In silico medicine drives medical research back into Pasteur’s quadrant

Traditionally, we separate science basic research, which quests for fundamental understanding of nature without any consideration of the possible use of such knowledge, and applied research, which aims to solve specific problems without any ambition of adding anything to the fundamental understanding.  If we draw a 2x2 table, the top left quadrant with no consideration of use and quest for fundamental understanding is sometime called the Bohr’s quadrant, while the bottom right quadrant no quest for fundamental understanding and consideration of use is called the Edison’s quadrant.  But there is a third type of research, sometime referred as the Pasteur’s quadrant, that while motivated by clear considerations of use, produces nevertheless fundamental understanding. Donald Stokes, in his book “Pasteur’s Quadrant: Basic Science and Technological Innovation”, advocates that this third type of research, although least common, is potentially the most rewarding for society.

I agree with Stokes, but I have an additional reason to believe that that falling in Pasteur’s quadrant is the best science. Too frequently “curiosity-driven” research turns out to be “opportunity-driven” research, where we carefully select research questions that can be rigorously answered with the methods and approaches available; in my opinion, this can be epistemologically dangerous, for example when it produces causal reductionism.

The radical specialisation of biomedical research in the last 30 years has produced a dramatic polarisation of large volumes of basic biological research, which turns out to be very difficult to translate into any application related to human health, and an applied medical research still too frequently built on shaky methodological and theoretical foundations.

So, pushing biomedical research back into the Pasteur’s quadrant would be a desirable thing. I believe the trajectory of in silico medicine is producing this positive effect. When in silico medicine started, its key feature soon became, especially within the European Virtual Physiological Human (VPH) initiative, the ambition of predicting how specific physiology determinants would change due to the progression of disease or interventions in each individual patient. To do so effectively, it was essential to rely as much as possible on mechanistic knowledge, that does not rely on population average generalisations.  This forcefully narrowed the scope of VPH models to those parts of human physiology for which reliable mechanistic knowledge is available, such as biomechanics, mechanobiology, electrophysiology, bioenergetics, etc.

But now I believe we are starting to observe a reverse effect, where in silico medicine is not only research on the application of the available knowledge but also drives the production of new fundamental mechanistic knowledge on physiology, pathology, and the mechanism of action of interventions, knowledge that subject-specific models need to be more useful supporting relevant clinical decisions. This is producing a completely different type of in silico medicine research, that while motivated by well-defined clinical problems, pursue the discovery of new fundamental knowledge.  Interestingly, this does not limit anymore in silico medicine to the use of computational methods, but rather promotes the type of circular synergy between modelling and experimentation that others advocated.

We as a community need to reflect on this new trend, and explore how the available funding instruments need to be adjusted to support this potentially rewarding development.

My personal Laudatio of Peter Hunter

On July 18th, 2017 the University of Sheffield awarded an honorary degree in Engineering to Prof Peter Hunter, of the University of Auckland.  I was delighted when they told this would happen, as there are very few people who have been as influential as Peter in setting direction of my academic career. I was also frustrated that the rigid rule of the ceremony required that the Laudatory speech had to be given by a specific colleague, i.e. not me.

But the day before Peter kindly agreed to give a seminar to the Insigneo staff, and I took that occasion to  explain my colleagues, co-workers and students why Peter had been so important to me.  Here below is the notes I made for that speech; they tell also something about my own professional history.

Prof Peter Hunter graduated in Engineering Science at the university of Auckland, and then worked for a number of years at the University of Oxford with figures of the calliper of Prof Denis Noble, with whom he developed the first electromechanical model of the human heart.  He returned in Auckland in 1979, where in 2001 he established the Auckland Bioengineering Institute, which is today the most important research centre in the world for in silico medicine.  He published nearly 250 papers, is co-Editor in Chief of Biomechanics and Modeling in Mechanobiology, and has a list of honours  a kilometer long including an honorary professorship from University of Queensland, an Honorary fellowships from Institute of Professional Engineers of New Zealand, and an honorary Doctorate by University of Nottingham.

