison, the Great Lakes Bioenergy Research Center.

“POSOH takes you into science in the natural world and helps you relate your concepts and understanding so that you understand science is all around you,” says Fowler. “Sometimes that’s what we miss in our classrooms. A lot of students are afraid of science classes. They don’t realize what a scientific world they’re living in.”

In developing POSOH materials, Amasino serves as the go-to guy for verifying the science. “The main thing I do is work with everyone to keep the science accurate,” he says.

Curriculum development and other POSOH activities are led by CALS researcher and POSOH co-director Hedi Baxter Lauffer, who has a rich background in K–12 science education. In a previous project she worked with California state universities in developing a multiyear math and science education program with diverse ethnic communities in the Los Angeles Unified School District. Alongside her work with POSOH, Lauffer directs the Wisconsin Fast Plants Program, which operates worldwide.

From the start Lauffer saw POSOH as a trailblazing effort. “We wanted to create a model for how a culturally responsive science curriculum can emerge from the community it is serving,” she says. “There’s nothing else like it.”

Lauffer knew her group was on to something during early curriculum design sessions with local educators, Native American community elders and students, particularly when she participated in a talking circle with seventh- and eighth-graders from the Menominee Indian School District. The kids were asked a simple question: “How do you take care of the forest—and how does the forest take care of you?”

“They had all kinds of stories about the plants and animals that live there,” says Lauffer. “They were saying things like, ‘I take my nephew into the forest and teach him to pick up his trash. He needs to know that it’s a beautiful place to play.’ It was clear that their connection to nature was strong—and that’s an opportunity for making science learning relevant and valuable.”

Initial steps for curriculum development included building key institutional partnerships and forming teams for curriculum design that brought in a wide range of Native American voices. Team members include scientists, assessment professionals, and teachers of science, education and Native American culture, some of whom are field-testing the materials.

The group is creating curricula for grades seven through nine. Seventh grade is complete, comprised of a fat lesson book and accompanying DVD with graphics and other enrichment materials. The other grades will be completed by the end of 2015, the project’s final year.

Other POSOH activities include after-school science clubs facilitated by undergraduate interns who also serve as informal mentors. This work is conducted in partnership with the Sustainable Development Institute at the College of Menominee Nation under the direction of Kate Flick BS’06, who studied community and environmental sociology at CALS and now serves as POSOH’s education coordinator.

Thumbing through the seventh- grade lesson book, it is immediately clear that cultural relevance is placed front and center. A typical textbook might pay tribute to cultural relevance with sidebars while the main text carries on with “science as usual.” With POSOH materials, cultural relevance is embedded in the meat of the text.

The seventh-grade curriculum, for example, is called “Netaenawemakanak” —Menominee for “All My Relatives”— and its six units focus on various scientific aspects of the Menominee Forest, such as organisms, microhabitats and ecological interactions. Students learn how such terms as evidence, protocol and conceptual models are used in science and, as a final lesson, how to formulate their own stewardship action plan based on what they’ve learned.

And it’s not just what the students learn, but how they learn it. POSOH incorporates forms of teaching and learning that are rooted in Native American culture, such as:

• Storytelling—Scientific concepts are imparted through stories involving the everyday lives of young Native American protagonists as well as figures from Native American legends and folktales.

• Perspective-taking—Students are invited to look at ecosystems from the viewpoint of animals, plants and other natural resources.

• “Careful noticing”—Students use all their senses when getting to know an environment, paying close attention to what is and is not present. In an exercise in the forest, for example, students are asked not only what they see, smell and hear, but also, “How do the woods make you feel?”

“These are age-old practices in indigenous pedagogy, but they aren’t widely seen as such. They’re so fundamental that I think they’re often overlooked,” says Linda Orie, an enrolled member of the Oneida tribe who taught middle-school science at the Menominee Tribal School. She now works on the POSOH curriculum team.

Orie considers POSOH a huge eye- opener for students. “It’s probably one of the first times they’ve seen anything in science class that has anything to do with Native Americans or Native American contributions to science and forestry,” she says. “Especially for a Menominee, that’s really important because most of them live on the reservation and a lot of their parents are employed through the lumber mill.”

“So they live and breathe the forest, but they don’t often get that instruction in the classroom,” Orie continues. “It was a huge gaping hole in the curriculum when I started teaching at the tribal school.”

By drawing upon indigenous ways of teaching and learning, POSOH helps bridge a gap between how students experience nature and how knowledge about it is imparted in the classroom. POSOH team member Robin Kimmerer, for example, says that as a professor of forest biology and as a Native American, she’s had to work hard to reconcile two distinct perspectives.

