Field of Science

New T-shirt

I was hoping to get a picture of my new T-shirt (a gift from a like minded individual who I will allow to remain anonymous). Sadly, I didn't. I did wear it today proudly as promised. From the public I encountered, I heard 4 positive responses and 0 negative responses, which surprised me. Anyway, below is the shirt and I recommend buying one for all your friends.

By the way, I think many people may be concerned that the T-shirt is insulting. However, I have thought about it and in fact I can not come up with an offensive message from the shirt, unless you believe it nullifies Jesus's accomplishments as a scientist. Enjoy!

On Being a Post-Doc

Over at Highly Allochthonous Dr. Rowan asks a question on the minds of many/most post-doctoral researchers. "How long do I have to do this before I can get a real fucking job?" I posted a rather long rambling answer to this there, but thought I would expand on it here a bit, because it is always timely.

By way of full disclosure, I did one post-doc before getting a faculty position. I also know of and have known dozens of post-docs over my career as an undergrad through the present. However, most of my thoughts originate from my direct experiences as a post-doc. Thus, these will not apply to everyone.

First, when you are completing graduate school and thinking about post-docs, think beyond the post-doc. Where do you want to end up? Do you want to be a research scientist at a tier one research institution or do you want to teach science at a small liberal arts college? Do you want to go into industry? Science writing? The possibilities are endless. However, if you don't have an idea of what you want to do in the long term, stop reading and go figure that out first. By the way, you can take some time after graduate school to figure it out, maybe doing a temporary post-doc in your thesis advisor's lab or a related lab nearby (however, I do not recommend this for more than a few months as the best course of action).

Ok, you know what you want to do. Now you need to find a post-doctoral mentor that can help you reach that goal.

If you want to go primarily into teaching, why would you go to a high powered lab with 5 other post-docs who are at least partially competing with each other to get the next Science/Nature/Cell paper? Not that you couldn't do well there, but what you really need, in addition to research and pubs, is some teaching experience. So find a post-doctoral mentor that will accommodate you being out of the lab to teach a section of undergraduates or a class at a community college. Also, just because you are primarily interested in teaching undergraduates, you may want to, or have to, continue doing some research. How about doing a post-doc in a bacterial or fungal lab? These organisms tend to be easy to handle in a small college setting. The supplies to grow and study them are fairly inexpensive and its possible to get a lot of data in a short time by asking the right questions using undergraduates. Remember you will not be doing this research much yourself, you'll be teaching 2-3 classes a semester. But think of the excitement and passion for science you can generate in your undergraduates by giving them readily doable (and publishable) projects!

If you want to go primarily into research (this is my track), then you need to be thinking about the research program you will have as a future PI. Here's a question you must ask when you interview with a potential mentor, "What aspects of the work I do can I take with me for my own lab?" If you don't ask that question in some clear way, you are a fucking moron. You might get lucky regardless, but morons sometimes do. You are striving to establish your own career, while working in someone's lab who is trying to maintain their own career, so this isn't trivial. The answer might be, anything done here, stays here. Isn't it better to know you will likely be directly competing with an established funded filled to capacity lab before you even unpack at your new position? If the answer is like this, find another post-doc with a different answer or plan on doing a second post-doc. You may get an "I expect you to work on this for me, but you can also establish your own projects to take with you." or "Whatever you want to take, take." answer. The permutations are endless, but you need this information! Also, talk to the current and former members of the lab, has the mentor scooped a trainee trying to start their own lab in the past? Its not common but it happens (regardless of the answers given above). Remember at the end of the day when an unpleasant surprise greets you, no one in your department, at NIH NSF or the DOE, on the tenure committee is going to give two shits about your "Its not fair!" approach. Its not fair, its sucks, and while I dont like to blame the victim, in most cases I've seen, its due to the victim not doing their homework or blatantly ignoring all the warnings.