I started my career in biomechanics in 1989.  For the first 10 years, my only interest was orthopaedic biomechanics, in particular that of total hip replacement.  But as I started to broaden my interests to other musculoskeletal biomechanics problems, I also started to realise that something was wrong in the way we approached the modelling of the human body.

What was wrong was that we all used scale separation assumptions from general engineering that in physiology were not acceptable. But at that time that was not very clear to me, I just had this felling something new was required to move on.

In August 2002 I attended the Fourth World Congress on Biomechanics, at the University of Calgary, Canada.  One of the plenaries was from this tall Kiwi, I never heard of (for my ignorance of course because he was already as famous as a pop star in the bioengineering community).

As he explained his vision for a multiscale modelling of the human body, a computational biophysics and biochemistry approach to human physiology, suddenly the light struck me, much like Saint Paul on the way to Damascus: that was what I wanted to do.  Period.

Peter Hunter told us two things that day: the first is that scale separation does not apply, and we need to model the human body using multiscale models.  The second, much more important is that it is not madness to imagine an engineering approach to human physiology, where patient-specific computer models can predict biomarkers that are impossible or very difficult to measure directly.

But as I came out of the lecture room, I noticed that while a few were struck like me, many liquidated Peter’s vision as totally unrealistic.

I went home and for the following two years I ruminated on Peter’s talk.  And slowly  I started to form a line of action: first, Peter’s idea was so powerful that confining it to physiology was a vaste, we had to take it to pathology, and start using these models in the clinical practice. Second, before we could even speak of such idea, we have to form a community of practice, because most of the bioengineers, forget the clinicians, thought we were crazy.

In 2005, three years after I listen Peter for the first time, in a small meeting in Barcelona the term Virtual Physiological Human was coined. In 2006 we started the Europhysiome support action, which in 2007 delivered the VPH Research roadmap, starting a chain of events of which the establishment in Sheffield of the Insigneo Institute for in silico Medicine is one of the latest one.  And Peter has been my helmsman, my guide, my inspiration, and in a few occasions my psychotherapist for 15 years.  And more important he has been, and will always be my friend.

The Immortal Life of Henrietta Lacks

I am on holiday, and this is the only time in the year I can afford enough neurones to reads some serious books.  This year I picked "The Immortal Life of Henrietta Lacks", by Rebecca Skloot.

This 2009 book tells the story of the HeLa cells line, the first immortalised cell line ever produced.  But it also tells the story of Henrietta Lacks, the black woman that in 1951 went for a visit at the Johns Hopkins Medical School and Hospital in Baltimore, and was found with an incredibly malignant tumour of the cervix.  Without her knowledge or consent, a part of the tumour was sent to George Gey, a cell biologist working in the same hospital, who derived from it the first human cell line that would replicate indefinitely, what is usually referred as an "immortal" cell line.  The line was named with the initial of the donor, HeLa.   To date PubMed reports 94,103 papers that cite the HeLa cell line; the list of discoveries that were made possible because of the HeLa cell line is impressive, starting from the key role it played in the discovery of the polio vaccine.

First, if you have any interest in life sciences, or in the ethics of research, please read this book.  The author develop a passionate parallel narrative of the HeLa cell line and of Mrs Lacks and her family; in doing this you realise what we all know and all constantly forget: there are people behind our samples, our diseases, our cures.  People with their beliefs, with their fears, they joys and pains, their greed and generosity, and their vision of the world.

I decided to write this blog to fix some ideas that I developed while reading this book.

