Friday links

  1. A last link on the facebook saga makes the observation that if facebook just includes some randomness in all decisions of what to show on the stream (which they might do just to improve their service), then any study which leverages this is a randomized observational study. And observational studies have much reduced ethical thresholds.

  2. An excellent summary of what is known about SSRIs. I really liked both the conversion of effect size to weight loss numbers and the discussion of how, whilst people can agree on the data, it gets very hairy when you start to use words such as “moderate depression” or “severe depression” to describe different numeric results.

  3. Some people who make more money than I do, can activate your DNA. Obviously, they are skeptical of ENCODE claims. This guy’s biography is perfect:

    Toby Alexander, is a coach, speaker, seminar leader and author. He is a leading expert in a variety of fields including energy medicine, emotional mastery, peak mental strategies for optimal performance, 15th dimensional physics, futures and forex trading, SAP, remote viewing, and distant healing.

  4. Next week, I’ll be in Lisbon for LxMLS 2014. Contact me if you want to get in touch there.

New Paper: Trypanosoma brucei histone H1 inhibits RNA polymerase I transcription and is important for parasite fitness in vivo

(This is a guest post by Ana Pena, who is  the first author of Trypanosoma brucei histone H1 inhibits RNA polymerase I transcription and is important for parasite fitness in vivo, a paper I had a small hand in).

 

Pena_Paper_Figure3(Panels A & B from Figure 3 in the paper, showing effects of RNAi knockdown of H1)

The organization of DNA inside the eukaryotic nucleus relies on what we like to call the “beads-on-a-string” structure of chromatin, in which nucleosomes are the “beads” and DNA is the “string” around. While we already know a lot about the histones that make up the nucleosome, the functions of the “extra” histone, histone H1, only now start to be uncovered in vivo.

Histone H1 is a small protein that sits outside the nucleosome “beads” and binds to the DNA between them. In this work we explored the role of histone H1 in Trypanosoma brucei, a unicellular parasite responsible for Sleeping Sickness. Genome-wide RNA expression revealed an interesting fact in this parasite: histone H1 acts mainly as a repressor of a particular cohort of genes, which are transcribed by RNA polymerase I and are essential for its differentiation and survival inside the host. To understand if histone H1 represses transcription at these loci, we performed metabolic labeling of nascent RNAs with 4sU for the first time in this parasite, showing that histone H1 silencing effect is exerted at the transcriptional level.

Full paper citation

Pena AC, Pimentel MR, Manso H, Vaz-Drago R, Neves D, Aresta-Branco F, Ferreira FR, Guegan F, Coelho LP, Carmo-Fonseca M, Barbosa-Morais NL, Figueiredo LM. “Trypanosoma brucei histone H1 inhibits RNA polymerase I transcription and is important for parasite fitness in vivo”. Mol Microbiol, 2014 Jun 19. doi: 10.1111/mmi.12677.

 

Dealing with a dry spell

In the last 12 months, I had 6 papers published [1] (two as first author, four as middle author). I currently have another 3 in review plus another two close to submission (two more submission before the end of the year are likely).

Awesome productivity, right? It wouldn’t be bad for a small lab to get a paper every two months and I’m just a guy with a laptop.

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Unfortunately, these numbers reflect not just the fact that I’m both extraordinarily productive and work long hours [2], but also the fact that for the previous two years I didn’t have anything come out.

During those days, all of my work got stuck in different stages of the pipeline without seeing the light of print. I did do other things, like move between countries (twice), I did have other things happen (like writing a PhD thesis and what not), but no papers published.

I did submit manuscripts. They got rejected after (sometimes long) reviews. Sometimes, they got rejected twice for good measure.

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This post will surely get some google hits from people who think it’s about how to deal with not having sex for a long time. It is not. But if it were, it wouldn’t be that much different.

When you keep submitting manuscripts and they keep getting rejected, you start to lose confidence, you lose your edge, you doubt yourself. This applies not only to the submission process per se (submitting the manuscript, where you start to procrastinate with more-or-less finished work) but to the everyday practice of science, you start to lose the scientific killer instinct. You succumb to analysis paralysis.

Fear is the mind killer.

Much of what I do (we do, as scientists) is try to swim in the ocean of analysis possibilities and false hypotheses to find a current which I can pursue to a pot of gold. It’s not a needle in a haystack. Needles may be difficult to find, but when you do find them, you are sure you have a needle. If you are (un)lucky, you just sit on the haystack and the needle will announce itself on your behind. Good scientific hypotheses are not like that. They hint at you, look very much like bad hypotheses, and are hard to distinguish from the morass.

I feel rather that I swim around trying to detect hints of a current. The currents are there, but so are waves and fish and other divers trying to confuse you. The trick is to feel the vague hints of a current and then systematically show that it is there. Most of the time, though, your hypothesis of a current turns out to just be a whale fart [3]. However, you need to have enough of a killer instinct to pursue these whale farts one after another until you find the right stream. When you lose confidence, you risk swimming around aimlessly, dismissing even true currents as whale farts.

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Eventually, though, the coin tosses of peer review started going my way [4].

In the meanwhile, this experience made reconceptualize a large part of the process. For example, I now no longer see submission as a goal, but as an intermediate milestone. At CMU, there is an annual event, called the Random Distance Run where the length of the race is decided randomly partway through the race.

The exact number of laps will be specified by the sum of two ENORMOUS FUZZY DICE rolls – one occurring just before the start of the race, and one just before the first runner finishes the number of laps specified by the first dice roll.

Getting a publication is the same, when you submit, you are at the point where a new die is cast. You may be near the end of the race or you may not.

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At one point, I commented with someone that all my stuff seemed to fail in review. They said something to the effect of it must be hard to keep failing and I just said when you’re in science, failing is the job.

