A piece of the puzzle

Among the most devastating human diseases is a group of rare genetic disorders called lysosomal storage disorders (LSDs). They are so rare, in fact, that charities and patient advocate groups representing these different diseases have come together to form a collaborative to improve treatments. LSDs are caused by inactivating mutations in proteins that normally contribute to the maintenance of a cell’s health.

Animal cells have multiple ways of dealing with old and defective cellular components, one of which is the so-called autophagy pathway. In this pathway (see the schematic below), a specialised organelle called the autophagosome engulfs old proteins and even whole organelles, including mitochondria. The autophagosome then fuses with other organelles called lysosomes. Lysosomes are acidic compartments containing enzymes that degrade macro-molecules, including proteins, lipids, and complex sugars. Once the macro-molecules are degraded, their component parts can be exported and recycled.

The faulty proteins that cause LSDs are usually lysosomal enzymes. Consequently, the unifying feature of these diseases is that cells in a patient’s body heap up the cellular “rubbish” that should be degraded by the lysosomes. The lysosomes also grow larger and more numerous. [For a recent review on LSDs, see Parenti et al, 2021.]

Fucosidosis is a specific LSD caused by inactivating mutations in the gene FUCA1, which encodes the lysosomal enzyme α-L-fucosidase 1 (FUCA1). FUCA1 is necessary for breaking down complex sugars by cleaving off a sugar molecule called fucose from larger macro-molecules, including proteins and lipids. Fewer than 150 cases of fucosidosis have been described in the biomedical literature (see Stepien et al, 2020). However, patients with homozygous FUCA1 mutations generally die of their disease, and its secondary complications, by the age of 30. The main symptoms are decreased mobility as well as developmental and neurological abnormalities; this is thought to be because nerve cells are particularly dependent on the degradation of proteins and organelles by lysosomes. Before our new open-access study there was only a limited amount of research on fucosidosis, so there were many questions about how the inactivation of FUCA1 leads to the disease.

A former post-doc in our lab at the CRUK Beatson Institute, Alice Baudot, started this work on fucosidosis because the lab has an interest in the autophagy pathway, and especially in its roles during cancer development. However, as so often is the case, the research led away from the initial question and Alice developed a new mouse model of fucosidosis.

Overview of autophagy: without the degradative enzyme FUCA1 the process stalls at multiple points (red crosses), including autophagosome-lysosome fusion, lysosomal degradation and recycling, as well as overall autophagic flux. Image created using the free version of BioRender.

Alice first observed what happens to mice lacking the FUCA1 protein. She found that both male and female mice without FUCA1 started showing signs of motor and neurological deficiencies during adulthood, and they did not survive as long as wild-type control mice. Examination of tissues from the FUCA1 knockout mice revealed that cells in multiple organs (including the brain, liver, pancreas and kidney) had accumulated large lysosomes – a process called vacuolation – and that these organs were less healthy than wild-type organs. The livers of FUCA1 knockout mice were also bigger than those of wild-type mice; this is a feature that has also been observed in some fucosidosis patients. Furthermore, when I studied the tissues from these mice, I noticed that they had accumulated mitochondria in various regions of the brain, suggesting that they were not being cleared by autophagy.

Following this examination of the mouse phenotype, Alice started conducting experiments on cells from these mice, either with or without the FUCA1 protein. It became clear quickly that the FUCA1 knockout cells had abnormal levels of various proteins involved in autophagy.

Following on from Alice’s experiments I tried to identify in more detail exactly how FUCA1 loss was affecting the autophagy pathway. We found that, although it looked like the autophagy process had gone into overdrive in the knockout cells, autophagy was actually stalling. Instead of going through the five-step process depicted in the schematic above, the whole procedure was stuck at various points. Maybe unsurprisingly, the lysosomes themselves were less able to digest proteins and sugars. Alice found that FUCA1 was needed to control other digestive enzymes, so that losing FUCA1 led to a domino effect of faulty enzymes in the lysosomes. The build-up of cellular components in the lysosomes caused a backlog in autophagy, thus slowing down the flux of autophagy cargo to the lysosomes.

Interestingly, I identified a specific step in the process that was going wrong, namely the fusion of autophagosomes with lysosomes (step 3 in the schematic above). The figure below shows a fluorescent microscopy image of a FUCA1 wild-type mouse cell (left): the lysosome is labelled in green (Lamp2 protein) and you can see that the autophagosome in purple (LC3 protein) is physically inside the lysosome, indicating successful autophagosome-lysosome fusion. In the FUCA1 knockout cell (right) the lysosome and autophagosome are next to each other and not fusing. I analysed a number of both wild-type and knockout cells and observed this pattern over and over again. Somehow – although we did not figure out exactly how – losing FUCA1 interferes with this fusion process, contributing to the overall abnormalities of autophagy.