The first theme is racism. While George Gey is described by the author as good person, driven by a positive ethics of research, the United States of the '50s are a profoundly racist country, where black people are perceived as lesser humans.  And once you accept this, even unconsciously, then even the good persons will end up acting with total disrespect for the fundamental rights of other human beens.

the second theme is the need for a rigorous enforcement of ethics in human and animal research.   Reading this book I learnt of the Tuskegee syphilis experiment, or the work of Chester M. Southam who injected HeLa cancerous cells under the skin of prison inmates from the Ohio State Penitentiary and to cancer patients without their consent.   I came to realise that for each rule we need to cope in biomedical research, there is in the past an horror story that motivated the introduction of that rule.  It might be obvious, but like many things, we tend to overlook them, or at least I did.  I think teaching applied research ethics starting form this historic cases can help our researchers in training to better understand where all this comes from, and why it is important.

As I found enlightening this book, I disagree with the proposals contained in its Afterward. Rebecca Skloot identifies two issues: the need for informed consent in tissue banking, and the unfair share of commercial profits built on someone tissue donations.  While I agree both problems exist, the solutions the author propose (full informed consent and sharing of commercial profits with the donor) are so american in celebrating the supremacy of the individual over the collectivity.

While I agree that no tissue should be used for research without the donor consent, the need for the development of tissue banks prevents the detailed informed consent that is typically used in clinical research, because at the time of donation we do not know which exact type of research will be conducted on those tissues. I believe that we can develop informed consents that provide general authorisation to research, and possibly offer opt-out for particular type of research that are know to raise moral issues in groups of citizens (such as biological warfare).

Also, I think that profit sharing looks at the issue in the wrong way.  Not only the donor, but also the researchers should be forbidden to make any profit out of tissue donations. The idea that one can patent a human gene is simply terrifying, and has already produced some horror stories in term of access to cure.  George Gey gave away for free his HeLa cell line to anyone who asked for it, and did not even try to patent some of the technologies he developed to support mass-production.  this idea that greed is a positive driver is crazy, and factually and historically wrong.  We need to tell our patients, our researchers in training, our doctors that we do what we do for the betterment of humanity, not to become rich.

My opening speech for the Insigneo Showcase 2017

Dear members of Insigneo, dear students and research associates, honoured guests, representatives of our academic, industrial and clinical partners, of the research funders, and of the management of the University and the Trust, I warmly welcome you to the Insigneo showcase 2017.

Today, through the presentations of 16 members of Insigneo, we will provide you sample, hopefully representative, of the extraordinary research and technological innovation work that this institute has undertook in the last 12 months.  The four sessions of the programme well represent our objectives:

We believe in silico technologies can transform fundamental biomedical research, and the session "In silico Science”, Chaired by Damien Lacroix, will provide you a small but representative sample of this important work.

At the core of Insigneo there are radical technological innovations that enable all we do; the session "In silico Technologies”, chaired by Andrew Narracott, will give you a taster of some of them.

After lunch we will focus on the clinical and industrial applications.  The session "In silico Medicine: Predictive Medicine” chaired by Paul Morris, will offer some examples of how in silico medicine is transforming clinical research; the last session, "In silico Medicine for Industrial Exploitation” chaired by Gwen Reilly, will instead offer a sample of the translation toward new biomedical products and technologies.

During the breaks please visit our poster area, where you can catch a much broader view of what we are doing, and stop at the booths where we and our industrial partners show some exciting ideas.

At the end, after Damien conclusions, please try to stay a bit longer if you can, for our drink reception, where we can relax, socialise, and network.

In October 2011, a bit less than six years ago, I started to work at the University of Sheffield, with the mandate to setup a research institute on in silico medicine.  The few of you who were into this adventure from the very beginning know with how much trepidation I started.  After 25 years working in the same institution in Italy, it was a big change, most was unknown.

but I got lucky.  Here I found Rod, I found Pat, Wendy and Richard, Paul and Simon, Damien joined us soon after, and slowly I started to be confident we would make it. And we did: in May 2012 the Insigneo institute opened its membership, and today we celebrate five years of uninterrupted success.

But this is not the end, it is just the beginning.