“In science we are asked to objectify the world, to view it in a strictly material, intellectual way,” says Kimmerer, who earned her doctorate in botany at UW–Madison and now teaches at the State University of New York. “In indigenous ways of knowing, we’re reminded that we can understand the world intellectually, physically, emotionally and spiritually—and that we can’t really claim to understand something unless we engage all four elements,” she says. POSOH team member Justin Gauthier, an enrolled Menominee who as a teenager attended a Native American boarding school, has come to think of science as another language for indigenous ways of knowing nature. In science, he says, “They’re using numbers, they’re using experimentation. It’s just different language.”

That recognition helped science feel more approachable to him.

“I used to perceive science as being outside of my experience. It was meant for scientists to do in a lab in a white coat. When I started thinking about how it tied into the ways that I was thinking, I felt that it had always been a part of my life and I had just never given it much credence,” he says.

Gauthier, a returning adult student, is earning his bachelor’s degree in English at UW–Madison and plans to teach in a tribal college after earn- ing an MFA in creative writing. He serves POSOH as a curriculum writer. Gauthier suggested naming the seventh- grade curriculum Netaenawemakanak (“All My Relatives”) because it is often uttered as a kind of one-word prayer when entering and leaving the sweat lodge. To him, among other things, the word expresses Native American regard for nature.

POSOH is not only helping fill a gap in science education. Project intern McKaylee Duquain, a junior majoring in forest science, notes that POSOH is filling a gap in cultural knowledge among young Native Americans as well. As an enrolled Menominee who attended tribal schools, Duquain confesses to not knowing what the Three Sisters were until late in high school—and she learned about it on her own.

“It wasn’t even offered when I was a student,” she says. “I’m not the most traditional person out there—I try to practice the traditional ways, but you can only do so much in this day and age. I feel like having that knowledge incorporated into your everyday learning life in school would definitely cement it in more.”

The program’s most enthusiastic ambassadors are the teach- ers and students who have been using it. So far the POSOH curriculum has been taught in 25 Wisconsin classrooms with the participation of some 135 students. Another 140 students have worked with POSOH materials in other settings, such as outreach programs conducted by undergraduate interns and the project’s high school club, called the Sustainability Leadership Cohort.

“I love that the POSOH curriculum brings science to a local level,” says Dan Albrent, a science teacher at De Pere’s Ashwaubenon High School, where he’s been piloting POSOH materials for the past two years. “Students a lot of times wonder why we are even learning all these complex things in science and just want a reason. POSOH does a nice job of bringing in real-life situations and issues that are literally close to home. And never in the curriculum are students sitting and listening to a lecture. They are actively talking and working with real data and real situations to solve problems.”

To him, POSOH represents the future of science education. “I truly believe this is how science should be taught,” Albrent says. “At the moment there is no better alternative for helping our kids realize the importance of learning science for our communities.”

Becky Nutt, of Oneida Nation High School, is just as convinced. She appreciates the program’s emphasis on reading and writing, which is not a given in science class—but important, she notes, in both communicating science and demonstrating understanding.

“Most important from my view is the integration of Native American culture into the materials,” says Nutt. “If, through these materials, we can foster better relationships between our Native students and their communities and other individuals and their communities, then we are on the right track.”

POSOH team member Linda Orie is taking a break from the classroom while earning her master’s degree in curriculum and instruction at UW– Madison—but she plans to return
to teaching in tribal schools and sees POSOH as a life-changing tool to bring with her.

“My career goal is to transform Indian education because it is stuck in this terrible rut,” Orie says. “Working in the tribal school I saw a lot of opportunity for growth. It was heartbreaking to see so much potential and not have colleagues that saw the same. And not seeing as many Native American teachers as there could be or should be in the schools. The kids need the best curriculum and the best teachers, and they’re not getting that right now. I want to be part of the change.”

That Orie, as an Oneida, backs the program so strongly speaks to perhaps the program’s greatest indicator of success—the acceptance it has earned in Native communities.

“We’ve been presenting POSOH to different schools, to different areas, to our boards of education and so on, and they’re very enthused about it— extremely enthused, I must say,” says College of Menominee Nation president Verna Fowler.

That enthusiasm is no accident, but the result of the program being developed within and in partnership with Native communities. Patty Loew, who is a professor of life sciences communication at CALS and an enrolled member of the Bad River Band of Lake Superior Ojibwe, just happened to be on hand during a POSOH presentation on the Menominee Reservation and was heartened by what she saw.

“I’ve been in a lot of situations where UW people try to engage with community members and it’s like pulling teeth for reasons that vary, but often come down to a basic mistrust of researchers,” Loew says. In those encounters, she says, “People are either being polite or they’ll have their arms folded and are just quietly listening or maybe hiding their resentment.”