Zooming in on a FUCA1 wild-type mouse cell: green protein represents a lysosome after fusing with the autophagosome labelled in purple. The histogram shows how the purple protein is inside the lysosome.
Copied from Baudot & Wang et al, 2022, Fig. S5
Zooming in on a FUCA1 knockout mouse cell: green protein represents a lysosome located next to an autophagosome labelled in purple; they haven’t fused. The histogram shows them as separate organelles.
Copied from Baudot & Wang et al, 2022, Fig. S5

One avenue of work that could be explored next is to find out whether treating the fucosidosis cells/mice with certain drugs could “force” or improve the flux of cargo through the autophagy pathway. This may alleviate some of the toxicity resulting from the build-up of cellular material. However, one major difficulty in treating this disease is that it affects all cells of the body to some extent, and therefore the drugs would need to reach all of them, and especially the cells in the brain. Although this kind of basic/discovery research will not, in the near future, lead to new treatment options for patients I think Alice and I have contributed a small piece to the puzzle of why fucosidosis is such a devastating disease.

References:
Baudot Alice D.*, Wang Victoria M.-Y.*, Leach Josh D., O’Prey Jim, Long Jaclyn S., Paulus-Hock Viola, Lilla Sergio, et al. ‘Glycan Degradation Promotes Macroautophagy’. Proceedings of the National Academy of Sciences 119, no. 26 (28 June 2022): e2111506119. https://doi.org/10.1073/pnas.2111506119.
Parenti G, Medina DL, Ballabio A. The rapidly evolving view of lysosomal storage diseases. EMBO Molecular Medicine 13, no. 2 (5 Feb 2021):e12836. https://10.15252/emmm.202012836
Stepien KM, Ciara E, Jezela-Stanek A. ‘Fucosidosis—Clinical Manifestation, Long-Term Outcomes, and Genetic Profile—Review and Case Series’. Genes 11, no. 11 (2020). https://doi.org/10.3390/genes11111383.

Philosophy IN biology & medicine, in Bordeaux

Last week I had the good fortune of taking part in a four-day workshop called “Philosophy in biology and medicine” as part of the University of Bordeaux summer schools. The workshop was organised by the PhilInBioMed network, which was founded five years ago.

Cathedral of Bordeaux – classes were held in a building just behind.

The practice of philosophy in science (PinS) can be contrasted to the more traditional approach of philosophy of science, which is what most philosophy departments teach. One way of looking at the distinction is to imagine philosophy of science as taking scientific practice as a philosophical subject and asking questions like, How do the sciences enable us to learn and know about the world? What roles do models play in science? Does science make progress over time? Does science aim at truth? What is the importance of team work in science? What roles, if any, do values play in science? And so forth. In contrast, PinS aims to contribute to scientific knowledge by fostering collaborations between philosophers and scientists. PinS “appropriates” the tools and knowledge of trained philosophers to shed light on tricky questions in the sciences. For example, two of the course leaders at the workshop were Thomas Pradeu and Lucie Laplane who have worked on the self/non-self distinction in immunology and the categorisation of cancer stem cells, respectively. The idea is not only that these philosophers, who sometimes also have formal training in biology, apply philosophical tools to the scientific question at hand, but – in the best case scenario – contribute to scientific advancement. In the case of Lucie Laplane’s work, for example, a better understanding of what cancer stem cells are – are they fixed entities in a given tumour or is “stemness” a property of the tumour as a whole? – could lead to better treatment options. In particular, it might change the strategies with which scientists/doctors approach cancer treatment.

Now, this might sound a bit dry when viewed from the outside, but don’t forget that all of this was happening in the southwest of France and instead of boring sandwiches we were provided with glass-bottled salads for lunch, and macarons and cannelés during the afternoon coffee breaks:

Assorted macarons and cannelés, a specialty of Bordeaux.

The workshop’s 36 participants came from all over the world, some were master’s students, most were PhD students, and a few were post-docs. About two thirds of the participants had a more philosophical background, with the other third being biologists/doctors with an interest in philosophy.

The workshop itself had a packed schedule consisting of various types of activities: we had lectures from some of the course leaders and active philosophers of/in science, including Thomas Pradeu, Maël Lemoine, Lucie Laplane, Angela Potochnik and Elliott Sober. They mainly tried to give a mixture of practical advice to aspiring “PinSers” and talked us through some of their collaborative work. As a counterpoint we also heard from some of the scientists with whom the philosophers had worked.

One of the main take-home messages was that this kind of collaboration can be difficult, in part, because philosophers and scientists sometimes “speak different languages” (e.g. the same word can have very different meanings in the two disciplines). To overcome this difficulty the course leaders emphasised that this work can take time, but is often ultimately rewarding. Related to this, all of the speakers stressed the importance of cultivating strong interpersonal relationships: both in general because collaborations can’t get off the ground if there isn’t some basic understanding between collaborators, and in particular because interdisciplinary work requires higher levels of interpersonal trust compared to non-interdisciplinary work. Since the specialised scientist will probably never be at the philosophical level of the philosopher and vice versa, being able to trust your collaborator is key. Importantly, you need to be able to trust your collaborator at the knowledge-related (epistemic) level as well as the moral level, trusting that your counterpart is both truthful and competent (see, for example, Andersen & Wagenknecht, 2013).

We also had the opportunity to do some slightly stressful speed dating with the course leaders: five-minute chats to introduce ourselves to each other and to establish whether we wanted to seek out further conversations with each other. Lastly, the whole workshop was organised around a small group project: all participants were sorted into one of six groups for the duration of the workshop with an assigned group leader and theme. (My group ended up working on the question of whether cancer is (self-)organising.) This exercise was meant to introduce us to the PinS approach in practice: we had a zoom meeting with a cancer scientist, read some literature, discussed a scientific question we might be interested in addressing, speculated about how answering this question might advance science, and came up with a short presentation.

