Toronto, Indianapolis, and the Breakthrough that Saved Millions of Lives (And How Similar Collaborations Can Defeat the Chronic-Disease Scourges of the 21st Century)
Remarks at the Economic Club of Canada
John C. Lechleiter, Ph.D.
Chairman, President and Chief Executive Officer—Eli Lilly and Company
January 19, 2016
Thank you, Michael [Bliss]. You came to Indianapolis a little over a year ago and gave a presentation at Lilly that moved and inspired me and a lot of my colleagues. You reminded us of the role that our predecessors at the company had played in developing insulin. I’m almost embarrassed to admit how much I, and everyone else in the room, learned on that day. Like many other organizations of a certain age—and we turn 140 this year, which is very old for a public company—Lilly is proud of its history in a general sort of way—but we don’t always recall the specifics, which makes it harder for us to grasp the full implications of what came before. You helped us to overcome that shortcoming where the development of insulin is concerned—and we’re the better for it.
One thing in particular that you said in Indianapolis stuck with me, and inspired me to come here today. You said that, “the Lilly-Toronto collaboration legitimized the whole idea of academic scientists working with private industry for mutual profit.” If that’s true—and I’m convinced that it is—then the Lilly-Toronto story needs to continue to be studied and shared, and that “whole idea” of cross-sector collaboration to advance medical care needs to be tested periodically for its ongoing viability. Goodness knows there is no shortage of health challenges that still require attention today.
Putting Lilly’s place in the story aside, were it not for you, Michael, it’s likely that one of the most important developments of all time in medical science would be known only in a fragmentary and superficial way. Your research and your book on The Discovery of Insulin served to correct mistakes in the historical record and to replace myths about the discovery of insulin with the far more meaningful realities. You’re certainly a master of your craft.
I will steal shamelessly from Michael’s work in my remarks today, and occasionally from another book that’s about to be published. The new book is called The Doc and the Duchess: The Life and Legacy of George H. A. Clowes. Rest assured that I have no “piece of the action” here but when the publishers heard that I was going to be giving these remarks, Indiana University Press sent up some flyers about the book, which are here in the room if any of you are interested!
The “Doc” referred to in the new book’s title, who was called “Alec” Clowes by friends and colleagues during his lifetime, was Eli Lilly and Company’s recently hired research chief at the time that an academic team was busy up here in Toronto exploring the potential of pancreatic extracts. As I’ll share in a moment, Alec Clowes is the reason that we can talk about a Toronto-Indianapolis connection to produce insulin and confront diabetes, which previously had been a swift and certain killer.
It’s a mystery to me why this is the first book ever published about Dr. Clowes—a larger-than-life character who continued to lead Lilly research for many years, contributing decisively to the development of liver extract to treat pernicious anemia and to the mass-production of penicillin, the world’s first true antibiotic. But it was worth waiting for. This book was a labor of love on the part of Dr. Clowes’ grandson—a physician and medical innovator also known as Alec—who finished the book just a few weeks before he died, much too young, of brain cancer last summer.
Having now established the quality of my sources, with one of them sitting in front of me to keep me even more honest, let me share what I want to accomplish in these remarks today. I’d like to tell the Toronto-Indianapolis story, at a high level but with enough color to do it justice. Then, I’d like to examine that story in terms of what it tells us today, about the essential requirements of research and development focused on chronic diseases. For example, the question of how we move forward against Alzheimer’s disease and other forms of dementia, cancer in its many forms, and the ongoing ravages of diabetes—all of which threaten to overwhelm us as our populations grow older—well, it’s a very urgent question. Finally, I’d like to apply these lessons to a particular problem that has harmed not just Lilly but the broader industry in Canada in recent years, and which has held Canada back in attracting R&D investment.
My rendering of the development of insulin will be a story of six pivotal developments, in six places, most but not all of them in Toronto or Indianapolis! In fact, the first of these developments occurred in Strasbourg, then part of Germany—some 30 years before our local heroes got into the act.