I want you to picture Insigneo today as one of those 5-year old boys, who runs around constantly, and cannot keep calm for all the gold in the world. It is like there is too much energy bottled up in that little body, can you see it?

OK that what I want Insigneo to be in the next five years.  a restless, over energetic kid, that enthusiastically explore every possible direction of development and improvement.

I want to see Insigneo Ltd, to commercialise our services; I want to see Insigneo international, to fight the effect of the Brexit.  I want to see large clinical trials fully augmented with in silico technologies, and more and more hospital specialists taking clinical decisions with the support of our subject-specific models.  I want to see the next generation of specialist trained in our new master spreading through the world, and make the vision of the Virtual Physiological Human a global reality; I even want to see a module of computational medicine in the standard curriculum of our medicine and nursing students, some time soon.

We do live interesting times. I am sure you have heard of the story of the wolves.  The grandpa tells the grandson that are two wolves constantly fighting inside each of us: one is anger the other is hope; which one will win, ask the grandson? The one you feed, answer the old man.

Well, in Insigneo we plan to feed only the wolf of hope, tolerance, and social justice.  Please dream with us of better futures.

The role of in silico medicine within biomedical research

The publication in 1823 of the first issue of Lancet symbolically marks the 19th century revolution of biomedical research. Out of this expansion, modern biomedical research organise itself around three fairly different paradigms, each trying to cope with impossible complexity of human body:

• Cellular and molecular biological research, driven by an aggressively reductionist agenda, which focus on small sub-units of the system;
• Clinical research, which largely treats the human body as a black box, and vastly relies on the statistical modelling of empirical observations;
• Physiological research, which tries to investigate the human body following the approach typical of physical and engineering sciences.

The third approach, undermined by the dramatic limitations of 19^th-early 20^th century calculus and instrumentation, has been the least successful of the three, and its importance has been progressively decreasing.

Two events we believe are changing this scenario: the first is the dramatic progress that physical and engineering sciences drove around biomedical instrumentation. Using x-ray, magnetic fields, ultrasounds, we can now imagine the inside of the human body with amazing accuracy; automated chemical analysers, spectroscopes, sequencers are offering a high-throughput biochemistry that open entirely new scenarios; the amazing capabilities of modern electrophysiology give us details on the working of the heart, the muscles, the brain; motion capture, dynamometry and wearable sensors offer a detailed view of the biomechanics of human movement.  In short, today we can collect a deluge of quantitative data on each individual patient that describe in full detail their anatomy, physiology, biochemistry, metabolism, etc.

The second is the amazing development of calculus, thanks to the advancements of mathematics, computational science and engineering, and of the raw computational power that modern hardware and software can offer to modelling and simulation.  This development is essential, because for the first time in history we can solve the enormous number of complex mathematical equations that can quantitatively describe many physiological and pathological processes; we can finally handle the complexity, and we do have the means to measure pretty much all we want to measure in each individual patient. 

The problem with complex living organisms is that they are dramatically entangled, so the functioning of each of their parts can hardly be assumed independent from the others; while large part of biological research ditch this problem with reductionism, and clinical research bypass it entirely by renouncing to the search for detailed mechanistic explanations, a biomedical research agenda based on the methods of physical and engineering sciences must face this complexity; and this is possible only if we use mathematical and computational methods to formulate our theories and quantitatively compare their predictions to experimental observations as primary mean of their tentative falsification.  

At the same time, once a theory resist extensive falsification, the predictive model that embodies it can be used to solve clinically relevant problems, as many of the grand challenges of modern medicine (prevention, personalisation, participation) would be easily addressed by an increased ability to accurately predict the course of a disease or the effect of different treatment option for each individual patient. 

Therefore, we believe in silico medicine is the main road through which the great physiologists of the past generation will be ultimately proven right, and a biomedical science based on the methods of physical and engineering science will become more and more successful.