Alrighty, you've got the perfect post-doc! How do you know when its done? My advice is be thinking about jobs from day 1, because success in getting a job is due to luck as much as skill. What you need to do is try your best to stack the deck in your favor. You will need publications, a strong rapport with your mentor, and contacts outside your current research center (independent funding is also a gigantic plus (a training grant/NRSA is not gigantic since these are primarily given to the mentor)). To be marketable for the research track, you will need at least 3 publications within 2-3 years, more is better and it can easily take a little longer depending on your field. Regardless, now is not the time to be dappling with 4 different projects. Also, to quote myself, publication quality matters more than quantity, but D'uh. Impact (not impact factor) is important, though often overlooked. If you are publishing high quality papers that are essentially in the "more of the same" variety this does not have as much impact as a paper establishing a new approach to study a problem, a new way of thinking about a problem, etc. If you are doing what everyone else is doing (albeit in your specific area) you can not set yourself apart from your competitors. BTW dont kid yourself, it is a competition and you generally don't get to see the competition in action. Obviously you want a strong rapport with your mentor, if you don't have that consider yourself terminally fucked (shouting matches with your mentor can often be an indication of a strong rapport). Finally, outside contacts to write you letters of reference is a great way to set yourself apart. If you can, skip your thesis advisor, its like asking a parent for a letter. Getting your mentor and 2-3 top researchers at top research centers to write letters is like gold. When you go up for tenure (if you are in a tenure-track position), you need outside letters and everyone knows it. If you can show the hiring committees that you are already establishing yourself, you've gained several strides on your competition. Finally, obtaining a post-doc to PI transition award is essentially a free pass to a faculty position (but these are not trivial to get and you shouldn't count on them).

Ok, you have interesting and important pubs, your god-like mentor adores you and departmental chairs across the nation are emailing you for help, now what? Pray and pray often, and dont be choosy about the deities you pray to. This is where it becomes a crap shoot. Again plagiarizing myself the issue is the job market and how your research area/skills fit into the job market. When you apply and go on the job search you need to leave the committees with an idea about what you will bring to the institution. Your specific research area will get you in the door, but how you approach science and think about things will get you an offer. What you cannot control is what research areas will be in demand (actually you can usually determine if an area will likely not be in demand, which can help).

As I said there is a ton of luck involved, although to a large extent you can stack the deck in your favor. I got a faculty position after 2.5 years of post-doc. This was not the norm nor am I some super-star, primarily this was being in the right place at the right time (this is the luck component and why I only got a few interviews). However, I also had a bigger view about my research area than the specific niche I was immersed in or at least I think I did and the projects I was involved with had broad ramifications (the stacking the deck component and why I got offers from every place I interviewed).

So, to all those soon-to-be and current post-docs out there take my opinions with a five pound tablet of salt along with this heart-felt "Good Luck!"

Evolution Steers Research Leads to Knowledge Potential Cure

This is a story about a transposon aptly named Sleeping Beauty, it could have been named Rip van Winkle, but I do think Sleeping Beauty is more apt. Now I am not going to go into the details of what a transposon is, that information can be found many places. Suffice it to say that transposons are small bits of DNA that hop around another organism's genome. There are bacterial transposons, yeast, drosophila, worm, fish, primate transposons. Basically there are transposons found in all cellular lifeforms. What is great about transposons for a geneticist is that if you can control when they hop, you can generate a series of essentially random mutations in a heartbeat. If the transposon hops into a gene whose product is required to make the amino acid arginine, your mutant will not be able to grow in the absence of arginine in the medium. This is great if you are interested in understanding how a cell makes arginine and this approach has been used since the 1960s to study and understand many basic cellular processes in bacteria and in eukaryotes. In the post-genomics universe, transposons are also a powerful tool because you know the DNA sequence of the given transposon you are using (if not get another job). So, once you have a mutant you are interested in, identifying the gene disrupted by the transposon is fairly trivial.

