The Prepared Mind
By James Martin
“So much happens by chance,” says Dr. Charles Scriver. It’s an odd declaration to hear from a man famous for putting in 15 hour days, seven days a week, for 40-something years — and, in doing so, helped shape the face of modern genetics. But there it is: Chance. The trick is being ready for it.
Beginning in 1961 in a converted cafeteria kitchen in the Montreal Children’s Hospital (moving 11 years later to the unused, unfinished seventh floor of the nurses’ residence across the street), Dr. Charles Scriver’s DeBelle Laboratory in Biochemical Genetics made genetics history. It was in that lab that he identified the genetic causes of many diseases, and put the lie to the widely held belief that genetic disease was incurable. Except, he insists, he didn’t do those things —“they” did. “Whenever I talk about something I did at the lab,” he notes, “it should be we, because I’m talking about a community of colleagues. That was the exciting thing about the lab: It was full of students — and aren’t we all students — who wanted to be there because they thought lots of good things were happening.”
“We” did the work that helped classify 30 inborn errors of metabolism (many of which are a defective gene that causes a dangerous abundance of some substance that, in normal levels, is benign), each of which proved eligible for some form of treatment. “We” classified several vitamin dependency genetic disorders, all easily treated with supplements. “We” also not only developed new ways to screen infants for the inherited condition phenylketonuria but showed that early detection, and therefore early treatment, dramatically improved health. (The importance of early PKU detection and treatment can’t be overstressed: It can mean the difference between extreme mental retardation and, with special dietary considerations, otherwise healthy development.) In the early 1970s, working with Claude Castonguay, Quebec’s Minister of Health, Family and Social Welfare, and colleagues in pediatrics across Quebec’s medical schools, “we” established the Quebec Network of Genetic Medicine, an early detection, screening and treatment program that drew admiration around the world for its forward thinking.
Which isn’t to say Charles Scriver, the lone man, has evaded the spotlight. He is, after all, in the Canadian Medical Hall of Fame. He’s a Companion of the Order of Canada. He received the Prix Wilder-Penfield from the Government of Quebec. He’s a fellow of the Royal Society (U.K.). Most recently, 2010 saw Scriver receive both the Pollin Prize for Pediatric Research, the only international award of its kind, and the American Pediatric Society’s highest honour, the John Howland Medal. He’s also played the role of vocal advocate for preventive measures, famously lobbying the Quebec government to fortify bottled milk with vitamin D, and, with the help of grocery store executive Arnold Steinberg (now chancellor of McGill University), thereby eliminating some 500 cases of nutritional rickets a year. Yet, for all the long hours he’s clocked, and for all the attention his efforts have garnered, he doesn’t think his success was inevitable. Were it not for an unexpected encounter here, a spot of good fortune there, everything could have been much different. Chance. “The trick,” he says, “is to prepare yourself to notice what Chance is offering. As Pasteur said, ‘Chance favours the prepared mind. ’ ”
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Born in Montreal on November 7, 1930, at the Royal Victoria Hospital, Charles Robert Scriver was the only child of Drs. Jessie Boyd and Walter Scriver. Jessie was a pediatrician at the Montreal Children’s Hospital. Walter was an internist at the Royal Victoria Hospital. Both held appointments at McGill. Each night at the dinner table, the three Scriver were joined by the fourth member of the family: the telephone. Young Charles was used to seeing his parents make housecalls after dinner; sometimes he’d tag along, getting a taste of a cross-section of Montreal that ranged from Westmount mansions to Hochelaga walk-ups.
“Growing up, what I saw was dedication,” he remembers. “My mother and father made it clear that medicine is a serving profession; they served their patients. They weren’t interested in anything else that came with it. They didn’t look for praise or prizes. They loved what they did.”
His parents “bent over backwards to not influence” Scriver to go into medicine himself. It worked. At first. He did an undergraduate humanities degree at McGill, studying geography and literature. Geography looked like “a pretty exciting profession,” and he seriously considered graduate studies in that field. There was, however, a little voice in his head that thought “medicine wouldn’t be terrible.” He loved his undergraduate human biology course with professor Norman Berrill, and he grew up with “two very good role models” who always kept people at the forefront of their medical practices: “Who do we serve? How do we serve? And why do we serve?” Medicine as an extended course in human biology? Could be interesting. So Scriver applied to medical school. But, unlike most aspiring doctors, he didn’t hedge his bets with multiple applications. He took one shot; if it didn’t pan out, he’d do something else. In the fall of 1951, he started med school at McGill.
