On the warfarin path, part 2

The first essay in this series is here.  Let’s turn now in our warfarin narratives to a few more developed accounts, including Karl Paul Link’s own published account.  [I have corrected a biographical error–Prof. Link’s Ph.D. was from Wisconsin, not Johns Hopkins (where William Tottingham, his Ph.D. advisor, had studied).  See here for an account.]

An account of the development of warfarin is included as part of a series of Biographical Memoirs of important scientists, including Karl Paul Link’s, published by the National Academies of Science.  The lead paragraph connects Prof Link’s work and his commercial successes:

KARL PAUL LINK was a carbohydrate chemist and plant biochemist, whose research changed direction abruptly when he initiated work on the isolation and characterization of the hemorrhagic factor produced in spoiled sweet clover hay. The isolation of a modified coumarin as the causative agent led Link and his colleagues to the synthesis of a variety of anticoagulants that have had wide medical application as anticlotting agents and that have also proved highly effective as rodenticides.

A feature of note in this summary is the abrupt change in direction in Link’s research.  We know from other accounts that this must be the visit by Ed Carlson to the lab, more details of which will come soon, but here, for formal science biography is not nearly so important as the connection of the isolation of compounds and synthesis of related compounds, leading to commercial products in medical-boon and rodent-bane.

We find from Link’s biography that he earned his doctorate at the University of Wisconsin in the early 1920s—the same time that heparin was being developed at Johns Hopkins University by William Henry Howell, who took over discoveries made by Jay McLean, a medical student.  We might wonder if Link had an interest in anti-coagulants well before the opportunity to develop one presented.  As Pasteur has it, chance favors the prepared mind.   The question might be, then, what kind of preparation should one be making?

We find another article (behind a paywall, sorry) that gives parallel narratives of both warfarin and heparin.

Link’s own work prior to the effort leading to the development of warfarin included showing that brown onions had a resistance to fungus that white onions lacked (1928).  One might think, the use of fungus susceptibility as a marker for the presence or absence of specific molecules of interest in plant chemistry was “in the air”.   Fleming publishes his account of penicillin in 1929.  Fungi presented as an important angle of approach to useful discovery, drawn from observations in the community world, directed at discovery of  specific chemical species, and using these discoveries to influence human physiology.

None of the narratives we have presented make any mention of this scientific context.  We might expect something of the form:  “In the early twentieth century, fungus became an important tool in the identification of biochemistry of value to human physiology.  Observations of fungus producing novel effects came from a variety of sources. One of these sources was the dairy industry, where farmers reported cattle dying after eating moldy sweet clover hay.”

As we turn attention to the central figure in the narratives, Karl Paul Link, we find noteworthy attributes.  According to a former student of his writing the National Academies biographical memoir, Link was among the agricultural chemistry researchers at the University of Wisconsin the best classroom instructor:

This was an impressive array of research talent, but Link was the best lecturer of the group. He taught with a flair. He dressed to attract attention and spoke with a booming voice that all could hear. He directed his remarks to the students, not the blackboard, and above all he kept people’s attention while he transferred a remarkable amount of information. He sometimes injected outrageous statements: slurs at the university administration, pithy quotations, or his own aphorisms to keep minds from wandering. He affected a spontaneity in his lectures, but in truth, he worked diligently on them to gain the optimal effect. Link was accepted as a showman, but he accomplished the goal of teaching, i.e., he conveyed information in a form that was absorbed readily by his students.

This sort of detail falls away in the summary account, as if is superficial, a kind of human interest but not relevant to the key points of the account.   But is this so?  One might wonder if Link’s approach, and dedication to, instruction also played a role in the work that isolated coumarin and led to the development of warfarin in both its bane and boon versions.  One might at least wonder whether anyone writing a swift, sure account of warfarin has made any thought on the matter.   A simple alternative narrative might be:  “A dedicated instructor with a flair for making an impression with technical information recognizes an opportunity to use his presentation skills to attract talented students to his research and encourage the adoption of a beneficial molecule, discovered in his agricultural chemistry research.”  One might think, then, that being a great instructor if not something of a showman of science may be an indicator for the market success of research results.  Maybe technology transfer offices would do better helping with curriculum, public speaking, and dressing to get noticed!