In 1889, at the medical clinic of the University of Strasbourg, two researchers established for the first time that a link existed between diabetes and the function of the pancreas. Based on the outcomes of surgeries on dogs, their powerful hypothesis was that an internal secretion of the pancreas regulated blood sugar—in other words, a substance other than the pancreatic juices already known to flow through ducts from the pancreas into the digestive system.
On the basis of that key insight, a fairly logical scientific agenda emerged. Did the hypothesized substance in fact exist? If so, what was it? Could it be isolated? Could it be introduced into patients with diabetes? And if it were given to patients with diabetes, would it have a beneficial effect?
In the normal way of medical science, the path to answering those questions was one of halting, incremental progress marked by dead ends and small steps that eventually built on each other. By the time Dr. Fred Banting came on the scene here in Toronto—a young Ontarian who had not even been born when the Strasbourg hypothesis emerged—only a few clear steps forward had been taken. Banting approached Professor J. R. R. Macleod about doing some experiments at the professor’s lab in the University of Toronto—in 1921, at our second pivotal moment.
Fred Banting’s proposal was to surgically cut off the ducts leading from the pancreas to the digestive system of dogs, causing the pancreas to degenerate . . . thereby isolating the internal secretion if there was one . . . which then would be accessed either by grafting the degenerated pancreas onto an animal with diabetes . . . or making an extract from the degenerated pancreas. Macleod needed some convincing. He didn’t necessarily expect a breakthrough in all of this, but since no one had ever tried what Banting wanted to do, Macleod figured that even negative results would be of value—in the spirit of ruling out another dead end. Or as he reportedly put it: “We must leave no sod unturned.”
Banting had no experience with the chemical testing that would be needed to validate his experiments, so a research assistant with that ability had to be recruited. Two of Macleod’s honors students presented themselves and apparently a coin toss was held. Legend held that Charley Best “lost” the coin toss, meaning that he would have to work during the traditional vacation months. But Michael argues convincingly that Charley in fact won the toss. Either way, Best became Banting’s research assistant in that pivotal summer of 1921.
Even compressed in that narrow window of time, medical science’s usual setbacks, trial-and-error, and moments of hope offset by hours of frustration continued to be the order of the day. But by early August the experiments had turned a corner. Banting ended up using pancreatic extracts rather than grafting, and he gave the extracts the name “Isletin,” since they were presumed to originate in the so-called “Islets of Langerhans” in the pancreas. Most importantly, the Isletin appeared to have a marked effect on a number of diabetic dogs—causing a reduction in blood sugar.
August gave way to a new school year in Toronto. Macleod returned from a summer in Scotland—where he had never lost touch with the experiments—and he agreed to give Banting a salary and better working conditions. Banting and Best stumbled on an important finding they didn’t fully appreciate until later, namely, that degeneration of the pancreas was not necessary to produce an effective extract. They gave a preliminary presentation to University of Toronto colleagues in November, and shortly afterwards completed their first scientific paper on the research. In mid-December, a biochemist named James Collip joined the team—soon to make critical contributions.
I’m providing a shorthand summary here for good reason: this was a period of intense discovery—marked by almost daily insights and adjustments. You’ll need to read Michael’s book to appreciate the full drama!
But we’ve arrived now at the third pivotal point. This one has a precise date: December 30th 1921. And the location was New Haven, Connecticut, at the annual meeting of the American Physiological Society. Professor Macleod persuaded Dr. Banting to present his research at the meeting, ahead of its first publication.
In a quirk of fate or Divine Providence, a Canadian scientist working in the U.S.—who had been home in Toronto a few weeks earlier and learned about the work of Banting and Best—shared what he learned with a certain Alec Clowes, who recently had left academia to assume the position of research director for Eli Lilly and Company in Indianapolis.
And so it happened that Alec Clowes left his home and family on the morning of Christmas Day, 1921, to board a train to New Haven. On the 30th, Clowes—along with a group of experts on diabetes—heard Fred Banting describe—or at least try to describe—the significance of his research. Dr. Banting was not a great orator to begin with, and he had a major bout of nerves that day, by his own admission. The much more eloquent Professor Macleod took over the discussion at a number of points. In the end, the audience left with “cautious interest,” at best, according to Michael Bliss . . . with one notable exception.