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His biochemistry courses didn’t come easily — not the traditional portent for a blue-ribbon career in human biochemical genetics — but Charles Scriver thrived in medical school, graduating with the gold medal for his year. In 1955, he began a residency in medicine at the Royal Victoria Hospital. He followed that with a residency in pediatrics at the Montreal Children’s Hospital, reveling in the “beautiful chaos” of daily rounds among rambunctious young patients. The chief of pediatrics, Alan Ross, encouraged his residents to gain experience with as broad a range of illnesses as possible. As a result of Dr. Ross’s planning, Scriver left his hometown to join the “house staff ” at Harvard’s Children’s Medical Center for a year.
One day, a woman, later known in case studies as only “Mrs. H.,” brought her baby daughter to the hospital. She begged Scriver for help: “It’s happening again.” It: mysterious seizures, indifferent to epilepsy medication.
Again: the same seizures that had killed her infant son.
Scriver found a journal article about pyridoxine dependency, a susceptibility to seizures caused by an inability to properly metabolize vitamin B6. He played a hunch, running an intravenous B6 drip. The baby’s seizures stopped. Although the actual convulsive mechanism behind the little girl’s disorder would elude researchers for 50 years, she continued to respond very well to treatment. (Today, Scriver takes obvious joy in noting that “she grew up to be a healthy, successful adult.”)
* * *
One morning, Dr. Ronald Christie, the Royal Victoria’s physician-in-chief, summoned Charles Scriver to his office. Christie was waiting with his second-in-command, Dr. John Beck. Scriver’s residency was almost over, and his superiors had some questions.
“So, Dr. Scriver,” Christie began with his characteristic candor, “what do you want to do with your life?”
“I’d like to be an academic physician like my parents.”
Beck was a little more forceful: “Why should we take you on? What will you bring to McGill that the dozen other interns wouldn’t? What are your interests outside of clinical medicine?”
Scriver admired the new aerial photography techniques that McGill geography professor Norman Drummond was using to map the crater on Mount Megan tic in southeastern Quebec. Interesting stuff indeed, but a tough fit for medicine. Christie and Beck suggested the young man take two weeks to figure out his future.
Charles Scriver had long cultivated an interest in art. As a teenager, he haunted Montreal galleries, intrigued by how artistic creativity combined ordered technique with the bolt-from-the-blue wild card of inspiration. When he and his high school sweetheart, McGill nursing graduate Esther “Zipper” Peirce, married in 1956, they vowed to buy one piece of Canadian art every year. (They started with an intaglio print by Yves Gauthier. It would hang in Scriver’s office for the next half century.) So, when the young doctor found himself facing rows of journals in the Royal Victoria Hospital library, it was second nature to let aesthetics be his guide. Cover after cover, nothing but rows of uninspired black type on white. Next. Next. Next. His hand stopped at an unusually bold graphic: three thick horizontal stripes, red on the top and bottom, white in the middle.
Volume 10, number three of the British Medical Bulletin was devoted to chromatography, the process of separating a mixture into its constituent parts for analysis. Scriver turned the pages. Too much math for his liking. He’d always been an excellent student — heck, he read Virgil in the original Latin while still in high school — but numbers were never his strongest suit. This wasn’t looking good. Then he came to the final article, a treatise on amino acid metabolism by Dr. Charles Dent and John Walshe of the University College Hospital Medical School in London, England. The authors argued that simple chromatographic techniques could be used to examine the metabolic and chemical content of human bodily fluids. “If an unknown substance is present … as a minor constituent in a mixture of great complexity … it can now be isolated almost certainly in pure state and in good yield,” they wrote. “One can reasonably expect great advances to be made soon in our knowledge of normal and abnormal amino acid metabolism.”
In the same way that aerial photography was shaking up geography, here was a new technology set to change medicine. Scriver’s parents taught him that the journey always begins with the patient, the person, sitting in front of you. Now here was a way to focus that journey with unprecedented accuracy: Why does this person have this disease right now?
Scriver was called back on the carpet two weeks later. It was agreed that he would learn chromatography from Charles Dent, then bring that knowledge back to McGill. Scriver and Zipper booked passage on the Empress of Britain and set sail for England.
