Some of my favorite meta-science posts from the blog

I recently was asked to join a faculty panel on writing for Penn Bioengineering grad students, and in doing so, I realized that this blog already has a bunch of thoughts on "meta-science", like how to do science, manage time, give a talk, write. Below are some vaguely organized links to various posts on the subject, along with a couple outside links. I'll also try and maintain this Google Doc with links as well.

Time and people management:
Save time with FAQs
Quantifying the e-mail in my life, 1/2
Organizing the e-mail in my life, 2/2
How to get people to do boring stuff
The Shockley model of academic performance
Use concrete rules to change yourself
Let others organize your e-mail for you
Some thoughts on time management
Is my PI out to get me?
How much work do PIs do?
What I have learned since being a PI

How to do science:
The Shockley model of academic performance
What makes a scientist creative?
Why there is no journal of negative results
Why does push-button science push my buttons
Some thoughts on how to do science
Storytelling in science
Uri Alon's cloud
The magical results of reviewer experiments
Being an anal scientist
Statistics is not science
Machine learning, take 2

Giving talks:
How to structure a talk
http://www.howtogiveatalk.com/
http://www.ibiology.org/ibioseminars/techniques/susan-mcconnell-part-1.html
Figures for talks vs. figures for papers
Simple tips to improve your presentations
Images in presentations
A case against laser pointers for talks
A case against color merges to show colocalization

Writing:
The most annoying words in scientific discourse
How to write fast
Passive voice in scientific writing
The principle of WriteItAllOut
Figures for talks vs. figures for papers
What's the point of figure legends?
Musing on writing
Another short musing on writing

Publishing:
The eleven stages of academic grief
A taxonomy of papers
Why there is no journal of negative results
How to review a paper
How to re-review a paper
What not to worry about when you submit a manuscript
Storytelling in science
The cost of a biomedical research paper
Passive-aggressive review writing
The magical results of reviewer experiments
Retraction in the age of computation

Career development:
Why are papers important for getting faculty positions?
Is academia really broken? Or just really hard?
How much work do PIs do?
What I have learned since being a PI
Is my PI out to get me?
Why there's a great crunch coming in science careers
Change yourself with rules
The royal scientific jelly

Programming:
The hazards of commenting code
Why don't bioinformaticians learn how to run gels?

Notes from a Chef Watson lab party

I recently read about Chef Watson, which is a website that that is the love child of IBM's Watson (the one that won at Jeopardy) and Bon Appetit Magazine. Basically, you put in ingredients and out comes crazy recipes, generates by Watson's artificial intelligence. Note: it doesn't give you existing recipes. No, it actually generates the recipe based on its silicon-based knowledge of what tastes good with what.

After reading this awesome review (Diner Cod Pizza?!?), I had to try it for myself. After doing a trial run with some deviled eggs (made with soy sauce, tahini, white miso, mayonnaise, onion–yum!), I somehow convinced everyone in the lab into holding a Chef Watson-inspired lab dish-to-pass. I thought it would be a good idea because it combines our love of food with our love of artificial intelligence. And here are the results:

Maggie: Appetizer Rhubarb Tartlets

Made with polenta, rhubarb, orange juice, boursin, tamarind paste, shallots, basil. I actually really like this one, although it was a bit tart.

Ally: Grapefruit potato salad

Didn't get the complete recipe details, but, umm, it had grapefruit and potato. I actually thought it was not too bad, considering I'm not a huge grapefruit fan.

Andrew: Bean... thingy

Made with kidney beans, pecorino romano, salami, tahini, pepper sauce, capers, chicken, green chiles, onions, mint syrup. This one totally rocked!  Consensus winner!

Paul: Crab soup

Hmm. Don't remember what all was in this, but there was some crab. And a bunch of other random stuff. This recipe was interesting. Very interesting. The crazy thing was how the flavors evolved in every bite. Started sort of like crab soup and ended with the taste of Indian food (to me). Did I mention interesting? It won the prize for most interesting.

Paul taking a sip:

"That was interesting!":

Sara: Banana Lime Macaroni and Cheese

Yep, that just about sums it up, ingredients-wise. This dish was fairly polarizing (sorry, didn't get a picture). I actually thought it was pretty good. Sara herself was somewhat less enthusiastic. Meanwhile, she was busy blowing bubbles for her son Jonah. Meanwhile, Jonah drank a bottle of bubble mixture.