“That was not the case on this day,” Loew says. “People were really engaged, they were discussing, they had ideas, it was emotional. It was clear to me that the community’s handprints were all over this project. They not only were hosting the research, they had shaped it, they were contributing to it, they were using the materials in their classrooms, they had a lot of pride in it. And I was really impressed.”

POSOH team member Justin Gauthier also knew about the mistrust firsthand—and saw it melt away.

“Historically in Indian Country there’s been this sort of stigma toward outside groups coming into the community, studying groups of people, taking data out of that community—and nary shall the two meet again,” Gauthier says. “But I really like and respect the way that the POSOH process is set up because, while the leadership team
is made up of people from within and without that community, the ideas—the voices at the table—are respected and integrated into the process. I feel like when we finish the project the curriculum and the relationships we’ve built are going to remain strong.”

“And that could be the big takeaway for me from this project,” Gauthier says. “Communities have the right to be wary of people coming in and studying them. But when you have a project like this, where the end result is meant to be a gift for that community, then you really see the beauty of cultures blossom and open up.”

That could be the big takeaway for Amasino and Lauffer as well. They and their team conceived of POSOH as an experiment in developing culturally integrated science curricula in a way that could be applied in various settings around the country.

“Our overarching mission is to build a transformational model for place- based collaborations dedicated to preparing all learners, especially those who are underrepresented in science and science education,” says Lauffer. “These community-based processes are what the project will share more broadly as it draws to a close. We plan to pass on lessons from POSOH to many other communities who can then build on our work and continue improving science teaching and learning.”

To learn more about POSOH, visit http://posohproject.org/. You can also watch the following video: http://go.wisc.edu/posohvideo

Class Act: Energizing the Classroom

When biochemistry senior Hong-En Chen first got involved with a student organization called Energy Hub, she knew she could bring something special to the table.

As the daughter of a preschool teacher, she’d interacted a lot with young children throughout her own childhood and adolescence. While in high school she worked as a teacher and tutor in music, math and reading in both English and Mandarin at the Einstein School in Madison, a private preschool and after-school enrichment center for elementary school students.

Based on her experience, she saw an important niche for Energy Hub: The group could go out to local elementary schools and hold after-school classes about energy.

“When kids are young, they’re like sponges. They absorb a lot of information and are enthusiastic learners,” notes Chen. “When we introduced concepts about energy use, conservation and sustainability, the kids impressed us not only by handling complex material, but also by applying ideas to their everyday lives.”

As outreach director of Energy Hub, Chen got other club members on board to pilot their project, working with second- to fifth-grade students at four Madison elementary schools. Based on that experience, they applied for and received a Wisconsin Idea Fellowship grant to further develop their curriculum during the 2012–2013 school year. They created a 10-week program that is going strong this year.

Hands-on activities are key, says Chen, whether using an educational science toy like Snap Circuits to teach the concepts behind powering lights and fans, or having students divide into the fantasy cities of Greenville and Coaltown to talk about how they, as residents, would use energy from various sources to get through a day. “It was a fun way to get them thinking about the costs and benefits of renewable versus nonrenewable energy sources,” Chen says.

Chen’s thinking a lot about that topic herself. She is researching compounds for solar energy conversion in chemistry professor Song Jin’s lab. And she is considering graduate programs in materials chemistry with an eye toward working in renewable energy research.

Learn more about Energy Hub at www.uwehub.org.

Stopping Multiple Sclerosis

A diagnosis of multiple sclerosis (MS) is a hard lot. Patients typically get the diagnosis around age 30 after experiencing a series of neurological problems such as blurry vision, a wobbly gait or a numb foot.

From there, this neurodegenerative disease follows an unforgiving course. People with severe cases are typically bed-bound by age 60. Current medications don’t do much to slow the disease, which afflicts around 400,000 people nationwide, with 200 new cases diagnosed each week.

Now a team of CALS biochemists has discovered a promising vitamin D–based treatment that can halt—and even reverse—the course of the disease in a mouse model of MS. The treatment involves giving mice exhibiting MS symptoms a single dose of calcitriol, the active hormone form of vitamin D, followed by ongoing vitamin D supplements in their diet.

“All of the animals just got better and better, and the longer we watched them, the more neurological function they regained,” says CALS biochemistry professor Colleen Hayes, who led the study and published her team’s findings in the Journal of Neuroimmunology.

While scientists don’t fully understand what triggers MS, some studies have linked low levels of vitamin D with a higher risk of developing the disease. Hayes has been studying this “vitamin D hypothesis” for the past 25 years. She and her researchers have revealed some of the molecular mechanisms involved in vitamin D’s protective actions, and also explained how vitamin D interactions with estrogen may influence MS disease risk and progression in women.

