Stress test

So perhaps it’s no accident that as an adult, Sajdel-Sulkowska was drawn to the study of stress—whether caused by burns, altered gravity, chemical pollutants, or bacterial infection—and its effect on brain development. In the course of her 57-year career, she has published more than 100 papers, chronicling her research in cells, in animal models, and with postmortem human brain tissue. She has studied the interactions between neurons and the glial cells that protect and support them, the changes in RNA transcription during brain development and in Alzheimer’s disease, and the role of the thyroid hormone in brain development, and published literature reviews on the role of the gut microbiome and gut-brain axis in autism and covid.

---

As a child, Sajdel-Sulkowska would tell anyone who asked that when she grew up, she wanted to be a professor like her father. At 10, she returned from the orphanage to live with her mother, who had remarried, and she eventually attended an all-girls high school in Łódź. When her metallurgist cousin Witold Vatha Kosicki, SM ’29, learned of her interest in science, he invited her to visit the US so she could interview at MIT, a school she’d never heard of. Getting accepted to Warsaw University’s highly competitive department of mathematics and physics helped her qualify for a visa to the US—and convinced MIT that she was qualified to attend the Institute. After arriving in the US in 1962 and completing a six-week English course (“I barely passed it,” she confesses), she started at the Institute in the spring semester of 1963.

At MIT, Sajdel-Sulkowska planned to study nuclear physics until she took a course on DNA and RNA with Gene Brown, a professor of biochemistry and a pioneer in the field of metabolism. The material was so new there wasn’t even a textbook. But Brown’s lecture on the discovery of the double helix inspired her to switch to biology. “It was fascinating,” she says. “The lectures were so incredible—I knew I wasn’t going back to physics.”

Sajdel-Sulkowska’s cousin had provided money for her to attend MIT for one semester. “The rest of it had to be kind of patched,” she says. So she washed dishes in the chemistry department, plotted soil stress on graph paper in the mechanical engineering department, collected animal urine samples, and for one year worked as an au pair.

During most of her time at MIT, Sajdel-Sulkowska lived with her mother, who had come with her to the US and worked as a technician in a medical lab on Ames Street. They initially lived on Beacon Street in Boston, in a basement room with exposed pipes and wires, sharing a bathroom with other families. But her advisor, Margaret Freeman of the Russian studies department, visited one day and was so appalled at the conditions that she invited Sajdel-Sulkowska and her mother to stay at her home in Belmont. Then, midway through her undergraduate career, she spent a year in McCormick Hall, which had opened in 1963.

---

Sajdel-Sulkowska’s time in McCormick was a “turning point,” she says. When she lived off campus, she studied and worked on her problem sets alone and assumed everyone else was doing the same. Her isolation was exacerbated by the language barrier, and she felt even more alone in the face of male peers brimming with confidence, relatives suggesting she switch to secretarial school, and an instructor who told her, after a bad experience with a rat in an animal laboratory class, that MIT was not the place for her. At McCormick, she says, she learned that “not everybody knows everything” and that “there are people helping you—that you don’t have to do it all yourself.”

Her first paper on stress was published in 1969, 16 years after the double-helix structure of DNA was discovered. At the time, the finding that stress could alter the body at a cellular level was a revelation.

Advertisement

Sajdel-Sulkowska started her career at a time when there were very few women in science. Though MIT began formally accepting women in 1882, she was one of only two or three women earning a bachelor’s degree in biology in 1967; her entire class of more than 900 had only 20 to 30 women.

Being one of those few women was not easy. In the 1960s and ’70s, when she continued at MIT for graduate school, the field of biology had a culture of what she calls “unchecked harassment.” There was no way to complain without retribution. “That kind of culture created intimidation,” she says. “If you go through incidents of harassment, you become more vigilant.” Male colleagues had to be treated as male colleagues, not as colleagues. Still, she says, there were “a lot of helpful people.”

Many of those helpful people were those she encountered in the Margaret Cheney Room, a Building 3 sanctuary for female students complete with a bedroom, shower, and telephone booths. “That was a haven,” she says—a place where she made lifelong friends. It was also there that she wrote her doctoral thesis—longhand, with her husky, Amis, at her side, over the course of three months. She would write for three hours, sleep for 20 minutes, and repeat.

Sajdel-Sulkowska earned an SM in nutrition and food science (or, as she calls it, “eukaryotic biology in disguise”) and an ScD in the same subject with a minor in neuroendocrinology. Her graduate work would be her first foray into the study of stress as she examined DNA-dependent RNA polymerase II, an enzyme that copies DNA into RNA, and its regulation by cortisol, the stress hormone. Through studies in rat liver cells and then, after a nudge from her committee, in live rats, she found that there is a physiological response to stress through regulation of RNA transcription. Her research showed that artificial cortisol injected into rats altered the RNA polymerase enzymes that synthesize the RNA component of ribosomes. Those ribosomes in turn synthesize the proteins that carry out functions in the cell. 

