Wednesday, October 31, 2007

Responsibility for Scientific Fraud

Who is responsible when a paper is declared to be the product of fraudulent research? This is a tough question to answer, and is becoming more relevant every day. Is it the first author? The PI? If you're the third author, or even the second on a paper that's found to be fraud, how responsible are you? Should it be allowed to negatively impact your career (it probably will)? Can you claim that you do not bear responsibility if you are not the "direct perpetrator" of the fraud?

Nature has an interesting proposal.

I'm not sure making one author sign such a declaration is necessarily the solution, but at least it has the advantage of holding the senior author truly accountable for the work that bears their name. I don't think one can force responsibility. I think that a really responsible PI will have checked the work in a paper, and one that is inclined to be less responsible will not be made more so easily. Perhaps enforcing accountability with a binding (although I don't know how binding this will be) signed document may lead to greater responsibility.


Friday, October 26, 2007

D'yer Mak'r

The inner dialogue: confessions of a Friday evening.

This postdoc's inner dialogue tends to be frenetic. "Was that 12 or 14 microliters? 12? no 14? How much did I add? ???? Sh*t forget it, its X.03mM instead of XmM" "Okay finish finish, Next Postdoc is signed up to start in the hood in ten minutes. Do all those cells really need to be split yet? Can all those cells be split in ten minutes? F*ck no way. So f*ck it, these cells will survive overgrowing better than those, so be it." "Ugh only halfway through the injections, ten more to go..." "F*cking A, the meeting with the Boss begins in three minutes, can I process three flowjo layouts in three minutes??" "F*ck f*ck F*CK"

And so on. There are calendars and to-do lists to remember, mice to take care of, experiments to design, papers to read, meetings to be gone to, socializing to be done and the special people to see and talk to. The average postdoc treadmill, and I love every minute of it-surfing deadlines, the pace, the multi-tasking, the nearly constant motion.

That said, the best inner dialogue is the silent one. It's 5.30 on Friday evening. The postdoc picks up all her detritus from the hood, puts it away. Mops up her bench, puts the media away. Sits down at her desk, collects all the little yellow stickies with cell counts, concentration calculations, dates of births and general experimental miscellanea and pastes them into the current lab notebook page. She looks at the calendar on the cork board in front of her, and everything is crossed out. The to-do list is similarly complete. All the mice are happily asleep or running around in their cages. The fluorescent lights hum, the lab is nearly empty, the radio plays on, for once not the driving rhythm of work but just music in the background. And the postdoc squirrels further into her chair and just listens to the sound of silence, the inner voice quiet.

Thursday, October 18, 2007

The Battle of Evermore

Antigen Presentation: The first in a series of basic concepts in Immunology

Recognition of a pathogen as a pathogen is one of the most fundamental functions of the immune system. The immune system can be divided into two basic classes, partly based on the ways in which pathogens are recognized: the innate and the adaptive, or acquired, immune system. The innate immune system is the early arm of the immune system, acting rapidly, within minutes of encountering a pathogen. Innate immunity is inherently broad in its specificity—cells of the innate immune system broadly recognize pathogens as pathogens, not specifically as X virus of Y bacteria. This is not to say that innate immunity is indiscriminate, far from it. The way in which innate immune cells recognize microbes tends to identify whole classes of pathogens, labeling a microbe generally as “gram-negative bacterium” instead of specifically “E. coli”. That is not the whole story, and will be the subject of another exposition another day.

What I want to discuss today are some of the ways in which the adaptive immune system sees pathogens. There two principal types of cells that constitute the adaptive immune system are antigen presenting cells and effector cells. (Though these distinctions are not hard and fast, some APCs are effectors and vice versa.) Antigen presenting cells, affectionately called APCs, “present” antigens to effector cells. What does this mean?

Starting with the effector cells, in this case T cells (see sidebar). T cells express an antigen receptor called the T cell receptor (TCR) that recognizes protein antigens presented to them by APCs. Once T cells recognize antigens, they react in a variety of ways: cytotoxic (literally: toxic to cells) T cells (CTLs) kill the cells that present the antigen to them, while helper T cells (TH cells) produce cytokines (see earlier) that communicate with other cells. Given that antigen recognition by a T cell can have powerful and far-reaching consequences, it is evident that it should be a tightly controlled process. And tightly controlled it is—by two elegant little biological caveats.