Putting the narrative of development in these alternative terms, however, makes evident the absence of a driver in many of the narratives about warfarin, both short and long.  The simple progression of research, discovery, commercialization is presented as natural, that the discovery of course led to commercialization, or led to commercialization because a commercialization agent, WARF, was so helpfully involved, or that the molecule discovered was in its nature so very good it could not help but inspire commercial products.  What is implied is that such a progression is plannable on the basis of market potential intrinsic in the discovery.  Nothing else is indicated or mentioned.  No other explanation.   If those creating public policy rely on such narratives, what sort of policy might they create to support breakthrough inventions?

One might argue that such innovation narratives are remarkably selective and potentially naïve.  Yet we find correlations between these narratives and policy statements that reflect similar attitudes toward innovation.  Do such similarities suggest something “in the air” about our representations of innovation?   Or is there a causal link, that the narratives we construct encourage selective, if not simplistic, expressions of policy?  Or are such narratives drafted with an eye for existing policy, as support for policy-endorsed outcomes?

There is not enough to go on here to track things down, but it is worth raising the idea that the narratives of innovation we routinely encounter are not primitives boiled down to the essential facts, nor are statistical measures any better in isolating the measurable elements of these narratives, such as the number of patents, at elucidating drivers for innovation.  It is not even an issue of whether one can write a sensible policy statement without a clear grasp of the flood of details surrounding research innovation events.  Rather, one gets to whether an organizational policy has any particular role at all in the occurrence of such events, one way or another.  Is policy a precondition for innovation?  A promoter or catalyst for innovation?  A harmless gesture?  A restrictive and oppressive overlay?

We do see in some of these narratives the appearance of luck.  Luck is a useful counter to planning.  Policy has a tough time with luck.  We do not find statements of intellectual property policy that say, “we implement this policy to improve our luck.”   Luck may may also be used as a substitute for lack of a better reason that would show connections or causal relationships.  Luck:  The arrival of a farmer out of a winter snowstorm a couple of months after Link has been introduced to the sweet clover hay problem while interviewing for a job at another university.  Luck:  The overdose and recovery of a navy recruit who tries to commit suicide on warfarin.  Luck:  The use of warfarin to treat the president of the United States after a heart attack, laying the foundation for widespread acceptance in the medical community.  None of these things was planned, but the line of events available clearly changed as a result.  One might think, then, that a commercial pathway from research to market might benefit by, if not perhaps need, such events of luck, and the job is to recognize these and respond.

We turn now to Karl Paul Link’s account of the development of warfarin.  This account was published in 1959, at perhaps the most auspicious point in the development of warfarin, its two uses clearly established “world wide”.  The account Link gives is extensive, vivid, entertaining, personable, so much so as to lead at least one other commentator to discount its details in places.  One might wonder, however, if it may be better to have such details to be discounted rather than omitting details, which cannot then be considered.  More details creates complexity, but complexity in turn requires interpretation, and interpretation reveals character and competence–and may reveal what we are looking for, the conditions under which university innovation gets into widespread use.

We will look at two parts of Link’s account.  First, the visit from Ed Carlson, the farmer with cattle dying from moldy sweet clover hay.  After that, we will look at the decision to develop warfarin-bane.

The visit to the lab by Carlson is presented as a pivotal moment.  Here we have Link’s account, which we will take in pieces, and in illustrative excerpts.  It is worth reading the entire piece.

