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Intelligent Design

Written by Joseph Caputo ’07
Photography by Andrew Lichtenstein ’88 & Linda Kohn '73

It’s easy for a scientist to think of a question that needs answering. Designing the experiment that answers the question isn’t so simple. But a creative scientist can transmute complexity into elegance, turn limitations—of time, technology, money, and knowledge—into strengths, and satisfy her inquiry, all with one well-designed experiment.

Experimental design is the heart of scientific investigation; when it’s done right, it can be close to an art form. Linda Kohn ’73, a mycologist, and Carol Shoshkes Reiss MS ’73, a neuroimmunologist, show us how it’s done.

The Magic of Mushrooms

In the summer of 1985, Linda Kohn ’73 was picking gnat-sized mushrooms 225 miles above the magnetic North Pole. Armed with a hand lens, pocketknife, tweezers, little boxes, and lunch, she spent her days in a lowland arctic oasis bounded by ice-covered cliffs. This stark landscape might seem an unlikely spot for mushrooms to thrive, but there were about 100 visible species, Kohn says.

There are projected to be 1.5 million species of fungus in the world, thriving in environments as diverse as the nutrient-rich rainforest and the frozen tundra. Kohn, one of the world’s few experts on cup fungi and professor of biology at the University of Toronto, has traveled to many of these far-flung locales over the past 30 years, collecting fungi, considering their life histories, and pondering their evolutionary success. But exactly how, she wondered, did this diversity of species come to be? This became the defining question of Kohn’s career when, 20 years after her northern expedition, she and her co-workers designed the first experiment to show adaptation in action, demonstrating its role in the evolution of new species.

Kaufman on the subway

Evolutionary biologists since Darwin have thought a lot about speciation, but by 2005, when Kohn began her research, there was not a lot of experimental evidence—just theory, she says. Watching speciation in action is difficult because it takes many generations and the right mix of environmental factors to occur. Popular model organisms like mice, zebrafish, and fruit flies are too complex and live too long for one scientist to conduct a revealing experiment within her lifetime.

Kohn, with her mastery of mycology, knew yeast would be the perfect fungus for the job. The yeast used for brewing and baking produces six generations per day in laboratory flasks, which makes it ideal for experimental evolution. Plus, unlike most other model organisms, yeast can be frozen, which means ancestors and descendants can be easily stored and revived at will.

“Yeast is a terrific system,” Kohn says. “We can do evolutionary drag races to compare different lineages.”

Kohn designed an experiment in which she watched the descendants of a single yeast cell in three different environments: normal, high salt, and low glucose. Would yeast offspring maintain the genetics of their parents, or adapt to the stressful environmental conditions? Kohn found that after 500 generations, yeast grown in high salt tolerated that environment much better than the others did; yeast grown in low glucose was similarly successful in a low-glucose environment.

But what was really interesting was that when a salt-adapted yeast was mated with a low-glucose-adapted yeast, their offspring were disasters: They were much less able to reproduce than their parents. There was clearly a penalty in bringing the two adaptations together in one individual—a good explanation for why species remain largely distinct from each other once they have evolved.

“This is at last, hard, empirical evidence of ecological speciation” and of the reproductive isolation that keeps species separate and cohesive, Kohn says about her laboratory model. In 2007, the results were published in Nature, and her protocol was recognized by the Faculty of 1000, a group that highlights the most interesting papers in science.

Drug Testing

Carol Shoshkes Reiss MS ’73, a biology professor at New York University, has spent her career investigating the evolutionary arms race between viruses and the immune system. Now, she hopes that her latest experiment will reveal a cure for viral encephalitis, an infection of the brain caused by foreign invaders, including the West Nile virus. Although viral encephalitis is rare, severe cases can result in long-term cognitive problems or even death.

Viruses, slivers of parasitic DNA or RNA that hijack a host’s cell machinery to produce their offspring, are a huge success from an evolutionary point of view: They can quickly mutate, replicate, and spread to a variety of hosts. Reiss’s laboratory uses mice to study how viruses function in the brain; lately, they have explored the role individual proteins play in infection.

These days, Reiss spends about 12 hours a day in her office, which is decorated with virology textbooks and posters of cellular pathways, advising the gloved graduate students in the lab outside her door, thinking about experiments, and editing the journal Viral Immunology.

A Graduate Student in Reiss' Lab

“With scientific research, every question you answer leads to three more questions,” says Reiss. “The questions I’m asking will translate into research that I hope will be able to cure people with viral encephalopathy. But you have to understand the basics first. You can’t do a shotgun approach.”

Recent experiments on infected mice—by Reiss and others—have found that West Nile virus sneaks into brain cells by attaching to fatty proteins on the cell membrane. These same proteins are targeted by a class of prescription drugs called bisphosphonates (one, Fosamax, is used to treat osteoporosis). Reiss will approach the question of how to cure viral encephalitis by pitting these drugs against the virus, first in test tubes and then in infected mice. She has tried this approach with other drugs, but the choice to use bisphosphonates for her next experiment is a direct result of her research on proteins. If she’s successful, a drug that’s already in your neighborhood pharmacy could be used to prevent West Nile virus.

Carol Reiss in her office

Curiouser and Curiouser

Linda Kohn, meanwhile, is delving deeper into the question of speciation and reproductive isolation. Although trained as a field biologist, she is using a new genetic sequencing method to compare the genomes of normal yeast to those that have adapted to high-salt or low-glucose conditions. She and her fellow researchers have determined the “speciation genes,” discovering which mutations clash and which convey an adaptive boost in the hybrid offspring of the different strains of yeast.

What’s surprising, Kohn says, is that not all of the evolved yeast have the same mutations. Some adapted to the toxic environment by altering their cell walls, while others changed the cellular pumps that remove unwanted molecules from the yeast. “This is all more complicated than simply one gene,” she explains. It offers new evidence that speciation is a complex and genome-wide event.

Which, of course, raises more questions. That’s not a problem for Kohn—or for Reiss: Curiosity fuels them both.

“Doing research is incredibly gratifying,” Reiss says. “People in science love what they are doing. When we get an answer we haven’t anticipated, we have to understand why.”

Kohn agrees. “Science is an art,” she says. “And creativity is key. I have the freedom to wake up in the morning and think ‘What am I going to do today, and how am I going to do it?’”

Yet another question for Kohn to answer, but that’s why she chose mycology. We have a lot to learn from mushrooms.

A Cup Fungus in the Arctic

Ellesmere Island

Testing in Process

Good organization is key to an experiment’s success

Linda Kohn working in the polar daylight at 2:30 a.m., 1985

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