'Tough as nails': How Dr. Caroline Bedell Thomas blazed a trail in heart research

Dr. Caroline Bedell Thomas, it's safe to say, is not a household name. Although you can find details about her work here and there, even the experts who follow in her footsteps or compile lists of notable women in cardiology are apt to overlook her.

Which, according to the people familiar with her pioneering research, is a mistake.

"She was a trailblazer" whose work was "well before its time and was incredibly insightful," said Dr. Paul K. Whelton, the Show Chwan Professor of Global Public Health at Tulane University in New Orleans.

After Thomas died in 1997 at the age of 93, Whelton wrote in the American Heart Association journal Hypertension that as a "remarkable physician, investigator and educator, she contributed much to our knowledge of hypertension and risk factors for cardiovascular disease early in life."

Starting in 1946, Thomas took measurements from a group of medical students at Johns Hopkins University in Baltimore. Eventually, she had 1,337. She then followed them for decades to see what happened. The effort became known as the Johns Hopkins Precursors Study.

Studies that track groups of people for decades to uncover the roots of diseases are common now. Famously, the Framingham Heart Study, which began in 1948, initially followed 5,209 people and now spans three generations. Other studies collect information from hundreds of thousands of participants. Such work has proven essential to unraveling the mysteries of heart disease and other ailments.

Thomas was first, said Dr. Michael Klag, dean emeritus of the Johns Hopkins Bloomberg School of Public Health. He directed the Precursors Study from 1988 to 2011.

In many ways, he said, the big modern studies are modeled on Thomas' work. "And they may not know it."

How far ahead of the curve was she? "As far out as you could get," said Dr. Henry Blackburn, a professor emeritus at the University of Minnesota in Minneapolis who has written about the history of epidemiology and cardiovascular disease. "She was really in front."

Her life in medicine

Thomas was born Caroline Cunningham Bedell in 1904. Her mother was a graduate of Smith College, and her father was a physics professor at Cornell University in Ithaca, New York.

She earned her medical degree from Johns Hopkins in 1930. After a fellowship at Harvard Medical School, she returned to Johns Hopkins in 1934.

It wasn't long before she was making medical history, helping show that antibiotic sulfa drugs could prevent strep infections and rheumatic fever, which can cause serious heart complications. At the time, rheumatic fever was a leading killer of young people.

According to a 1996 article in the Johns Hopkins Gazette, Thomas' findings were "met with opposition and discouragement." But further research, including by the Navy, meant half a million troops were given sulfa drugs during World War II to prevent strep infections and rheumatic fever. Thomas was later honored by the American College of Physicians for her work in preventing rheumatic fever.

In 1946, she turned her attention to the causes of heart disease and high blood pressure.

Asking the right questions

At the time, Whelton said, medical researchers were sharply divided about what caused high blood pressure. Many thought it was simply something that some people inherited while others didn't.

Thomas was among those who thought otherwise. The term "risk factor" hadn't been coined. But she thought "there would be a series of what she called 'kaleidoscopic psychobiological stressors,' if you will, or precursors," Whelton said.

And she set out to prove it.

She submitted a short proposal for a grant to take measurements from medical students and follow them afterward, Klag said. The study was originally dubbed "The Precursors of Essential Hypertension and Coronary Artery Disease."

To test her ideas, she collected all kinds of data. "She wanted to measure every aspect of a person – their psychology, their personality, their family history, their health behaviors," Klag said.

In 2001, Johns Hopkins Magazine reported that baseline measures included electrocardiograms and blood pressure readings. She asked 11 pages of questions about how much salt the students ate, how much coffee they drank and how many cigarettes they smoked. She made them plunge a hand into a bowl of ice and measured their blood pressure to assess the response to stress. And long before it was the norm, she measured blood cholesterol levels.

The result was 2,501 variables, all recorded by hand in an era before widespread use of computers.

"She was a visionary in that she knew that you would have to cast a very wide net" to find all the possible roots of a slow-developing problem such as heart disease, Klag said.

