my blog

Volume rendering: is this localization-based super-resolution?

Project outcome published in Biophysical Journal in 2010.

  • Esposito A*, Choimet JB, Skepper JN, Mauritz JMA, Lew VL, Kaminski CF, Tiffert T, “Quantitative imaging of human red blood cells infected with Plasmodium falciparum“, Biophys. J., 99(3):953-960

Most papers have an untold backstory that we cannot reveal in it so to focus on a main message and the most relevant discoveries. This one has a little one I wish to share. Volumetric imaging of red blood cells is not the most difficult thing I have ever done. However, accurate morphological and volumetric imaging of red blood cells infected by Plasmodium falciparum, the causative pathogen of malaria, caused me a few headaches. Let’s forget the time spent waiting for the cultures growing at the right speed to deliver bugs at the right stage of development, undecided if to sleep before or after the experiment, and always getting the decision wrong. Let’s not speak for now about the optimization of the sample preparation that that by trying and failing lead to other interesting observations. And here we focus on the very simple concept of accurate volume rendering.

In one way or another, volume rendering and estimation will require some sort of thresholding on the data so to discriminate the object from the background. As imaging conditions change even slightly from experiment to experiment, setting this threshold might confound the final outcomes. When you deal also with a sample that undergoes major morphological transitions, a simple problem soon became one for which I spent a lot of time to identify a solution for. As it happens, one perhaps does not find the best, most elegant or even the simplest solution, but the solution that they can find with their skills and tools. Mine was a brute-force solution of isosurface volume rendering, iteratively deformed by local refitting of a random sample of vertices in order to respect a specific model set for the transition of object to background. This was a method that permitted us to preserve high resolution morphological descriptions, at high accuracy and reproducibility for volume rendering.

This work was carried out while many of my colleagues were focusing on super-resolution, e.g. maximizing the spatial resolution in optical microscopy. Then, it was simple to notice that fitting a surface onto volumetric data delivers volume estimates at higher precisions than what the optical resolution of a microscope should permit. Indeed, whenever you have a model for an object, in my case the boundary of a red blood cell, in single-molecule super-resolution methods the point-spread-function of an emitter, it is possible to fit this model with a precision that is not (fully) constrained by diffraction, but – in the right conditions – only by the signal-to-noise ratio, the analytical tools and the adequacy of the model for the object.

In this Biophysical Journal paper, we focused on the biological application and, together with other published work, on the modelling of homeostasis of infected red blood cells. Also to avoid criticisms from referees, probably legitimate ones, I decided not to mention the concept of super-resolution. As my research focus is on biochemical resolution and its utilization to understand cellular decisions in cancer, I will not pursue this work any further, but I thought to write this little story.

While writing this brief story, I recalled my friend Alberto Diaspro often citing Toraldo di Francia on resolving power and information. I believe that my work was far from being breakthrough from an optical standpoint, but I wished to use it as a reminder of a fundamental issue that, often in biomedical applications, get forgotten. The resolution at which we can observe a phenomenon, irrespective of the tools used, depends both on the qualities of the instrument used and the quality of prior information we can utilize to interpret the data. Once technology permitted to image single emitters in fluorescence microscopy, the prior of point-like sources could be use to analyse images so to reveal the fullness of the information content of an image that is carried by photons.

In an experiment, information content is the most precious thing. Irrespective of the methodologies used, our protocols are designed to maximize signal-to-noise ratios and, thus, maximize information content, precision and resolution. However, as trivial as these statements are, in the biomedical sciences we often do not follow through the process of maximizing information content. Significant information can be provided by our a priori constrains and models. Moreover, a thorough understanding of information theory related to a specific assay can provide levels of precision and resolution that go beyond what we assume, at first, possible. However, priors and information theory are far too often neglected. This happens out of necessity as most people do not have the training and understanding of both biological and physical processes, and even those that might, have to invest their limited resources carefully. I wish that in the future there will be more collaborative work between the life sciences, physicists and mathematicians, aimed to better understand how to extract maximum information from experiments in the biomedical areas.

So… was our volumetric imaging super-resolution? I am not sure I care to really answer, but I wished to provoke some thoughts and make you think a little bit about the relevance of information theory in biomedical research.

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Photon partitioning theorem and biochemical resolving power

Project outcome published in PLoS ONE in 2013.

  • Esposito A*, Popleteeva M, Venkitaraman AR, “Maximizing the biochemical resolving power in fluorescence microscopy”, PLOS ONE, 8(10):e77392

After my 2007 theoretical work on photon-economy and acquisition throughput, I occasionally worked on a more general framework attempting to falsify my hypothesis that multi-channel or multi-parametric imaging techniques can deliver better results than other simpler techniques.

My proposal to develop instrumentation to achieve spectrally and polarization resolved lifetime imaging (later defined as HDIM) was met with scepticism by many. The recurrent question was: if you struggle to do a double exponential fit with the small photon budget we have available in biological applications, how could you possibly dilute these photons over several channels and analyse them with more complex algorithms?

Here, there are a few fundamental misunderstandings. First, the analysis should not be carried out on each “detection channel” independently, but the entire dataset should be used to exploit all information at once. Second, the use of dispersive optics rather than filters permits to acquire a higher number of useful photons. Third, limitations in current technologies (e.g., speed or photon-collection efficiency) should not be an obstacle to the development of these techniques because these are not conceptual flaws, but simply technology obstacles that can be removed.