Claire: Corn bread

All in all, this was really good, and relatively normal. Only "weird" thing was honey, which I thought added a nice sweetness, although Claire thought it was a bit much. This picture is great, as much for the food as for the highly sceptical look on Todd's face!

Lauren: Chips and Salsa

Non-Watson, hence less outlandish. But tasty!

Stefan: Sausages

Non-Watson, but homemade and delicious.

Me: Asian Sesame Oil Pasta Salad

Japanese noodles, tahini, mayo, thyme, sherry vinegar, peanut, green pepper, yellow pepper, broccoli, sweet onions, apple. Forgot to take a picture, but not bad. Perhaps a bit bland, but tasted good with some chili pepper oil.

Verdict: Overall, I think Chef Watson is great! It definitely suggests flavor combinations that you would likely never think of otherwise. I think one lesson was that you probably want to flip through a bunch of recipes until you come across one that sort of makes sense. The other lesson is that Watson isn't so great at getting proportions and cooking times right. You definitely have to use your own judgement or things could get ugly. Anyway, I for one welcome our robotic cooking overlords.

Update 7/11/2015: Some people strongly disagree with my sentiment that Chef Watson is great. I view it as glass half-full: Watson gives you interesting ingredients to use, but the first time you combine them you probably won't get the proportions right. But they are definitely combinations you would not have chosen otherwise. The glass half-empty version is that we already have tried and true recipes. Why mess with success? Well, I guess I'm just an optimist! Rhymes with futurist! :)

When to say yes

As a junior PI, you get a lot of advice about when to say “no”. One PI I know told me that he and his other junior PIs have a rule that they have to say no to at least one thing a day. And it is sage advice. The demands on our time are huge, and so every minute counts.

Sometimes I worry, though, that the pendulum may have swung too far in the other direction, to the point where the received wisdom to say no to everything prevents us from saying yes every once in a while. Say yes and you might just end up on a new adventure you may not have anticipated with cool and interesting people. Say no and you will never know.

I started thinking about this when I read this excellent blog post with advice for new PIs. All great tips, and one that really resonated with me was the tip to “Be a good colleague”. Basically, the point is that while there are some reasons you might think it a wise to do a bad job on something so that nobody asks you again, it’s far better to do a good job. I think the same holds for interpersonal interactions. I think it’s important to make time for the people you care about in your work life. Sometimes you might do a favor for a senior (or junior) colleague. Then you might have lunch and end up with an awesome collaboration. Or maybe the favor doesn’t get repaid. That’s okay, too, happens. And some people are just not going to make fun collaborators, and you might get burned. It takes time to get better at identifying those beforehand, and I know I still have much to learn about that. But I’m also learning not to be quite as suspicious of every request, and also trying to just go with the flow a bit. It’s led to some really great collaborations from which I've learned a lot.

My point is that by reflexively saying no to everything, I think we’re denying ourselves some of the richness of the life of a PI that comes through interactions with colleagues and their trainees, which I’ve found to be very valuable. And enjoyable. That’s the point, right?

Biking in a world of self-driving cars will be awesome

While I was biking home the other day, I had a thought: this ride would be so much safer if all these cars were Google cars. I think it’s fair to say that most bikers have had some sort of a run-in with a car at some point in their cycling lives, and the asymmetry of the situation makes it very dangerous for bikers. Thing is, we can (and should) try to raise bike awareness in drivers, but the fact is that bikes can often come out of nowhere and in places that drivers don’t expect, and it’s just hard for drivers to keep track of all these possibilities. Whether it’s “fair” or “right” or not is beside the point: when I’m biking around, I just assume every driver I meet is going to do something stupid. It’s not about being right, it’s about staying alive.

But with self-driving cars? All those sensors means that the car would be aware of bikers coming from all angles. I think this would result in a huge increase in biker safety. I think it would also greatly increase ridership. I know a lot of people who at least say they would ride around a lot more if it weren’t for their fear of getting hit by a car. It would be great to get all those people on the road.

Two further thoughts: self-driving car manufacturers, if you are reading this, please come up with some sort of idea for what to do about getting “doored” (when someone opens a door in the bike lane). Perhaps some sort of warning, like “vehicle approaching”? Not just bikes, actually–would be good to avoid cars getting doored (or taking off the door) as well.

Another thing I wonder about is whether bike couriers and other very aggressive bikers will take advantage of cautious and safe self-driving cars to completely disregard traffic rules. I myself would never do that :), but I could imagine it becoming a problem.

