Another tool in the fight against cancer

Cancer is many things, so one tool or technique cannot be used against all, but even so, it is good news every time a new tool has been discovered that can help fight some cancers.

From ScienceDaily: Light switch wakes sleeping cancer cells and makes them vulnerable again

Some cancer cells evade treatment by entering a dormant state triggered by stress hormones. ETH Zurich scientists have created a light-controlled molecular switch that selectively destroys the receptors responsible for this survival mode. In laboratory lung cancer cells, the approach woke sleeping tumor cells and could help make future cancer therapies more effective while minimizing damage to healthy tissue.

It sounds counterintuitive that you want the cancer cells to be active, but the ScienceDaily article explains it:

In certain forms of cancer, including some types of lung cancer, stress hormones can trigger this response. Specialized proteins called glucocorticoid receptors detect those hormones inside tumor cells. Once activated, the receptors can push the cells into a dormant state where cell division slows dramatically. As a result, many therapies become far less effective.

So, in other words, we can only fight them effectively when they are active.

The ScienceDaily article is based upon the paper Light-controlled disruption of cancer cell dormancy via photoswitchable stress hormone receptor degraders by Karina M. Freitag et al in PNAS.

I will freely admit that the actual paper is a bit above my biochemistry level, but the “significance” section is fairly understandable, especially combined with the ScienceDaily writeup

Stress hormone signaling through the glucocorticoid receptor (GR) induces a reversible, drug-tolerant dormancy state in cancer cells. However, systemic GR depletion is not viable due to its essential roles in non-pathological physiology. In this study, we developed light-responsive Proteolysis Targeting Chimeras (photoPROTACs) that enable reversible, wavelength-specific control of GR degradation. PhotoPROTACs featuring arylazopyrazole photoswitches showed potent, isomer-dependent GR degradation and high target specificity at nanomolar concentrations. In addition, transcriptomic profiling in lung cancer cells revealed that only the active isomer disrupts dormancy-associated gene networks, highlighting the potential of photoPROTACs to target GR-driven dormancy exclusively in cancerous tissue.

Barriers to reproducibility

I came across an interest research article in PLOS One:

What helps and hinders reproducible research? Researchers’ perspectives from a cross-disciplinary interview study by Magdalena Kozula et al.

Debates and policy initiatives addressing research reproducibility have expanded considerably in recent years. Yet, many of these measures remain generic and risk overlooking the lived realities of research practice. This study aims to explore researchers’ perspectives on the barriers, facilitators, and motivators that shape reproducible research across diverse fields and career stages, using qualitative methods. Semi-structured interviews were conducted with 60 researchers affiliated with universities and research institutions across the European Union and the United Kingdom. Participants were sampled to ensure diversity in discipline, career stage, gender, and geography.

As is set forth already in the abstract, there are five themes for barriers and facilitators influencing reproducibility:

  • navigating the research ecosystem – incentives and policies of institutions, journals, and funders
  • social and cultural dynamics as drivers and barriers – disciplinary norms, generational differences, competition, and collaboration
  • resourcing reproducibility – skills, infrastructure, guidelines and standards, time, funding, and awareness
  • inside the research process – field-specific constraints, methodological transparency, research material sharing, and external restrictions
  • personal commitment to shared responsibility – reflective motivations, pragmatic drivers, and perceptions of accountability

Looking at these themes it is hardly surprising that we are still facing reproducibility issues. As the abstract goes on to explain

Researchers described reproducibility as less of an individual choice but as a socially and institutionally mediated activity, dependent on enabling conditions such as supportive policies, adequate infrastructure, and equitable resource distribution. Reproducibility reform cannot rely solely on individual researcher commitment or one-size-fits-all policies. Effective interventions must account for disciplinary and methodological diversity, provide targeted resources and training, and realign incentive structures to reward transparency and rigour. These findings highlight reproducibility as a collective responsibility across the research ecosystem, requiring coordinated action by researchers, institutions, funders, and publishers. Promoting reproducible practices in this systemic, context-sensitive manner is essential for fostering a more credible, equitable, and sustainable scientific enterprise.