Her first paper on this work was published in 1969, 16 years after the double­helix structure of DNA was discovered; a second paper followed in 1971. At the time, the finding that stress could alter the body at a cellular level was a revelation.

It was an exhilarating time to be studying biology, says Sajdel-Sulkowska; while she was working on her doctorate, researchers at MIT, Caltech, and the University of Wisconsin, Madison, discovered reverse transcriptase, the enzyme that copies RNA into DNA (the counterpart to the RNA polymerases she studied), for which they would later earn a Nobel Prize. “I was working in the laboratory, I was in a great group, things were happening—it was exciting!” she says.

Reflecting on her time at MIT, Sajdel-Sulkowska says she loved the atmosphere (“I liked the fact that you could work late in the evening”) and the energy. The challenges she had to overcome to succeed at the Institute were worth it, she says: “I wanted to do it, and I did it.”

After earning her ScD in 1972, she interviewed for a faculty position at Northwestern University and was offered the job. But she had recently met Adam Sulkowski, a psychiatrist and postdoctoral fellow, who had just arrived from Poland via France on a visa sponsored by Boston University and could not relocate. She returned to Boston, they married that October, and she became a postdoctoral fellow at Brandeis, where she continued to study RNA polymerase in yeast. Two years later, the first of their four sons was born.

---

Sajdel-Sulkowska carved out a career that was both broad and deep at a time when combining scientific work and motherhood was extremely rare and accommodations for US working mothers practically nonexistent. When her oldest son was born, in 1974, her three-month maternity leave was unpaid. After her second son arrived while she was completing another postdoc, at Shriners Burn Institute at Harvard Medical School (HMS), the cost of day care for two children exceeded her salary. So with no day care, her husband watched the two boys in the morning, and she found herself under a “tremendous amount of stress.”  

And at Shriners, stress was again the subject of her work. In guinea pigs that have suffered severe burns, she discovered, an increase in cortisol inhibits DNA synthesis in the thymus, which plays a key role in immune function. Her research revealed that removing burned tissue as soon as possible leads to a faster return to normal thymus function and a faster recovery from burns.

In 1980 she became a lecturer in the HMS department of psychiatry with an appointment at McLean Hospital, and she was named an assistant professor six years later. Over the next two decades, she would work on a wide range of topics, including the relationship between mercury and autism, the mechanisms of Alzheimer’s disease, and the role of the thyroid hormone in brain development. She balanced work and motherhood with the help of her mother and her husband, who was supportive and proud of her. “Where there is a will, there is a way,” she says.

In 1989, Sajdel-Sulkowska spent a sabbatical in the lab of Nobel laureate Walter Gilbert at Harvard, gaining experience in cloning, sequencing, and polymerase chain reaction (PCR)—a time she sees as another turning point in her career. In the Gilbert lab, which she describes as a large, vibrant group of young and older scientists, everyone’s work and opinion mattered. “We frequently met as a group and could freely discuss our experiments,” she says. The experience gave her confidence. “At that point I felt that I may be able to start something by myself,” she says.

Once back at HMS, she strove to create the same sort of atmosphere in her lab and began pursuing grants to fund more independent work. When inspiration struck for an especially ambitious research project a few years later, in 1998, Sajdel-Sulkowska embraced the challenge. She’d been watching Star Trek with her sons when she came up with the idea for an experiment examining the effect of yet another kind of stress: altered gravity. In recent NASA brain research on pregnant rats on the space shuttle Columbia, more than half of the rat pups had died. She wrote a grant proposal to work with NASA’s Ames Research Center to study altered gravity’s impact on rats’ brain development. For her study, she positioned pregnant rats in cages at different points on a 24-foot centrifuge, exposing them and their developing pups to varying levels of greater-than-Earth gravity for 42 days, through pregnancy and lactation. Then she measured the length of time the rat pups were able to stay on top of a motorized rotating cylinder (what’s known as a rotarod test) and discovered that hypergravity decreased motor function. Rat pups that developed at 1.65 times Earth gravity could only stay on the spinning wheel for as little as 10 seconds before falling off, while the pups that developed at Earth gravity were able to stay on for almost a minute. 

Her research suggested that this may be because the higher gravity increases oxidative stress (an excess accumulation of free radicals that can damage the body’s cells) or suppresses thyroid activity, a problem that she had previously found to decrease the mass of the developing cerebellum.She also showed that hypergravity decreases the number of a crucial type of neurons in that region of the brain, which is responsible for movement, among other functions.Curiously, she found that male developing brains were more sensitive to hypergravity than their female counterparts. At the end of the experiment, the cerebellums of the male pups were visibly smaller than normal. 