And you thought Tim Hunt was bad?

I’ve been sort of following the ink trail on Tim Hunt’s comments (which, incidentally, seems to have made the trail following Alice Huang go cold (just like in politics!)), so the topic of sexism in academia has been on my mind. I don’t think I have anything useful to say on the Hunt thing beyond what’s already out there. Even before Tim Hunt, I have a lot of female trainees in my lab, and I thought I had a sense of the sort of serious obstacles they face, including the sorts of comments like those from Hunt. And yes, comments like those are a serious obstacle. Disappointing and damaging, but not entirely surprising to hear stuff like that, although perhaps not in such a public forum.

It is in that context that I was absolutely shocked to hear someone I know tell me about her experiences at a major US institution. Seriously inappropriate comments in the workplace, including heavy-handed sexual advances. Women being groped and physically pushed around behind closed doors. Men in power using that power to touch women inappropriately, and as was intimated without details, worse. Worse to the point that a woman has a physical reaction when a certain man enters the room. And an institution that essentially protects these predators.

My jaw was on the floor. And the response to my shock was “Arjun, you have no idea, this stuff is happening all the time.” All the time. (To be clear, this institution is not Penn.)

The woman said that it seems to be much more of a problem with the older generation of men. I suppose we can wait for them to retire and go away. My sense of justice makes me feel like these people should have to pay for what has likely been a career of preying on women. And any institution that enables this sort of behavior needs some pretty deep soul searching. Even if such behavior is less prevalent in the newer generation, that is no guarantee that it is eliminated. And even having one such person around is one too many.

I am purposefully not naming any names because this is some pretty serious stuff, and ultimately, it’s not really my story to tell. I just wanted to bring it up because while I think we have come a long way, for me, it was a wake-up call that we still have a very long way to go.

Also, I want to make sure that this post isn’t misconstrued as some sort of minimization of the negative impact of Tim Hunt’s frankly bewildering statements. Words matter. Actions matter. It all matters. Indeed, I see the reaction to Tim Hunt’s comments as a strongly positive indicator of how far the discussion has come. Rather, I also want to point out that the reason the discussion is where it is comes from the tireless efforts of women through the decades who have put up with things I couldn’t even imagine, whose very decision to stay in science can be regarded as an act of deep courage and bravery. The thing that blew my mind is that women are still making those decisions to this day.

RNA-seq vs. RNA FISH for 26 genes

Been meaning to post this for a while. Anyway, in case you're interested, here is a comparison of mean number of RNA per cell measured by RNA FISH to FPKM as measured by RNA-seq for 26 genes (bulk and also combined single cell RNA-seq). Experimental details in Olivia's paper. We used a standard RNA-seq library prep kit from NEB for the bulk, and used the Fluidigm C1 for the single cell RNA-seq. Cells are primary human foreskin fibroblasts.

Bulk RNA-seq vs. RNA FISH (avg. # molecules per cell)

Bulk RNA-seq vs. RNA FISH (avg. # molecules per cell), linear scale

Single cell RNA-seq vs. RNA FISH (avg. # molecules per cell)

Single cell RNA-seq vs. RNA FISH (avg. # molecules per cell), linear scale

Probably could be better with UMIs and so forth, but anyway, for whatever it's worth.

Gene expression by the numbers, day 3: the breakfast club

(Day 0, Day 1, Day 2, Day 3)

So day 3 was… pretty wild! And inspiring. A bit hard to describe. There was one big session. The session had some dancing. A chair was thrown. Someone got a butt in the face. I’m not kidding.

How did such nuttiness come to pass? Well, today the 15 of us all gave exit talks, where we have the floor to discuss a point of our choosing. On the heels of the baseball game, we decided (okay, someone decided) that everyone should choose a walk-up song, and we’d play the song while the speaker made their way up for the exit talk. Later, I’ll post the playlist and the conference attendees and set up a matching game. The playlist was so good!

(Note: below is a fairly long post about various things we talked about. Even if you don’t want to read it all, check out the scientific Rorschach test towards the end.)

