Hello and welcome to this lecture. My name is Claas Kirchhelle and I'm a historian working at University College Dublin. In what follows, I want to give you an introduction to some of my research on the history of antibiotic innovation by guiding you through that now over 100 year old history of antibiotics, but also talk a bit about the value of history as a discipline in not only untangling problems of the past, but also making the past meaningful for solutions in the presence. In order to do so, my talk will first introduce you to the value of history when it comes to analyzing antibiotic innovation. After that, I'll talk a bit about some of the most famous grand narratives we tell ourselves about antibiotic innovation as well as the broader structural context of the golden era of antibiotic innovation and I will then end this very brief lecture by focusing on the more recent past of the empty pipeline or the dearth of new antibiotics entering markets. Now, as you will hear again and again in the course of this lecture series, we live in a time of crisis. Since the mid 2000s, global health leaders and most notably among them, the UK is former Chief Medical Officer Dame Sally Davies have all warned about a looming antibiotic apocalypse. An apocalypse in which the drugs that we use to treat and combat infectious disease no longer work. The factors driving this apocalypse, are manifold. At its heart is the biological phenomenon of antimicrobial resistance, or AMR. This is a phenomenon that capability of bacteria that predates the antibiotic era but has been exacerbated by decades of human antibiotic use that have consistently selected for resistant bacteria and resistance genes. At the same time, human innovation has not kept up with microbial evolution. A complex problem like AMR, requires a complex inter layered approach when it comes to unraveling it. This entails not just studying AMR as a biological phenomenon, but simultaneously understanding the social factors driving drug usage, affecting drug innovation and affecting humans response to the risk scenarios that have been created around AMR. History as a discipline within the social sciences is almost ideally placed to play a constructive role when it comes to this. Not only are the antibiotic infrastructures we take for granted in medicine and food production very old, history is also very well-placed to identify path dependencies, constraining action when it comes to mitigating AMR not just in the short-term but in the long term and at its most productive, highlighting alternatives when it comes to moving forward. As I hope to show you in the next couple of minutes. One way of doing so is paying particular attention to the grand narratives, we tell ourselves about our antibiotic past. To understand the power of these narratives when it comes to shaping not only our understanding of the past, but also of likely solutions in the presence and the value of history as a critical discipline in deconstructing them, let's turn to the most well-known story of antibiotics there is. At the center of this narrative is the man you can see behind me here, Alexander Fleming, who in 1928 allegedly accidentally discovered penicillin when coming back to his laboratory and finding that a penicillium tartan mold had started growing on one of the petri dishes he was using to culture bacteria that a substance being produced by the small penicillin was inhibiting bacterial growth. According to the myth, Fleming with a prepared mind but still essentially working by himself, realize the implications of this discovery and thereby in this moment of lone genius kick started the antibiotic era. This narrative has proved extremely attractive. Unfortunately, very little of its underlying premises are true. Not only would it take another 11 years for a team of clinical researchers working at Oxford to recognize the potential of penicillin and begin to turn it into the iconic drug that it would become. Fleming was also not a lone genius working at the beginning of the antibiotic era. In fact, his work was taking place in the midst of great acceleration and the dawn of a much more systematized era of antibiotic discovery, then this myth of the lone genius implies. Starting around 1900, researchers across Europe, North America, and parts of Asia, had begun looking for so-called magic bullets. The term was coined by Paul Ehrlich, we can see behind me here, to describe substances that would only target specific bacterial cells, but also later on cancerous cells, whilst leaving other human and animal cells unharmed, and thereby eliminating disease without causing dangerous side effects in the people being treated. Ehrlich used this notion of magic bullets to launch a program of drug screening for syphilis and other diseases, initially, which resulted in the discovery of salvarsan, together with his Japanese colleague, Sahachiro Hata, around 1900. The success of discovering salvarsan, which was then soon replaced by neosalvarsan, triggered investment by other companies into systematized research programs, where working together teams of industrial microbiologists and chemists would screen thousands of compounds for antimicrobial effects, select promising compounds, purify them, test them for toxicity, and then modify them to enhance their efficacy. The first team that had a big breakthrough using this method was the team surrounding Gerhard Domagk at Bayer and at [inaudible] pharm in the early 1930s. Using the method that had been effectively taken an upscale from Ehrlich's initial attempts, the team isolated prontosil, the first chemical sulfonamide, thereby really triggering the antimicrobial era of mass produced antimicrobials that were affordable and humans by broad segments of the population. Domagk's success not only triggered the rapid