The first is that TCRs only recognize small fragments of said protein antigens called peptides, usually between 8 and 15 amino acids in length. T cells are very picky about the length and nature of these peptides, and APCs therefore have to “process” whole proteins down into the precise fragments the TCR can see. This process of degradation usually happens only inside a cell and requires the cell to have a fairly extensive and specialized “antigen processing” machinery. So not just any cell can present antigens to T cells, and the ones that can, cannot present just any antigen.

The second is that TCRs can only see peptides when they are carried on the surface of the APC on specific carrier proteins called MHC molecules. MHC expands into major histocompatibility complex (and I am violating every canon of science writing that says you have to define your term before you use an abbreviation, but the expansion only clouds the issue here), and refers to a set of genes that encode proteins that present antigens, called antigen presenting molecules. Something I won’t go into now is that these MHC genes are what determine whether organs are compatible (histo means tissue) for transplants, they are called HLA molecules in human, HLA typing anyone? Anyway, the function of MHC molecules is to carry peptides and present them to T cells. This is particularly nifty because T cells are restricted to recognizing only the antigens presented to them by self-MHC, which basically says that the T cells in my body only recognize antigens presented on the MHC molecules my body has.

So a T cell is constrained to recognize antigens only in a certain form, and then only when self-MHC molecules present those antigens. MHC molecules fall into two classes (of course, its not that simple, but its broadly true), MHC class I and class II. MHC class I molecules present peptide antigens that are made inside the cell and MHC class II those that are swallowed from outside the cell. Cells only make proteins from a microbe when they are infected by that microbe, and MHC class I molecules signal that a cell is infected by presenting the microbial protein as an antigen. The best way to deal with an infected cell in to destroy it, and cytotoxic T cells see antigens presented by MHC class I and kill the cells that present them the antigen. MHC class II molecules on the other hand present antigens from proteins they find floating around outside the cell, to helper T cells. Microbial proteins floating around indicate that there in an infection somewhere around, not necessarily in the cell that is presenting the antigen. So when helper T cells see their antigens on MHC class II, they don’t kill the messenger, but send out cytokine summons to all other immune cells to come a-hunting for the infection in the area.

Thus does antigen presentation form a critical part of immune recognition, battling on evermore in the standoff between bugs that don’t want to be recognized and bodies that want to recognize and eliminate them. The evolution and function of antigen presentation is an absorbing and continuous field of study, and has lead to some fascinating insight into the ways in which cells organize their insides. Some other areas that continue to interest are the sources of various antigens, and the ways in which T cells are educated to recognize foreign antigens but not the body itself. While antigen presentation is the most basic platform of immune recognition, it is also the jumping off point for some truly awesome research. Coming up in future posts…

Thursday, October 11, 2007

Good Times Bad Times

Inspired by one of Sunil's posts, at balancing life.

The key question is whether one can put a value on all the research that isn't published. Anyone who does research knows that there are good times and bad times, and that one has very little control over when those times occur. Postdocs need hot papers to get academic jobs-assuming, for the moment that we are talking about postdocs who want academic positions. Grad students would also like to publish high, but its less critical at that stage in one's career. It's usually the quality of one's postdoctoral work that is evaluated for jobs.

So what happens if one's well designed, innovative and technically superb project has no results? No publishable, sexy, revolutionary results? That the null hypothesis is true? It is extraordinarily difficult to publish negative results, especially since one can always encounter the ultimately dismissive critique that one hadn't tried everything yet. Does that mean that the two years spent on the project are toast? One's thought, analysis and expertise are worthless because they cannot be proved in print? Five more years as a postdoc?

So how then can we quantify effort and ability if not by publications? If its an especially technically difficult field, years of experience should count for a lot. If the idea behind the project is not mainstream (as Sunil discusses) and doesn't have any of the fashionably fund-able keywords, should one get points for risk-taking? The willingness to take on challenges without guarantees, at least the guarantees implied in "current-hot-topics" research, is uncommon and to be prized. So should CVs include a paragraph briefly describing one's project and the ideas behind it? Or will that just be seen as an attempt to flesh out the CV in the face of the conspicuous absences in the publications section? Probably.

