Adolfo de Bold once said, without a verbal grimace, that his pathway to becoming a world-renowned researcher whose discoveries revolutionized medicine’s understanding of the mammalian heart only emerged after a 12-year period during which he endlessly examined ground-up heart tissue from more than 100,000 lab rats.
To that labour he would later attach the maxim, “In science there are no exhausted problems, just exhausted scientists.”
His unrelenting doggedness is one of the reasons Dr. de Bold, who died in Ottawa on Oct. 22 at age 79, came to exemplify the best of recent science in Canada.
Adolfo José de Bold was born Feb. 14, 1942, in the northern Argentine city of Parana to Ana Patriarca, a housewife, and Adolfo Guillermo de Bold, a bureaucrat. After getting a degree in clinical biochemistry at the University of Cordoba, in 1968 he and his scientist wife, Mercedes Kuroski de Bold, a former classmate, immigrated to Canada.
The move, he would later say, was motivated by two considerations. The first was his frustration with the insularity of Argentine science, specifically that nobody could show him how to get his research published in international journals. Leaving Argentina was also a kind of youthful, almost existential leap of faith into otherness. He would later write that as a couple they came to Canada, “with no plan whatsoever for the future.”
Following the career path of a colleague from Argentina, both de Bolds enrolled in a graduate pathology program at Queen’s University. There Dr. de Bold began to look at mysterious granules found in the heart’s upper chambers. While they bore a resemblance to hormone-laced bits found in the pancreas and other endocrine glands, their functions in blood-pumping hearts were still a mystery.
It was a mystery that for more than a decade Dr. de Bold, in conjunction with his wife, Dr. Kuroski de Bold, used various techniques to try to resolve. One of the hypotheses they began to pursue was that the mysterious structures might relate to a hormone the heart secreted to balance the effect of salt and water changes on blood and blood pressure.
The connection had been proposed before but not substantiated in part because the concept of a heart-generated hormone secretion seemed to many scientists not just unlikely but almost physically impossible. This was, as University of British Columbia physiologist John Ledsome would later say, because “most of us figured the heart already had enough to do.”
But Dr. de Bold wasn’t stopped by the power of the unlikely. Rather he, in connection with his wife and University of Toronto physiologist Harald Sonnenberg devised a way of collecting the mystery extract and then conducted various animal experiments to uncover its effects.
The first experiment they conducted was a classic example of a laboratory screw up. The injected blood had become contaminated with potassium and as a result the rat died of a heart attack. But a second experiment produced exactly the salt-and-blood-pressure-lowering result one would expect from a hormone – a phenomenon that mimicked insulin’s lowering of blood sugar.
The discovery of this wholly new heart function seemed destined to become what is called in science a “Eureka moment.”
But the original results generated almost more skepticism than Eurekas. Dr. de Bold’s 1981 paper reporting on his findings was turned away by a leading scientific journal and only printed in a less prestigious one.
Dr. de Bold understood that there was a significant causative connection underlying his peers’ skepticism. Believing there was “something” in the heart samples that produced the salt/water reaction was different from testing the effect of an actual hormone.
“For me,” Dr. de Bold would later reflect on the situation, “there is no single moment when you can say ‘Eureka’! You must always try to shoot down your hypothesis.”
To confirm he had found a hormone being made in the heart, he had to sequence the substance he had discovered (eventually named atrial natriuretic factor or ANF), inject it into a rat and observe the result. Even people who had doubts about Dr. de Bold’s potential paradigm shift in the heart’s physical functions couldn’t ignore that.
What then arose was what might be called the Heart Hormone Patent Wars. After other scientists reproduced his results, various labs around the world immediately began to try to synthesize ANF with the aim to patent it. The belief was that the patented substance might become the heart’s hormone equivalent of insulin and if so could be used to treat heart conditions and/or diagnose heart attacks.
But when it came to translating the discovery into clinical applications, Dr. de Bold was at a big disadvantage. He had been working, with very little financial support, in the most primitive of laboratories. He later described the space he first was given when appointed to the Queen’s faculty in 1973 as “an office, half a lab bench, an old incubator and a microscope to start. Mine was a windowless office in the basement, across from the autopsy room.”