development of further sulfonamides, either based on isolating new chemical compounds or modifying existing chemical compounds, but also triggered growing interests in biological antibiotics. Antibiotics produced by biological substances to compete against bacterial organisms, resulting in breakthroughs such as the discovery of gramicidin by Rene Dubos, on the eve of the Second World War, and streptomycin by Selman Waksman during the Second World War. Fleming's discovery of penicillin was still a significant discovery due to its later upscaling during the 1940s. But his prepared mind and the strop of him as a lone genius at the beginning of the antibiotic era, clearly denies this broader underlying structural process of discovery. As you can see from the pictures behind me here, the notion of lone innovators working alone in their offices, also glosses over the fact that from its very beginning, antibiotic science was a big science that relied on public sector, but also private sector institutions bringing together large teams of scientists and experimental workers from different disciplines, females and males, in contrast to the pictures we often see hanging on walls, that were experts in microbiology, structural chemistry, a deep fermentation, etc., to bring a drug from the bench to upscaling and ultimate manufacturing by industry. Why do we continue to put Alexander Fleming, arguably, a not so important person in the overall narrative I've just presented, in the middle of our historical accounts of the antibiotic era? Well, on the one hand side, it is a beautiful story of eccentric breakthroughs. But at a deeper level, it also confirms deeply held Western values of the status of innovation and creativity within science that is faced around notions of individuality. It also confirms notions of national scientific leadership, which became increasingly important, especially after the Second World War when British science was trying to compete with its big brother, American science. In many ways, it is a classic, just so narrative, confirming our position and using segments of the past to do so. However, by accepting it uncritically, we risk glossing over the underlying structural factors driving innovation, such as the role of these large-scale, big science research infrastructures that drove antibiotic innovation not just in the case of penicillin, but also with preceding antimicrobials such as the sulfonamides, the role of knowledge exchange, and also the importance of know-how when it came to upscaling drug production that turned these insights at the bench into mass produced and mass available drugs. Era of antibiotic innovation and antibiotic demand continued to carry on for around 30-40 years, but gradually started to lose steam from the 1970s onwards. In the case of industry, the 1970s and 1980s witness an almost perfect storm for antibiotic innovation. Not only were lucrative patterns for first-generation blockbuster antibiotics running out, there were also higher R&D costs associated with research and development, including increased trial requirements to prove the non-inferiority and safety of new drugs entering the market. As well as increasing the lower yields from the classic bacterial logical screening technologies that had underpinned this first wave of antibiotic innovation. In the leadership structures of these pharmaceutical companies, a new generation of marketing experts were also pushing companies to focus more resources on the most lucrative treatments. Which included cancer treatments, for example, and divesting resources from antibiotic innovation. This was coupled with a trend towards the outsourcing of innovation on the part of large pharmaceutical companies who increasingly relied on innovation that was underpinned by venture capital and small and medium-sized enterprises to produce some drugs which could then be bought in if they should prove successful by big pharmaceutical companies. Thus de-risking investment for these larger players. It was also and parallel to this outsourcing of innovation, there was also an outsourcing of manufacturing going on, which larger companies in the US and Europe increasingly outsourcing the production of generic antibiotics of the active pharmaceutical ingredients for antibiotics to lower cost production sites in India and China, which subsequently emerged as the real powerhouses for antibiotic manufacturing in the current era. There's an almost perfect rupturing of this ecosystem that drove the initial wave of antibiotic innovation during this period. Initially, concerns about the slowing of innovation were very limited. However, when they did start to increase problem diagnosis, did not take a broad look at the structural factors underpinning the described R&D rupture but tapped into the grand narratives of antibiotic innovation that we encountered earlier. Starting in the mid-1990s, and accelerating during the 2000s, and thereby mirroring similar waves of attention we see for AMR, a growing number of experts began to warn about the so-called empty pipeline for new antibiotics. However, the narrative of market failure these experts chose to describe the pipeline with and thereby also frame potential solutions for the pipeline not only mirrored the geographic background, but also often their close ties to industry and background in neoclassical economics. By describing startling innovation as a result of low profits and stewardship concerns, experts glossed over the wider structural factors underpinning the breakup of post-war innovation. This narrative also then subsequently led to calls for very narrow, industry-focused interventions which did little to revive original ecosystems and were based on the premise of using public money to push and thereby de-risk pre-clinical innovation at the level of