Although I have a lot of (unpublished) work I used to describe performances of multi-channel systems, I achieved a breakthrough only when I understood I had to focus my efforts on the description of the general properties of the Fisher information content in fluorescence detection rather than the Fisher information in a specific experiment. Fisher information is the information content that an experiment provides about an unknown we wish to estimate. Its inverse is the smallest variance ever attainable within an experiment, or what is called the Rao-Cramer limit. In other words, by maximizing Fisher information, we maximize the precision of our experiments.

Photon-partitioning theorem

The second breakthrough was the understanding that the best description of precision in biophysical imaging techniques was possible only defining the concept of biochemical resolving power that is a generalization of the resolving power of a spectrograph to any measured photophysical parameter and then to its application to biochemistry. The biochemical resolving power is proportional to the square root of the photon-efficiency of a microscopy technique and the number of detected photons. Maximization of Fisher information leads to the maximization of photon-efficiency and, therefore, net improvements in biochemical resolving power. This definition complements the definition of spatial resolution in microscopy and allows to define when two objects are spatially and/or biochemically distinct. It is worth to mention that this is equivalent to stating that two objects are spatially and photo-physically distinct, but we use the photophysics of fluorophores to do biochemistry, hence my nomenclature. I see possible implications for other techniques, including super-resolution and, perhaps, this will be the subject of a future work.

The third breakthrough was the utilization of numerical computation of Fisher information rather than the analytical solutions of equations that are not always available. This process is very common in engineering but not in our field. Therefore, we can now optimize the properties of any detection scheme in order to attain the highest performance.

This work is a very specialist one and I assume there will be not many people interested in it, although the implications of this piece of theory for everyone’s experiment are significant. I believe that this is my most elegant theoretical work, but I guess it is a matter of opinion. The paper in itself had to be expanded well beyond what I wished to publish during the refereeing process and it is now including examples, software, etc. I think the theoretical introduction and the mathematical demonstrations are the best part and the description of the numerical optimization of Fisher information the most useful.

NOTE: there are two typographical errors in the published manuscript within the definitions of photon economy and separability. These are described in a comment on PLOS ONE

Women in science (Cambridge Science Festival 2018)

This is one of the initiatives we have prepared for the Cambridge Science Festival 2018. Credit: Dr Suzan Ber.

We are committed to the best quality of scientific research and to facilitate the translation of scientific knowledge into improvements in healthcare. To improve people lives, we need the brightest minds and the most skilled individuals to team up and work together. This is why we see no distinction of nationality, gender, ethnicity or faith, we simply look for skills.

Our SCRATCH whack-an-oncogene game is aimed to engage young girls and boys in programming, because we need biomedical researchers to be quantitatively-minded, computationally skilled and working with tools from diverse disciplines. However, too often we lose talented young girls somewhere along the way to becoming a scientist, engineer or mathematician. We think that, sometimes, this is caused by a perceived lack of female role models.

Do you know the many bright female physicists, mathematicians, chemists, biologists and clinicians that made wonderful discoveries? If not, play our women in science puzzle [see here copy for printing, or copy for display on screen]! Does this mean we wish to motivate only young girls to be the great scientists of the future? Not at all. We want the Albert Einsteins and Maria Goeppert Mayers of the future to work together as equals, because then we can be more efficient and improve people’s lives more profoundly and positively.

Cambridge Science Festival 2018
Khushali and Pablo are testing one of the activities we designed for the Cambridge Science Festival 2018

 

The dysfunctional digital office (emails)

January 2018 has been a watershed moment for me for something very simple and important such as… emails. Back from Christmas Holidays after visiting family and friends in sunny Italy, I was confronted with a wall of emails like many other professionals and colleagues. I had experienced this every year for many years, but this time was different. I simply could not cope with it, I avoided responding emails for a while and I became ridiculously inefficient. I gather that this was some type of ‘dysfunctional digital office’ syndrome, that caused to me that extra level of anxiety that made me hopeless.

Most of you will understand the basic elements of what I am describing, but only those of you that have a very strong digital presence (or is famous, but that is not my case), no personal assistant, nor a every good method might have experienced this digital black-out.

I have always rejected advice on how to organize my emails, abhorred the concept of using random passwords (I’ll come to that), inbox rules (I like to see all emails I have to respond in the same place), split my personal and work emails (I have difficulties to separate my personal and work life anyway), etc. etc.

However, now that I have experienced this black-out and I had to invest weeks of work to re-emerge from this mess, I wish to not just give you some practical advice (there are plenty of websites for this), but to explain what others did not explain to me before: without an articulated strategy, if your digital presence is significant, soon or late you will not function. Better investing now, proactively, then later.

SPAM SPAM SPAM

Let me do a step back. The first symptom that something was going wrong is when I’ve lost a PhD student about one year ago. She wrote to me an email, but it went straight to the Junk e-mails folder and I noticed this only a month or so later, when it was too late to confirm my willingness to host her. A few false positives later, I disabled the SPAM filter. Flooded by SPAM, I simply deleted emails as fast as possible and started to complain with our IT Department (sorry guys! you have been great in helping me out). However, this was not the issue. I never had identify the root cause of he problem.

Moving again forward between January and February 2018, I discovered the problem, in the hard way. It was not just SPAM, which was about accounting to a third of my email traffic, but also the various mailing lists I subscribed for work (another third of emails), and various accounts of private use (TV, electricity company etc) making another significant fraction of the rest. Fixing this mess was going to be hard work, but one key element changed: the realization that the issue was not SPAM, but was just, er, … me.

Password management

One issue I faced immediately is that I could not look after all the tens of account I had created over the years. I use strong passwords, but all with a certain meaning to me and pattern. However, each website has different rules and my well-thought system included too many exceptions to remain memorable.