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At lunchtime, Scriver and his Dent lab colleagues would take their sandwiches across the street to the university. There, they’d sit in on biochemistry lectures by the heavy hitters of the day, people like Roland Westall, Ernest Baldwin and Eric Shooter. It was a heady time, a whirlwind of learning and discovery. After six months, Charles Scriver was depressed. Sure, he’d learned a lot — about amino acid metabolism, about making chromatograms, about interpreting chromatograms — but he wasn’t making the kind of progress he wanted.
A friend from Harvard, Irwin Schafer, wrote to Scriver, suggesting that they use the new chromatographic methods to see if something would turn up in a puzzling patient. Schafer sent blood and urine samples. Scriver ran the samples and discovered that an excessive amount of one amino acid, proline, accumulated in the patient’s blood, but three amino acids were present in the urine: proline, hydroxyproline and glycine. The hyperprolinemia, they discovered, was a new inborn error of metabolism. But why the discrepancy between the blood and the urine? The mystery deepened.
The details of Scriver’s eureka moment are burned into his memory. He’s walking down the corridor outside Dent’s lab. Late morning light streams through the window. Shoes squeak on linoleum. He’s been reading about enzymes and how they might work. Could a corresponding protein act as a transporter to move a chemical substrate across an unfriendly boundary, a so-called “hereto- there-ase”? Could such a carrier serve to transport a group of amino acids? Scriver turns the corner at the glass cupboard, shifts his weight from right foot to left and —“Of course!”
The excess of proline sits on the shared transporter and displaces the other two amino acids. But how to test that hypothesis? Scriver spends the next 18 months injecting himself with a proline infusion, to induce hyperprolinemia, then analyzing his urine to confirm the triple aminoaciduria. (“I don’t think that would be approved by the ethics committee today,” he chuckles a half-century later.) His self-experimentation leads to evidence that supports his hypothesis of a shared transporter that allows water-soluble molecules to traverse lipid barriers to go in and out of cells.
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All too often, stories end with the screech of rubber and the twisting of metal. But, sometimes, they start there, too.
Scriver returned to Montreal with three things rattling noisily in his head: the little Boston girl’s response to vitamin B6, the newly discovered inborn error of amino acid metabolism, and his transport hypothesis. The ideas percolated. In 1961, the journal Nature published “New Renal Tubular Amino-acid Transport System and a New Hereditary Disorder of Amino-acid Metabolism” by Scriver, Schafer and London colleague Mary Enron. It was Scriver’s first big paper. He presented the work at the spring meeting of the American Society of Clinical Investigators. The ensuing buzz helped Scriver land a five-year Markle Scholarship to concentrate on his research.
With the Markle money pending, Charles Scriver concentrated on studying for the Quebec pediatrician accreditation. One November morning in 1961, Scriver and Zipper packed their three young children into their black Volkswagen Beetle, a souvenir of their time in England, and set off for Quebec City. Just past Daveluyville, halfway to Quebec, they were broadsided by another car. The VW barrel-rolled through the air. This was it. Charles Scriver called out to his family: “It’s been great!”
The totaled Bug sparked to a wobbly halt upside down, having passed between cars in the oncoming traffic. There were scratches and bruises and tears and howls, but everyone was okay. Scriver knew he’d been given a gift of life, and it was time to write the exam and get on with his work in the lab. He knew they were on the trail of important things. Besides, he wasn’t about to forfeit his registration fee. Later that same day, he wrote his exam. He never found out his grade, but he passed.
* * *
For over 50 years, Charles Scriver worked. Up at 6:30, breakfast, then “off to business.” An important part of every day was talking to people. Sharing ideas with colleagues, of course, but always listening to patients. Over the years, his research branched out in different directions. He was involved in the inception of the Human Genome Project. He created a database of all known mutations associated with phenylketonuria, even drawing upon his human geography training to identify the history of human migration as a possible explanation for why some PKU mutations favour people of European descent, while other mutations target Asians. “That’s an interesting research question for someone,” he says, “but not for me now.” The “we” will continue to do the work, only without Charles Scriver. It’s time, he says, to get reacquainted with some of the things that interested him before he went into medicine. Poetry. Literature. Music. Philosophy.
“I’ve declared victory and announced retirement,” he says with a chuckle. “I’m happy to not write any more grant applications.”