The scientific process is still the best way to find out things, but unfortunately, our current system rewards new findings over reproducing findings. New discoveries get papers in Science, Nature etc. while attempts at reproduction at best get a foot-note, unless they fail, and show some theory or discovery to be wrong. And even then, most of the time, they won’t get an paper, but at most a retraction of the original paper.

I work in the world of software development, where we have the concept of technical debt. This is stuff that we ought to do, or redo, but which we postpone until the costs and consequences of the “debt” is too high to ignore. It might be some complex piece of code, that really needs to be simplified, but which works – but every time anyone needs to change anything in it, something important breaks, and a lot of time needs to be spent on fixing it.

In my opinion reproducibility is the technical debt of the science fields. It can be ignored, until the costs are too high, and it turns out that the fundament a lot of work is based on, is deeply flawed.

One way of handling technical debt in software development, is to set aside a certain percentage of your time to go back and “pay” the debt. I.e. time where you actually revisit the issues and fix the problems instead of pushing it ahead in an ever increasing pile.

Maybe something similar could be done in research. Make sure that a certain percentage of resources are set aside to replicate findings from other peoples’ research. Not in order to debunk the work of others, but in order to make sure that the fundament the current research is built upon, is firm.

Anyway, please read the article, it is interesting and also shows clearly why we are nowhere near removing the barriers to reproducibility.

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Something completely different; while reading the PLOS One research article, I couldn’t help think about a 2019 American Economic Review article:

Does Science Advance One Funeral at a Time? by Pierre Azoulay, Christian Fons-Rosen, and Joshua S. Graff Zivin

We examine how the premature death of eminent life scientists alters the vitality of their fields. While the flow of articles by collaborators into affected fields decreases after the death of a star scientist, the flow of articles by non-collaborators increases markedly. This surge in contributions from outsiders draws upon a different scientific corpus and is disproportionately likely to be highly cited. While outsiders appear reluctant to challenge leadership within a field when the star is alive, the loss of a luminary provides an opportunity for fields to evolve in new directions that advance the frontier of knowledge

I can’t help we would something similar in regards to reproducibility. If there is a grand old man (and it is pretty much always a man) in a given field, it is highly unlikely that he and his disciples’ findings would be challenged on the grounds of reproducibility. However when the grand old man leaves the field, this might change and people will start question the validity of the original research, and try to reproduce it.

USA – 250 years later

Today is Independence Day in USA – the 250th since the original one in 1776.

In 1776, Independence Day was about the USA becoming independent from the UK, and no longer be under the rule of the British King. Reading American history books, this is when Democracy was introduced in the US, often ignoring the fact that slavery was still ongoing, and that generally only property-owning/tax-paying white men could vote (for a more nuanced look, see the timeline of voting in the US).

Since the bírth of USA, a lot of things have happened – there was a large land purchase, a civil war, another large land purchase, an invasion, an annexation (later abandoned), numerous wars, Civil Rights Acts increasing democracy, and a number of other things. Looking at the situation 20 years ago, most would say that the US was a robust democratic country with some glaring flaws, especially related to race – but even in this area, the country was improving.

There were some democratic problems like the lack of voting for congress for Washington DC and Porto Rico and for convicted felons, even after they had served their time.

But all in all things looked good, and we expected it to improve.

That was twenty years ago though. Now, the situation is much different.

Trump, the GOP and the current US Supreme Court has dismantled the railguards of democracy, nearly killed the Civil Right Acts, removing bodily autonomy from women, and making partisan decision allowing the GOP to gerrymander and disfranchise people. Now, I can best describe the US as a near-totalitarian kleptographykleptocracy where one party is enriching itself, and trying to keep in power by all means. And this doesn’t even begin to address how the rampant bigotry and oppression of marginalized groups.

I hope the midway election can change this, but in order for this to happen, the voters must vote out the GOP every way the can, in every position – the GOP has shown that they can use every position available to create mayhem, oppress people and disrupt democracy.