Eventually, I gave up and I really advise you, if you did not do it yet, to surrender. Get a password management system.

Yes, when I login to an account now I am slower than before as I need to open a digital password management system with a very strong password, and copy&paste a completely random and long password to each specific account. Of course, now my digital presence is secure, the time I used to waste resetting passwords is recovered and, very important, I have a constant overview of all accounts. This was a very important step to reorganize all that followed.

Rules, rules, rules

Next, I had identified the main problem (too much email traffic that did not require response) and secured all my accounts. Rather than focusing on getting rid of SPAM, for once, I decided to clear my inbox from emails I did not need for work (but were not unsolicited emails), or that at least did not require immediate response, if at all. I created various rules, one that captures most traffic from our procurement system and deliver the emails to a procurement folder. One that capture all emails from professional mailing lists, one for literature alerts, one for private emails and so on. The trick is to have the fewest possible set of rules and sub-folders. Pay attention, you will need to maintain these folders and rules on a weekly basis, or every day. This reorganization took several days (may be weeks) of full-time work. However, I have now got rid of a large majority of emails that are likely to never require response. Once a day, I check the lists and, in less than a minute, I clear several tens of emails and, occasionally, I respond or archive for follow-up a very few of them. This time-consuming, but trivial trick, saved my sanity (probably).

Private emails

I cannot deal with one InBox, why should I deal with two? It seemed a smart thing to redirect all my emails to my work account. Yes, for many years this worked, but finally it stopped to. With a password management system and with inbox rules, I got to have a clear picture of what could go away. Do I need to keep my electricity bill in my University email InBox? I have reviewed all my forty-something accounts, log in into each of them, reviewed alert (read SPAM) options for each of them, used my gmail account for anything that is private. The decision on most accounts is trivial, some is more challenging. Some of my social media accounts (LinkedIn and Twitter) and my website are private, but I use them for work. However, do a bit of work on your social media accounts to reduce notifications, or even add them into your SPAM filters. After all, Twitter users will contact you by twitter! Now, with the number of private emails minimized, there is even more clarity in front of your computer when you login in the morning. Do I wish to check private emails? Sure, I can do it once a week, not every day.

SPAM, SPAM, SPAM, and SPAM again

Who am I kidding? Of course SPAM is a huge problem, but now I have those few tens of emails that counts in the right place on screen and I need to get rid of the evil SPAM emails only, the rest is secured away. Unfortunately, the SPAM filters are rather ineffective, at least for me. SPAMmers (may they get Norovirus infections on a weekly basis) tend to be smarter than SPAM filters. When SPAM filters are tight, you lose emails as false positives. I am unsure if I got it right, but my strategy was to download an up-to-date list of known SPAM servers. This cuts a significant amount of SPAM, others can be flagged daily as Junk emails. However, these filters are still inefficient and what I do is to update my SPAM rules daily. I have just two. They scan for words in the headers or email addresses. All together, very effective and, after the initial work, time-efficient to maintain.

SPAM, SPAM, SPAM, still SPAM

In my case, at this stage of re-organization, my tens of good emails were the majority of emails in my InBox. Those few false negative are simple to handle. However, some colleagues at University of Cambridge and suppliers decided (you criminals!) to setup legitimate mailing lists utilizing commercial email re-distributions systems. Well, yes, they are SPAMmers and I have a few false positives. What I do is to add exceptions for the very few mailing lists or email addresses I consider important. The rest can get lost and colleagues or suppliers that use third-party services will not be able to reach me, which is the minimum they deserve considering they are giving my email address away. Most importantly, I give a fast check to the Junk email folder every morning, I rescue the now rare false positive and purge the rest straight away.

Professional chats

Now that SPAM is minimized and emails that do not require a response are dealt with, in my mailbox, I have mostly work-related emails that requires a response in my mailbox. However, several of them are brief messages from colleagues asking something, often cc-ed to many. These emails clutter the mailbox. They might be useful to keep for a while, and some contain important files and links that could be useful even after a long time. So, why not re-diverting all this email traffic to a specialized application?  For me, Slack was the solution, at least for the team of people I manage. I always thought that Slack was merely a glorified chat. Technically speaking it is true. However, Slack (or similar tools) can really help to avoid missing that very important emails that you really need to reply. Slack might even be a platform useful as a team-building experience, where employees may feel more as part of a team. Just be patient at the beginning. Some people experience insufficient uptake, and this will require proper management. I have experienced madness, with a Giphy storm that made me question the usefulness of Slack at first. However, after the first few days, my team started to use Slack efficiently. The occasional jokes, animated gifs, or ludicrous channels (e.g. SporeTrek), just help enjoying the working day, without accumulating rubbish in the mail inbox.

A new dawn at the office

I know, most of you, well, those two people that arrived to read my post until here, will consider what I have written an exaggeration. However, if you are a professional with a digital presence, I really advise you to take action before it is too late. Now, I come in the morning to the office and I do not dread opening Outlook. I feel like a ‘winner’, despite the occasional setbacks, and I spend a couple of minutes checking the self-archiving folders I have created, purge them and flag the rare email I wish to follow up. Then I move to the main mailbox, archive everything not important but worth archiving, delete what does not need to be remembered and immediately reply (and archive) everything that is simple (‘thank you for your assistance’, ‘we’ll meet later at 10’, etc etc). After that I have only a very few emails that requires significant amount of time to respond.

It is a few weeks that I have my main InBox with fewer than ten emails at the end of the working day. Now, I can keep track of what is important, I have still an archive of everything else, but – most important then everything else – I feel in control.

