stultissimus

PDX is a double edged sword. Human tumors are engrafted into mice with no immune system. Immune-cancer interface is incredibly important, yet completely lacking in these models. Consider that some of the greatest cancer drugs ever work specifically on the immune system (e.g. checkpoint inhibitors like Keytruda).

> If you don't mind me asking, how do you deal with this kind of culture, where a normal process is being purposefully obstructed with such behavior from the reviewer?

A huge part of the explanation is survivor bias IMO. The vast majority of undergrads who start in life science labs wind up leaving after a few months due to some bad experience (or at least lack of a sufficiently positive experience; life science is mostly failure). A large proportion of PhD students leave for industry jobs (tech, biotech, smaller subset to finance/consulting) because academic faculty jobs are very hard to come by and require making very little money for a long time. The only people left for the long haul are sufficiently motivated by the upsides (see below) to deal with the bureaucracy and problems of academic life.

> Do you ever call people out who sprinkle their "reviews" with such passive aggression? What is their defense?

Reviews are anonymous (this is now becoming controversial), and most people wouldn't jeopardize the acceptance of their paper just to call out a reviewer being an asshole. Slight saving grace is that the journal editor (who sits between authors and reviewers) has the final say, and can override unreasonable reviewers (in principle).

> What highlights does your profession have that make it worth putting up with this?

In fairness, some upsides if you make it: intellectual freedom (carte blanche to study anything you can get funded), sense of significance of advancing the frontier of medicine, freedom to work on and profit from startups if your tech is translatable (there is a surprising number of millionaire++ biology professors), very good job security, etc. Some would argue that many/most biotech companies take from 1 to N technologies that academic labs brought from zero to one. Some examples: mRNA vaccines, numerous cancer immunotherapies, CRISPR/Cas genome editing, recombinant insulin. Just look at the Nobel Prize in Medicine list – nearly all academic work.

In general we can conduct 'directed evolution' (selective breeding is an example). In this example, however, we're talking about improving the resistance of Halderia to the possible future mutations the viruses could develop to exploit them. This is a much, much larger harder to search space; the cost function is not well defined.

> 1. the parent raised questions in a neutral way. these questions seem essential for validating experimental design. why would peer reviewers present such questions in passive-aggressive ways, and how can we fix this?

Peer review is obviously a complex and controversial issue, but some key points (at least in life/medical sciences) include:

A. Your reviewers are very often your competition. Reviewers are supposed to be subject matter experts in your area of research, and academic science is a small world. The other subject matter experts are exactly the people competing with you for grants, to finish projects first, for trainees, prizes, etc. (You can typically ask that specific people do/don't review your paper, but it's at the editor's discretion. Some fields are simply too small to take such preferences into account.) You can often identify your (supposedly anonymous) peer reviewers because they respond with a critique that your paper should cite some specific papers, and they are the common name on the bylines of those papers.

B. Peer review is uncompensated work by academics, very often done for for-profit publishers. Hard to be thrilled with that paradigm (though some scientists feel it's a reasonable 'academic duty').

C. The mindset in peer review is often more about gatekeeping the journal hierarchy than about simply ensuring good experimental design. Publishing in top journals is often a career-making achievement. It is incredibly common for reviewers to ask for (often very time consuming) additional experiments based on their opinions about what is interesting, what a paper in the journal should look like, etc. There is a bias where reviewers don't want someone else to have an easier time publishing in X journal than they did.

D. Not exactly a critique of peer review, but I think it's important to realize that peer review is not even intended to address one of the major problems in science – irreproducible results and/or scientific fraud. Reviewers have to take all data presented on face value. At best, peer review is simply a check against poor experimental design, errors in reasoning, and authors making claims stronger than what the data supports.

> 2. could you kindly recommend services/consultancies to validate experimental designs? if not, would you be open to consulting and doing what you did here -- suggesting ways to control for key variables? experiments relate to cancer research. contact info in bio.

As mentioned, CROs are the companies in this space, though I'm not familiar with any that focus specifically on vetting experimental design.

Biophysicist here. Excellent questions – these are the kind of points peer reviewers would raise (though typically in far more esoteric and passive aggressive ways...).

(1) could be addressed in experiments where the algae-consumers in question are studied in monoculture (purified and grown in test tubes) with virus added artificially. This experimental design excludes the possibility that any middle man is present; if uptake is still observed, it must be direct.

(2) Measure viral replication, perhaps in a similar monoculture experiment as above. If the viruses are infecting (exploiting) the Halteria, they will have non-negligible replication (they are stealing the Halteria's resources to advance their own replication). Viral replication could be assayed by qPCR (counting viral genomes) or similar assays.

(3) This would require biochemical studies to determine the mechanism of uptake of viral particles. Typically, viruses are taken up (endocytosed) by cells as a result of interaction with receptors on the surface of target cells (prominently CCR5 in HIV, Ace2 for the COVID-19 causing virus). Of course, what biological systems are `trying` to do begs that we anthromorphize Halteria (or at least evolution), but one could conduct an evolutionary analysis to see if Halteria have progressively evolved receptors that improve viral uptake efficiency.

As an aside, the discovery of virovores hints excitingly (albeit remotely) at the possibility of creating virus sink cells/technologies that could eliminate viral particles in humans. An important question will be whether viruses, which evolve far faster than eukaryotes like Halderia (let alone than humans), can turn the tides in the evolutionary arms race and become the exploiters of the Halderia. Perhaps it's reassuring that we exist (mostly) symbiotically with our microbiota, despite their far faster evolution.