As her hypergravity research was underway, Sajdel-Sulkowska also examined the effect on brain development of another environmental stressor that had become pervasive: polychlorinated biphenyls, or PCBs, a group of toxic synthetic chemicals used so widely from the 1930s through the 1970s that they contaminated the air, water, and soil. She subjected rat pups that had been exposed to PCBs from before birth to rotarod tests and found that their performance decreased as well. So did the mass of their cerebellums, and as with hypergravity, the effect was greater in males than in females.

---

In 2010 Sajdel-Sulkowska, who had lost her husband to cancer in 2002, was devastated when her youngest son died at the age of 23 as he was recovering from an accident. Work would prove to be a lifeline. She moved back to Poland, where diving into new research “helped me survive,” she says. First as a visiting professor in veterinary medicine at the Warsaw University of Life Sciences and then teaching and doing research at the Medical University of Warsaw, she had an opportunity to work with many young scientists. Her research collaboration with Katarzyna Czarzasta, who is now an assistant professor at the Medical University of Warsaw, was particularly fruitful—and continues today. “She is a very good mentor,” says Czarzasta, who adds that she treated her students as equals.

While teaching in Poland, Sajdel-Sulkowska encountered many students who suffered from depression. “I also observed great stigma associated with psychiatric disorders in Poland, specifically with depression during pregnancy,” she says. That got her thinking about recent research on the use of probiotics—which are readily available in the grocery store—as an alternative treatment for depression. And that led to several projects on perinatal depression that she hoped would lay the groundwork for a study on probiotics as a treatment for it.

The differences in stress response between males and females are at least partly due to the sex hormones. Testosterone increases cortisol levels, so the stress response is greater in males.

In one, she applied chronic mild stress to rats just before pregnancy to model perinatal depression, which she verified by measuring cortisol levels and time spent grooming. Then she studied their pups and documented negative effects on their neurodevelopment and cardiac development. The effects differed in male and female offspring, and the sex-­dependent cardiovascular effects in females persisted as they aged, potentially affecting the following generation as well. The study added to the growing body of research showing that the impact of environment and behavior—also known as epigenetic effects—can be passed along to offspring. 

In the past, Sajdel-Sulkowska says, experimental work, including research on depression, was performed only on males, so that researchers wouldn’t have to control for women’s monthly hormone fluctuations. But thanks in part to pioneering studies like hers, scientists are beginning to recognize the importance of studying the sexes separately. 

The differences in stress response between males and females are at least partly due to the sex hormones, says Sajdel-Sulkowska. Testosterone increases cortisol levels, so the stress response is greater in males; the effects of stressors on the thyroid hormone, too, are different. But beyond that, she points out that each sex has different issues when it comes to health in general: different microbiota, different disease risks, and different disease progressions and mortality rates. As a result, treatments for many diseases may need to be tailored specifically for males or females to be effective. (See “Depression is different for women. One-size-fits-all drugs aren’t helping.”) And even once both environmental factors and sex differences are considered, individual differences, such as a person’s unique microbiome, are likely to matter too. Sajdel-Sulkowska foresees a day when artificial intelligence will make it possible to correlate the differences in individuals’ microbiomes with disease, ultimately leading to individualized probiotic treatments for a variety of conditions—perhaps including depression. 

---

Sajdel-Sulkowska would remain in Poland for a full decade, returning to the US in September of 2020. A year later, after 35 years as an assistant professor, she was forced to retire from HMS when Harvard didn’t renew her faculty appointment. Having focused on research without giving much thought to advancement, she was suddenly without an academic home. In 2022, she joined the National Coalition of Independent Scholars (NCIS) so she could continue her work without being affiliated with a particular university.

Sajdel-Sulkowska never had the security of a tenured position and estimates that over the course of her career, her average salary was $35,000 a year. (“I never realized that I could name my compensation,” she says.) But she was never in it for the money; she was driven by the work itself. And in her home country, she received some of the recognition that eluded her at Harvard. During her decade of research and teaching in Poland, she was awarded the country’s highest academic honor when she was named a Presidential Professor by Polish president Andrzej Duda.

Upon returning to the US during the pandemic, Sajdel-Sulkowska tackled a literature review to look for connections between covid, the microbiome, and the gut-brain axis, the physical and biochemical signals that go back and forth between the digestive system and the central nervous system (see sidebar). But the theme of stress continued to intrigue her; she published a paper on maternal stress in rats in 2021 and has another in progress. This recent research closes the circle opened with her doctoral thesis at MIT, she says: “I did my PhD thesis on stress—and I’m ending my career with [studying] stress.”

Sajdel-Sulkowska sees how her current work might apply to her own life. Her mother endured extreme stress during World War II, and she experienced extreme stress herself as a child born just before the Warsaw Uprising. Now, she wonders how that might affect her own children—in humans, the epigenet­ic effect of stress is known to stretch for multiple generations.

---