Stanford scientist recalls falling in love with microbes

On an autumn day in 1997, Paula Welander watched an invasion in a Petri dish. Millions of rod-shaped Escherichia coli cells squiggled through jelly-like agar smeared on the plate, while predatory bacteria pursued and attacked the rapidly dividing cells.

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The high-speed transformation of the bacterial hordes under her microscope drew Welander, who is now an associate professor of Earth system science in Stanford’s School of Earth, Energy & Environmental Sciences (Stanford Earth), into a new world.

“I just fell in love with microbes. I could put a drop in a culture tube and in a few hours have a complete population of these organisms,” she said. “And I had access to their genes and their proteins. Here was a system that would allow me in its simplicity to answer very complex questions. I could use microbes as a system to study life.”

Welander is petite and quick to laugh. Listening to her describe her work in her sunny office on the Stanford campus, in a time before the coronavirus, microbes can begin to seem like both creative, scrappy beings and impressive machines. “Microbes have found different ways over billions of years of evolution to use their environment so they can just grow. We would never think to breathe arsenic; they breathe arsenic, or they’ll breathe iron and form rust as a byproduct. The only thing we can make is water and carbon dioxide.”

Welander caught that first glimpse of the diversity of microbial life and the power of what she would later come to know as bench science as an undergraduate student at Occidental College in Los Angeles, California.

The campus lies less than 30 miles from Welander’s childhood home, but her work in labs there helped her find a path that had been all but invisible in her upbringing. Her parents, who immigrated to Los Angeles from Mexico as teenagers in the early 1970s, had encouraged her to pursue medicine or law. “The idea of an academic career wasn’t something they had been exposed to,” Welander said.

When a college professor and mentor encouraged Welander to pursue a career in bench science, Welander recalled, “I was like, wait, what does that even mean to be a scientist?” What it meant for Welander was starting out after graduation as a technician in a lab, where she studied the immune systems of mice dealing with herpes infections that go dormant and then suddenly reactivate.

Working with mice made Welander realize something: She missed microbes.

“Statistically, the number of mice we were looking at was just so low,” Welander said. “With microbes, for statistical significance, I could kill a million of them and then start a new culture the next day.”

For Welander, who has begun most days since high school with an early morning run, the daily repetition demanded by laboratory research had hooked her from the start. “I fell in love with the ability to take a protocol and get a result, and if it doesn’t work, then you redo or rethink the experiment.”

In grad school, at the University of Illinois at Urbana-Champaign, Welander worked in a lab studying the only microbes that generate methane. The experience expanded her thinking from questions about how microbes affect human health and disease to how microbes exist with the Earth. “I realized that the reason the planet looks the way it does today is because of the life that’s on it,” she said. “The ecosystem would fall apart without microbes. That was true 100 million years ago, two billion years ago, even four and a half billion years ago when life was first starting to evolve.”

After grad school, Welander worked as a postdoc with both a geologist and a geobiologist, and she began learning how to frame questions in a way that fed her curiosity about basic molecular biology while also enabling geologists to better interpret ecological records. She often found herself building intellectual and cultural bridges – familiar territory for a child of immigrants.

“As a kid of immigrants, you’re bridging two worlds, because you’re at home and you’re speaking Spanish and you have these cultural norms, and then you’re shipped off to school where you’re then speaking English and you have these ambitions and goals and things that maybe don’t correlate well with what the goals are at home. You’re negotiating those two worlds,” Welander said. “I had to explain things to my parents and I had to explain things to my teachers and peers. It might have been why I was comfortable then making the leap from microbiology to studying molecular fossils.”

Welander says that over time, she has grown more comfortable grappling with big questions about the early days of Earth and complex life. “I like systems that I can use to ask a very specific question and answer it in very fine detail, and then step back later to see if it has any implications for a bigger question,” she said.

By examining fatty molecules made by marine bacteria, for example, Welander and colleagues have been able to show that a biomarker once thought to be produced only by flowering plants might also have been created by ancient bacteria – long before flowering plants evolved. And by deleting and mutating proteins in a type of microbe that thrives in extreme environments like Yellowstone’s highly acidic hot springs, she helped to prove a decades-old hypothesis about how the organism protects itself while simultaneously shedding light on its evolutionary origins.

It’s the thrill of discovery at the smallest scales that still drives Welander’s work.

“I’m uncovering biology that people have thought should happen but had no idea how it’s happening. A question will sit there for 40 years,” she said. “Then we find an answer by discovering new proteins, or a new fossil, or a new molecule made by some ancient organism. With microbes, you can always find new biology. We have just begun to scratch the surface of what’s there.”