In this sense, we believe in silico medicine is not only a new family of technologies we can use to investigate the human body, but it may enable a paradigm shift in the sense proposed by philosopher Thomas Kuhn, “a fundamental change in the basic concepts and experimental practices of a scientific discipline”.

Viva the United Kingdom, or how to get your permanent residency

I moved to the United Kingdom when I started to work at the University of Sheffield, on October 1st, 2011.  So in October this year I matured the five years required to apply for permanent residency, which would then allow 12 months after to apply for citizenship, if you want.

The timing was not the best: in June UK voted for the Brexit, and the Guardian published every day horror stories of dutch mothers of three living in UK since the 19th century, who when applied for the residency were offered instead expulsion.

Like most EU citizens I admit I was quite concerned.  I did a first search and I found the infamous 80 pages application form; I saved it and forgot about it.  During the Xmas break, I allocated a whole day to fill in this crazy thing, which required among the other things to list all my trips abroad (dozen every year).  I did it, but then I was so distressed that I never found the will to complete the procedure and submit it.

In February I decided it was time to be a bit more rational.  But his time I spent a little bit more time seeking information. My situation is the simplest of all: I am an Italian citizen (thus an EU citizen), who have a permanent employment contract with an good salary in a UK university, and for the moment I do not need to get residence for any other family member.  If you also are in this situation you should use this on-line application.  If you do you will realise that the process is infinitely simpler than the 80-pages form.  It took me three hours, but this because I am obsessive-compulsive and I scanned every document I sent them.  My application was submitted on Feb 26th, 2017; the documents were sent by post a couple of days after.  The application tells you it may take six months, so I relaxed.

A week ago I got an a note to pick up a parcel, but I could go only today.  The parcel contained my permanent residence, all my original documents, and a very nice and detailed letter that explain that now I can do pretty much what I want in this country forever, as far as it is legal.  The whole process took less than two months.  But the best part of the story is that my permit is retroactive to the date I matured the five years, which is October 1st, 2016.  So, if I want, in October this year I will be able to apply for full citizenship.

Last point: yes, you need to submit some P60, some bills, some bank statements, and a proof of nationality.  If you come from a country that provide ID cards like Italy, that is fine; sent them my ID, and kept my passport to travel.  If not, you need to get an appointment in an office (nearest is Manchester I think) where they look at your passport, give it back, and submit your application for you.  so no need to send them your passport.

I was not happy when the majority voted for the Brexit.  But this is still a great country, and they clearly want me to stay.  I lived in Italy 20 years while the majority of my countrymates voted for Berlusconi, I can surely live here after 52% of British voted to leave Europe.  Now I only need to come to term with the idea of becoming a subject of her Majesty the Queen ...

Reproducibility and negative results

Finally the molecular biology research community is being scolded for its publishing practices.

The new European Code of Conduct for Research Integrity writes: "Authors and publishers [must] consider negative results to be as valid as positive findings for publication and dissemination".

Recent Nature news are bouncing back against the Cancer reproducibility study that wanted to test the reproducibility of the experiments described in 50 papers.   The blogger even cite "who watch the watchman?" question.  And journals ask you to fill forms over forms as a measure to ensure reproducibility.

But no one seems to point to what to me appears as the central issue: individualism and science are incompatible.  Look at this definition of science, which I use in my "How to write a scientific paper" lecture for graduate students: "The scientific method is the process by which scientists, collectively and over time, endeavour to construct an accurate (that is, reliable, consistent and non arbitrary) representation of the world" (Wilson, E. B. An Introduction to Scientific Research, Courier Dover Publications, 1990).

No individual scientist discover anythings alone, because any true discovery is made of all the papers that showed what something is not by reporting negative results, and and all the papers that replicated that first positive experiment.

The predominant behavioural model for biological research, made of papers on Nature, labs named after the principal investigator, and and the mirage of big bucks from big pharma if you spot the "magic bullet" must come to an end.