Monday, July 30, 2007

Can a Life in Academia be Balanced?

I'm not sure, and this is why.

Many jobs require marginally insane hours, as many jobs require attention on the weekend and during other purported off times. An academic job requires insane hours at times and makes the distinction between time on and time off blurry at best, but the killer is that so much of the success of an academic job depends on the individual holding the job.

A lab makes or breaks because of the ideas of individuals: initially the PI's and later other members of the lab as well. Grant money is awarded to an individual based on their ideas and their ability to sell their ideas. Individual charisma goes a long way to making a story sell-able, how much more likely are you to remember a PI who gave a fantastic talk at a meeting? And how much more likely are you to be accepting of a bumper publication on that topic? The personality, drive and energy of the PI are critical to the success of a lab, and on a smaller scale, the personality drive and energy of a postdoc (and to a lesser extent a grad student) are essential for visibility, contacts and eventually a job.

Here I must say that I think balance involves a certain degree of dissociation from the job, but this is personal and may not be the case for others. With dissociation comes relaxation, perspective and professionalism, all of which make for a happier work experience. The things is, I cannot see how dissociation goes with the extraordinary degree of personal commitment that an academic job requires. The very basis of a successful academic career is an intense driving personal involvement, or at least it is in all the Biology labs in the United States that I have seen. So I don't if balance is possible with an academic job-in Biology, in the United States.

Do I have it wrong? Have I just worked in really intense environments? Which I have loved by the way, I love the buzz of achievement under pressure as much as any one. Is it different in other fields? Do I have an unrealistic view of academic positions? I don't know, and would to like to hear your perspectives, because I am increasingly coming to believe that an academic position in today's environment may not lead to the kind of balance that I believe is necessary.

Thursday, July 26, 2007

Back in Lab in Under 11 Hours

Sighs. It has been a busy couple of weeks, and I have been back in lab in under 9 hours even, the intervening time covering sleep shower and breakfast.

Now that's a good thing. It means I have things to do, it means that there are Experiments in progress. There may even be a Paper coming out of all of this in two years. Hours of endless echoing puke coloured hallways, dirty linoleum, fluorescent strip lighting, latex gloves, laminar flow hoods, the smell of FBS-it's all worth it in the end right? Who would want a squashy couch, hardwood floors, books, food and company instead?

Funnily enough, half the time I don't want the couch etc. instead. Its the postdoc Zone I guess, nothing like the prospect of experiments working to bring one back to the lab. Even though they may only be prospects at this point, a tiny possibility is better than none at all. There's something zen about the eerie echoing hallway, the lab chair fits my spine better than any couch and the world starts to be clearer under those fluorescent lights.

Its the Zone people, the Zone. Research in the zone-let's see how long it goes.

Friday, July 20, 2007


Eeeeeee I cannot wait.
Who will live who will die?
Is Snape good?
Whither the Horcruxes...

Cannot wait. And have to finish the book tomorrow and avoid the Internet till I do finish. All those a**h*les with their spoilers. I'm also pretty annoyed with the New York Times who posted a review of the book yesterday, with the supremely self-serving justification that their reviewer found a copy at a bookstore on the street and if a book is on sale, it is fair game to be reviewed. F*@kers.


Then the discussions, which is even better!

Thursday, July 19, 2007

How to Choose a Postdoc Lab

My cousin has just "defended" his thesis and I was talking to him about what he was planning to do postdoc-wise. It brought back memories of the my own postdoc job search early last year. I was trying to draw on my experiences and be helpful, but as I thought about it more and more, I became less and less coherent. So I decided to put down what I thought here, and see if any of you who have searched for postdoc jobs have any further insight.

There are many things that are good to keep in mind while job hunting and I'm going to the list the things that I think are key, the most important thing to remember is that the job that meets all your criteria does not exist. Period. I would try and identify a few things that would make you most happy and try and have those. The rest, well, deal.

So in no particular order:
1. The two-body problem: This is probably the hardest problem for most; if you are a couple, each invested in their career, you have to move together. You have to align expectations for two different people, possibly at different stages in their career, even two different fields or industries. That said, this is probably the career stage at which the two-body problem is easiest solved since postdoc positions are more frequently available than any other.

