Last year, the University of Wisconsin–Madison turned 175. The university has been celebrating this impressive milestone by hosting campus and statewide festivities and by highlighting UW’s most significant scientific advancements and other contributions to society.

From UW’s very early days, the agricultural and life sciences have been at the heart of the institution’s enterprise. As the state’s land-grant public university (so designated in 1866), UW is charged with studying and teaching practical disciplines, such as agriculture, science, and engineering. The College of Agriculture (now the College of Agricultural and Life Sciences, or CALS) was established in 1889 to help support that mission. Over the past 135 years, the college’s faculty and staff have made many groundbreaking discoveries that have changed the world for the better.

So CALS is celebrating, too. As part of the celebration, the past two issues of Grow have spotlighted various aspects of the college’s rich history, including the evolution of the university’s agriculture library and its Agricultural Research Station system. And the celebration continues here with a sampling of notable scientific breakthroughs stemming from CALS. (Here’s a more complete list of notable achievements.)  These discoveries have made a lasting impact on the state, the nation, and the world, and they serve as models and guides for CALS as it looks to the future.

Super Silos

In the late 19th century, when dairy farming and cheesemaking were just taking root in Wisconsin, farmers weren’t sure about the best way to keep cows fed through the long, cold winters. A common form of animal feed growing in popularity in the U.S. at the time was silage.

Composed of fermented hay, corn, or other plant materials, silage can be used all winter long if stored correctly. Two early CALS faculty members contributed greatly to the improvement and adoption of silos for this purpose. In an early trial, in 1881, UW researchers started with a square-shaped structure. They built a stone cellar with cement walls on a UW research farm and filled it with corn and clover. When the silo was opened months later during winter, some moldy clover was discarded; but the corn fodder was in good shape, and the cows that ate it showed healthy weight gain.

William Henry, the first dean of the College of Agricultural and Life Sciences, who was involved in the study, advised farmers to utilize silos and shared details on silo-building methods and materials.

But square silos had their problems. Chiefly, the silage would go bad in the corners. F. H. King PhD 1910, a professor of agricultural physics (later called agricultural engineering, now biological systems engineering), became a big proponent of an alternative. He studied the merits of the cylindrical silo and conducted the initial engineering research on the structure. He reported that round silos prevent the spoilage seen in square silos, and they are easier to load and structurally stronger. Like Henry — and in keeping with the Wisconsin Idea to ensure university research helps the citizens of the state —King published the first-ever bulletin with instructions for how to build round wooden silos.

The King Silo, or Wisconsin Silo, as it came to be known, became ubiquitous across the rural landscape, allowing farmers to have planned, dependable animal rations throughout the year. Eventually, it became an iconic symbol of the dairy farm as virtually every farm in Wisconsin featured a red barn and a silo.

Vitamins Unveiled

In the early 1900s, a team of researchers at UW embarked on an important nutritional study to understand the basic components of a healthy diet. The team devised an experiment to feed groups of cows “purified foods” from single grains — oats, wheat, or corn — so each group of animals received a chemically balanced diet of the three macronutrients: protein, carbohydrates, and fat.

The corn-fed cows were healthy. But cows receiving the oat and wheat-based diets exhibited blindness, stunted growth, and stillborn births. These findings told the researchers there was something essential in the corn-based diet that wasn’t present in the others. The results, published in 1911, left a big question unanswered: What was the critical component missing from the oat- and wheat-based diets?

Enter UW biochemist Elmer McCollum, who had been hired to help analyze the samples for the purified foods experiment. He decided to pursue this question and brought on Marguerite Davis as a researcher — originally as an unpaid volunteer — to conduct the experiments using rats as a model organism.

They started out by replicating the cow study in rats, which yielded the same results. Next, they began adding supplemental components to the two deficient diets — such as fats in the form of milk fat, lard, or olive oil — to find what could make a diet complete.

The rats given the milk-fat supplement grew, while rats that ate olive oil or lard continued to be sick and stunted. Milk fat clearly gave the rats some kind of health benefit. Next, the researchers extracted fat-soluble compounds from milk fat and added them to the olive oil and lard. The rats consuming this fortified oil and lard turned out just as healthy as the milk fat-fed rodents.

Davis and McCollum published their findings in 1913. Their coauthorship on this study is significant because, at the time, women were often excluded from professional societies and denied credit for their discoveries. Davis’s work in this area is just one example of the important and often underappreciated contributions women made to the nutritional sciences in the early 20th century.