A lot of work is still ahead. I am a techie, but so low tech when comes to management. Now that my digital communications are sorted (mostly), with my public digital presence already looked after, I would have to roll-out digital project management solutions and digital laboratory notebooks. Lots to do, but after the madness I had experienced with something as simple as emails, I want to find the time, and invite you to if you still did not, to identify appropriate solutions to your digital problems. Otherwise, when your business will grow, you will experience outages of some sort and you will be surprised to find out that the main issue was, well, … you.

 

Are sexual harassment and misconduct issues at Universities?

Over the last year, the widespread occurrence of sexual harassment and misconduct in the movie industry hit the news helping, with the amplification of social media, to raise the extent of the problem to public awareness, not just in Hollywood, but in everyday life of women. Have you wondered if sexual harassment is an issue at your workplace?

After more than 20 years of University life, either as a student or as an employee, I did not notice sexual harassment in my work environment—and this is part of the problem. We do not speak about sexual harassment because it is a very sensitive topic. Even those employers that take swift actions aimed to protect the victims will have to restrain their public disclosures to protect the victims. Therefore, I asked senior colleagues, and they confirmed that incidents do occur, even where the working culture is openly hostile to any type of harassment.

Breaking the silence

Before writing a few more words on this topic, I cut to the chase, and say that any type of harassment, but sexual harassment, in particular, are under-reported and, when they are reported, they are not advertised publicly. Thus, I here pledge my unconditional support for the initiative ‘Breaking the silence – preventing harassment and sexual misconduct’ and I invite anyone who did not feel comfortable in reporting instances of sexual harassment, harassment in general, hate crimes or sexual misconduct to at least report anonymously so that everyone can understand better the prevalence of the problem and if the mechanisms implemented by the University are sufficient to prevent or intervene in these cases.

But, let’s be clear that if you feel you have been a victim of sexual harassment (or any type of harassment or misconduct), try to find the way to get support. You are entitled to be helped to resolve any uncomfortable situation and, of course, to be protected from severe offences and misconduct.

[YouTube Breaking The Silence – University of Cambridge]

“Little girls don’t stay little forever. They grow into strong women that return to destroy your world.”

I was deeply touched by this sentence, and by the many public accounts and statements that I read or watched on regard of Larry Nassar. Nasaar was a doctor who looked after thousands of young female athletes, including the USA gymnastics national team, abusing at least hundreds of young girls. Nasaar was allowed into the hotel rooms of young girls and was able to escape justice for decades, based on the fact that his abuse was masqueraded as a legitimate medical intervention. Nasaar was able to do what he did for so long because he was able to sell himself as a great Doctor, one who forges great athletes. I did not see many people, after the trial, defending Nasaar.

So, people who criticise actresses or models that accused producers and photographers after many years should always remember that those people could do what they did, simply because they were great in their job. They became untouchable because of their capability to intimidate, some of them willingly, others perhaps unwillingly. Sometimes, they abused young girls as Nasaar did, young girls who became experienced actresses only later; other times, the abused more experienced women. Sometimes they forced themselves onto their victims, other times they accepted consensual exchanges of sexual favours having established, or at least allowed a toxic working culture. Not because they were adults having fun, but only because those were the expected business transactions, nothing to do with merit and talent.

Most of these abusers would have been considered dangerous serial rapists or child molesters would not have been for their professions.

Did these actresses and models do the right thing in reporting abuse so late? Yes. The movie, fashion and sport industries (just to list those mentioned so far) are guilty to have created toxic and abusive work environments, where the powerful were protected and employees were not. It is only nowadays that we have more tools to campaign against any type of abuse, and those abused women and men found the right moment and tools just now.

What Hollywood or Nasaar have to do with Academia?

Nasaar and Weinstein have nothing to do with Academia, directly. However, they are examples about how entire industries let their own people down. We should avoid that any industry, of course Academia included, falls or continue with similar gross failures.

Universities have to establish healthy working environments, including, of course, protection from sexual harassment and misconduct. Universities often have a duty of care for thousands of students and employees. The University of Cambridge, for instance, employs ten thousand people, educates twenty thousand students, and host other tens of thousands of contractors, suppliers and collaborators. How many interactions, conversations, jokes, relationships happen every day?

It is thus unavoidable that incidents happen, but it is essential that Universities make sure to have established an empowering and healthy work environment. No abuse, small or big, should be tolerated, on campus or off-campus.

I invite any of you that encountered this post to think, proactively, about what you can do to establish the right working culture, wherever you work, a culture where any uncomfortable situation is dealt with appropriately, abuse is never tolerated, victims are protected and abusers adequately penalised.

Pay attention; not even a scientific fact is objective.

Well, for the Church and many scientists back then, the Sun was rotating around the Earth, for Galileo and others, it was the other way around. We, scientists, are acquainted with disagreement, so it should not be surprising that any type of harassment has a subjective component. This may be one of the possible reasons why for the many people that voiced their indignation towards any type of sexual harassment, many other preferred to express their concern we are going too far. So, let me complete my post with the remark that sexual harassment is difficult to deal with, also because often there is a subjective component to it.

However gross a misrepresentation Nasaar was giving about his ‘medical practices’, this is how he was ‘selling’ his abuse and how some victims accepted the ‘treatment’. For us, now it is all clear that those were abuses. And this is a rather obvious distinction to be made.

Other times, things can be more difficult. An established, well-known scientist may flirt with a younger less established colleague hoping to find consensual sex, the younger colleague may be feeling intimidated and uncomfortable, yet not openly saying it. A colleague may try to be funny; another may feel offended. We should not be paranoid about our interactions at work because we do want to work in good and relaxed environments.