I think the workshop had two aims: first, to introduce young/early-career researchers to PinS, and second, to start forming a community of people who might promote this kind of work. The course organisers certainly succeeded in their first aim; only time will tell whether they achieve their second aim too. One resource that will hopefully emerge from the workshop is a list of science and philosophy journals that are interested in this sort of collaborative work. Personally, it’s been great to experience what doing philosophy in science might look like although I’m not convinced that that’s the kind of philosophy I want to do if I decide to pursue more philosophy after the MA in philosophy (of science).

Lastly, on one of the evenings we went to a wine bar. They had wine vending machines; what more can I say. It was a great week.

Wine vending machine at aux quatre coins du vin…

References:
Andersen, Hanne, Wagenknecht, Susann. 2013. Epistemic dependence in interdisciplinary groups. Synthese 190, 1881–1898. https://doi.org/10.1007/s11229-012-0172-1.
Laplane, Lucie. 2016. Cancer Stem Cells: Philosophy and Therapies. Cambridge, Massachusetts, USA: Harvard University Press.
Laplane, Lucie, and Eric Solary. 2019. ‘Towards a Classification of Stem Cells’. ELife 8 (March): e46563. https://doi.org/10.7554/eLife.46563.
Pradeu, Thomas. 2012. The Limits of the Self: Immunology and Biological Identity. Translated by Elizabeth Vitanza. Oxford University Press.
Wagenknecht, Susann. 2015. Facing the Incompleteness of Epistemic Trust: Managing Dependence in Scientific Practice, Social Epistemology29:2, 160-184, DOI: 10.1080/02691728.2013.794872

Cancer stem cells in pancreatic cancer

Since I neglected this blog somewhat towards the end of my PhD, I completely failed to write up a short report on the findings from my research! I will try to rectify this now by giving a brief overview of the results.

Rute Ferreira, who started this project, and I, together with our wonderful co-authors and collaborators published our paper at the end of 2019. Rute initially set out to answer the question why some cells in the ducts of the pancreas are more likely to grow into tumours when they contain a genetic mutation in the Kras gene than other cells containing the same mutation. We thought that this question was important because patients with pancreatic ductal carcinoma (PDAC), the most common form of pancreatic cancer, face a poor prognosis, with only a little over 5% of patients in England surviving for longer than five years after diagnosis. We hypothesised that if we could figure out what made some of these pancreatic cells cancerous at the very beginning of the cancer, we might find clues about what makes PDAC such an aggressive cancer later on.

In our mouse models of pancreatic cancer, Rute found that those pancreatic ductal cells that did start becoming cancerous – those cells that became “transformed” – expressed higher levels of a protein called CD9 compared to cells that remained indolent. CD9 is a membrane protein in the tetraspanin family – its crystal structure was solved in 2020 but we knew from other members of this family roughly what the protein would look like. In the representation below, the four cone-like helices in dark red, light green, turquoise and blue represent the four parts of the protein that span the cell membrane, whereas the orange and khaki parts face the outside of the cell.

The crystal structure of human CD9 from the Protein Data Bank – published by Umeda et al., 2020 under CC BY 4.0 license.

Rute then noticed that cells expressing high levels of CD9 were relatively rare – only about 5% of all cancer cells – in full-blown PDAC tumours. At the time we were doing this research our lab had an interest in the so-called cancer stem cell (CSC) hypothesis. This hypothesis states that CSCs make up a rare subpopulation of cancer cells in a given tumour, but that these CSCs have certain special properties: being able to self-renew (generate more CSCs) and being able to differentiate into other cancer cells that are no longer CSCs. This concept was first proposed by Reya et al. (2001). The idea is that CSCs sit, metaphorically, at the top of a hierarchy of cancer cells and that these CSCs can basically re-grow new tumours as long as they are not eradicated. Many cancer treatments, Reya et al. argued, are good at “debulking” tumours (i.e. killing the non-CSCs) but do not kill CSCs, and these CSCs then become responsible for tumour relapse.

We therefore investigated whether the CD9-high cells could indeed act as CSCs in PDAC. Rute and I compared the growth of CD9-high versus CD9-low cells in a number of different experiments. We observed that CD9-high cells grew into more and bigger organoids when we grew them in Petri dishes, and that the CD9-high cells also grew bigger tumours in mice. Interestingly, the tumours that grew from CD9-high cells were not only bigger than the ones that grew from CD9-low cells, but the tumours looked histologically, at the microscopic level, much more like the original tumours the cells had come from. This finding suggested to us that CD9-high cells can indeed give rise to tumours that were as complex as the original tumours, similar to what we would expect if they were CSCs. The growth of these complex secondary PDACs is illustrated in the diagram below:

Schematic overview of how pancreatic cancer cells expressing high levels of CD9 in a tumour also exhibit altered metabolism compared to other cells in the tumour, and are then able to re-grow new tumours. Image copied directly from Wang et al., 2019 under CC BY 4.0 license.