The scientific tandem went on to call their extracted fat-soluble compounds “fat-soluble A,” later renamed vitamin A. They had isolated the very first vitamin.

Next, Davis and McCollum identified leafy greens as another source of vitamin A. This explains why the corn-fed cows and rats thrived: The corn rations had been processed with grains, stems, and leaves.

The biological method of analysis Davis and McCollum employed — the combined use of diets and animals — made UW a pioneer in the discovery of dietary essential minerals for animals and humans. This body of work opened the door to the discovery of other vitamins, the foods that contain them, and their role in human health and nutrition.

Later CALS research in this area led to the eradication of numerous vitamin deficiency diseases in many parts of the world. For example, biochemistry professor Conrad Elvehjem’s work on vitamin B-3 in the 1930s contributed to a cure for pellagra, a deadly, nutrition-related disease that reached epidemic proportions in the United States in the first half of the 20th century. And before this, in 1923, biochemistry professor Harry Steenbock devised a way to fortify foods with vitamin D through exposure to ultraviolet light. The innovation helped nearly eliminate rickets by the mid-1940s and launched a long history of groundbreaking and life-changing vitamin D research at CALS.

Warfarin, the Wonder Drug

In 1933, Ed Carlson, a farmer from Deer Park, Wisconsin, drove 200 miles to Madison to figure out what was killing his cows. They were suffering from a known sickness called sweet clover disease, which causes uncontrollable bleeding in animals and was a persistent problem for cattle herds across the northern U.S. at the time. But the root cause of the condition remained a mystery.

After finding the office of the state veterinarian closed — it was a Saturday — Carlson ended up at the laboratory of UW–Madison biochemist Karl Paul Link BS 1922, MS 1923, PhD 1925, a coincidence that altered the trajectory of Link’s career. Sweet clover disease was already linked to moldy hay. For the unfortunate cows that ate this bad hay, their blood would not clot, and they would hemorrhage to death. Link set out to find the chemical culprit. Link’s research team determined the chemical structure and then synthesized the compound in 1940. The Wisconsin Alumni Research Foundation (WARF) quickly patented this molecule, which scientists had named “dicumarol.” In 1941, dicumarol entered human trials as a blood thinner to treat blood clots and prevent strokes at the Wisconsin General Hospital and the Mayo Clinic.

Subsequently, Link and others in his lab synthesized more than 100 compounds structurally related to dicumarol. Each of these analogs had a slight difference in chemical makeup, but all produced some kind of anticoagulant effects. Link and his collaborators began exploring which of these analogs was best suited for practical use.

One analog, number 42, showed commercial promise. In particular, it made a great candidate for rodent control. Link named the compound warfarin — in honor of WARF — and it was patented in 1947 by Link and graduate students Miyoshi Ikawa and Mark A.

Meanwhile, research continued to identify which of the analogs was the safest and most effective to use as a blood thinner in human patients. The result was surprising: It turned out to be analog 42 (warfarin) again, which worked even better than dicumarol. A water-soluble version, known as warfarin sodium, was approved for human use in 1954 and went on the market under the brand name Coumadin.

In 1955, word got out that President Dwight D. Eisenhower had been given Coumadin following a heart attack. This contributed to the adoption and popularity of the drug. In short order, warfarin became both the most widely used rat poison and the most widely prescribed blood thinner (Coumadin) in the world.

While new types of anticoagulants have been gaining in popularity over the past decade or so, Coumadin remains one of the most common treatments for blood clots to this day. Experts estimate that around 100 million prescriptions for Coumadin are still issued globally each year.

Synthesis of the First Gene

Today it’s possible for researchers to place an online order for a custom strand of DNA— with next-day delivery. So, it might be hard to imagine a time when we didn’t understand the genetic code or how the information coded in DNA works (via messenger RNA, or mRNA) to produce the proteins in our bodies.

But that was still the situation in 1960 when Har Gobind Khorana joined UW–Madison to serve as codirector of the Institute for Enzyme Research and a faculty member in the Department of Biochemistry. While at UW, he conducted research that helped crack the genetic code, revealing the biological instructions that tell living cells what to do (i.e., what proteins to make) to perform the vital functions for survival.

As a first step, Khorana used nucleotides — the building blocks of genetic material — to create short strands of mRNA. He then looked at the proteins produced from these mRNA strands, focusing on how the order of the specific nucleotides can influence what proteins are produced. The order was a type of informational code, it turned out, dictating the type of protein formed, and he was able to figure out its meaning. For this work, completed during his tenure at UW, Khorana shared the Nobel Prize for physiology or medicine in 1968.