universities and companies, but also pull traditional big players back into the field of antibiotic innervation, via predictable profits with the help of Netflix subscriptions to antibiotics higher prices, etc. This was very much the premise also on which a new set of funders entered the field in the form of CARB-X, GARDP, and AMR Alliance. Following the WHO's global call to action on AMR in 2015. Similar to the Fleming myth we discussed in part 1of this lecture, framing the empty pipeline primarily as a problem resulting from market failure and lack of innovation. Unfortunately, also had the results of glossing over the broader structural changes that had led to the dissolution of this initial phase of antibiotic discovery between the 1940s and 1970s. By focusing their calls for public investment at the beginning of the pipeline, so at the stage of pre-clinical research and at the late state of the output of the pipeline so to put big manufacturers, big industry players, back into anti-biotic innovation, boosters ignored the fact that the translational bridges that had been so instrumental for this initial era of antibiotic innovation, we're no longer in existence. But that actually these big science projects, both in the public and private sphere that had been such a characteristic of the post-war era, had fragmented during the 1980s, both at the level of industry with the rise of SMEs and the outsourcing of manufacturing. But also at the level of universities, with the breakdown of these larger ecosystems of knowledge-sharing. Diagnosis of the empty pipeline primarily as a market failure that should be resolved by bringing big industry actors back into the field also tended to underplay the inherent tension of aligning the goals of private R&D, which focuses on profitability with the needs of public health and global health to guarantee accessibility to affordable products, not just for one antibiotic, but for many new antibiotics coming out and how to do this the long term without permanently subsidizing industry. With many generic manufacturers of patent antibiotics also struggling to make a profit during this period, there was also insufficient focus on guaranteeing the manufacturing of innovative products resulting from public subsidies, should these appear. Despite individual successes and best intentions, it is this little wonder that existing public-private initiatives have so far failed to sustainably reinvigorate the empty pipeline. In this situation, looking back might be able to offer alternatives when it comes to going forward. Well, industry and for-profit innovation have undoubtedly been primed drivers of antibiotic innovation since the 1930s. There are also numerous other historical models we could look to when it comes to solving the empty pipeline going forward. One of these models is the model of public research and development. This work east of the Iron Curtain, in the case of this Triptych Romans, but also west of the Iron Curtain and the capitalist world. In the case of penicillin, the iconic wartime antibiotic, which resulted from large-scale public R&D activities across both sides of the Atlantic, with no patent being filed on penicillin and the subsequent up-scaling of production by industry and international agencies with non-exclusive licenses across the world for the public global goods. The second interesting historical model to think about when it comes to designing innovation moving forward is the model of non-profit innovation, which was really pioneered by Institut Pasteur in France from the 19th century onwards, which used a mix of public subscriptions, royalty donations by its researchers, stage purchasing guarantees for its products, as well as strategic licensing to industry produces to scale up research and manufacturing of public goods, whereby research from the Institut Pasteur in the form of vaccines and therapeutics would be made available to the global public. But proceeds with all sustainably finance, innovation, and public research, non-profit research moving forward. Rather than relying on public and non-profit actors to drive the entire research and development process, another interesting model is to build public infrastructure to speed innovation of public goods which may still be produced by commercial actors. An interesting example of this is the US Army's use of its own soldiers and research facilities to screen and trial promising antimalarials, which will then subsequently be handed out to industry to produce from the 1970s and 1980s onwards. When none of these models by themselves offers a silver bullet for all of the problems hampering antibiotic innovation and upscaling in the current age, the historical success does complicate simplistic narratives of antibiotic innovation problems resulting simply from market failure. Instead, they point us to the importance of historical infrastructures, both in the public and private sector in terms of creating a sustainable ecosystem driving the innovation of public goods. To conclude, as I hope to have shown you today, history is more than anecdote. It's more than nice stories we tell ourselves about Mr. Fleming and antibiotic innovation. Instead, embracing the discipline of history is to critically embrace the complexity of the past. To identify the long-term, medium-term, and short-term path dependencies that have brought us into our current situation. Also to challenge the grand narratives that make the situation seem inevitable. This also means that history is not always, even though it often is quite depressing in terms of mistakes made in the past that seem obvious in hindsight. Instead, history is also often to encounter alternative pathways, alternative futures that might be productively but to bear on the presence, new narratives are possible. Thank you very much.