Our next task was to investigate whether the protein CD9 was only acting as a marker of these CSCs, or whether CD9 itself played a part in making these cells behave as CSCs. To address this question I took mouse PDAC cells and experimentally either reduced or increased the levels CD9 in the cells. Cells with lower levels of CD9 grew fewer and smaller organoids in vitro, and smaller tumours when grown in mice. Conversely, PDAC cells with boosted levels of CD9 grew more and bigger organoids, and bigger tumours in mice. These results pointed towards the conclusion that the CD9 protein has some function(s) that contribute to the CSC behaviour of the cells expressing high levels of CD9.

Tetraspanins generally act as scaffolding proteins for other proteins. So to find out how CD9 makes CSCs so aggressive I performed, together with another PhD student at the time, Jorge Almagro, a series of biochemical experiments to discover which other proteins CD9 was physically interacting with in PDAC cells. Among the proteins CD9 interacted with were a number of proteins in the solute carrier family, whose function is to transport all sorts of metabolites into and out of cells. In particular, CD9 interacted with the proteins MCT1 and ASCT2, as shown in the diagram below. MCT1 can shuttle lactate across the cell membrane, whereas ASCT2 is best-known as a glutamine importer. CD9-high cells had higher levels of ASCT2 at the plasma membrane compared to CD9-low cells; deleting CD9 in organoids also removed ASCT2 from the membrane. We therefore concluded that CD9 stabilises ASCT2 at the plasma membrane.

Schematic overview of CD9 interacting with the metabolite transporters MCT1 and ASCT2 in the cell membrane. Image copied directly from Wang et al., 2019 under CC BY 4.0 license.

This conclusion led us to our next hypothesis: do CD9-high cells, via the interaction with ASCT2, import more glutamine and use this metabolite to fuel their aggressive stem cell-like behaviour? Together with Nathalie Legrave and James MacRae from the metabolomics facility at The Francis Crick Institute we tested this hypothesis. Among other things we found that PDAC cells lacking CD9 are unable to take up glutamine efficiently, correlating with their reduced growth as organoids. However, this organoid growth could be rescued, or increased again, when the cells lacking CD9 were either given extra glutamine or artificially high amounts of the protein ASCT2. Taken together, these experiments suggested that one of CD9’s function in PDAC is to facilitate the import of glutamine into CSCs.

Lastly, we wanted to gain some insight into whether these phenomena we were observing in mouse PDAC cells and models might also hold true in human PDAC. From previously published data we ascertained that PDAC patients with high expression of the CD9 gene survive, on average, for a shorter amount of time after their diagnosis compared to patients with lower CD9 expression. Moreover, together with Theo Evan, who was a clinical fellow in our lab, we managed to repeat the CD9-high versus CD9-low organoid experiments using human PDAC cells that we obtained from surgeries. Using the human cells we also saw that CD9-high cells formed more and larger organoids compared to the CD9-low cells. Overall, this last set of experiments hinted to us that CD9-high cells in human PDAC might also be acting as CSCs and might therefore be a worthwhile target in these tumours. However, much more work would be needed to find out whether these findings could eventually be harnessed into new treatment options for patients.

Alongside our article, Nature Cell Biology also published a News & Views article, almost certainly written by one of the peer reviewers of the paper. If you haven’t had enough yet and/or would like more clarification, please check out their summary here.

Lastly, I want to note that the idea of cancer stem cells is not only interesting from a biological but also from a philosophical point of view. Are CSCs “fixed”? Are they always the same cells? If CSCs are depleted, can non-CSCs somehow give rise to CSCs? Are the properties of CSCs intrinsic to certain cells or do these properties belong to a tumour as a whole system? Lucie Laplane has written an interesting book addressing these questions; but this topic will have to await a different blog post.

References:
Laplane, L. Cancer Stem Cells: Philosophy and Therapies (2016). Harvard University Press.

Reya, T., Morrison, S., Clarke, M. et al. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001). https://doi.org/10.1038/35102167

Umeda, R., Satouh, Y., Takemoto, M. et al. Structural insights into tetraspanin CD9 function. Nature Communications 11, 1606 (2020). https://doi.org/10.1038/s41467-020-15459-7

Wang, V.MY.*, Ferreira, R.M.M.*, Almagro, J. et al. CD9 identifies pancreatic cancer stem cells and modulates glutamine metabolism to fuel tumour growth. Nature Cell Biology 21, 1425–1435 (2019). https://doi.org/10.1038/s41556-019-0407-1

Zhu, X.G., Birsoy, K. Deciphering cellular heterogeneity of pancreatic tumours. Nature Cell Biology 21, 1305–1306 (2019). https://doi.org/10.1038/s41556-019-0419-x

On giving up cancer research (for now), and beginning again

I recently decided – after months and months of indecision, internal as well as external arguments and a few psychotherapy sessions – to leave my job as a post-doctoral cancer researcher, to give up the associated prestigious fellowship, and to move to Toronto to study philosophy of science. The purposes of writing about this are two-fold: firstly, and self-servingly, to help me find some closure about this choice; secondly, to put this sort of life decision in the context of some philosophical literature on well-being and the search for meaning in life.