From there, the rest of the puzzle was relatively straightforward: This same type of code is reflected in DNA, which serves as the long-term storage of genetic information. While still at Wisconsin, Khorana began his work to synthesize the first artificial gene made of DNA.

He left Madison in 1970 to join the Massachusetts Institute of Technology, and, shortly thereafter, Khorana and his colleagues announced that they had synthesized two genes crucial to protein building — the world’s very first synthetic genes. This pioneering work, started at UW, has revolutionized biotechnology. Early on, researchers could only make short strands of DNA, but science has advanced to the point today where entire genomes — the full genetic blueprint for a living organism —can be assembled from scratch. Custom-designed pieces of DNA are widely used in research labs, and they have played a role in countless advances in medical, agricultural, and basic research.

A Compendium of Colds

The common cold is nature’s most ubiquitous human pathogen. In a given year, adults often endure two to four infections, while schoolchildren can catch as many as 10. Cold viruses are responsible for millions of illnesses each year at an estimated annual cost of more than $40 billion in the U.S. alone.

In 2009, a multi-institutional team of researchers led by Ann Palmenberg, a biochemistry professor and affiliated faculty at UW’s Institute for Molecular Virology, reported the genome sequences for all 99 known strains of the cold virus, providing for the first time a detailed genetic blueprint for the virus, including information about its structure and how it operates. The sequenced cold viruses were collected from human noses worldwide. This work shed light on the organism’s evolution as well as its vulnerabilities, revealing pressure points that could lead to new antiviral drugs and other approaches to prevent or mediate infection. Palmenberg’s team went on to develop a method for propagating rhinovirus C, a “missing link” cold virus first identified in 2006 that is associated with severe respiratory infections in children, especially those with asthma. The method enabled further discoveries by the team, including the identification of the 3D structure of the virus and the revelation of peptides that might block it from causing disease.

Over the years, Palmenberg’s viral genome and physical structure research has led to the creation of new antivirals, vaccines, and high-demand research reagents used in thousands of labs around the world.

To recognize the impact of her work, in 2020, Palmenberg was named a fellow of the National Academy of Inventors, an honor that acknowledges innovators who have made an impact on quality of life, economic development, and the welfare of society.

Forward into the Next 175 Years

Milestones are a great time to reflect on the past —and also to chart a course for the future. The faculty, staff, and students of CALS today are looking ahead for the next high-impact discoveries that will position society for a better tomorrow.

Last fall, CALS leaders hosted two “visioning sessions” focused on research priorities. These interactive discussions brought together the college community to identify research areas where CALS is strategically positioned to solve grand challenges. In particular, participants were asked to consider the broad areas of sustainable agriculture and the life sciences, and then identify where the college has multidisciplinary teams that can work to solve some of the major problems of the world.

“We held these sessions to help inform the college’s strategic hiring, our infrastructure investments, and our fundraising efforts,” says CALS Dean Glenda Gillaspy. “We had great participation over the two sessions and received a lot of innovative ideas for research priorities. We also talked about [the spaces we need] to help us improve our research impact.”

In the realm of sustainable agriculture, these discussions identified three areas of focus: decarbonizing food production systems; creating systems for water sustainability; and developing innovative agronomic systems. In the life sciences, identified strengths revolved around human health: feeding the world through synthetic biology; promoting healthy aging through gut microbiome and nutrition; and preventing vector- borne diseases.

Earlier in 2023, the college completed a facilities master plan, which includes an analysis of current infrastructure and guidance for the future. The plan recommends consolidating research space, including building new multidisciplinary research facilities.

“We’ll be constructing big buildings that accommodate multiple departments and are designed to promote transdisciplinary research and discovery,” says Gillaspy. “It’ll be a new look for CALS, something different. It’s the way of the future.”

This article was posted in Basic Science, Features, Food Systems, Health and Wellness, Spring 2024 and tagged 175 years, Ann Palmenberg, Biochemistry, biological systems engineering, Biotechnology, common cold, DNA, Elmer McCollum, F.H. King, gene synthesis, Genetics, har gobind khorana, Karl Paul Link, Marguerite Davis, Mark A. Stahmann, Miyoshi Ikawa, Nobel Prize, RNA, silos, virology, vitamin A, vitamin B, vitamin D, vitamins, William Henry, Wisconsin Alumni Research Foundation (WARF).