Scientific discovery to benefit human health requires academic, industrial, and government to work together, but how?

The Institut Pasteur is a nonprofit private foundation named after Louis Pasteur, who made seminal breakthroughs contributing a founding basis to our modern understanding of biology, microbiology, immunology, and medicine (http://www.pasteur.fr; http://www.pasteur-international.org). From the beginning the mission of the institute has been: excellence in fundamental biomedical research to the benefit of global public health. For over a century the researchers of the Institut Pasteur have dedicated themselves to the study of host-pathogen biology, microorganisms, and vaccine development, maintaining the institute at the vanguard of the battle against infectious disease [1]. Consequently, Pasteurian researchers have been responsible for breakthrough discoveries, milestones enabling medical science to control public health threats, including virulent diseases such as rabies, diphtheria, tetanus, tuberculosis, poliomyelitis, influenza, yellow fever, and the plague. Since 1908, 10 Pasteur Institute scientists have been awarded the Nobel Prize, the most recent in 2008 for medicine and physiology: the discovery of HIV. This proven success is concrete testimony to the remarkable nature of the Institute Pasteur that with the benefit of hindsight has become inspiration to many seeking to design optimized, reproducible, and robust models for successfully operating transnational scientific research frameworks and infrastructure [2–5]. Optimization of the sophisticated governance of such collaborative research frameworks is unarguably necessary to tip the balance in favor of useful scientific discovery, and it is in this sense that the Pasteur model is singularly compelling because in itself it presents us a somewhat remarkable example of how productive academic, industry, and government (AIG) partnerships can emerge at the grassroots level nourished by a dedication to the vision of fundamental research science. Indeed, the founding of the Institut Pasteur in Paris, and the synergistic emergence of the Institut Pasteur International Network (IPIN) has proven itself a robust and successful example of transnational collaboration during over 100 years, bringing it under scrutiny as a case study example of a transnational (transformational) scientific network [3, 4]. Understanding why the Pasteur model works so well as a transnational network might help to extract a recipe for improved AIG partnerships more likely to facilitate scientific discovery (including drug discovery) for the global benefit of human health and the environment. This chapter explains my views on this matter extrapolated from a small selection of learned works on the subject, to which I strongly urge the motivated reader to refer in looking for the details on this rich and fascinating history.

The Institut Pasteur International Network

The IPIN is a scientific community of regional centers and institutions (Table 26.1) spread out across 5 continents, and uniting 10,000 people, most of whom are recruited locally. It provides us one of the rare examples of a durable scientific network that operates successfully on an international scale, arguably because its founding mission has remained for 120 years a private institute dedicated to research, public health, and education. The Institut Pasteur’s international mission dates back to its creation in 1887. The contributions that permitted the founding of the Institut Pasteur in Paris came from many countries across the world. Pasteur scientists in the institution’s earliest days traveled around the world to study and combat epidemics, and this diaspora of Pasteurians led naturally to the founding of research and public health outposts that gave birth to the IPIN. Facilities were often located in, or near pandemic areas. The first Institut Pasteur outside France was created in 1891 in Saigon in Vietnam with the collusion of a Pasteurian cohort leadership: Eugene Etienne (an influential French colonialist party leader) and Albert Calmette (a military doctor) who aimed to vaccinate people against rabies and smallpox, by establishing locally the means for vaccine production [6]. In its success this model rapidly led to other institutes being founded in Tunisia and Algeria. That these expansions initially occurred in French colonial enclaves has brought many historians to question the imperialist subtext of the IPIN model [6]. While undeniably French colonialist interests were involved in these initiatives, it seems this feature should not be in any way considered anything more than context; it has nothing to do with any prerequisite feature of the IPIN model itself. Supporting this view is the modern cartography of today’s IPIN, which is distributed across five continents in a manner distinct from any perimeter that might reflect direction per se by French government, or diplomacy. Furthermore, the continuous growth of the IPIN during 120 years has been sustained at a remarkably constant rate of one new institute every 4 years (see figure and table). The average growth rate has progressed unabated by two world wars, three global economic depressions, and extreme patterns of change in the ebb and flow of French diplomatic policy on so-called colonial outposts. The IPIN growth trend does betray microcosm inertia due to socioeconomic factors (these are discussed in Reference 4), but overall, it is a linear trend. So, while undoubtedly French and other government interests did, do, and will play a part in the growth of IPIN, just as for any other AIG partnership founding transnational research infrastructure, it is unlikely that we will find therein the driving parameters, or impetus to this remarkable growth curve. Any role of influence at this level should be considered merely tactical when compared with the more fundamental constants to be found at the higher level of vision and strategy of the founding Pasteurians. The genesis of the IPIN as a model for transnational scientific research infrastructure can be considered from the perspective of a higher level by appreciating the history, vision, and context of the founding of the Institut Pasteur in Paris, where Louis Pasteur and his collaborators shared a common ideal in a mission aimed to enable the largest number of countries to benefit from scientific discoveries in the fight against infectious diseases. It is at this level that we find some understanding toward explaining the startling level of sustained IPIN growth.