Link’s lab sets up in January, 1933 to look at ways to create a hay lower in coumarin, a substance in plants that was most closely associated with the hay that caused trouble when it went moldy.  When Carlson arrives at the lab a month later, on a Saturday in a snowstorm, the lab has little to offer him but the standard advice to change out the hay and transfuse the cows.  Carlson leaves the cow, the blood, and the moldy hay and heads back out into the storm.  In the lab, however, Link describes a different scene.  Eugen Schoeffel, Link’s German laboratory assistant is visibly moved by the visit:

“Vat vill he find ven he gets home? Sicker cows. And ven he and his good voman go to church tomorrow and pray and pray and pray, vat vill dey haf on Monday? MORE DEAD COWS!! He has no udder hay to feed-he can’t buy any. And if he loses de bull he loses his seed. Mein Gott!! Mein Gott!! Vy didn’t ve anti-shi-pate dis? Ya, ve should haf anti-shi-pated dis.”

Is this just entertaining banter, reconstructed decades later?  Or is it marking something deeper and significant, an enduring connection among people that informs the research?  What does Schoeffel mean, for researchers to anticipate such a personal need?   Could that be the driver for research direction, the personal commitments of researchers, rather than some abstract definition of research topics?  Do such commitments mislead and cloud judgment with passion, or do they inform and guide toward the things that matter?  We will leave that as a question for now.

The lab changes direction as a result of the visit, shifting from looking at ways to create a strain of hay with less coumarin to trying to identify chemically what was causing the problem.   One might say, the lab changed from something that could have been near the top of the list of practical things to help Wisconsin dairy farmers to something that would sort lower down the list.  In the end, Link’s lab did not produce anything directly to assist dairy farmers with their problem with hay (though he may have helped them control rats and deal with stroke).  Who would have set those goals for a researcher in agricultural chemistry working with plants?

From 1933 to 1939 the lab works on the problem.  The breakthrough comes when Campbell, one of Link’s students, isolates dicumarol, a product resulting from the oxidation of coumarin.  Campbell does an assay to prove that it is the active agent in preventing the blood to coagulate.   Another of Link’s students, C. F. Heubner, ascertains the chemical structure and produces a synthetic version.  More of Link’s students then work for two years to prepare related compounds for study.

One of the problems faced by Link’s development of dicumerol for use in the clinic was what he calls the “bonds of the usual pattern of thought.”  The idea emerged in response to dicumerol that it was dangerous and its effects could not be reversed safely.  It took a decade for clinical studies to show that indeed vitamin K could reverse the action of dicumerol, if given in sufficient doses.  As Link puts it, “surmise, faulty thinking, and not enough trying kept vitamin K from being the corner building stone in Dicumarol therapy that it deserved to be from the outset.” That is, the discovery of a compound with useful characteristics was not sufficient to create widespread acceptance.

Link identifies three stages in the development of Dicumerol:  an initial enthusiasm, which is replaced by a muddle, which then leads to consolidation.  The period of muddle involves conflicting positions by enthusiasts and skeptics.  In a muddle condition, we might take a closer look at the motivations of both enthusiasts and skeptics to ascertain whether their statements arise from usual patterns of thought—repeating what they want to hear—or have economic or political affiliations regarding, or perhaps arise from friendships or rivalries.  More broadly, we might wonder if this sequence of enthusiasm, muddle, and consolidation offers a template pathway for innovation.  Might we can expect generally there will be a time of muddle, and the job of technology transfer is to help to sustain work during the muddle time?   Muddle time would appear to be something rather different than what goes by the name “funding gap” or “valley of death”.  For that one might say that a muddle involves competing claims and uncertainty, while a funding gap requires more research to get from initial discovery to validation.  Certainly there may be competition in the funding gap for which things are worthy of more study, but that would appear to be different from the muddle proposed by Link.

What tools and practices might navigate the muddle, prevent a muddle from forming, or avoid it when it does?  There is a practice question that does not generally arise, and certainly would not from the simple accounts of the development of warfarin.   The simple stories of warfarin tell us that university research provided a commercial product.  There is no muddle period in the simple stories.  The challenge is commercial development, not clinical skepticism and rivalry.