This was the context of my decision. I had moved to Glasgow from London three days before the first COVID-19 lockdown in March 2020 to start a job as a post-doctoral researcher at the Cancer Research UK Beatson Institute. I spent the first two months working from home and applying to the Wellcome Trust for a fellowship. Eventually, initially in six-hour shifts, I started coming to the lab to begin setting up experiments and initiate collaborations. By the end of 2020 I felt I hadn’t achieved much in terms of experimental results, but I had gone through two rounds of assessment of my research proposal and been awarded the fellowship. Psychologically this meant I could put the past nine months behind me and focus on the next four years of funding. But my motivation did not nearly match the monetary value or the prestige of the award, or the security it provided. It’s not my intention to blame particular people, including myself, for this lack of motivation. I’m also not claiming that this situation was unique; I’m sure many others, inside and outside academia, have been experiencing similar things during the pandemic. The atmosphere in the lab and wider institute was dominated by low mood, lethargy, and irritation, presumably because of general anxiety about living in a pandemic as well as the public health measures, which, for many good reasons, restricted certain scientific practices that lead to productive engagement (e.g. frequent coffee breaks and animated discussions at scientific presentations). After another nine months of trying to be patient with myself and waiting for the external situation to improve, I couldn’t or wouldn’t take it any longer.

While I was wrestling with the question of whether or not to leave my research post, and also when I had made the decision and was telling people about this decision, I noticed the following. The conversations with family, friends, colleagues, and collaborators and their reactions about whether or not to leave my job, and what to do instead, came in three flavours:

a. Overwhelmingly, people told me “to do what makes me happy”.
b. Fewer people, but still a substantial minority, told me “to do what I want to do”.
c. Very few people, maybe two or three, said that I need “to do what’s right for me”.

What do these reactions show about my decision? What do they say about my relationships to the people I discussed it with? Can we learn anything about the connections between what to do in life and happiness and/or meaning?

The first thing I noticed was people’s genuine concern for my welfare, which I was glad about. I had been afraid people would reproach me for giving up early, that they might find me weak for not seeing the fellowship through to the end, that they might blame me for wasting my potential and/or the funding. Instead of these reactions, my friends and colleagues expressed their sympathy. It turned out that a lot of the obligations I felt to keep going – especially to keep this fellowship, which was a privilege to have been awarded – came from within myself.

The second thing that crossed my mind was whether, to some extent, by focussing on my happiness and my desires, the people around me were extricating themselves from responsibilities they may have had towards me and our shared relationships. Singling out the peculiarities of my life seemed to highlight the atomistic nature of our lives while at the same time obscuring the close links between our lives. I suspect that happiness and meaning in a given life are more strongly coupled to other lives than we realise or admit day-to-day, but I won’t go into this any further here.

The third thing I noted was how many people seem to hold “happiness” in very high regard. I want to understand what this means. When people said to me, “you should do what makes you happy”, this was often followed by, “you should do something you will enjoy”. Is “happiness” in this colloquial sense the same thing as “pleasure”, or something more than “just” pleasure? At a rather naïve level, I interpret this combination of expressions to mean, “you should do something you find pleasant or pleasurable”. On the one hand, I agree with the implicit assumption of this searching-for-pleasure attitude, which is that experiencing unpleasant things, or being unhappy in a broad sense, is to be avoided. And I was often unhappy – bored, frustrated, unstimulated – doing this job. On the other hand, while I think it’s nice to experience pleasant things, or be happy in a broad sense, I don’t tend to make pleasure or happiness my aims.

It will help here to bring in some philosophical classifications of well-being, or theories about “what makes someone’s life go best” (Parfit 1984: appendix I). The moral philosopher Derek Parfit addressed this question in an influential appendix of his 1984 book Reasons and Persons. Importantly, “well-being” as a philosophical term has a broader meaning than in everyday English, where it is often primarily associated with good health. Parfit described three basic theories of well-being:

A. According to hedonistic theories, increasing the amount of pleasure and decreasing the amount of pain in your life is what makes your life go best. In other words, pleasure is the only value worth considering when thinking about your well-being. These theories are entirely experiential, i.e. the extent of your well-being just is how pleasurable your life feels.

B. According to desire- or preference-fulfilment theories, your life goes best when as many of your desires or preferences as possible are fulfilled, even if this would not increase your pleasure. For example, although giving up your seat on a long bus ride for an elderly person would decrease your comfort and pleasure, this act would increase your well-being if you had wanted to give up your seat. Similarly, on these theories, if you wanted to avoid stepping on the cracks in the pavement, avoiding to do so would increase your well-being.

C. According to objective list theories, there are a number of different, objectively valuable elements that can contribute to your well-being. Examples could include pleasure, creating and maintaining loving relationships, knowledge, significant achievements, and living a morally good life. These elements can contribute to your well-being without being pleasurable and/or without you desiring them.

I assume that most of my friends and colleagues are not explicitly aware of these three theories of well-being, and yet it struck me how neatly the first two of their responses to my career quandary seemed to fit into the first two of these theories. Does it follow that people who told me “to do what makes me happy” are simply hedonists? That those who told me “to do what I want” are desire-fulfillers? Or are they actually trying to say something else? I will have to ask them to find out.

The main difference between hedonistic and desire-fulfilment theories, on the one hand, and objective list theories on the other, is that the former rely entirely on what the person whose well-being is in question feels or wants, whereas the latter go beyond that to ask what might be valuable in a life independent of how something feels or whether it is desired. An appeal to objective list theories raises several questions: are there such objectively valuable elements? If so, what elements should be on this list? Is the list the same for everyone? And linked to these questions: what is the relation between well-being and objective value and meaning in one’s life? Where does this leave the third response of doing “what’s right for me”?

