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The Cuban Cure
Reason and Resistance in Global Science
By S. M. REID-HENRY
The University of Chicago Press
Copyright © 2010 The University of Chicago
All right reserved.
ISBN: 978-0-226-70917-8
Chapter One
A Biotechnology Story
It is late November 2001 and I am talking to Pedro López-Saura, one of Cuba's foremost experts on interferon. López-Saura is a vice director at the island's flagship biotechnology institution, the Center for Genetic Engineering and Biotechnology (CIGB). We are seated at an international conference reporting recent work on interferon and cytokines. Interferon itself has made its own contribution to the larger story of biotechnology science, and the Cubans have worked on interferon since the very beginning of their interest in biotechnology, he tells me. Indeed, it is almost impossible to find an account of Cuba's genuinely remarkable biotechnology project that does not on some level fall back on the agency accorded this innocuous protein, which is naturally produced by animals in response to infection. But for all that this is a popular story, it is a narrative that obscures as much as it reveals.
Fast Science
Interferon was first discovered over fifty years ago, in 1957, by Jean Lindenmann and Aleck Isaacs, who had been studying how cells are protected from infection by one virus as a result of prior infection by another. Subsequent work revealed the role of interferon in this process; it worked as an immune system regulator. It was not until the late 1960s that interferon first caught widespread scientific and public attention, however, when an American researcher in Paris, Ion Gresser, discovered that interferon also stimulated the production of tumor-killing lymphocytes (white blood cells) in mice. And it would be a further decade before interferon could be obtained in sufficient quantities to support any greater experimental, let alone clinical, practice. As Lindenmann himself later noted: "Beginning as a rather esoteric laboratory phenomenon ... [interferon] passed through a sort of cottage industry to end up part of the metropolis of modern biotechnology." By the late 1970s, when the Cubans first took an interest in interferon, it was still curiously poised, therefore, as a drug whose inherent properties many thought might make it a magic bullet—perhaps even the drug to beat cancer—yet one which was also extremely hard to produce. Like everyone else working on interferon at the time, the Cubans would have to figure out not only how to produce interferon in theory; they would also have to solve the problem of producing it in sufficient quantities to actually do anything with it.
One of those heavily involved with interferon research at the time was American oncologist Randolph Lee Clark—president of the M. D. Anderson Hospital in Houston, Texas: America's first cancer hospital. Clark had set up the Anderson Hospital back in 1946 when, as a young physician emerging from the war and fascinated by the global scale of modern medicine, he developed a lifelong international outlook. By his later years he had become a sort of scientific statesman. He advised President Nixon on cancer research and he traveled often, regularly touring medical facilities abroad. When he heard in late 1980 that a tour of Cuban health facilities was being proposed by US Congressman Mickey Leland, he took little persuading to come along. "Healthcare has no dialectics," a colleague of Clark's said when inviting him to come along. "We, Cubans and Texans alike, have common goals in caring for our people."
The idea behind the visit was to initiate a series of scientific exchanges between the two countries, outside the political stalemate of the time; an impetus that dovetailed perfectly with Clark's enthusiasm for science in developing countries. "This is a real 'going Jessie,'" he confided to his diary on the last day of the visit, "hinged on one man, as far as I can tell. [Y]ou're going to hear a lot from him—he's going to be a sounding board but he's going to talk the language they need to hear in the third countries." He was referring to Fidel Castro, and during the trip the two men met face-to-face. Clark had dedicated his career to searching for a cure for cancer. That he had begun his work in a converted stable on a donated family estate appealed to Castro's sense of the dedicated professional. Castro impressed Clark too. Not least, the two of them had the diplomatic instinct for the globally unspecific. "A bit vague?" one of Clark's students is supposed to have remarked. "Vague is much too precise a word."
By the time Clark left Cuba, he had rather more certainly left Castro with the sense that interferon was the drug to be working on. He had also offered to host a guest researcher from Cuba at his hospital, to which Castro responded by asking if Clark would be kind enough to take two. While the arrangements were finalized by Clark's office in Houston, the Cuban interests section in Washington, and Castro's office in Havana, Clark forwarded the latest in scientific knowledge on interferon to Cuba, where it was channeled to some of the country's most promising scientists.