Failing is the job.

Fail. Fail again. Fail better.

—Samuel Beckett

[1] Onetwothreefourfive, and six (post forthcoming).
[2] Even though both of these are true.
[3] I’m pretty sure that whales fart. Whales probably have an awesome microbiome.
[4] Yeah, yeah, peer review is not only random.

Saturday Links

1. Bioimage informatics conferences in Leuven and in Oporto

2. BBC Horizon 1977-1978 on the introduction of computers The only thing that is outdated about this documentary are the fashions. Mike Cooley, an union leader claims:

It may be necessary for individual nation-states to make clear decisions about what kind of development and society they want, and, if necessary, be prepared to protect themselves from the ruthless introduction of this kind of equipment [automation using computers] by the multinational corporations.

3. New face of biology? Outsource wetlab work, keep analysis in house? For many studies this makes way more sense than the often proposed opposite (do wetlab in house, outsource analysis to the cloud).

Two more links about the facebook study

From Wired,Everything You Need to Know About Facebook’s Controversial Emotion Experiment, making the argument that an IRB reviewing the study would likely have approved it:

The [hypothetical] IRB might plausibly have decided that since the subjects’ environments, like those of all Facebook users, are constantly being manipulated by Facebook, the study’s risks were no greater than what the subjects experience in daily life as regular Facebook users, and so the study posed no more than “minimal risk” to them.

Also, see here:

[C]ritics of the Facebook experiment should at least be aware that we are talking about a mode of research that existed long before Facebook, and that federal ethics advisors and regulators specifically decided that it should proceed.

Facebook was probably ethically wrong, but morally OK in studying user emotions

Facebook did a study of how its users react to different sorts of stories in their feeds, namely by looking at emotional words in posts and giving different users different mixes of posts. Turns out that there is a tiny but measurable effect in what people write afterwards. Several people were immediately outraged that facebook would do a thing like this and publish it.

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Much of the discussion between scientists centered around the fact that Facebook did not get Institutional Review Board (IRB) approval and they probably got US public money so according to the law, they needed to go through an IRB process. In fact, yes, if you are working with human subjects, then you need approval from one of these IRBs to conduct your research.

This whole thing reads to me incredibly legalistic (even more because Cornell’s IRB might have given them a yes, but it’s not clear whether all the protocols were followed correctly). At one extreme, it even felt a bit like “we scientists in academia have to jump through all sorts of bureaucratic hoops, why shouldn’t others do the same? Not fair!”

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Even if facebook is at fault for not following the rules, it’s a different point from whether what they did was wrong. Sure, if they did not follow some regulation related to their Federal research funding, maybe the funding agency should cut their funding or give them a warning to improve their practices or what not. But was it morally wrong? Here, I just don’t see a strong case for the prosecution.

Reasoning by etymology is fallacious, but, at these times, the relationship between ethics and etiquette just jumps at me. When I tell my daughter that she needs to ask politely, she excitedly asks in a nice voice with a please at the end. She knows that now I’ve already given in, the rest is just procedural, follow the form, the etiquette, the ethics protocol. Is the problem that Facebook did not ask please?

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This sort of study is standard for private companies, except that it’s normally done to increase profits not knowledge. Any company tries out new things on its users, from the corner coffeeshop owner who asks me what I think of the new Ethiopian brew, to large-scale A/B testing done by internet companies. A/B testing is when an organization tries randomly two versions of its website and sees which one works best in whatever metric (clicks, purchases, or donations being the common goals).

For a company the size of Facebook, several of these experiments will be running at any given time. Do people share more if photos of friends are shown above or below the text? Will this cause them to share more photos themselves? To “Like” them more?

Now, this is rarely phrased as “manipulating users emotions”, but, really, what else is it? This whole brouhaha started with another commercial entity manipulating its users’ emotions to sell more advertisement, namely the press writing inflammatory stories about the facebook study [1].

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If a company does this all the time to increase profits, what’s the harm done to the human subjects if they do it and publish it?

Hilary Mason wrote that cultures are not consistent, which is a fine conservative sentiment, but it is not enough to just say “this is how it is, take it or leave it.” The inconsistencies should at least give us some pause and make us question our emotional certainties.

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Following a sort of Goldwin’s Law for ethics, the Tuskegee Syphilis Experiment was immediately mentioned by several people (this is an infamous experiment when black Syphilis patients were left untreated “to see what happened”). I don’t see, however, how it remotely applies. Even forgetting for a minute that syphilis is much worse than a small (but measurable) impact in use of emotionally laden words; what I see as the fundamental difference is that mistreating syphilis patients is bad (illegal even) outside the context of a scientific study. It is not enough to say “it’s OK, because it’s for science”. Or to put it in another way, individual rights cannot be trampled just for scientific benefits. However, what facebook is doing is perfectly fine, except if it is for science. This is fundamentally different from the problems of misusing individuals for the greater good.

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I just cannot shake the idea that facebook was fine until they published their results through the traditional scientific process. That was their mistake.

Facebook probably learned its lesson and will no longer attempt to publish any of its studies. They will still do them internally to understand their business better and make more money, just not publish them. This knowledge will now spread through word of mouth and at tech conferences without making it into the scientific literature [2].

This is a loss.

[1] The paper has actually been out for a month. PNAS-reading scientists did not seem to care to o much until they were riled up by press and social media.
[2] Also, it won’t be peer reviewed, but, hey, it’s psychology, their publication standards are way lower than whatever rule facebook uses to decide to change the font on its website (because facebook’s website font matters more than academic psychology).
[2] Also, it won’t be peer reviewed, but, hey, it’s psychology, their publication standards are way lower than whatever rule facebook uses to decide to change the font on its website (because facebook’s website font matters more than academic psychology).