These are old questions in philosophy, and I don’t expect to come up with new answers. What I will do instead is highlight one aspect of this debate – whether the objective list would look the same for everyone – that has come to my attention via three philosophers: Joseph Raz, Thomas Scanlon, and Susan Wolf. (Undoubtedly, many others have thought and written about this too, but I’m a baby philosopher and have only read so much.)

Let’s assume, with Raz, Scanlon, and Wolf, that there is indeed some objective value in the world and that there are valuable things for us to do. This means that their accounts of a person’s well-being go beyond the purely experiential hedonistic and desire-fulfilment theories. Although all three of these philosophers may be biased in their own assessments towards intellectual pursuits and achievements as items on an objective list, they recognise that there is a plurality of value. Given this large range of valuable ways in which we could be spending our time, they argue, it follows that there are too many options for a single person to pursue during their lifetime. It’s simply not possible for each of us to do everything that is objectively valuable.

We have to whittle down our choices. It seems to me that this happens in a way that is both natural and largely influenced by our circumstances. Let’s say you grow up to be an athletic person; if you were born in Australia it’s unlikely you will turn into an alpine skier, and if you were born in Austria it’s unlikely you will become a surfer. Over time, people choose to shape their lives in certain ways within the constraints of their circumstances. According to one of Raz’s versions of an objective list theory, “One’s well-being […] depends in the main on the degree to which one succeeds in pursuing valuable relationships and projects which one adopted as one’s own” (Raz 2004: 277). In other words, once you have chosen to go down the route of a professional alpine skier, the fact that you are not also a professional surfer does not reduce your level of well-being.

Scanlon agrees with Raz that there are objectively valuable relationships and projects, but adds that “a maximally comprehensive [life] goal […] would be a conception of ‘how to live,’ but it would be misleading to call such a goal a conception of well-being” (Scanlon 1998: 130). For Scanlon the idea of well-being, especially from a person’s point of view, is only part of figuring out how to live. “From the point of view of someone deciding which comprehensive goal to adopt, it may be true that such a goal should be selected with the aim of finding the plan that will make for ‘the best life’. But what this term means here is the most choiceworthy life” (Scanlon 1998: 131). According to Scanlon “the best life” is not necessarily the one that maximises a person’s well-being, because there are some objective goods that are good above and beyond their contribution to someone’s success in their chosen aims, and hence their well-being. For example, the professional skier has to train hard and forego many pleasures and other worthwhile pursuits, maybe sacrificing time spent with family and friends. It’s possible for this skier to have had a life of higher well-being if they hadn’t become a skier, but their life as a skier might still have been the most valuable and therefore most choiceworthy.

Similarly to Raz and Scanlon, Susan Wolf advances the position that meaningfulness in one’s life constitutes an element of well-being. According to her, “meaningful lives are lives of active engagement in projects of worth” (Wolf 1997: 209). She thus, like Raz, connects well-being to projects that have some objective value. Wolf also posits that, “meaning arises when subjective attraction meets objective attractiveness” (Wolf 1997: 211). Here she emphasises that not all objectively attractive projects will be appealing to everyone.  

With this background in mind, I think that the response to do “what’s right for me (now)” can fit into the framework of an objective list theory of well-being. Doing “what’s right” acknowledges that there are right (and wrong) decisions when it comes to deciding about or shaping one’s career – there are many “projects of worth” but not all projects are valuable. This also holds for life choices more generally. For example, pursuing lab-based research and a career in science in itself is an objectively attractive choice. But doing “what’s right for me (now)” also leaves room for recognising that lab-based research might not be subjectively attractive to me here and now.

View from the CN Tower in Toronto

Instead, I am lucky enough to be able to choose to study philosophy (of science). Although I agree with Scanlon that living a good life is not reducible to living a life of high well-being, this decision will nonetheless hopefully contribute to my well-being in several ways, ways that might correspond to multiple elements of an objective list of well-being. First, gaining new knowledge, and knowledge of philosophy (of science) in particular, is an objective element of well-being that I am also subjectively attracted to. Second, the accompanying steep learning curve will hopefully, at least most of the time, be pleasurable to me. Although I’m not a hedonist, I do think that pleasure contributes to well-being. Third, philosophy is, among other things, an inquiry into how to live a good life; living a morally good life can also constitute an objective element of well-being. Finally, moving to a new city and meeting people will provide opportunities for forging new friendships and strengthening existing relationships. Building and maintaining strong interpersonal relationships would, I wager, feature on most people’s lists.

[The subject of well-being, and its relation to ethics, is huge in the philosophical literature; I’m hoping to explore some of these papers in more depth in future.]

A few references:
Hooker, Brad. 2015. ‘The Elements of Well-Being’, Journal of Practical Ethics, 3: 15-35.
Hurka, Thomas. 2021. ‘Against ‘Good for’/‘Well-Being’, for ‘Simply Good’’, The Philosophical Quarterly, 71: 803-22.
Parfit, Derek. 1984. Reasons and Persons (Oxford University Press: Oxford).
Raz, Joseph. 2004. ‘The Role of Well-Being’, Philosophical Perspectives, 18: 269-94.
Scanlon, Thomas. 1998. What We Owe to Each Other (Belknap Press of Harvard University Press).
Wolf, Susan. 1997. ‘Happiness and meaning: Two aspects of the good life’, Social Philosophy and Policy, 14: 207-25.
Wolf, Susan. 2010. Meaning in Life and Why It Matters (Princeton University Press).