I was somehow up first. (See if you can guess my song. People in my lab can probably guess my song.) The question I posed was “does transcription matter?” More specifically, if I changed the level of transcription of a gene from, say, 196 transcripts per cell to 248 transcripts per cell, does that change anything about the cell? I think the answer depends on the context. Which led me to my main point that I kind of mentioned in an earlier post, which is that (I think) we need strong definitions based on functional outcomes in order to shape how we approach studying transcriptional regulation. I personally think this means that we really need to have much better measurements of phenotype so we can see what the consequences are of, say, a 25% increase in transcription. If there is no consequence, then should we bother studying why transcription is 25% higher in one situation vs. the other? Along these lines, Mo Khalil made the point that maybe we can turn to experimental evolution to help us figure out what matters, and maybe that could help guide our search for what matters in regulation.

Barak led another great point about definitions. He started his talk by posing the question “Can someone please give me a good definition of an enhancer?” In the ensuing discussion, folks seemed to converge on the notion that in molecular biology, definitions of entities is often very vague and typically defined much more by the experiments that we can do. Example: is an enhancer a stretch of DNA that affects a gene independently of its position? At a distance? These notions often from experiments in which they move the enhancer around and find that it still drives expression. Yet from the quantitative point of view, the tricky thing with experimentally based definitions is that these were often qualitative experiments. If moving the enhancer changes expression by 50%, then is that “location independent”?

Justin made an interesting point: can we come up with “fuzzy” definitions? Is there a sense in which we can build models that incorporate this fuzziness that seems to be pervasive in biology? I think this idea got everyone pretty excited: the idea of a new framework is tantalizing, although we still have no idea exactly what this would look like. I have to admit that personally, I’m not so sure that dispensing with the rigidity of definitions is a good thing–without rigid definitions, we run the risk of not saying anything useful and concrete at all. Perhaps having flexible definitions is actually similar to just saying that we can parametrize classes of models, with experiments eliminating some fraction of those model classes.

Jané brought in a great perspective from physics, saying that actually having a lot of arguments about definitions is a great thing. Maybe by having a lot of competing definitions and all of us trying to prove ours and contrast with others will eventually lead us to the right answer, and myopia in science can really lead to stagnation. I really like this thought. I feel like “big science” endeavors often fail to provide real progress because of exactly this problem.

The discussion of definitions also fed into a somewhat more meta discussion about interdisciplinary science and different approaches. Rob is strongly of the opinion that physicists should not need to get the permission of biologists to study biology, nor should they allow them to dictate what’s “biologically relevant”. I think this is right, and I also find myself often annoyed when people tell us what’s important or not.

Al made a great point about the role of theory in quantitative molecular biology. The point of theory is to say, “Hey, look at this, this doesn’t make sense. When you run the numbers, the picture we have doesn’t work–we need a new model.” Jané echoed this point, saying that at least with a model, we have something to argue about.

He also said that it would be great if we could formulate “no-go” models. Can we place constraints on the system in the abstract? Gasper put this really nicely: let’s say I’m a cell in a bicoid gradient trying to make a decision on what to do with my life. Let’s say I had the most powerful regulatory “computer” in the world in that cell. What’s the best that that computer could do with the information it is given? How precisely can it make its decision? How close do real cells get to this? I think this is a very powerful way to look at biology, actually.

Some of the discussions on theory and definitions brought up an important meta point relating to interdisciplinary work. I think it’s important that we learn to speak each other’s languages. I’ve very often heard physicists give a talk where they garble the name of a protein or something like that, and when a biologist complains, the response is sort of “well, whatever, it doesn’t matter”. Perhaps it doesn’t matter, but can be grating to the ear and the attitude can come across as somewhat disrespectful. I think that if a biologist were to give a talk and said “oh, this variable here called p… oh, yes, you call it h-bar, but whatever, doesn’t matter, I call it p”, it would not go over very well. I think we have to be respectful and aware of each other’s terminology and definitions and world view if we want to get each other to care about what we are both doing. And while I agree with Rob that physicists shouldn’t need permission to study biology, I also think it would be nice to have their blessings. Personally, I like to be very connected to biologists, and I feel like it has opened my mind up a lot. But I also think that’s a personal choice, perhaps informed by my training with Sanjay Tyagi, a biologist who I admire tremendously.

Another point about communicating across fields came up in discussing synthetic biology approaches to transcriptional regulation. If you take a synthetic approach to regulatory DNA, you will often encounter fierce resistance that you’re studying a “toy model” and not the real system. The counter, which I think is a reasonable argument, is that if you study just the existing DNA, you end up throwing your hands in the air and saying “complexity, who knew!”. (One conferee even said complexity is a waste of time: it’s not a feature but rather a reflection of our ignorance. I disagree.) So the synthetic approach may allow us to get at the underlying principles in a controlled and rigorous manner. I think that’s the essence of mechanistic molecular biology: make a controlled environment and then see if we can boil something down to its parts. Sort of like working in cell extracts. I think this is a sensible approach and one that deserves support in the biological community–as Angela said, it’s a “hearts and minds” problem.