We should, however, acknowledge that harassment comprises a very broad spectrum of cases, most of which could be resolved speaking frankly between people (which is possible only in an open working culture). Other times, when there is no consent, when actions are repeated even after warnings or when the working culture is such that people who feel harassed or abused, do not feel safe to seek help, there is something very wrong to be fixed.

For those of you, I suppose the most, who feel will never harass or abuse anyone, colleagues included, you should still think you have a duty to create the right working culture where anyone can strive, at any time, including when harassment or worse might happen. You could merely speak with colleagues, or – if you did not do it already – volunteer for training and committees that will permit you to grow personally and make a difference.

Update [05.02.2018]

Professor Graham Virgo at the University of Cambridge has published a comment about the anonymous reporting tool, part of the Breaking the Silence campaign. Unsuprizingly, sexual harrasment and miconduct are underreported. Hopefully, this campagin is raising awareness about the type and prevalence of the problem. Above all, the Breaking the Silence campaign should be seen by the victims as a message of unconditional support to them and an open threat to abusers.

It is still early times and I do not have access to the fulls statistics, but it seems tha most prevalent problem is student-on-student sexual misconduct. I was suprized that those students who started to work in my team in October had to attend a sexual consent workshop. When, back then, I asked for the reason, I was informed about the issue of student-on-student misconduct.

I would like to praise CUSU for their activities, and advertise another of their initiatives, the Sexual Consent Campaign. The majority of students abhore sexual harassement, and many are activly campaigning against. However, the fact that too many young people arrive at University not knowing how to treat others respectfully is really concerning and evidence that sexual harassment and miconduct are more common than we may think in society.

We have the responsibility to ensure that University is a safe place for all and we must lead societal change.

Of course, it is not just students, and even a single case of staff-on-staff or staff-on-student misconduct is devastating. Hopefully, Academia is ready to send a clear message to their students and staff: no harassment tolerated, whoever you are.

Moral hazard in academic governance (the University of Bath, emerging protests and leading changes in society)

Moral hazard

Over the last decades we have seen everything about the good and the bad of free market economy; we have learnt a lot about the consequences of moral hazard. Moral hazard is the tendency for one person to engage in riskier behaviour when the consequences of this behaviour will be dealt by others. One example might be an insured shop owner, struggling, who will not have any incentive in investing in a new fire system as, after all, a fire would permit them to collect the premium of the insurance. The insurer does not have complete information on the behaviour of the insured or their intentions, therefore will incur a higher risk than the risk of fire in itself. However, this typical example does not adequately illustrate when moral hazard occurs at the level of management.

The 2006/7 financial crisis was an astounding example of moral hazard, where many groups of people accepted higher risk they should have done (banking management, intermediaries and the recipients of sub-prime mortgages). Let’s focus for a moment on the management within financial institutions as it is a more appropriate example of what I will have to say. Before the financial crisis unfolded, executives were either aware of the problem, and they defrauded millions of people, or they were not, they were just incompetent. Were they deserving their jobs and the substantial compensation schemes they had and still are receiving? Is the market setting this compensation packages? I will come back to this point later. Either way, the initial response of Governments was difficult: bailing-out private institutions, reinforcing the possibility for moral hazard to incur in the future, or let the system fall in an uncontrolled manner? Considering the situation, most Governments decided for supporting financial institutions, therefore reaffirming that management of financial institutions may have operated under moral hazard: as the fall-out of their riskier behaviour was, in very large part, handled by States, Governments and the People.

But this blog-post is not about the financial crisis.

The University of Bath ‘affair’

Over the last few weeks, national news in the UK reported on protests of employees and students at the University of Bath on regard of the high salary earned by Dame Prof Glynis Breakwell, their Vice-Chancellor (~£468,000 and benefits). Reports were initially accurate, but they got occasionally derailed by attempts from various academics to defend high salaries for academic governance in general or Prof Breakwell specifically. Let’s clarify immediately, I do not have an opinion about how much a Vice Chancellor should be paid. Half a million may be the right number, or it may be too low or too high, I just do not know enough. But a few things bothered me in this debate: responsibility, accountability, and gender equality.

The market sets compensation schemes, does it?

I have read the commentary written by Prof. David Blanchflower and published by The Guardian, entitled “University vice-chancellors deserve more pay, not less. Here’s why”. The reasons for high salaries described in this article are clear and even agreeable at first instance. Universities have to hire their governance in a global market with competitive salaries. I have nothing to debate about this truth, but I am afraid there is another truth, not too hidden, that went unnoticed here. The protests were not a generic complaint about the high salary of academic leadership, it was a specific complaint about an almost 4% salary increase for the highest paid Vice-Chancellor. Allegedly, compensation for the governance at the University of Bath was established with insufficient transparency, with an undeclared conflict of interests and a motion from the Court of the University was hindered by those that should have left the room during a vote because of conflict of interests. This is not my opinion, but the informed and competent judgment (I suppose) of HEFCE, the Higher Education Funding Council for England. If you are interested in this story, please read their report.

Is moral hazard or the market that set salaries?

I am no economist, but my naïve opinion is that this is a typical case of moral hazard in management. As discussed, moral hazard takes many shapes and forms, but it has been identified as a dominant reason for the uncontrollably increasing compensations for executives in Industry. It is true that Academia recruits on a global market, but Academia must shape the global market both training adequately future executives and leading by example.

There is a debate, until now unrelated to Academic governance as far as I know, about the compensation of executives that appears to have become untenable, influenced by executives themselves, paying marginal consequences when their actions damage the brand they represent.

