I’ve just walked out of a wonderful meeting that has kind of left me on a “science high”. The Raj Lab (my new scientific home in Philadelphia), Thomas Gregor’s lab from Princeton and Dan Larson’s lab from the NIH had a get-together, talking science, methods, data. It was really great, with loads of lively discussion. But I don’t want to discuss any of the actual science here. Instead, I’d like to share some ideas about scientific terminology, how a given word might have different “baggage” attached to it depending on your background/training, and whether fuzzy definitions may actually be useful in biology.
Update 15/04/2105: Crowdfunding just went live! If you’d like to donate, go to our experiment.com site!
If you’re a regular reader of this blog, you might have noticed a lack of posts over the last couple of months. This was largely because I’ve been busy setting up a new project with two friends (and former collaborators) of mine: to sequence the genome of Lil Bub, an internet celebrity cat – with the help of crowdfunding. We’ve christened the project the LilBubome, and after many months of preparation we’ve finally launched our blog, our twitter and our facebook page. The crowdfunding will start in 4 days.
Sometimes genetics is like a world-class whodunnit. Imagine: Uncle Donald, a millionaire with an attitude, is found dead in the library, having bled to death from a gunshot wound. The murder weapon is quickly identified as the army revolver belonging to Sir James, the master of the manor, who also had a motive, as he will be inheriting Uncle Donalds fortune. He is arrested and sent to jail, but over the years uncertainty about his conviction grows: a murder just doesn’t fit his profile (he quit the army because he couldn’t stand blood). Then, two years later, a new inspector comes to town: she is convinced that modern methods in forensics can shed new light on the case. Indeed, it does not take long until she discovers fragments of skin from the neighbour, Madame Guillotine, on the weapon, and, in addition, uncovers that Madame was actually a master target shooter in her youth.
Noone is surprised, Madame is known for her vicious temper and had a violent argument with Uncle Donald on the evening of his demise. There is no direct evidence for her guilt, but enough circumstantial data to sway any jury. Then a new witness comes forward: Dr Robinson, an arctic explorer, has just returned from a lengthy mission, where she was studying polar bears, cut off from the world, unaware of the drama unfolding in her home town. She tells the police that she saw someone pour anti-coagulant into Uncle Donalds wine on the evening of her leaving party in the manor. The culprit was neither Sir James nor Madame Guillotine, but Robert, the gardeners adopted son, who is really Uncle Donalds illegitimate child. Robert has a prior conviction for pushing his former girlfriend down the stairs – so a domestic accident, with Uncle Donald bleeding to death would fit his MO. Sounds complicated? Well, in the molecular genetics world, this is more less what has been happening to the FTO locus. Continue reading
There are certain norms that should not be questioned. I mean, take birthdays. Personally, I love my birthday: it’s in early May and normally there’s beautiful spring weather. Sometimes it overlaps with a May Day bank holiday. All in all, pretty good. However, I know people who really hate the date of their birthday, and so, a couple of years ago, I came up with a great idea: what if we could choose the day we celebrate our birthdays? Every year you could pick a different date (or the same, if you wanted), and obviously, you could pick only one day per calendar year, not to deflate the value of birthdays, as with unbirthdays:
It seems a simple and practical solution to the birthday problem to me, but when I pitch this idea to people, many are up in arms about it. There seems to be a widespread belief that celebrating your birthday on the anniversary of the day you were born is a custom set in stone, which must not, under any circumstances, be changed. Of course, this is not true. For refugees who cannot prove their date of birth, immigation officials often put 1st Januray as a placeholder. Some immigrants embrace this new birthday as a symbol of a fresh start. Then there are religions, where celebrating birthdays is not part of the culture anyway. So, really, if you look at the bigger picture, birthdays don’t have to be on the day you were born at all. But if you’ve grown up following this tradition, normally you don’t question it.