Alec Clowes’s interest was not cautious! He sent a three-word report by telegram back to Indianapolis, saying, “This is it.” Clowes spoke at length with both Banting and Macleod while the three were still in New Haven, offering Lilly’s services in commercializing “Isletin.” The academics responded politely to Clowes—and Macleod said they’d keep his offer in mind—but they made no commitments, believing that a partnership with Lilly either was premature or unnecessary. Both views turned out to be wrong.
In fact, the pace of progress accelerated. As if driven by the skepticism he encountered from most of the group in New Haven, Banting persuaded Macleod almost immediately after returning from that trip to subject Isletin to a human clinical trial, if you could call it that. The extract had the appearance of a thick brown muck, according to the physician involved. And preliminary safety-testing in humans apparently consisted of Banting and Best giving injections to each other! In any case, pivotal point number four had arrived, at Toronto General Hospital, on January 11, 1922. The patient was a 14-year-old boy named Leonard Thompson, on the verge of death weighing 65 pounds, after enduring the only known treatment for diabetes at the time: a near-starvation diet.
After an initial improvement in his blood-sugar levels, Thompson quickly developed serious side effects from the impurities in the extract, and the Isletin treatment stopped with what the scientists described as “no clinical benefit.” Fortunately, James Collip—the biochemist who had joined the team just a month earlier—had been working on developing a more purified form of the extract. He succeeded—94 years ago tonight, it is believed—stumbling on the right concentration of alcohol added to the mixture, at which the active substance precipitated out of the pancreatic tissue of beef, with fewer impurities.
On January 23rd 1922—this still is just three weeks after New Haven—Leonard Thompson got his first injection of Collip’s new, much purer extract, which the Toronto team soon started calling “insulin.” It worked—with no serious side effects—saving Thompson’s life.
So Alec Clowes had been right about the timeliness of an effort to manufacture insulin on a large scale. And soon, he was proved right about the difficulty of that effort as well. Word of the Toronto breakthrough soon spread far and wide. Academic specialists clamored to be part of larger-scale human trials. Doctors, patients, and families inquired in desperation about how to obtain insulin. All the while in Toronto, the scientific hurdles in the way of producing consistently pure insulin grew and grew—while the supplies did not.
Through the late winter and spring of 1922, Alec Clowes had made himself as much of a pest as a proper Englishman could be, writing and telephoning Macleod frequently to remind him of Lilly’s offer. Macleod soon decided that he wasn’t dealing with a pest but with a potentially essential partner. And so, pivotal point number five took place about 10 minutes’ walk from here, starting on May 22nd 1922, in the King Edward Hotel. I’m told you call it “the King Eddie.” Macleod and company sat down with Alec Clowes, who brought with him a chemist and a patent lawyer, as well as a vice president of the company named Eli Lilly—the grandson of our founder.
Over the course of a few days, this crew got comfortable with each other and hammered out an agreement that would govern the development of insulin and allow the substance to reach as many patients as possible . . . as quickly as possible.
The University of Toronto would apply for patent rights to the discovery, while granting Lilly a one-year exclusive license to manufacture insulin, which the company would provide free of charge or “at cost” to clinical research efforts. Researchers in Toronto and Indianapolis would work closely with each other to develop an optimal manufacturing process. The agreement bound Lilly to secrecy about the process that emerged but not the University of Toronto. And after the one-year period of exclusivity for Lilly, Toronto could grant licenses to other manufacturers, which all would pay royalties to the university on the same terms.
The group also agreed in principle—though the issue caused tension and required further negotiations a year later—that Lilly could manufacture and sell insulin under the brand name “Iletin,” slightly changed in spelling from Dr. Banting’s original name.
The King Edward Hotel agreement required a leap of faith and a high degree of trust. While that faith and trust occasionally were tested over the course of the next year—this was virgin legal territory, after all—they never broke down. As a result, the University of Toronto enjoyed a steady stream of royalties until patents expired. Lilly got a brief head start on manufacturing—since it developed the large-scale process, after all—and a very valuable brand, as long as the company assured the safety and consistent quality of the branded product. Clinical researchers got the insulin they needed. And most importantly, a life-saving medical breakthrough quickly reached tens of thousands of patients.