Link also identifies another source of uncertainty.  After the lab synthesized dicumerol, it produced over 100 related compounds, each having various properties and effects.  As Link puts it, “Synthesis ran substantially ahead of biochemical appraisal.” To study the behavior of these molecules, the lab used a range of animals—mice, rats, guinea pigs, rabbits, chickens, cat, and dogs.   Link:  “Certain chemical properties were also considered: the degree of purity readily attainable (absence of taste and odor), the cost of making them, and the property of being convertible to stable water-soluble salts.”   This sort of research would now be called “departmental research”—funded by the institution, not by an external sponsor of research, and subject to a range of controls and documentation of the use of animals.

What practice insight might we draw from this work?  For one, that a scientific breakthrough was followed by an investigation of a range of related compounds, looking for other characteristics that offer benefits in production or use.  We might call this a form of exploration, making use of analytical techniques and knowledge of chemistry, but not doing “science”of the form of hypothesis and testing.  The goal of the lab is not at this point to find the specific mechanism of action—that comes decades later.  Rather, the goal is to explore the chemical territory, producing variations and observing effects.  What were they looking for?  How would they know?  According to Link, “Our goal was to make real a substance that abolished the clottability of cattle blood in agricultural practice.”  This goal might be rather unexpected from the stories that get told.  Link’s lab was trying to find a better cow poison, not a better antidote!

Is this sort of work the scientist’s dream or is it drudge work?  The perfect cow poison.  Yet, having found one, what is the best one that one could make?  One might think that if the only way to fund such work today is to find a sponsor, then much would appear to depend on what sponsors value.   If making a big splash is the thing, then the exploration after a breakthrough is like washing dishes after the party has left.  What sponsor would want to look for a better cow poison?  How does that solve anyone’s immediate problems?

If we look at the ways in which sponsored research opportunities are presently announced, awarded, and evaluated, it might be that the productivity proxies of invention and elite publication are distant from the exploration necessary to map out the consequences of an insight, well before anything is rushed to the patent office or into commercial development.  One might then posit that funding gaps arise to a large degree because one moves too soon to claim an invention for commercial development, before the exploration and muddle phases have run their course.  Let’s consider the case of warfarin further on this point.

Thus far we have a laboratory generally interested in an agricultural problem–onion susceptible to fungus–changing its course of work in 1933 through a deeply moving personal encounter–farmer, snowstorm, dead cow, pail of blood, silage–making six years later, in 1939, a breakthrough, discovering the cause of the problem, synthesizing the molecule and showing that the synthesized form has the same effects as the natural form.  From there the lab creates from 1940 to 1942 an array of related molecules and starts testing them for their properties.  Meanwhile their first molecule, Dicumerol is put into clinical use.  That might otherwise be the end of the story, but according to the short accounts, we have not even got to the story–this is all just university research leading to discovery.

While recovering from a recurrence of tuberculosis in 1945, Link spends his time reading about the history of rat control and gets the idea to look at the lab’s array of compounds for a better rat poison.  This is also quite a shift, and Link calls it out in his account.  Rat poison?  And yet, he has all the resources for this—an array of unexplored compounds, animal test protocols, a set of properties to select from and to evaluate, and access to test animals.  It makes some sense.  And yet what is the driver for this change?  Link points out that a paper published in 1948 suggests that Dicomarol, his compound for human use, could be used as a rat poison.  Commentators have pointed out this would not necessarily be a good thing for a drug being established for clinical use.  Link spends a long footnote arguing that the rat poison idea would not work—the dose would have to be so high that other animals and children would be at risk as well, among other things.  Despite this objection, Link gives O’Connor, the paper’s author, credit for motivating the “backward pest control workers” into considering anticoagulants for rat-bane.  That is, it is O’Connor suggesting something that would not work that creates the conditions ripe for finding a new compound for the job.