López-Saura was one of these scientists, but it was two other researchers, Manuel Limonta and Victoria Ramírez (a hematologist and gastroenterologist respectively), who were chosen for the trip to Houston. The two Cubans worked solidly for over a week there. Limonta's concluding report points to the exhausting training they had received—peppered with the occasional perk, including a flight over Houston by helicopter. Evidently enthused by his experience, Limonta penned an informal note at the end of his report that is almost as telling as his accounts of their growing experimental proficiency with the drug: "The advise [sic]," he commented, was of particular use "not only because of the great experience and knowledge of the different fields of medicine he [Clark] has achieved in so many years of intensive work, but also because of the great sensibility and deep wish to help humanity." In other words, what the Cubans had just been taught about interferon was not just valuable as scientific knowledge; it was valuable for its social content too. Indeed, Clark had also informed the Cubans that the best place for advanced work on interferon was in the Helsinki laboratory of Kari Cantell, where they were to head next.
Kari Cantell had been the first to isolate interferon from human leukocytes back in the seventies. From his laboratories at the State Serum Institute in Helsinki, Cantell produced the raw material of natural leukocyte interferon for use by researchers around the world. Once Limonta and Ramírez returned to Cuba it was, accordingly, to Helsinki that another working group of cuadros, as they are known in Cuba, was organized to travel. Cantell's method was, after all, widely accepted as the industry standard. It was this second group that Pedro López-Saura was invited to join: "The group was made up of six people," he told me.
We were all doctors, but three of us were also biochemists. I had been working for a while on a project to improve the quality of clinical studies and also for a while on yeasts when this issue of going to work on interferon arose, in early 1981. We spent one week in Cantell's laboratory, observing the techniques involved in the process. Afterwards we took another week [as] it was necessary to make inventories and to purchase some of the equipment and materials needed.
Cantell was famously generous with his purifications. One of the few able to produce significant quantities of high-quality interferon, Cantell also viewed it as a basic resource to be shared. Famously, he never took out a patent on his procedure—which was why, in the hype that followed initial results suggesting interferon's possible antitumor properties, the American Cancer Society was able to initially order $1 million of interferon from Cantell, only to purchase but a third of it from him and the rest at twice the price from an American company set up using Cantell's own method and owned by the president of the self-same American Cancer Society.
With Cantell, the Cubans had again found a form of scientific solidarity that cut across the political constraints to their desired line of work. And with them Cantell willingly shared not just the product but the means for the Cubans to make it themselves. In consultation with Cantell, a former luxury house in Havana was fitted out as a laboratory with all of the equipment that Limonta and his group would need to produce interferon. The six scientists began working in the laboratory, known simply as House No. 149, the day after their return to Havana. There, for several weeks, Limonta, López-Saura, and the others set about retracing Cantell's method according to his own instructions. As an added incentive perhaps, Castro, who had taken a personal interest in the project, would often stop by in the afternoons. He personally saw to it that the scientists were supplied with whatever they needed. The costs of such a small-scale and dedicated approach were evident, of course: an extremely narrow focus based, for the time being, on just one drug. But the compensating advantage was speed. While it had taken some groups up to a year to perfect Cantell's art of purifying interferon, it took the Cubans just a few weeks. Limonta's letter to Clark, informing him of their progress, put it succinctly: "On April 12 the group arrived in Cuba after twelve days training. On April 18 a place was adapted to start the laboratory work. By the middle of May the first purification of interferon was done."
Just a few days after the Cubans made their first breakthrough with interferon, the island was struck by a virulent strand of hemorrhagic dengue fever, which at its height saw 11,000 new cases diagnosed each day and over 116,000 people hospitalized in total. It was the first of this particular strand of dengue, for which mosquitoes act as the transmission vector, to have appeared in the hemisphere.
The outbreak prompted suspicious words by the Cuban government directed at the United States, while the country's health system was mobilized in response. But even Cuba's extensive health-care institutions were unable to cope. Some form of active medical response was needed, and some looked to the recent work on interferon. A then director of one of Havana's principal schools of surgery, who I met on the veranda of his institute in the Vedado district of Havana, explained what happened next.
"I wrote a letter to the Ministry of Public Health stating my interest in the idea of using interferon in children with acute hepatitis B: we were a long way from producing a vaccine for it then ... but I had started to apply interferon with Manuel Limonta on sporadic cases of hepatitis, visiting patients between 11 and 1 in the morning because we were in the lab all day actually producing interferon. We had to be extremely careful—there was no publication with which we could work by, so we had to be extremely careful given the possible side effects."