A T(h)read Through 2020

This year April really was the cruelest month. The fear and uncertainty of the new situation gripping Europe and North America – let’s face it, our media does not report similar situations in other parts of the world with such urgency – decreased our already limited attention spans. I found I couldn’t settle into any book at the beginning of the pandemic despite (or maybe because of) being between jobs and having just moved to a new city (and technically a different nation). Doom-scrolling and skim-reading the news kept distracting me; asking how many new cases, how many new deaths. Eventually, as I got more used to the general feeling of uneasiness in the air, I got back into reading. Three of the books I read this year stood out to me and here I would like to give a flavour of each and of how I think they might be linked.

My year in three books: The Living Mountain by Nan Shepherd (1977), Potiki by Patricia Grace (1986), and The Structure of Scientific Revolutions by Thomas S. Kuhn (1962). [My own image.]

Nan Shepherd was born in Aberdeen in 1893 and also died in Scotland in 1981. She was a teacher and educator, wrote modernist novels and a collection of poetry. Shepherd started writing The Living Mountain in 1944 and finished it in the years following the Second World War. The book wasn’t published until 1977. The Living Mountain is just over one hundred pages long and almost impossible to classify: it is certainly non-fiction and it is first and foremost about the Cairngorm Mountains in the Scottish Highlands, pictured below. Beyond that it is part nature writing, hillwalking guide, memoir, philosophy.

Shepherd sought “to know its [the mountain’s] essential nature”:

To know, that is, with the knowledge that is a process of living. This is not done easily nor in an hour. It is a tale too slow for the impatience of our age, not of immediate enough import for its desperate problems.

The Living Mountain, page 1.

She goes on to describe the Cairngorm plateau – although it has individual peaks of over 3,000 feet known as Munros, these sit collectively higher than their surroundings – its recesses and waters (burns, streams, lochs, springs), its air and its lights. This was her home turf, her ‘house mountain’ as we say in German, where she spent an inordinate amount of time “merely to be with the mountain”. Shepherd then turns her attention to the plants and animals of this habitat, describing the majestic Golden Eagle with as much reverence as the heather and the “inconspicuous things that creep in heather”. She learns from her experiences and her time spent with the mountain, she knows about the (natural) history of the area and listens to her “scientist friends”, and comes to the following, simple conclusion:

The more one learns of this intricate interplay of soil, altitude, weather, and the living tissues of plant and insect (an intricacy that has its astonishing moments, as when sundew and butterwort eat the insects), the more the mystery deepens. Knowledge does not dispel mystery.

The Living Mountain, page 59.

Elsewhere she writes that “Knowing another is endless. […] The thing to be known grows with the knowing.” Both these statements ring true to me, maybe especially as a scientist. When you spend time looking at cells, studying them, experimenting on clumps of cells, yes, of course you learn more about them, but they remain mysterious, and you realise there is more you didn’t even know you didn’t know.

Importantly, Shepherd describes this living mountain from her subjective point of view, never pretending to be an objective or omniscient narrator, always situating herself “within” the mountain as a part of what makes it come alive. Although sparingly, humans feature too in this little book, and are portrayed in the same tone of voice as all the other constituent parts of the mountain. Shepherd interacts with tourists, crofters, farmers, their wives in much the same way she does with the granite, juniper, ptarmigan, and stag: respectfully, curiously, giving them the time they deserve. The focus of The Living Mountain is thus the mountain and its ecology, with human beings a part of this ecosystem.

The short novel Potiki by Māori writer Patricia Grace, published in 1986, tells a parallel story set in New Zealand: it is about a Māori community working together to keep their ancestral land – a shore land, “a neutral place – not land, not sea – there is freedom on the shore, and rest” – out of the hands of capitalists trying to turn their homes into a for-profit “development” (think amusement parks, water sports, clubs and restaurants, parking).

Potiki is a parallel story insofar as it has, at its core, the people of this Māori community and how they interact with each other and the natural world around them. Despite being set at the opposite end of the earth, the values the characters live out and embody are very similar to those reached by Shepherd: attention to one another, respect for their surroundings, over a prolonged period of time. Roimata, one of the narrators, partly sums this up:

At the same time we could not help but remember that land does not belong to people, but that people belong to the land.

Potiki, page 106.

Hemi, Roimata’s husband, expands her sentiment to people when, in the face of adversity, their family and community come closer together:

It was meant, everything was meant, and people hadn’t forgotten how to care. Much had been lost, but people hadn’t stopped knowing how to care for each other. It was good.

Potiki, page 57.

From an ethical point of view, then, both The Living Mountain and Potiki show us aspects of “the good”. They showcase how being attentive to and relating to the places and people in our surroundings, over one or multiple lifetimes, leads to living a “good life” (which is not the same as an easy life). Both books echo the Buddhist view that personal identity is first, not the most important thing about a person, rather it is one’s identity intertwining with other identities; and second, personal identity is not a fixed entity, but rather something that changes over time*.