Accomplishing all of that still depended, of course, on pivotal point number six: the development of a viable mass-production process in Lilly’s Indianapolis facilities. When he spoke with my colleagues and me a year ago, Michael accurately described this as a “crash program,” with Lilly people “pushing themselves to the brink of breakdown and sometimes over the brink.” Our chief chemist at the time—named George Walden—achieved the key breakthrough when he applied a technique called “isoelectric precipitation”—adjusting pH levels in the tissue solution to the point at which the maximum amount of insulin precipitated out.
As a result, by the winter of 1923, Lilly was able to produce 80 to 90 thousand units of stable, pure insulin every week. And by October 1923, when the lessons of clinical research had been gathered, and educational materials for doctors had been prepared to assure its safe use, Iletin could be launched as a product.
So many aspects of this story still leave me with a sense of wonder, but none more so than the speed at which it occurred. Think about it! In the summer of 1921 in Toronto, the first glimmers of a clinical hypothesis about insulin emerged in a two-person lab. Barely two years later: a product existed, reaching patients in mass quantities and saving thousands of lives. And that happened in a time without email, Skype, electronic databases, or jet airplanes—not to mention sophisticated scientific tools. Charley Best later recalled Alec Clowes making 25 trips from Indianapolis to Toronto in the year after the King Edward Hotel agreement, all of them without the benefit of Air Canada’s daily non-stops!
Frankly, such a timeline would be unthinkable today—in which the average trajectory to cover similar ground is in the range of eight to 10 years. Part of the explanation is that the University of Toronto and Lilly operated in a world in which there was no regulatory approval of new medicines. Yes, you heard me right! Nothing in the law of the 1920s required Lilly to wait for clinical research and to develop educational materials before putting insulin on the market, or to assure the consistent quality of its product.
Not for a moment would I suggest going to back to a world without stringent regulatory oversight. Even putting that factor aside, however, the insulin story played out at amazing speed and it’s worth looking for other explanations. Grappling with those explanations also may help governments—in Canada, the U.S., and elsewhere—to figure out what kinds of policies make sense to drive biomedical innovation and the economic growth that tends to surround it.
I see at least three explanations for the speed of insulin development, all of which have implications for how we can sustain and even accelerate biomedical innovation today.
It starts, paradoxically, with the appreciation of step-wise innovation. Professor Macleod’s willingness to “leave no sod unturned” might well have led to some incremental insight, as he expected. Instead, it led to a rare breakthrough. Recalling what happened in Toronto is a warning against discounting incremental progress and refusing to value treatments against cancer and other diseases that may not be cures but nevertheless demonstrate improved outcomes over what’s already available—and provide the essential stepping stones for long-term, sustained progress against disease.
The second explanation that I would offer for the speed of the insulin breakthrough is the high level of openness that existed between the two sides in Toronto and Indianapolis, which led over time to an implicit trust.
Alec Clowes didn’t make 25 trips to Toronto in one year because he loved the weather, necessarily! He came because that’s what it took to develop close, trusting relationships with the team in Toronto. In their books, Michael Bliss and Alec Clowes’s grandson both recount some great stories about the visits of the Canadians to Indianapolis, where they encountered open doors and open minds.
Confidentiality with regard to proprietary data and tools of course is vitally important in a competitive marketplace. But what the insulin story teaches us, and what we’re gradually learning again today, is that there’s a time and a place for confidentiality—and it’s not always and everywhere. One example at Lilly is our Open Innovation Drug Discovery initiative, “OIDD.” It is a kind of virtual “open door,” linking us with scientists in academic centers around the world. OIDD is a web-based platform that provides external researchers with a point of entry into Lilly’s drug discovery process—including our molecule-screening efforts—so that they can test their own discoveries.
More than 300 universities, along with research institutes and biotech firms representing 26 countries, have an OIDD connection. I’m happy to say that there are nine Canadian universities on the list, including the University of Toronto! In return for access to Lilly’s technology and tools, we retain first rights to negotiate an agreement with each partner—modern-day equivalents of the King Edward Hotel understanding. If no such agreement results, then external researchers receive no-strings-attached ownership of the data report from Lilly to use as they see fit in publications, grant proposals, or further research.