Tests using interferon were given the go-ahead and initially undertaken on three hundred people, over half of whom were children. A tense few days passed before early results showed the Cuban-produced interferon to have a marked immunoregulatory effect. Shots were immediately administered as a prophylactic to the most vulnerable, and within a few months the epidemic had largely died down. It was, as the government has since represented it, an "epic" battle between society and nature which soon also saw the mosquito stamped out of thirteen of the country's fourteen provinces in an environmental health program overseen by the authorities. Interferon may therefore not have been a central part of overcoming the illness (which quite arguably owed more to rapid diagnosis, the early hospitalization and rehydration treatment provided, and the mass involvement of 10,000 volunteers). Nevertheless political awareness of these modern medicines had been raised, along with a sense of how they might play an important role in addressing the nation's problems.
At this point it pays to stand back from this narrative for a moment and to reflect on some of the developments afoot as this small troop of scientists sought to develop interferon into a lifesaving formula under scrutiny of the state. Such was the national scrutiny, in fact, that their work was also somewhat removed from most forms of international oversight. The Cubans' fast-track approach to developing new drugs required breaking down the boundaries between experiment and application, a controversial approach justified on the basis that any potential risks were outweighed by the likely social benefit. Such an unusual degree of overlap between the clinical development of the drug and its application was possible because the scientists undertaking the research were also the doctors administering it to patients. The spaces of the laboratory were thus in a certain sense being folded into society itself. Such an approach resonates today with more recent arguments about the need to rapidly develop drugs that have a clear public health application (with respect to debates focused in particular on the clinical application of HIV drugs prior to the full demonstration of clinical efficacy and safety through completion of randomized clinical trials). But in 1981 the Cubans were early starters with such an approach. Moreover, the linking of clinical application with research in the context of the "war footing" of the dengue epidemic did not remain unique; it quickly became the norm.
The emergence of hemorrhagic dengue thus provided the impetus for a change of direction both in the clinical development of interferon in Cuba relative to other countries and in the experimental ethos of Cuban work on biotechnology. The application of interferon was an uncertain process, but the state's need to respond effectively to the public health crisis meant that standard regulatory processes of proving efficacy and safety were partially suspended in order to accord primacy to the demonstration of population-level change and, more important, to enable a rapid response.
In short, the scientists involved in this particular event were given greater freedom in order to ensure that whatever the means, the ends of overcoming the crisis were met. A clear difference between this early foundational biotechnology work in Cuba and that taking place elsewhere was thus already emerging: biotechnology in Cuba was driven by public health demand (which, as one informed observer put it, "is highly unusual: it is normally a case of industry into biotech") rather than a push for innovation and profitable research from within science. In place of an economic imperative, therefore, were the social demands that the Cuban scientists apply the products of their research as soon as possible. What Clark and Cantell had proffered as a maxim, the Cubans had thus developed as a methodology.
This was not lost on Clark. In October of 1981 he met briefly again with the Cubans as they passed through Texas:
[Limonta] was on his way to San Francisco to meet at the interferon conference there this weekend and I arranged for them to see Hersh and Gutterman thinking that they should know of this opportunity to work with Cubans who would have much less regular constraints in their advancement of clinical trials, and would have the whole of the Cuban population to call upon. Apparently this is backed directly by El Presidente and he sent his regards today.
Having committed his thoughts to Dictaphone, Clark then sat down to respond personally to Castro. "Dear Mr President," he wrote. "It was indeed a pleasure to receive your emissaries, Drs. Manuel Limonta and Luis Herrera, this week and to learn about your remarkable progress in establishing a laboratory for the production and use of interferon." The business dealt with, he moved on to the personal element. "May I also take this opportunity to thank you for the magnificent wooden box filled with your special Havana cigars, the record album and the bottle of Cuban rum ..." Rarely had scientific diplomacy been so simple and yet so acute.
Slow Paradigms
"It is tempting to begin by describing what was known," writes François Delaporte at the start of his essay on the birth of tropical medicine. In uncovering the emergence of a particular approach to biotechnology in Cuba, Delaporte's temptation must indeed be resisted. The above narrative recounts the emergence of a rather particular approach to science. Certainly it is true that, through a form of international solidarity, the Cubans were able to obtain the intellectual and material resources they needed to successfully manufacture first-quality purified interferon and, ultimately, recombinant engineered interferon as well. They put this globally disparate suite of work together into a highly focused project that found an immediate application for use in dengue patients in Cuba. But that this story says all that needs to be said about what it is that makes Cuban science different is manifestly not the case. What is most interesting in the above account of the way Cuban work began and developed through an initial specialization on interferon, in fact, is what lies silent within.
(Continues...)
Excerpted from The Cuban Cure by S. M. REID-HENRY Copyright © 2010 by The University of Chicago. Excerpted by permission of The University of Chicago Press. All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
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