Let’s say you have the right not just to ask a pay rise, but to vote in favour or against. Let’s say that you give yourself a million pounds per year, irrespective of outcomes, in addition to a complex package of benefits that may depend on the performance of your company. After one year of work, your company goes bust and you have lost the value of your shares and options. However, you have just earned 1 million in 1 year, that is an amount of money that corresponds to 37 years of median salary. So, corporate executives raise their pays (not all of them!), constantly, to capitalise on short-term investments, possibly (even unintentionally) misjudging the consequences of their decisions as their livelihood, and those of their families, contrary to the vast majority of people, do not really depends on their productivity. This is moral hazard.

Executives are entitled to ask for an increase of income, but the procedures for these extraordinary compensation packages (from the point of view of people paid ‘normal’ wages or unemployed) shall be transparent and not just justifiable but justified.

I do not believe that this is a common issue at Universities, but how the story unfolded at the University of Bath resemble one of these cases. Let me do an example.

Dame Prof Breakwell is paid a high salary because she has to look after public relationships and take important executive decisions for a large business and an important brand. True. Complaints about the pay rise should have been expected, so a high degree of scrutiny. The Council voted down a motion of the Court requesting more transparency. In authorising the pay rise in a period of protests about wages and trying to quench the formal protest at the University Council, some (let’s be clear not all) academics accepted the risk. This was a misjudgement, and now the University brand will pay the consequences. At the time I write, Dame Prof Breakwell will retire, after six months paid sabbatical and with a written-off loan: isn’t this moral hazard?

Are Vice Chancellors paid too much?

It is not that Vice Chancellors are paid a too high salary, but the problem is transparency, respect of the opinions of your employees and ‘customers’ (the students I suppose), respect for the brand one represents and, a better understanding of societal changes. I hope that other Vice-Chancellors will be proactive, not in cutting down their incomes (this is a different matter), but in understanding and shaping societal changes.

Universities have the moral duty to shape society not to be just the mirror of it. What some people might not appreciate is that the uncontrolled rise in executives compensation (in Industry) is causing damage to business three folds: by draining resources from investment to disproportionate personal wealth, by inducing short-sighted selfish behaviour with no incentive for long-term investment in assets and people, and bad publicity to industry creating a sense of complete disconnect, distrust and unethical behaviour that damage the brands they should promote. The latter point is often neglected, but it is very important. A chancing society and pressure groups, if neglected, can cause a lot of damage to a ‘brand’. This is not in Academia but in the world of Finance and Big Industries. Are we walking the same path now? Most people will say no, as compensation packages for academic governance are far from the excesses of USA corporations (true), but as I tried to say a few times by now, the issue is not necessarily the pay level, but the process and incentives in place.

Fully justify high salaries and adopt transparent decision processes, but also do not disregard the growing intolerance for inequality. Do not speak, in an abstract manner about the market, be specific. Moral hazard is part of the market, it is an unfruitful degeneration of it, which goes against the principles of free market economy. Most Academics and University employees dedicate their lives to improve society. Sometimes we are wrong, other times ineffective, but most of us, Vice-Chancellors included, are well-intentioned and passionate to make of the future UK, a competitive global and fair Nation. Therefore, do not let greed, or simply lack of due process, to damage our brand and collective efforts.

Was gender an issue?

There is another ‘inequality’ that bothers me: gender inequality. The top-level academic world is dominated by man. I am a white nearly middle-aged man, with the ambition to become a ‘fully-fledged’ academic. However, I cannot avoid noticing that women representation among academics is still low and it pains me that to get in the line-of-fire was a successful woman. I do not know statistics about Vice-Chancellors and gender-balance, but I did check the Russel Group. I count six female Vice-Chancellors and seventeen males, ~25% female representation, a figure we are too often familiar with. I am sure that all Universities are committed to improving, we feel very strongly about this at the University of Cambridge, but the historical heritage of male-dominated academia take a while to change.

The Guardian published another letter in support of Prof. Bakewell, this time signed by several female academics of the University of Bath, which start with “Being a successful woman seems to attract a disproportionate degree of negative criticism”. I am sure that this is true, but I should clarify that gender, for me, did not matter, and also for the articles and material I had the opportunity to read. The highest paid Vice-Chancellor in the UK was, by chance, a woman. HEFCE criticised procedures that were opaque, behaviours trenched in conflict of interest. When a woman raises at a position of power is, first and most importantly, laudable because being one of the best in their area irrespective of gender. Second, a woman in a position of power in a male-dominated environment is also laudable because of the many obstacles that women still experience in career progression, particularly at the top of the scale. However, people of power should accept the increased scrutiny and the responsibilities that come with the higher salaries they are paid, irrespective of gender and background.

Leadership for the future

My hope for the future is to see inequalities of all types to diminish and eventually disappear. I hope to see more women in academic governance. Irrespective of gender, I wish our leadership will keep fighting to improve the society we live in, fight against the profound inequalities we experience even in the United Kingdom, be this income or gender inequalities. I wished we trained the economists, the bankers and the lawyers that will reach the apex of various Industries to lead change. Because the only way we can defend a free market economy is to ensure that the right checks and balances are in place, monopolies are not created, packets of extraordinary wealth (corporate or individual) do not exist (otherwise they distort the dynamics of competition as much as a monopoly).

Let’s never say “it is the market that decides” because it is always people that decide, and it is ok if we follow due process.

What is life?