Finally, I believe that the speed and ultimate impact of insulin’s development had a great deal to do with the respect for intellectual property that its key players showed. Patents, like those assigned to the University of Toronto for insulin, and strong product brands, like the one that Lilly insisted upon for Iletin, provide both the security and the incentives needed to bring high-risk innovation to the people who need it.
The security of patent protection allowed the Toronto team and their Lilly collaborators to invest their resources and time with confidence during those crucial months of 1922-23, into making insulin pure, safe, and available in large quantities for patients. And when I use the term “incentives,” I’m not just speaking of incentives to make money. Patents—and brand names—give their holders incentives to assure that those innovations conform to the highest standards of quality and reliability. Yes, Lilly profited from the “Iletin” brand, but only by ensuring that “Iletin” was a product of the highest possible quality that doctors and patients could trust implicitly.
And in the end, of course, the profits made in Toronto and Indianapolis accomplished vastly more than to make a few people wealthy. They funded decades of additional research in labs of the University and Lilly—on how to improve insulin and on a host of other biomedical challenges entirely.
Intellectual-property protection—“IP protection,” for short—is more important today than ever. Yet IP protection remains perpetually at risk—including in Canada. As you may be aware, the pharmaceutical industry has been worried for a number of years about the handling of our IP in Canada. Many other organizations agree, including the Canadian Chamber of Commerce.
As background, you should know that patents on medicines typically last for 20 years, but that clock starts ticking when most medicines still are in the early stages of development. Often, just eight or 10 years of patent life remain by the time medicines reach patients. That helps explain our industry’s reaction to losing some patents even earlier in Canada.
Based on something called “the Promise Doctrine,” Canadian courts since 2005 have revoked 22 drug patents in this country—including five of Lilly’s—for failing to be “useful,” by requiring evidence that goes well beyond what is required in the patent approval process. The courts then allowed generic manufacturers who challenged the patents to copy and sell these same drugs—supposedly “useless” drugs—to Canadian patients.
In reality, the question of whether a medicine is safe and effective enough for human use isn’t for the patent office or the courts to decide; it’s for Health Canada to decide! And in fact, the drug patents that were revoked in Canada under the promise doctrine were for medicines widely and beneficially used by patients. Hence the interest of generic firms in copying them!
No other developed country evaluates patents in this way. IP is the lifeblood of our industry, and a country’s failure to protect this valuable property can have a chilling effect on industry investments, when trade-off decisions between different R&D locations and partners are evaluated in company boardrooms.
It concerns us that Canada’s patent rules have led to arbitrary results, in which patents for useful medicines are revoked. Along with other companies and organizations, we look forward to working with the new Government of Canada to find a better way forward.
I believe that the three characteristics of the Toronto-Lilly story that I’ve highlighted—appreciation of step-wise progress, openness between the parties involved, and respect for intellectual property—are even more important today than they were in the last century. They comprise the formula for collaboration that gives our societies a fighting chance to overcome the chronic diseases of aging populations, which otherwise threaten to harm every family and overwhelm our nations’ health-care budgets.
There’s a lot left to do. About fifteen years after those two scientists in Strasbourg made their essential discoveries about the cause of diabetes, another German scientist—Dr. Alois Alzheimer—first described the disease that now bears his name and the markers it leaves in the brain. Yet, a century later, we have no “insulin” for Alzheimer’s disease. We have no durable answers for many forms of cancer. And diabetes itself—especially so-called “Type 2” diabetes—is today, unfortunately, a global epidemic. It can be treated but not cured by insulin and other successor products. Its long-term ravages continue, and demand our enduring attention.
I’m very grateful for your interest today and I hope that I’ve helped to boost the understanding—alongside the pride and passion—that I believe we must keep alive in Toronto and Indianapolis about the story of insulin. It’s a story that speaks to us across 90 years about what it will take for our societies to overcome the remaining scourges of chronic disease. Thanks for listening to that story, and for thoughtfully considering what it means.