In the current study, funded by the National Multiple Sclerosis Society, Hayes’ team compared various vitamin D–based treatments to standard MS drugs. In each case, vitamin D–based treatments won out. Mice that received them showed fewer physical symptoms and cellular signs of disease.

Hayes’ team compared the effectiveness of a single dose of calcitriol to that of a comparable dose of a glucocorticoid, a treatment now in use. Calcitriol came out ahead, inducing a nine-day remission in 92 percent of mice on average, versus a six-day remission in 58 percent for mice that received glucocorticoid.

“So, at least in the animal model, calcitriol is more effective than what’s being used in the clinic right now,” says Hayes.

But calcitriol can carry some strong side effects—it’s a “biological sledgehammer” that can raise blood calcium levels in people, Hayes says. After experimenting with various doses, her team arrived at a regimen of a single dose of calcitriol followed by ongoing vitamin D supplements in the diet. This one-two punch “was a runaway success,” she says. “One hundred percent of mice responded.”

While she is excited about the prospect of her research helping MS patients someday, Hayes is quick to point out that it’s based on a mouse model. The next step is human clinical trials. A multicenter clinical study is currently being designed. If trials are successful, people experiencing those first warning signs—the wobbly gait, the numb foot—could receive the new treatment and stop the disease in its tracks.

“It’s my hope that one day doctors will be able to say, ‘We’re going to give you an oral calcitriol dose and ramp up the vitamin D in your diet, and then we’re going to follow you closely over the next few months. You’re just going to have this one neurological episode and that will be the end of it,’” says Hayes. “That’s my dream.”

The Secret Lives of Bacteria

CONSIDERING HOW WELL STUDIED THEY ARE, SOME LARGE GAPS remain in our scientific understanding of bacteria. For instance, we don’t yet know how bacterial chromosomes are separated into daughter cells during cell division or how their complicated chemical language really works. Using techniques from a broad spectrum of fields—including biochemistry, genetics, materials science and engineering—biochemistry professor Doug Weibel is designing advanced microtools and novel experimental setups to answer, for the first time, persisting questions about these surprisingly complex microorganisms. Through this basic work, he’s finding novel antibiotics and other interesting drug candidates.

Why are there still so many major unknowns about bacteria? How can that be?

The issue with bacteria is they are so small. By comparison, eukaryotic cells are enormous! For a calibration point, a human hair is about 100 microns in diameter. That’s about the thickness of a piece of scotch tape. And a eukaryote—when it’s spread on a surface—is maybe 40 microns in diameter. But the bacteria we look at are about one micron long, and their short axis is just several hundred nanometers. Until recently it was very difficult to look at them under a microscope and see anything useful going on inside the cell. Fortunately, there’s been a revolution in optical microscopy techniques over the last five years, and now we can see inside them with pretty good resolution.

How has our understanding about these microorganisms grown in recent years?

Historically, bacteria have always been thought of in the context of the way that we studied them: as individuals. They were always freely suspended in liquid nutrients and were dilute enough so that they never made physical contact with each other. But it’s pretty clear now that many bacteria in the ecosystem exist in tight-knit communities.

And during certain developmental stages, bacterial cells will display collective dynamics, where they are no longer acting as individual cells—as little one-bit processors—but are actually making collective decisions. In these cases, they are communicating and acting more like a multicellular organism—as something a lot more sophisticated than we’ve ever really appreciated.

Tell me more about this collective behavior.

A lot of people know that bacteria swim in solution, but they also swim in groups on surfaces. This collective movement on surfaces is called swarming.

As the bacterial community moves across a surface, the cells mix—and this mixing ensures that all of the cells get nutrients and growth factors to continue replicating. Swarming allows the cells to grow explosively and to colonize whatever niche they’re provided with.

What are you trying to learn about swarming in your lab?

We’re trying to figure out two things. One has to do with behavior: How does the motion of individual cells on a small scale lead to the pattern formation—the continuous mixing—of the swarm on a large scale? The other question is really the biochemistry of how it works. How do cells sense the surface and then change their morphology to interact with it?

This work should tell us some basic rules about how cells sense things outside of themselves—from fluids to surfaces to other cells. I think this is super interesting.

Many bacteria in the ecosystem exist in tight-knit communities.

Can you describe one of the microtools you’ve developed to study bacteria?

Sure, but let me give you some more context first. In addition to studying the physical interactions between bacteria during swarming, we’re also interested in the role that chemical communication plays in the development of swarms. And swarming is just an early stage of biofilm development, so we are also interested in biofilms, which are basically bacterial communities that are firmly attached to surfaces.
One question that’s been in the field for a long time is, what is the length scale over which these chemical signals can be propagated? That is, if you have a swarm or a small early-stage biofilm that’s secreting signals, how far away does another biofilm have to be before it can no longer eavesdrop? To answer this question we created a microtool that we call the waffle.