At this point, one might also imagine the concern that one might have if a product from one’s lab is being proposed to go from the clinic-boon to rat-bane.  It also makes some sense that the proposal has to have a substantive response, not just an objection.  Does Link turn to rat poison because he wants to save Dicumarol for the clinic?  Does he step up his focus on it because the idea is out in the open that if cows can die from this compound, so could rats, and who should have the best rat data across all the possible related compounds but Link?  That is, one might argue, that the idea came to Link,  but it was not a research objective, not in 1933, not in 1939, not in 1942.  But later, 1945 to 1948.

From this we can ask, what motivation is at work?  Is it purely commercial opportunity?  Pressing public problem?  Curiosity and reflection as a result of enforced absence from the lab?  Protection for a product already on the market?  Competitive spirit?  Motivation is a topic that attracts attention in the study of narrative fiction and the composition of history.  Motivation informs choices and events.  Motivation, however, appears to drop out of simplistic accounts of success, or, rather, the motivation is implied to be the outcome, the success, whatever that is chosen to be.  Folks did these things to succeed, and lo! success.  That’s motivation for you!  Now, let’s build management systems that do just that, plain and simple, and put policies in place to make our work really stick.

Here, however, as we work through narratives, we begin to see how competing motivations may be at work, not just a motivation for “success”–whether “commercial” or “financial”.  We might point out that nowhere in these accounts do we find the motivation being to get to the root of the science, to advance scientific study, to figure out how the biology works–as Richard Feynman would have it, “the pleasure of finding things out.” It’s enough that the effect is useful and predictable and controllable.  Nor do we find the motivation being to share findings widely, so that all have access.  Certainly we may add these to the list.  But they simply do not come up anywhere, and they don’t even appear relevant.   Clearly, Link’s lab does publish its findings.  But it also holds onto its compounds.   In present discussions of academic innovation from the point of view of technology transfer, we find the motivations of commercial success placed against advancement of science and sharing of results, as if the former is bad and the latter are good.  Or we find the opposite, that there’s no point to research if there’s no commercial impact.  All that sharing and science for science’s sake is about academic laziness and disconnection with the practical world of real people and real problems.

Furthermore, nowhere in any of these accounts do we find a meaningful role for patenting and licensing.  It must be there, but it is nearly entirely suppressed, even at the WARF site.  We might find that of some concern for policy matters.  Is patenting suppressed because it is unimportant?  Because it is complicated and hard to weave into a narrative about science leading to success?  Because people do not realize the role it actually plays?  Or is it that things have changed and now stories are expected to start with inventions and patents, rather than to have these happen midway through, or not at all?

In 1948 Link assigns a student to work through a set of compounds specifically looking for rat-bane properties.  Link chooses compound #42 for this purpose.  At this point, in 1948, WARF supports the development necessary to turn this compound into a useful, commercially available rat poison, which Link names warfarin.  It must be pretty cool to have a poison named after your organization.  But those were heady days.   Fifteen years after the lab-changing event, and nearly a decade after the basic science, we get to the juicy stuff, something going big commercially.   The lab is well away from figuring out anything to help diary farmers with their hay, well away from the science that informs anticoagulants in humans.  This is another direction, one might say opportunistic, but not planned until right before the course is chosen.

It is at this point also that other products—Tromexan and Marcumar–are showing up in the clinical market based on related compounds that have been considered and discarded by Link’s lab.  Link reviews the clinical literature and the requirements clinicians really want in an anticoagulant, and by 1950 he has the idea that a version of warfarin, based on its performance in rats, is actually well suited for human use.  It is water soluble, can be administered any number of ways, and is readily controlled.  The problem is making the move from rat poison to the clinic–just the opposite direction Link may have feared for Dicumarol.