Similar set-in-stone “norms” and traditions are also abound in science. Continue reading
Yesterday a paper (Exonic Transcription Factor Binding Directs Codon Choice and Affects Protein Evolution) from John Stam’s lab at University of Washington was published in Science. They claim that „We found that ~15% of human codons are dual-use codons (“duons”) that simultaneously specify both amino acids and TF recognition sites. Duons are highly conserved and have shaped protein evolution, and TF-imposed constraint appears to be a major driver of codon usage bias.” For the non-scientists reader, this means they claim that a some portion of the human genome, which has a function (to code for proteins), also has a second, unrelated function (to be bound by a special class of proteins, called transcription factors (TFs), which control which regions of the genome are activated). They call these regions with double function „duons”, and also claim that the second function imposes constraints on how the first function is achieved and can evolve. When I read the paper, my gut reaction was this:
Cats are cool. Everybody knows that. Cats can also have very characteristic traits. Everybody knows this, too, particularly since Andrew Lloyd Webber’s musical Cats, where he popularised T.S.Eliot’s collection of poems Old Possum’s Book of Practical Cats. Remember them? Gus, the theatre cat? “His coat’s very shabby/ He’s thin as a rake/ And he suffers from palsy that makes his paw shake”. The Old Gumbie Cat? “Her name is Jennyanydots/ Her coat is of the tabby kind with tiger stripes and leopard spots”. And the list goes on.
Yet, not only lovers of literature and music are enthralled by the diversity of features that cats display. Geneticists have also long discovered this phenomenon, which can be very useful to figure the genetic changes that are responsible for a given trait (geneticists call these traits “phenotypes”). So, ok, obviously noone has ever found the Mr. Mistofelees-mutation or the Rum-Tum-Tugger allele, but some of the other things they’ve been looking into is still pretty amazing. Continue reading
It has been a low-key week: with deadlines rapidly approaching I been busy writing applications for postdoc fellowships. And while I have been developing some ideas for longer, multi-part blog posts, they are not yet ready to be published. But, while I was going through the literature for my applications, I actually came across a rather heart-warming example of a great… corrigendum. OK, this might sound strange, but I think thorough follow-up of critique to a scientific paper can be just as essential to a paper as the initial results. Being wrong or making mistakes is OK, but not acknowledging this, is not. After all, an essential part of science is peer-review. And this includes not only the peer-review associated directly with the publication process. A really good example of really bad, unscientific behaviour, is the “bacterium that can grow on arsenic” story, which was widely contested (see here and here), but – I believe – the authors never officially retracted the paper (?).
So, the post today is about a corrigendum, which is just like my vision of how a corrigendum should be like.
The story started about two years ago, when Matthias Selbach’s group in Germany published a research paper in Nature. They described a rather straightforward experiment to test how protein abundance is related to mRNA abundance, and how transcription and translation rates influence this relationship. In essence, they measured the abundance of proteins by mass spectrometry, and the abundance of the respective mRNAs by RNA-Seq in cultured cells. Moreover, by labeling newly synthesized proteins and RNAs they also measured transcription and translation rates. Yet, while theoretically straightforward, the experiment was technically challenging (made possible only through recent advances in sequencing and mass spectrometry technology), and definitely very timely, because previous, similar studies had only ever looked at a selected subset of genes. The Selbach paper found that ~40% of the variance in protein levels could potentially be explained by their mRNA levels, but including data of translation rates could very much increase the predictive power, indicating that translation rates have an important role in determining protein levels. As part of their analysis they also calculated absolute protein copy numbers. For this, they used proteins of known concentration, mixed them with their sample, and included them in the mass-spectrometry measurement. They then used these known amounts of proteins to calibrate “iBAQ intensities” (units obtained in mass spec), and subsequently converted the iBAQ values of the cellular proteins to molar amounts based on this calibration.
So far, so good.
However, in March this year, they published a corrigendum/erratum. It starts with: “Mark Biggin […] contacted us, noting that our mass-spectrometry-based protein copy number estimates are lower than several literature-based values.” How wonderful! No wishy-washy beating-about-the-bush. Instead: a precise explanation of the problem. Next, they explain how they checked their published data and identified a mistake in their calibrations (they used the calibration values from an unrelated experiment in their analysis pipeline). But it gets even better. They state: “To further validate copy numbers” and describe two more tests they performed for validation, one based on comparing band intensities on Western blots and another mass-spec approach, called selected reaction monitoring.
So, all in all, I think that’s pretty decent, and – at least for this week – it restored my faith in the scientific community. I wish I would always perform two additional experiments, when someone points out a potential flaw in my work. Luckily, their error did not influence the major findings of their original paper, but I hope they would have been so open about correcting their mistakes, even if it had.