Preamble

In this assay, I describe reflections on biological systems and the nature of life. If you do not know it, the title is an obvious reference to the famous Schrodinger’s assay that motivated many physicists to create the branch of science that is Biophysics. In its current stage, these words are not written with the intent to be precise or complete, but to guide my own thoughts in the understanding – however superficial – of which are the general principles, opposite to specific molecular mechanisms, that drive biological processes and that are more likely to help us in the understanding of human physiology and pathological states. I will often express trivial observations from which, perhaps, less trivial considerations may be built upon.

From disorder to self

A living organism is an active chemical system, one that is constituted by an identifiable ensemble of molecules that manifest cooperative behaviour. For life to be observed, it has to be identifiable. As trivial as this observation is, identity is a founding character of the chemical systems we call life.

Life, as we know it, is based on the basic chemical unit that we call ‘cell’. The boundary of the cell is defined by lipids, amphipathic molecules that are made of a portion that likes water and another portion that does not. A basic characteristic of amphipathic molecules is their capability of spontaneous self-assembly. The polar, water-liking, head of lipids will try to contact water molecules, whilst the water-repelling tails will associate with each other trying to exclude water molecules, like oil in a glass of water.

Local reduction of disorder (or entropy as often we call it) is a feature of living systems. Reduction of entropy can occur only as consequence of irreversible chemical reactions that convert energy to order the local environment, like a person burning calories to tidy up their home, that in the process generate waste that they dump into the external environment. However, self-assembling systems are spontaneous and reversible processes that increase order at no entropic cost to the environment. The best example for this are colloidal suspensions. If large spheres are mixed with smaller spheres, large spheres will start to organize in ordered structures. In fact, around the large sphere, there is a volume of solvent that is inaccessible to the small sphere (because of steric hindrance). The entropy of a system of a mixture of large and small sphere is higher when there is a level of organization in the large spheres. Another example of such process is the spontaneous ordering of polymers. Even without amphipathic properties, there are molecules such as polymers that can interfere with the internal bonding of water (water molecules like each other) and are therefore driven into ordered structures. The net effect of this process, driven by so called entropic forces, is to maximize the entropy overall, primarily increasing the entropy of the solvent by maximizing the number of states available to water molecules; at the same time, polymers or other macromolecules are driven into ordered, low entropy, structures.

Therefore, given the right conditions of solvent and molecules, a spontaneous process of self-organization will drive compartmentalization of chemical systems. It is very important to stress that one of the first fundamental steps that initiate life, i.e. establishing an identity through a boundary between the self and the environment, is a thermodynamically favoured process that occurs at no entropic cost to the environment. This step results in the maximization of the internal entropy but, counter-intuitively at first impression, generates order and define a self at the same time.

Such compartmentalized systems do give raise to special environments where chemical reactions can occur at high efficiencies. Furthermore, the constant supply of energy provided by the sun, can readily start catalysis in these compartmentalized systems and drive these systems far from the equilibrium. Of the many compartmentalized systems that can naturally and spontaneously occur, however, only those that will be stable in time will be able to evolve into nowadays ‘living systems’.

From transient to stable

What we call a living cell requires the preservation of its own identity for long enough to give birth to life as we recognize it—a living organism must exhibits mechanisms to ensure its own integrity over time: the integrity of its boundary and the integrity of an active internal chemical system. Both require the existence of favourable conditions such as suitable operational windows of temperature, pressure, pH, etc. All systems incapable of maintaining integrity within a range of conditions that may occur in time extinguish themselves as soon as environmental factors change even slightly. It appears, therefore, that the maintenance of integrity over time necessitate that a primordial biochemical system exhibits some sort of “thermodynamic resilience”, i.e. its chemistry can operate and its identity maintained in face of environmental challenges. We can easily postulate that any primordial biochemical system was simple in nature and manifested comparatively little resilience to environmental changes. Reversible processes of self-organization would be constantly counter-acted by more energetic stochastic events inducing a relentless process of creation and destruction of such thermodynamic systems. Natural selection forged life from the very beginning, enabling only those systems capable of increased “thermodynamic resilience” to survive.

There is experimental evidence that simple self-assembling systems such as lipid vesicles can grow by uptake of other lipids from the environment and trigger fission in smaller vesicles spontaneously. The propensity to fusion and fission events of the early proto-cell may have represented both a challenge and an opportunity to the evolution towards an early system. Fission and fusion can be seen as a challenge to thermodynamic resilience as the identity and composition of this proto-cell is extinguished when fusion and fission occurs unregulated. At the same time, simple mechanisms that would minimize fusion and regulate fission, for instance specific composition of proto-cellular membranes, under the empowering thrust of natural selection would lead to the emergence of a ‘replicator phenotype’. This replicator phenotype could be thermodynamically favoured in specific environmental conditions and, hypothetically, better supported by simple internal chemistry that would favour a stable process of fission.

During this phase, inheritance of characters could be only of one kind, structural inheritance. Composition of amphipathic chains of specific types may favour self-assembly with other chains of the same type and stochastically divide into multiple “daughter” entities that constituted by the same elements, different ever so slightly by chance, would be still favouring the same self-assembly processing to occur, but randomly accommodating variation in the composition of the boundary and inner content. At the same time, irreversible reactions stabilizing this process may emerge by increasing efficiency in the utilization of energy to maintain structural integrity.

Once that the cycle of relentless creation and destruction is replaced by a cycle of relentless replication, natural selection will favour the optimal “thermodynamic resilience” for a given environment.

From random to self-governed

In face of environmental changes a primordial system to survive into a life form will require adaptation of its active chemistry supporting different chemistry active on different operational windows. Gains in thermodynamic resilience may occur by: i) stabilizing thermodynamic variables (e.g., temperature, pressure, volume) within optimal windows (homeostasis), ii) migrating to a different environment (taxis) or iii) adapting the internal chemistry to the different conditions (through evolution or, on shorter time scales, by allostasis).