Chance Favors the Prepared Mind

By the 1880s, somewhat toward the end of his career, Louis Pasteur had already enjoyed great success as a research scientist. His early breakthrough experiments using his knowledge as a chemist delineated the bases for industrial fermentation processes and led to his pioneering research in bacteriology. Pasteur’s importance and contribution cannot be overestimated: he discovered the principle of sterilization, which came to be known as “pasteurization,” and from among his other discoveries came the universal practice of surgical antisepsis, today the basis for modern hospital procedures and still the only useful practice to limit the risk and spread of nosocomial infection. However, the catalyst to the founding of the Institut Pasteur, considered by many as by far his most important discovery, was his invention of the rabies vaccine.

Rabies is a viral disease that causes acute encephalitis (inflammation of the brain) in warm-blooded animals. The disease is zoonotic, meaning it can be transmitted from one species to another, such as from dogs to humans, commonly by a bite from an infected animal. For a human, rabies is almost invariably fatal if postexposure prophylaxis is not administered prior to the onset of severe symptoms. The rabies virus infects the central nervous system, ultimately causing disease in the brain and death. Early-stage symptoms of rabies are malaise, headache, and fever, progressing to acute pain, violent movements, uncontrolled excitement, depression, and hydrophobia. The primary cause of death is usually respiratory insufficiency. In short, rabies is a miserable and painful death, and the dramatic details of how Pasteur came to produce a vaccine cure for humans set the stage for the founding of the institute that would eventually bear his name.

The practice of “vaccination” (inducing immunity from disease) has multiple origins that historically can easily be traced back to therapies developed in India, China, and the Turkish Ottoman Empire in the seventeenth to eighteenth centuries, but likely goes back much further to 1000 BC.^* However, it was the Englishman Edward Jenner that brought the first scientific presentation of the method in its application to smallpox, presenting his results to the Royal Society in 1796. Nearly 100 years later, Louis Pasteur’s contribution to understanding the mechanism by which vaccine inoculation could protect from infectious disease was emerging in the light of Germ Theory. In parallel to the studies of Robert Koch (who would soon publish his seminal “Koch’s Postulates” in 1890) both scientists were working on the idea that specific pathogenic agents were responsible for infectious diseases and proposed that such agents could therefore be isolated and were likely players in induced immunity. In 1879, working on the disease called chicken cholera, Pasteur’s contribution had exploited the chance observation that an accidental exposure of laboratory chickens to cholera culture isolated from diseased animals, cultured and then “attenuated,” resulted in induced immunity. This linked Germ Theory to infectious agents in a way that would eventually help debunk the popular dogma of that era “spontaneous generation” of disease, thereby revolutionizing rational strategies for inoculation and vaccine production. However, that the cholera vaccine experiments had used only laboratory isolates and animals meant that there was no evidence to suggest this idea could be extended to humans. Pasteur was also working on developing an emerging rabies vaccine in a series of experiments in dogs inoculated with the infectious agent extracted from rabbit bone marrow. His results showed similarly that inoculation with attenuated preparations could protect healthy animals from becoming infected upon exposure to live (nonattenuated) preparations. However, as for chicken cholera, he remained far from any proof of efficacy in humans.