At the time, the study's size seemed "immense," he said. But the Precursors Study helped show that bigger would be better to tease out lifestyle connections to heart issues. Later studies would build on that knowledge.

"It's amazing what we didn't know when she started this study," Klag said.

Medical students in every Johns Hopkins class from 1948 through 1964 were enrolled, and annual follow-up surveys were sent out. Follow-up measurements would be taken by the doctors themselves and proved to be quite accurate over time. Klag, who contributed to several studies that used data from Thomas' work, helped verify that. Because of the graduates' loyalty to their alma mater and Thomas, 95% responded in any five-year period, he said.

"What Dr. Thomas did was truly innovative," said Dr. Pamela Lutsey, a professor of epidemiology and community health at the University of Minnesota. At the time, researchers were primarily interested in heart attacks, a problem that was thought to afflict mostly older men.

"For her to start at younger ages was truly a novel step forward for the field," said Lutsey, a cardiovascular disease epidemiologist. So were some of the issues Thomas looked into, such as inflammation, a topic that has only recently begun to be fully explored for its connections to heart disease, Lutsey said.

"She clearly was onto things," Whelton said.

Some of Thomas' earliest findings were about mental health. "She put this study together with medical students with the idea of following them to see who got heart attacks," Klag said. But heart disease usually takes years to pose visible problems, and the earliest deaths she recorded weren't heart-related. They were from suicide, which troubled her, Klag said, because she knew the students in her study well. "And so the first papers are about suicide and predictors of suicide."

Later, the data she collected would help examine links between depression and cardiovascular disease.

Significantly, the study also was able to reveal "a whole variety of factors relating to cholesterol," Klag said. One of them was a 1956 paper in the American Journal of the Medical Sciences that suggested a link between cholesterol and heart disease – a year ahead of the Framingham study.

It took decades for some of the measurements to bear fruit, Klag said. In 1993, he and colleagues used Precursors data to publish their own study showing connections between cholesterol and heart disease in the New England Journal of Medicine.

Directly, Precursors data – moved over the years from notations to punch cards to magnetic tapes on huge mainframe computers to floppy disks – has fueled studies on topics ranging from diabetes to divorce to end-of-life care. Indirectly, Klag said, if you look at subsequent studies that have had a big impact, "in many ways, they were modeled on the Precursors Study."

Klag, who got to know Thomas when she was in her 80s, said he once discussed another pioneering work, the Harvard Alumni Study, with her. That study, which examined links between physical activity and heart attack, was led by Dr. Ralph Paffenbarger Jr. At the mention of his name, Thomas recalled, "Oh yeah, Paffenbarger – he came around to visit. A lot of people came around."

They wanted to know how she did things.

How she did it

In addition to scientific brilliance, Thomas had other traits that enabled her success.

Klag recalls Thomas as being tenacious, "incredibly smart and incredibly literate." And, using a word that comes up often in descriptions of her, he called her tough.

"She was just tough as nails," Klag said.

A longtime assistant told the Baltimore Sun that during snowstorms, Thomas would be the only person who made it into work. When people were upset by the presence of a dead rat in a restroom, Thomas was the one who marched in and disposed of it.

Klag recalled one story about how when an employee called in sick, Thomas went to her house, examined her and brought her to work, telling her, "You can work. You're not that sick."

Thomas was also dedicated. She found ways to keep the study alive when grants ran out. "There were times when it was down to her, and she didn't draw a salary," Klag said. At one point, she tried to use a chair she possessed from legendary physician Sir William Osler as a bargaining chip. "She was going to sell it for a million dollars," Klag recalled. That didn't work out.

What happened?

Work from the Precursors Study has been highlighted in all kinds of media. But for all of Thomas' "enormous" contributions, Whelton considers her to be underrecognized.

So does Dr. Thomas Pearson, an emeritus professor of epidemiology and medicine at the University of Florida in Gainesville. He directed the study immediately after Thomas retired and worked with her for several years. There are several possible reasons why she and her work aren't better known, he said.

As groundbreaking as it was, the Precursors Study included a relatively small group of mostly white men.