That said, personally, I’m not so sure that it will be so easy to boil things down to its parts–partly because it's clearly very hard to find non-regulatory DNA to serve as the "blank slate" to work with for synthetic biology.  I'm thinking lately that maybe a more data first approach is the way to go, although I weirdly feel quite strongly against this view at the same time (much more on this in a perspective piece we are writing right now in lab). But that’s fundamentally scary, and for many scientists, this may not be a world they want to live in. Let me subject you to a scientific Rorschach test:

Image from here

What do you see here?

1. A catalog of data points.
2. A rule with an exception.
3. A best fit line that explains, dunno, 60% of the variance, p = 0.002 (or whatever).

If you said #1, then you live in the world of truth and fact, which is admirable. You are also probably no fun at dinner parties.

Which leads us to #2 vs. #3. I posit that worldview #2 is science as we traditionally know it. A theory is a matter of belief, and doesn’t have a p-value. It can have exceptions, which point to places where we need some new theory, but in and of itself, it is a belief that is absolute. #3 is a different world, one in which we have abandoned understanding as we traditionally define it (and there is little right now to lead us to believe that #3 will give us understanding like #2, sorry omics people).

I would argue that the complexity of biological regulation may force us out of #2 and into #3. At this meeting, I saw some pretty strong evidence that a simple thermodynamic model can explain a fair amount of transcriptional regulation. So is that a theory, a simple explanation that most of us believe? And we just need some additional theory to explain the exceptions? Or, alternatively, can we just embrace the exceptions, come up with some effective theory based on regression, and then say we’ve solved it totally? The latter sounds “wrong” somehow, but really, what’s the difference between that and the thermodynamic model? I don’t think that any of us can honestly say that the thermodynamic model is anything other than an effective representation of molecular processes that we are not capturing fully. So then how different is that than a SVM telling us there are 90 features that explain most of the variance? How much variance do you explain before it’s a theory and not a statistical model? 90%? How many features before it’s no longer science but data science? 10? I think that where we place these bars is a matter of aesthetics, but also defines in some ways who we are as scientists.

Personally, I feel like complexity is making things hopeless and we have to have a fundamental rethink transitioning from #2 to #3 in some way. And I say this with utmost fear and trepidation, not to mention distaste. And I’m not so sure I’m right. Rob holds very much the opposite view, and we had a conversation in which he said, well, this field is messy right now and it might take decades to figure it out. He could be right. He also said that if I’m right, then it’s essentially saying that his work on finding a single equation for transcription is not progress. Did I agree that that was not progress? I felt boxed in by my own arguments, and so I had to say “Yeah, I guess that’s not progress”. But I very much believe that it is progress, and it’s objectively hard to argue otherwise. I don’t know, I’m deeply ambivalent on this myself.

Whew. So as you can probably tell, this conference got pretty meta by the end. Ido said this meeting was not a success for him, because he hasn’t come away with any tangible, actionable items. I agree and disagree. This meeting was sort of like The Breakfast Club. It was a bunch of us from different points of view, getting together and arguing, and over time getting in touch with our innermost hopes and anxieties. Here’s a quote from Wikipedia on the ending of the movie:

Although they suspect that the relationships would end with the end of their detention, their mutual experiences would change the way they would look at their peers afterward.

I think that’s where I am. I actually learned a lot about regulatory DNA, about real question marks in the field, and got some serious challenges to how I’ve been thinking about science these days. It’s true that I didn’t come away with a burning experiment that I now have to do, but I would be surprised if my science were not affected by these discussions in the coming months and years (in fact, I am now resolved to work out a theory together with Ian in the lab by the end of the summer).

At the end, Angela put up the Ann Friedman’s Disapproval Matrix:




She remarked, rightly, that even when we disagreed, we were all pretty much in the top half of the matrix. I think this speaks to the level of trust and respect everyone had for each other, which was the best part of this meeting. For my part, I just want to say that I feel lucky to have been a part of this conference and a part of this community.

Walk-up song match game coming soon, along with a playlist!