Now transposon were used to study primarily "simple" organisms, such as bacteria and yeast for half a century. However, transposons were not used for genetic studies in mammalian organisms because active/functional transposons did not exist. This despite the fact that a major part of our (and other mammals) genome is composed of nothing but transposons and transposon remnants. Although many transposons are intact within the genome, they are non-functional because they contain mutations that have accumulated over time. (Tangential creationist bash - one tenet of the creationist/ID movement is that mutations are uniformly bad. From the perspective of the transposon these mutations are bad, from our perspective having transposons hopping around in our cells is a bad idea so the mutations are good).

In 1997 Ivics and colleagues published a paper in Cell that changed all this. They looked at a non-functional transposon called Tc1/Mariner, which is found in fish humans and other organisms. The idea was to recreate a functional transposon from these Mariners that all contain mutations. However, a transposon can move through a population vertically (think mother to child) or horizontally (think person to person, like the flu although this is not to suggest that transposons are infectious.) So if a transposon picks up mutation in one cell then all the descendants of that cell will have a transposon with that mutation due to vertical transmission. The idea here is that just because all the Mariner transposon in a salmon have a given nucleotide at some position in the sequence does not mean that the nucleotide is not a mutation. So how do you figure out the original "functional" transposon sequence? Ivics obtained the Mariner sequence from 8 different fish species and aligned them using standard sequence analysis computer programs. From this they established a consensus sequence, that is the DNA sequence of Mariner found most often in the different species and identified the important domains (Fig A) of the transposase (the enzyme that carries out the transposition reaction).

When compared to the salmon Mariner a number of mutations were identified (Fig B). Ivics and colleagues then first fixed all the premature stop codon mutations to the correct amino acid (changing SB1 to SB3. The protein expressed from this sequence still did not do too much.

Next, they changed a number of amino acids to make SB4, the protein made from this sequence was not functional as a transposase, but it did localize to the nucleus! This is an important step forward as the transposase needs to be in the nucleus to carry out its function. The researchers then went through a number of steps SB5-SB8 and finally obtained a protein capable of binding DNA, and 2 steps later they generated a functional transposase. This transposase also works when introduced into mammalian cells. Genetic researchers working on vertebrate organisms rejoice! This is why Sleeping Beauty is an apt name, the transposon was relatively simply to reactivate and has been essentially sleeping in our genomes for hundreds of millennia but is now such a powerful tool for understanding ourselves it is indeed beautiful.

Step forward to 2008, by introducing the transposon into mammalian cell lines or into mice, we have a system where we can generate essentially random mutations when and where we want simply by turning on Mariner (the transposase) when and where we want (this is done using specific promoters). The transposase is expressed causing the transposon to hop into new sites in the genome, some of which will have an effect you are interested in. For example, this approach has been used to identify genes involved in the progression of specific type of cancers (do a pubmed search for sleeping beauty for a ton of references). In short, adapting transposon mutagenesis to higher eukaryotic organisms is revolutionizing our understanding of ourselves.

So lets go back to the beginning, if you doubt evolution and believe in creation/ID you must not allow any medical benefits arising from this research to be used on you. How do you justify the approach taken by Ivics and colleagues without evolution? From evolutionary theory, it makes perfect sense to take Ivics' approach. In order to think you can regenerate an active Mariner from these disparate sequences from different species, you have to assume that there was an original active Mariner in the ancient history of the ancestor of these species. After speciation occurred the Mariners could accumulate mutations that inactivated them. However, these mutations occurred independently in the different lineages. Because this happened, it is possible to predict what the ancestral active sequence was by determining the consensus sequence. Now its possible that the ancestor sequence was already non-functional, but that is not the case here. Regardless, how do you begin this research project from a creationist don't, it makes no sense whatsoever. What about an ID perspective? Well I guess if you believe the designer is a sloppy lazy stupid drunk, then maybe you could go down the right path, but I have yet to hear an IDiot say they thought god was either sloppy, lazy, stupid, or drunk much less all four simultaneously.