Homeostasis is defined as the capability of a system to maintain certain parameters nearly constant. For instance, the human body is kept at around 37°C where cell biochemistry operates optimally. Homeostasis is the incarnation of thermodynamic resilience, where this is ensured by an active process of self-government, another founding property of life. There are many different terms to define this property of biological systems (e.g., homeorhesis and allostasis), but homeostasis is the one encompassing all of them. For instance, allostasis is the process by which a system maintain its homeostasis through a change. Let’s consider a simple biochemical system where its internal chemistry depends on pH. In order to be thermodynamically resilient, this system will require the capability to buffer pH either by chemical composition or by utilizing regulated proton pumps that will ensure a stable pH. However, when these mechanisms are insufficient to guarantee pH stability, a system can shut down those internal machineries that generate variations of pH as a by-product. A partial loss of efficiency (read as fitness) in such a system will however guarantee maintenance of other fundamental reactions and, therefore, overall fitness.

Another possibility is to engage in taxis, the active movement towards a more permissive environment, for instance searching for those conditions of nutrients, temperature, pH, etcetera where a system operates optimally. Taxis is another property shared by all animate being. Either plants trough growth, or other organisms through migration, all organisms are capable to sense the environment and trigger movements to seek for their optimal environment where their metabolism will operate more efficiently. For instance, a plant will adapt its growth to seek for sunlight, bacteria sense gradients of chemicals to find food and higher organisms migrates to places where abundance of food and water, and environmental conditions are suitable for them.

Homeostasis and taxis are manifestations of self-government that can be established only once that a biochemical system acquires the capability to process information from its internal and the external environments to execute specific actions to ensure thermodynamic resilience.

Conclusive remarks

I am no expert in any of the topic I discussed here. However, I have the impression that thermodynamics aspects of life are often far too emphasized. The question is not if life contradicts the second law of thermodynamics (it does not), the question is how much the second law can teach us about living beings. Often, a connection with entropy, its evolution towards higher values, is seen as a necessary link to justify the spontaneous occurrence of life. Even if this was true, does it matter, if a much simpler justification is available in the process of natural selection as a fundamental law of Nature? And even if natural selection could be justified with a thermodynamics description, would this help us to understand life, or to resolve the many afflictions that living beings are cursed with?

I firmly believe that research in thermodynamics of self-assembly systems and the role of entropic forces in biology are essential to a better understanding of life. However, the question about why life has evolved and if this conflicts with thermodynamics has been already addressed. It seems, sometimes, there is a conflict between the laws of physics and biological mechanisms, but – of course – there is none. Life is a complex phenomenon, the emergent property of a highly compartmentalized ensemble of chemically active molecules that abide (again, obviously) the basic laws of physics, but which description as a system, may not be properly described by thermodynamics. This is why systems biology is branch of biophysics that was born for this purpose exactly.

The most elemental aspects of life are identity as an active biochemical system (i.e., its compartmentalized metabolism), its capability to maintain integrity (i.e., its homeostasis, its capability to replicate) in face of environmental pressures and to be autonomous (i.e., the capability to process information and undertake decision).

For those of us working on a disease such as cancer, it is thus unsurprising that cancer is intimately linked to deregulation of all of these fundamental characteristics of life.

References

I’ve written this assay in different periods reading literature beyond the scope of my own research. Therefore, I cannot reference my text properly, but these are the material I’ve read and may be of interest to you.

Devies et al. (2013) “Self-organization and entropy reduction in a living cell” Biosystems

Spanner (1953) “Biological systems and the principle of minimum entropy production” Nature

Prigogine (1971) “Biological order, structure and instabilities” Quarterly Reviews of Biophysics

England (2015) “Dissipative adaptation in driven self-assembly” Nature Nanotechnology

Frenkel (2014) “Order through entropy” Nature Materials

Schrodinger (1944) “What is life?

Yodh et al. (2001) “Entropically driven self-assembly and interaction in suspension” Phil. Trans. R. Soc. Lond. A

Bray (1990) “lntracellular Signalling as a Parallel Distributed Process” J Theor Biol

Bray (1995) “Protein molecules as computational elements in living cells” Nature

Bray (2003) “Molecular Networks: The Top-Down View” Science

Mc Ewen and Wingfield (2003) “The concept of allostasis in biology and biomedicine” Hormones and Behaviour

Ray and Phoha “Homeostasis and Homeorhesis: Sustaining Order and Normalcy in Human-engineered Complex Systems

Sterling “Principles of allostasis: optimal design, predictive regulation, pathophysiology and rational therapeutics” in “Allostasis, Homeostasis, and the Costs of Adaptation” by J. Schulkin

Berclaz et al. (2001) “Growth and Transformation of Vesicles Studied by Ferritin Labeling and Cryotransmission Electron Microscopy” J Phys Chem B

Markvoort et al. (2007) “Lipid-Based Mechanisms for Vesicle Fission” J Phys Chem B

Mostafavi et al. (2016) “Entropic forces drive self-organization and membrane fusion by SNARE proteins” PNAS

Stachoviak et al. (2013) “A cost–benefit analysis of the physical mechanisms of membrane curvature” Nature Cell Biology

Although I never found the time to read it, the following book seems to cover exactly the topics I discussed. Having browsed through its pages now and then, it is likely I have been influenced by it:
Radu Popa “Between necessity and probability: searching for the definition and origin of life