P4 Ecosystems: Personal reflections on a journey of 20 years. Introduction and Chapter 1.

Michael Rebhan 21-Nov-2024 Basel, Switzerland

The picture above was first published in a LinkedIn article by Bernier et al. that relates to later chapters in this series, namely: Revolutionizing Health Care Management: The 8Ps Value Proposition

Introduction: As a biomedical scientist who is intrigued by the idea of finding the “not so obvious” connections between knowledge built by scientific / medical disciplines (and their communities), I recently reflected on the 20 years of history of “P4 Medicine” and its contemporary derivative, the discourse on “P4 Ecosystems” (e.g. via #p4ecosystems on LinkedIn). Not only celebrate those 20 years as an anniversary, but also to reflect on what we learned, and where we struggled to learn - and what remains today of things I was excited about many years ago, being a bit more na?ve perhaps.

What was “P4 Medicine” about, in its early days 10-20 years ago, and how did it evolve into the contemporary discourse about “P4 Ecosystems” ? In brief, in its essence, it is a principle-based approach to the science-based modernization of medicine, healthcare and population health, based on 4 guiding principles (the 4 Ps). In other words, it is about the paradigm shift from “reactive care to proactive care”, beyond the old (“reactive care”) paradigm of waiting until a patient has symptoms so strong that seeking healthcare becomes urgent.

Guiding science-based innovation efforts aimed at “reimagining medicine” towards improved prevention, prediction, personalization and participation, in projects and programs that were designed based on those principles. Where prevention often is more than just secondary prevention, which is easier, when a patient was diagnosed and is therefore already in contact with the healthcare system, on topics and processes that are a follow-up to that diagnosis. To prevent complications, for example. As technology and other scientific progress now enables increasingly better predictions, e.g. related to increased risk of soon experiencing specific health problems, at an individual level, in a certain timeframe (often in the next months or years). As science and digital health progress enable increasingly better personalization, to the needs of individuals, their particular disease subtype and needs. As more participation is clearly needed, to make real progress, including understanding populations with bad outcomes that are “hard to reach”, topics like self-care, and neglected voices. Where the humans that can increasingly participate are not only patients who already have a diagnosis, but also those at high risk for a specific disease or health issue, and even those humans who do professional work in healthcare systems.

In other words, enabling a principle-based approach to the transformation of healthcare, towards a more sustainable model that helps us deal with mega-trends that challenge us innovators in healthcare space. Which is, based on P4 principles, more preventive, predictive, personalized and participatory. To better understand this, let’s go step-by-step, and start 20 years ago, around my personal journey as a scientist, after my first encounter with Leroy Hood and his vision in Asia.

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Chapter 1: Singapore – the early days of P4

During the years 2003 to 2004, I lived and worked in Singapore, in South-East Asia. Contributing to the implementation of an “innovation hub strategy” focused on anticipating the next wave of biomedical innovation. Which involved a deep dive, understanding and building big data, digital and data science capabilities for that next wave of innovation, including what we usually call “bioinformatics” in science-based biomedical innovation settings. Some of those digital capabilities were already, to a large degree, established before my arrival, creating a “connecting role” I enjoyed growing into, to connect across new digital and already established biomedical scientific capabilities in the labs better, for more innovation output, monitored at national level with several KPIs. With that position being located in a bioinformatics research institution that was created by the government based on that long-term strategy. To position this small country in Asia with a population size roughly similar to Switzerland. Based on a history of previous transformations guided by similar strategic work. Betting early on transformational effects in science-based biomedical innovation coming to a large degree from increasing digitalization.

Creating a kind of triangle between the digital groups, the scientists in the labs working at molecular level, and those who were passionate about modernizing healthcare by connecting with those other two.

In this local / historical context, Leroy (Lee) Hood from Seattle, the “father of P4 Medicine”, and a visionary in an international network driving a systems approach into biomedical science, was invited to Singapore, to give an inspiring keynote speech around the opening of the fancy new Biopolis campus. To help people understand key elements of the next wave, including enabling technologies and but also mindset shifts in how we do science. A bit Elon Musk style, we may say nowadays, but focused on systems thinking in the biomedical sciences, and what it may produce in terms of impact in 10-20 years. As there was quite a lot of excitement in science during those days, about things like the sequencing of the human genome and its potential impact, on how we can now study biological systems, in health and disease, at a molecular level, with more precision, in humans and animals. With data mostly meaning sequences, of the genome, and RNA products the genome likes to generate in cells. With a shift from simple 2-group comparisons e.g. healthy vs. diseased samples, towards a deeper understanding of system dynamics and state transitions in disease progression.

While there was fast progress visible, at the level of working in the labs with such DNA and RNA sequences, our understanding of protein sequences was falling a bit behind, in all that excitement about post-genome science. Lee Hood emphasized not only how exciting such developments in proteomics were, and how they could help us build “a more precise” medicine. As many in the community were dreaming about “getting to the root of the problem” in many diseases, beyond medicines that only address symptoms but not the key mechanisms.