He would recount how “relatives of dead people would sit in his office until people from morgue could attend them,” his wife said.
Secondly, neither Dr. de Bold nor Queen’s had much experience in negotiating partnership deals with drug companies, which was necessary for a finding to be translated into an application. On top of that, Dr. de Bold was, he would admit, always a kind of research outlier. His aim for doing medical science was not to come up with drugs or treatment applications but rather to understand how the natural world operated.
“It is a contest between you and nature – to see who outwits whom,” he said.
Eventually, he was able to beat the other laboratories in synthesizing the hormone. “Against all odds we won the race to sequence ANF,” he remarked in 1983.
What didn’t follow from that was a huge financial benefit for Queen’s nor Dr. de Bold, in part because some of the discovery translation issues already mentioned, and also because the hormone breaks down quickly in the body. In 1986 Dr. de Bold moved to Ottawa to work at the Ottawa Heart Institute, eventually becoming its director of research. When asked in 1989 about his future research directions, Dr. de Bold responded with the almost spiritual open-mindedness that had led him to the ANF discovery. “We know a lot about the heart, but we don’t know what makes it tick,” he said. “It’s like trying to understand God.”
After his initial discovery, a cascade of awards and recognitions showered on the man who came to be known as the father of cardiovascular endocrinology: appointment as an officer of the Order of Canada, induction into the Canadian Medical Hall of Fame, receipt of the Grand Prix scientifique de la Fondation Lefoulon-Delalande from the Institute de France and even a Nobel Prize nomination, among others.
He eventually filed for four patents and engaged in drug company collaborations. But the most consequential result of his discovery was that tens of thousands of scientific papers were written, based on experiments trying to understand ANF. With them the world’s sense of what the heart did was fundamentally transfigured.
“It led to a rewriting of the textbooks. It led to changes in how we perceive the heart; how we teach medicine,” Canada’s chief science adviser, Mona Nemurs, said at Dr. de Bold’s 2014 induction into the Canadian Medical Science Hall of Fame.
Despite his far-reaching accomplishments, Dr. de Bold remained a humble person. Hugo Ramos, an Argentine cardiologist who collaborated with him, said he never spoke of his awards “and you only learned about them from reading a newspaper.”
He was also tremendously hard-working. His wife recounts that when her parents visited from Argentina during his early research days “he would come home, eat and then return to the laboratory.” This was because he had to take instruments from the coroner’s facility, disassemble them, move them to his lab and then reverse the process to return them for the next day.
This dedication to finding what nature did was an exemplar for students who studied under him. “He taught me how to be a scientist. He taught me how to mentor (and some cases how not to). I am the scientist I am now because I learned from him how science should be done,” said his former student Benoit G. Bruneau, now director of Gladstone Institute of Cardiovascular Disease in California.
But he was more than just a scientist in his life pursuits. He was also a proud immigrant who was glad to have lived and worked in a peaceful Canada. And Canada was proud that he stayed, so proud that he is one of the immigrants whose lives are highlighted on the federal government’s Immigration Matters website.
Dr. de Bold also remained a proud Argentine. His five children learned Spanish. The family regularly spent a month vacationing in Argentina. He tried to set up a program in Parana where scientists would speak to children there about science and becoming scientists.
However beyond all of this he had a transcendent and non-scientific passion. When summing up his life at the Medical Hall of Fame, he said he was most grateful for “the ability to work in the field that I wanted and having the family that I dreamt of.” He had originally wanted 12 children but his wife had said five was enough. None of their children went into science as a career, but Dr. de Bold didn’t mind. He always said: “I don’t care what you do as long as you do it really well,” according to his son David, a United Nations diplomat.
He lived by the principle himself, blithely proffering extraordinary fatherly acts. The eminent researcher was once asked to help coach his children’s soccer team because, of course, all Argentines know all about soccer. Except Dr. de Bold knew nothing about the game, not even the basic rules. But being a lifelong learner, he did what a smart, devoted father should do: He went to the encyclopedia and taught himself how to play soccer.
Dr. de Bold leaves his wife, Dr. Kuroski de Bold; his children, David, Alex, Cecilia, Gus and Paul; and five grandchildren.