This link to Ancient Eastern philosophy will now make the leap to The Structure of Scientific Revolutions by Thomas S. Kuhn, originally published in 1962, and very much rooted in “Western” traditions of science, history and philosophy, a large one. Kuhn, a physicist by training who subsequently became interested in the history and philosophy of science (primarily physics), postulated that scientific knowledge is not merely a steady accumulation of facts over time, one fact building neatly on top of a previously discovered fact. Instead, Kuhn argued, scientific development occurs “as a succession of tradition-bound periods punctuated by non-cumulative breaks”. Let me try to explain this.

Kuhn, borrowing ideas from historians of other human activities (e.g. music and literature), recognised and named the parts of the structure according to which, he claims, science advances. During periods of so-called “normal science”, which is governed by a certain “paradigm”, scientists are essentially puzzle-solving, trying to gather more data and facts that fit into this paradigm. At the time of a given paradigm, accepted by a field of scientists, the concepts, methods and open questions of this paradigm can be laid out in textbooks. Examples of such overarching paradigms include the pre-Copernican idea of the world in which the earth is the centre of the universe, or the idea that life as we know it came about as an act of creation by a deity. Kuhn goes on to argue that, working in such paradigms, scientists (or natural philosophers as they were called before the nineteenth century) will then start observing anomalies, i.e. facts that do not fit into or wouldn’t be predicted by the given paradigm. He says:

Novelty ordinarily emerges only for the man who, knowing with precision what he should expect, is able to recognize that something has gone wrong. Anomaly appears only against the background provided by the paradigm.

The Structure of Scientific Revolutions, page 65.

(As an aside: any scientists, and biologists in particular, reading this will wonder how it is possible, then, that approximately every second publication has found something “novel”. Kuhn would argue that almost everything we call “novel” isn’t.)

Once these anomalies accumulate and can no longer be ignored, scientists then articulate new and competing theories in order to replace the old paradigm. Note that this is rarely, if ever, a conscious process; scientists don’t sit down at their desks and think, “Today I will come up with a new paradigm.” Nevertheless, the science conducted after Copernicus, after Darwin was different; the scientists working in their wake saw the world in a different way. The paradigms had shifted; science had gone through revolutions. Importantly, Kuhn argues, the ways in which “normal science” are carried out before and after such revolutions are “incommensurable”. He means many things by this, including that some scientists working under the assumptions of the older paradigm will never be “converted” to the new one because they fail to see the world in light of the new paradigm; he also means that a lot of what had previously been established as fact under the old paradigm gets lost or is dismissed under the new paradigm. (The paradigm shifts brought about by Copernicus and Darwin are extreme examples of this, of course). If this view of scientific development is broadly correct, which I believe it is, then this means that science is not, as most people, lay people and scientists alike, think, a slow and steady accumulation of knowledge towards “the truth”. Rather, it is a relatively unstable construct, which, as the statue pictured below, could topple if newer, “better” hypotheses, theories and paradigms emerge that can explain the natural world more accurately.

The Paradigm statue designed by Conrad Shawcross in front of The Francis Crick Institute in King’s Cross, London. [Image from Wikimedia Commons.]

You might now be asking how I’m going to tie all of this together. Valid question. I read Structures first, in May, Potiki in October/November, and The Living Mountain in December. I didn’t think of them as connected until I decided to write about them. None of the three books preach and none of them are, on the face of it, about environmentalism, climate change or the climate crisis, but in one way or another they teach us about the preconditions and the tools we need to lessen and, where possible, reverse the impacts we humans are having on our environments, as a collective effort. Stretching the argument from Structure, one could say that the current paradigm for our interaction with the world is one of (late?) capitalism, globalisation, neoliberalism and individualism. Potiki and The Living Mountain clearly suggest alternative ways of living, which can be experimented with by each one of us. “Think global, act local”, a sentiment formulated by Patrick Geddes, a Scottish biologist and sociologist, over a hundred years ago, is another way of putting it. We can ask, what kind of shift is necessary to address the climate crisis and our alienation from one another (the two are clearly linked)? Nan Shepherd may have articulated part of the answer (note that you could love anything, not “just” a mountain; cells, for example):

So, simply to look on anything, such as a mountain, with the love that penetrates to its essence, is to widen the domain of being in the vastness of non-being. Man has no other reason for his existence.

The Living Mountain, page 102.

All three books touched parts of me that I somehow knew were there but aren’t often accessed: attention to the local (natural) world, to one’s community (whatever this might mean during a pandemic), attention to how I, or we as scientists, do things. Together, these books are giving me hope that things can be done differently, life lived differently, in better ways. Maybe more slowly, with more attention, kindness and, yes, love.


Acknowledgements. Despite being less able to meet with and talk to other people in person this year, many of the thoughts about these books didn’t come to me in isolation. Thank you to CF (who recommended Structure), MT, EK, PS and book club people (with whom I discussed Potiki) for all our conversations this year.


*I wish I had the determination, IQ and time to read and understand Derek Parfit on this subject, e.g. in his essay “Personal Identity” (1971) in the Philosophical Review and his 1984 book Reasons and Persons.


P.S.: Some of the books I am looking forward to reading in 2021 are: The Glasgow Effect by Ellie Harrison (2019), one of Virginia Woolf’s novels though I haven’t yet decided which, Winter by Ali Smith (2017), By Night in Chile by Roberto Bolaño (originally published in 2000).