As I now realize, 20 years later, how I was influenced personally, by those discussions in Singapore, including the encounter with Lee Hood. Realizing as well how good Lee Hood’s predictions were about what would happen in the next 1-2 decades, as he laid it out in his vision for the field and Biopolis. In the early days of P4 about 20 years ago, what were the seminal papers related to that vision? And how did that P4 medicine vision emerge from the scientific discourse in fields like Systems Biomedicine and Functional Genomics, as “systems thinking” was creating new interdisciplinary teams?

Here are a few samples from that time, with a few comments to put that paper into this context:

Integrated genomic and proteomic analyses of a systematically perturbed metabolic network (2001) Ideker T et al. (including Lee Hood and Ruedi Aebersold, who later moved to Switzerland, to build up proteomics-enabled Systems Biomedicine research programs e.g. at ETH in Zurich)

o?? A sophisticated transdisciplinary approach to build, test and refine a computational model of a biological cellular mechanism, using data from many different sources that capture various aspects of the phenomenon, incl. transcriptomics (microarrays), quantitative proteomics, and databases of known protein interactions, in yeast - as the data capture how that cell reacts to 20 different perturbations

o?? The idea of using such a modeling approach to integrate biological data, to iteratively improve our ability to predict how a cell would react to particular stimuli & perturbations, at a molecular and cellular process level – to validate if the model really captures the most relevant behaviors of the system, including those that are displayed in “unusual situations” (outside homeostasis, as a system shifts beyond normal health states)

o?? Focus here is on metabolic pathways, i.e. galactose utilization (as relevant enzymes are expressed when galactose is present and glucose is absent), informed by learnings in Systems Biology that metabolic pathways are easier to study at that level, using mathematics that connects across different parts of the system

o?? The paper can be regarded as a prototypical “systems biology” study, at that time – which inspired many scientists to “think more in terms of systems” as a complement to the well-established, classic hypothesis-driven approach to science (it was one aspect of the “mindset shift” Lee Hood talked about in his keynote speech)

A new approach to decoding life: Systems Biology (2001)

o?? What is Systems Biology about? What are the questions the field is interested in, and why?

o?? In other words, a higher-level view aligned with the above Ideker et al. (2001) paper

o?? Various metaphors used here may have influenced scientific debates in the last 20 years, an example is the idea of building a transdisciplinary capability that can learn, in terms of an iterative refinement of our understanding of complex biological systems, measured by our ability to improve our predictions of the behaviors of those complex, living system

o?? This may lead us to questions related to challenges with pharma pipelines, e.g. where disappointing trial results come from

Systems biology, proteomics, and the future of health care: toward predictive, preventative, and personalized medicine (2004) Andrea D. Weston & Lee Hood

o?? One of the earliest discussions of P4 medicine, building on the 2 above papers and discourses

o?? The authors anticipate a key role for enabling technologies such as proteomics (enabling a systems perspective on the role of proteins), in “creating a predictive, preventative and personalized approach to medicine” (i.e. 3 of the 4 principles of P4 medicine are discussed, with the exception of participatory

o?? Stating “the issue of how to use systems biology to improve the health of individuals must be a priority”, pointing to an increasing role of Translational Research (see below)

o?? “As systems biology emerges as a discipline, it is becoming increasingly clear that it will catalyze fundamental changes in the future of health care. We predict that a paradigm shift in medicine will take place within the next two decades replacing the current approach, which is predominantly reactive, to one that can increasingly predict and prevent cellular dysfunction and disease.”

§? In 2024, it will be 2 decades, since this paper. Hence the idea of an anniversary as a stimulus to this text here.

§? In other words, it’s related to the shift from a “reactive to a proactive system”, in the current discourse

o?? From the Institute for Systems Biology in Seattle (Lee Hood), which was created to develop a new approach across many scientific disciplines to this problem, i.e. laying the foundation for the science of P4 medicine

o?? In the following years, a network developed around the world, inspired by that vision, including the efforts around Rudi Balling in Luxembourg, focused on specific medical problems e.g. Parkinson’s disease, and around Ruedi Aebersold and his blood proteomics projects in Switzerland

Systems biology and new technologies enable predictive and preventative medicine (2004)

o?? Builds on the above ideas about Systems Biology, Systems Biomedicine and P4, but with more focus on what is measurable in blood, and the role this could play in Translational Research, and in shifting healthcare towards more personalization, prevention and prediction (3 of 4 key principles of P4 medicine)

o?? What we can measure in blood is today, 20 years later, still one of the most exciting areas in this science innovation space today, as technology improves, and becomes easier to deploy in translational settings. As the Theranos scandal shocked the scientific community interested in such innovation.

o?? It captures many key thoughts investigated by the “Swiss branch” of the P4 network around Ruedi Aebersold in Zurich, and relates to the progress made in proteomics

Next, on this channel, in chapter 2: Basel and Boston as twin hubs in P4 science and its translation: Reducing it to practice, is it possible? Where is translation amazingly hard?