Klag agreed that the Precursors Study had limits. Research using responses recorded in a pre-digital era sometimes involved going back to examine records by hand. And measurements in some categories don't fit the modern mold – because it hadn't been cast.

"The problem was that there were no standard methods to do this at the time," Klag said. She couldn't pull standardized questionnaires off the shelf because they hadn't been created yet. "She had to do everything from scratch."

Pearson said that while he "always got on well with Dr. Thomas," in later years she was "quite set in her ways." Statistical methods and follow-up plans had to be updated. She had struggled to secure funds for the study, which had run out of money by the time he took over, he said, so securing grants became his role.

He thought she personified persistence and considered her "a strong-willed person whose diligence and commitment deserved respect." But, he acknowledged, "women researchers in the 1950s faced a number of barriers compared to those at present."

Whelton, who mentored Klag at Johns Hopkins and briefly knew Thomas toward the end of her life, said "I'm sure she must have had huge challenges and impediments. It was just a very difficult environment to be a leader as a woman at the time."

Her husband, Dr. Henry M. Thomas Jr., was on the faculty at Johns Hopkins. The couple had three children in an era where working mothers faced disdain. Blackburn related the story that when challenged by a party guest about the propriety of leaving her children in the care of someone else, she replied, "Some mothers drink. I work."

Thomas had earned the title of full professor at Johns Hopkins in 1970, becoming only the third woman to do so.

Starting in the 1950s, Blackburn worked on another pioneering research effort called the Seven Countries Study. He said that when epidemiologists held informal gatherings throughout the 1960s, Thomas would be the only woman in attendance. "And she was always a shock for all of us," he said, admiringly. "She was so tough, and she was so proud, and she was so different in her interests."

Women didn't become leaders in cardiovascular epidemiology until the mid-1970s, Blackburn said. "There were many nutritionists, a few nurses and administrators who were very important to studies, but they weren't academically involved in the field," Blackburn said. "She was a pioneer, and she was very refreshing."

Over her career, the needs of what it took to lead a large study also shifted.

To blaze a trail with something like the Precursors Study, Whelton said, "I think you have to be very strong-willed and resolute and take no prisoners – and really do whatever it takes to get the resources and to get the job done." But once the model was established, the work required a collaborative approach. Whelton, who has led many large multicenter studies himself, said that requires "a very different personality."

Klag said that for all she excelled at, Thomas was not a self-promoter. She was still coming to work in her 80s, and he encouraged her to be a co-author with investigators using her data. "She wouldn't do it," he said. "She said, 'No, thank you very much, but you should go ahead and sort of plot your course.'" Then she gave suggestions about what the researchers should do.

Thomas died in 1997. The last questionnaires were sent out and collected in 2019, said Dr. Alden Gross, an associate professor of epidemiology at Johns Hopkins who oversees the Precursors data. Some of that data continues to be used in research, he said, but not as much as in the past.

Even so, the ideas she advanced have endured, such as the concept that traits early in life can affect someone across their lifespan, Pearson said. "This idea is alive and well today."

Lutsey herself is a leader in studies that do work similar to Thomas' but on a much larger scale. The Atherosclerosis Risk in Communities Study she works with, for example, has nearly 16,000 participants.

When Lutsey attends epidemiology conferences, she's hardly the only woman in the room. A 2017 study in the journal Epidemiology found that women outnumber men in the field, especially among doctoral students, although men held more senior positions.

Lutsey considers the field "very open and supportive of women investigators. I, myself as a woman in the field with three children, have had tremendous mentorship from both men and women that definitely have helped propel my career and hopefully advanced science in the process."

She acknowledged that before being asked about Thomas, she knew nothing about her. Lutsey is not sure what has kept Thomas from being better known. "I mean, based on the innovative things that she's done, she deserves to be recognized among the early leaders of cardiovascular disease epidemiology," she said.

But if her legacy isn't as well known as he would like, Klag suspects that Thomas would not be one to complain.

She told him that a women's organization once asked her to talk to young women about being a woman in medicine. "You know what I told them?" he recalls her saying. "If you're looking for a sob sister, that isn't me."