We have here two innovation narratives running together.  First there is “cow poison to drug” moving from coumarin to Dicumarol.  Next we have a transition, from cow poison to rat poison.  And then we have a second narrative, “rat poison to drug”.  We can see that simple accounts conflate the two narratives and omit the transition altogether.  But it is the transition that is crucial, for it is the lateral move from cow poison to rat poison and the drug that comes from it that become the world-wide successes, displacing Dicumarol in the process.

This is where two lucky events come into play.  First, in 1951 the navy recruit takes warfarin over a period of days to end his life, but has time to think about it, regrets the decision, and heads for the hospital, where a transfusion and vitamin K save his life.  Suddenly there’s a clear, dramatic demonstration of warfarin in action in the clinic.  Link calls this event the “catalyst”.  It was not one that could be realistically proposed via government research.   It was not in any business plan or assessment of commercial potential.  There was no next step of this sort.  Clinicians were not going to be giving rat poison to humans.  It was a pure form of luck, apparently.  The achievement in Link’s lab was figuring out how to make water soluable warfarin.  Link then goes to a friend at a commercial lab, who agrees to manufacture the new compound—warfarin with sodium replacing a hydrogen.  Thus, Coumadin Sodium.  There must have been a patent license in there somewhere, but we get no account of it.  Perhaps business was simple in those days, and licensing straightforward.

The second lucky event is Eisenhower’s heart attack in 1955.  With the clinical use of Coumadin Sodium in the president’s case, Link’s anticoagulant becomes a legitimate clinical rival for heparin.  This second event, however, does not appear so pivotal in Link’s account as in those of others.  For Link, Eisenhower’s use is a confirming event for the clinical use of warfarin.  While the event is dramatic, it is more that of poetic drama, the kind with which to end a narrative, a point of closure chosen for that reason out of the flow of events, to stand as a significant event to show that warfarin in its clinical form had become a success.

Link’s account does not end with this success, however.  He has one last paragraph, in which he calls out the “combined effort of many students.” Indeed, his account is full of students and assistants doing the work.  It is William Schoeffel who responds to the farmer’s visit and plays supporting roles throughout, such as setting up field trials.  Schoeffel, Roberts, and Smith showed the limitations of existing assays.  Campbell and Roberts showed that new created a special line of rabbits on which to test compounds.  Campbell isolates Dicumarol and does the bioassay to characterize it.  C. F. Huebner figures out the chemical structure and synthesizes it.  Overman and Sullivan show that the natural and synthetic forms have the same effects.   Researchers and clinicians in other institutions contributed studies as well.  Ikawa makes many of the compounds that are tested—one of which will be warfarin.  L. D. Scheel works through the various compounds for their characteristics.  Collin Schroeder developed an improved process for making warfarin sodium.  Even Ward Ross of WARF is called out for his support.  That’s something that one does not see so much these days from faculty inventors!

Link has this to say in recognition:

In closing I wish to indicate that what my laboratory has achieved in the past 2 1/2 decades represents the combined effort of many students. It is fun to be the reporter or narrator of this highly successful adventure.   To use the words of the late Allan Gregg, my students represented much ‘emergent ability.’ I think the secret of their success is 3-pronged: they never ceased to wonder,  they kept on trying, and they were on a project directed toward doing mankind some good instead of trying to destroy it.

The message here is not simply that the activity was complicated, with many hands filling various roles.  Clearly, such recognition counts for something.  The common element is, of course, by the time we have this narrative, Link himself.  And yet it appears that he does more imagining and directing and selecting than bench work.  Is it that Link is a gracious lab director, giving credit and recognition?  Is it that Link is given place as an inventor for his role in directing, when it is his students who are doing the work?  Might it be that such graciousness and recognition is more than ornament for the narrative, but rather is a core feature of the teamwork and exchange that informs the progress of events?  What would an innovation policy look like that selected for graciousness and teamwork rather than commercial potential and clear title to patent rights?  Would these approaches look anything like one another?  This is what we will take up next.

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