After all new fields are created by people who can think out of the box. And sometimes luck only shows up late, and it takes three failed attempts to come up with truly revolutionary ideas. Or, the three failed attempts could reflect the complete absence of any BS-detector. Which is it? Does one always need to have a publishable side project, which will generate small reliable papers, thus demonstrating that one can actually do publishable research as well as study risky and unusual subjects? That one's out-there ideas are the product of intelligent thought, hopefully as demonstrated by the stuff that did get published.

Seriously though, is this a workable solution? Most postdocs I know do have two projects, just in case and to keep oneself occupied, particularly in immunology, where some experiments just take so long. Isn't it somewhat ridiculous to require people to have two projects? Or more?

Or, should one just ascribe it to the nature of the game, and let it go if things don't work out? After all, there are just way too few academic positions, and luck may just be another way to filter people out. Just because some intelligent and qualified people get thrown out with the bathwater, that doesn't mean that other equally intelligent and qualified people don't get lucky, publish and get academic positions. This way of thinking goes against everything I personally believe, because it just is not fair.

But who said life would be fair?

Friday, October 5, 2007

What is and What Should Never Be

Will asking postdoc mentors to document their mentoring help the current mentoring-or-lack-thereof situation?

I don't know, seems like yet another opportunity to write things in a grant proposal that you don't necessarily mean to do. More verbal padding, more watchwords. On the other hand, writing the watchwords may start you think about them. Will it change what is, and what should never be, or have been for that matter?


Stairway to Heaven

The Great Mofo Delurk 2007

I may be late, but you can still jump on the comment stairway! De-lurk please, I would love to meet you.

From Schmutzie

Wednesday, October 3, 2007

No Quarter

(Persevering with the Led Zeppelin theme)

Can you succeed in academia only if you are a shark?

This is something I started to think about when I came to the USA. In India, in my experience, academic scientists are idealistic, workaholic, fatalistic and gossipy. Money is always tight and you rarely get to publish in the good journals (and I'm not talking only about the big three or five) because of where you're from. The salaries for PI-level scientists are nowhere as high as they are here, and respect from the public and one's peers in other countries can be in short supply. The keen-edged aggression that one sees among scientists (specifically, biologists) here is not at all common. But, and this is crucial, once you enter the system of government science labs, you will have a career. Every X years you will be promoted, every Y years you will get a salary. You have tons of holidays, your kids have opportunities. Many post-postdoctoral scientists I know in India have jobs and some measure of security.

Many things are common between the scientific world in India and the United States, the most glaring absence in the latter is the absence of any prospects of security in academia until you have tenure. So the situation is then that you have really bright people who work and work and work, with limited pay and even more limited prospects. To make things more interesting, these people are often enormously motivated and justly ambitious: So where does all the energy go?

We all know there aren't enough PI positions. There aren't very many non-PI permanent researcher positions either. So the only thing to do then is to fight for the positions there are, right? To give no quarter, to your peers, to the possibility of failure, to your life, or to yourself. To be aggressive and up-to-date, to work harder, better and more successfully than everyone else. To know things and have connections that others don't have. Not that there is anything wrong with any of these things, I get a buzz out of the hunt just as much as anyone. My point is that it is not really sustainable.

Or not sustainable for the majority anyway. what happens to the people who cannot, do not want to or will not be sharks? The laws of luck and averages dictate that some such will succeed in academia, but in the balance I think the sharks don't succeed. Then you have a situation in which the system "selects" for the most aggressive people, and often does not encourage other more nurturing or considerate professional behaviour. The lack of consideration and sensitivity, coupled with a reluctance to show "mommy qualities" because that would invite professional ridicule, leads to bosses who demand and do not teach, who hector not mentor, and whose personal advancement is their primary goal.

Shark eat shark then. Which doesn't seem like much fun to me, and maybe to more people. Why is it that the system is ok with people who are excellent scientists but dreadful people? Why is that acceptable? I don't know. However I do see some incremental changes (not where I work at, but), and I think the key to any improvements in the system can only occur with recognition of these issues. I hope so, because the joy of research is being subsumed by the nastiness of its execution.