During the late summer of 1885 a 9-year-old Alsatian boy, Joseph Meister, had been badly bitten in an attack by rabid dog, which left him mortally injured. Despite being advised by a local physician that the young boy was certain to die, having no chance to escape the rapid onset of this devastating and uncontrollable infection, Joseph’s distraught parents brought him to Paris demanding an audience with Louis Pasteur himself, having heard the popular rumors of his successful experiments curing dogs with the disease. However, Pasteur was a chemist, not a medical doctor, and had not begun any clinical experiments with humans. Nonetheless, he was moved by boy’s case and the insistence of his distraught parents, perhaps relating to them through his experience of having lost three little daughters from tuberculosis and typhoid fever. In this dramatic context, and against the impassioned objection and contrary advice of one of his closest colleagues, the medical doctor Emile Roux, Pasteur agreed to try to help the boy. This decision was not taken lightly, and Pasteur knew full well that the treatment itself, an injection of rabbit bone marrow in which the virus was “attenuated,” might kill the boy outright. It is not parenthetical to consider this dilemma from today’s perspective where the regulatory authorities that dominate the necessary protocol controlling translational progression along the preclinical to clinical research path. In the absence of such authority in late nineteenth-century Europe, it was merely collegial ethics, the rule of common law, and one’s own sense of personal responsibility that were to be taken into account on matters of regulatory affairs. Pasteur was risking the boy’s life and his own stature as a scientist, researcher, and member of the College de France, where his maverick ways had already risked isolating him, despite his genius. So, after several weeks of daily treatment by excruciatingly painful injections performed in complete secrecy except for under the surveillance of two clinicians and the boy’s mother, when Joseph survived, apparently cured, it was both a joyful triumph and considerable relief!

Institut Pasteur Paris: A Private Foundation with a Public Health Mission

The news of the extraordinary story of Joseph Meister spread rapidly throughout France and beyond, resulting in literally hundreds more patients arriving in Paris during the following months, seeking treatment. In the nineteenth century, rabies was prevalent across Western Europe, and much of the rest of the world too. It was a terrifying disease scourge, compelling the zeitgeist of that time (press and pundits) to deem Pasteur’s discovery as more than remarkable and earning him the popular title “Benefactor of Humanity” [1]. The impact of these results was compelling, and on March 1, 1886, Pasteur relayed his results to the Academy of Sciences, revealing how he had succeeded in curing all except one of the nearly 400 rabies-infected patients that had come to him since hearing of the cure provided by his treatment. Pasteur seized this opportunity to request the Academy’s support to create the institute of which he had so long dreamed: a research institute dedicated to the study of microbiology, delving into the experimental research analyses of infectious disease, and applying those results to better public health. These ideas would, of course, be illustrated by the new institute’s commitment to specialization in the development and production of a vaccine against rabies. The Academy, astounded by the results, provided unanimous support, and even went so far as to launch an international fund-raising campaign toward establishing the Institut Pasteur, which was founded on June 4, 1887. A month later, laboratory construction began, while Jules Grevy, President of the French Republic, signed a government decree recognizing the Institut Pasteur as a “foundation directed to the public benefit” and approved its statutes [1, 7]. This compelling context gave impetus to the rapid progression of events, which made it for the first time possible for Pasteur to create infrastructure that adhered to his goal for a scientific institute that could operate in liberty, guided by a vision of fundamental biological research aimed to the benefit of applications in public health.

From the moment Grevy signed the statutes, the birth of the Institut Pasteur in Paris was assured financial benefit from the State. Particularly, the early construction work consumed all of the first public subscription, leaving nothing for operating costs (see Reference 4, and references therein, e.g., [8]). Furthermore, the initial lack of funds was later redressed upon successful development of an effective serum for diphtheria that assured a second public subscription (1890). Additional income was provided when the public purse was used to purchase the serum, destined to be used for public health and military field care. However, in the statute of the newly founded Institut Pasteur, from the very outset, was the insistence of autonomy and independence, particularly imbibed in the liberty to operate as a private institution with a public health mission recognized by the state as such, yet independent from it. This distinction that may seem trivial by comparison to the science that belied the context, was without precedent, and even today is rare if not still unique. The reason is simple: this positioning is intrinsically ambiguous, beckoning the question of how a private enterprise (albeit a nonprofit), generating its own lines of income, can at the same time consume public funding in a privileged manner, and yet still be independent in its governance. A legal quagmire of a sort, this fuzzy, mixed definition of charter and statute has served a founding principle, allowing the institute to maintain itself successfully during over 120 years, through multiple sources of funding, including private enterprise income; donations from private individuals, societies, and companies; and government funding. Consequently, among science historians and policy analysts the ambiguity of the legal statute of the Institut Pasteur has come to be considered a core premise of the Pasteurian model [3, 6]. The duplicity of the founding statute set precedent allowing the institute to access diverse (private and public) funds while still leveraging independence of governance from the state. This defining quality is argued to be the distinguishing characteristic that brought the model to propagate so directly and rapidly outwards into an extensive global scientific network, enduring and still growing for one hundred and twenty120 years.