2. The place: This is something that mattered a lot to me personally. I went to an undergrad college is the veriest village, and as a result am a total city junkie. Whichever way you go, city, village, out in the country, this is important because if you don't like where you are, life will automatically be more difficult. Also, your milieu is directly related to where you live, whether you meet like-minded people or constantly feel like you have to be circumspect in your interactions with people.

3. The projects: The biggest question, will you have a separate clearly defined project of your own. I cannot emphasize how important this is. Its all very well to agrre with the PI that you will take over X person's project-what if they haven't left by the time you have arrived? Academia is very flexible, and sometimes people prolong their career transitions for long periods of time. So if you don't have a clearly different project, well hone your thumb-twiddling skills. Also, determine before you accept a position which portion of a project is clearly yours. Territorialism is a rampant trait of scientists, protect yourself. What's the point if you have your heart set on a project and join a lab only to find that it has been given away? Discuss this.

4. The P.I.: This is obvious, but anyway. Make sure you can talk to your boss. They do not have to be your friend, and very likely will not take as much care of you as a good Ph.D. mentor, but they should still be respectful and willing to listen to you. Also, different people have different preferences for a boss, but in general my feeling is that a micromanager would be a bad postdoc boss because the whole point of a postdoc is that you become independent. Micromanagers rarely like to set you free.

5. The Lab: Anyone who has ever read a blog knows how much this impacts our lives. Seriously, find at least two people you can get along with, who are going to overlap with you for at least some time. Its hard to be friends with all 15 members of a lab, but all you need is a couple of people you are glad to see everyday. Nature papers are all very well, misery sucks. It really does and working everyday in a lab where you and others are miserable is almost impossibly hard.

6. The Department: There are some really great labs that are one-off labs in their departments. These labs do great work, but you may end up somewhat isolated in your department. The departmental seminars will not deal with your work, you will not be able to network with people in your field, which you absolutely need to do if you want to stay in academia. On a more day-to-day basis, you won't have any one but your lab to talk to about your work. And that may not always work out well.

7. The prospects for funding independent of the boss: Funding sets you free. Postdoctoral fellowships are a boon, as soon as you have one, your life improves in so many ways. Your boss will be thrilled not to pay your salary (the single biggest expense in most Biology labs), you demonstrate that you can write fund-able proposals , you feel good about yourself , and most fellowships pay above average postdoc salaries.

8. The Nature of the Actual Work: For example, brain cancer research sounds so cool. But, how would you feel about dissecting out mouse brains on a daily basis? Injecting things into a mouse's skull? Evaluating mouse health based on how much pain they are in? Or else, would you be dreadfully bored pipetting 30 96-well plates a day for real time PCR or screening X or Y? Think about it. Lab work is icky, is it beyond your ick threshold?

9. The Portability of the research: Would your future boss be willing to give away part of your project to you should you want to leave and start your own group? Most bosses should be aware of this possibility and be open to it, what you should do is communicate! I cannot emphasize that too much.

10. The salary and benefits: She surely jests, you must be thinking. Well, partly, but there are actually places where postdocs get both competitive pay and decent benefits. If you have children or loans or are sick of being on the lower end of the pay scale, think about it and look for places that pay better.

11. The Language: Seriously, even in the USA as a native English speaker, cconsider what is the native language of the lab. Why make yourself an outsider?

12. Children or not? If you're considering having them, sound out your future boss and talk to current lab members about their child-bearing related experiences.

13. The Weather? If this is a big criterion, re-consider you career choice carefully.

14. The Prospects for alternative careers: Not all postdocs become faculty, anyone can try to do the math. Many of us who embark on a postdoc do so in the full expectation (hope?) of succeeding and becoming PIs. Doesn't always happen. So be prepared. I'm not saying one should anticipate failure, but on case you decide to change career tracks, you should be in an environment that lets you. Teaching opportunities, writing editing and publishing, the biotech industry, these are all things you should try to get exposure to.

This has turned into an incredibly long post, so I'm going to stop here. There are a lot of things that go into making a career decision, and these are some of the things that I think are important to think about while deciding where to postdoc. Ph.D to postdoc is the easiest career transition one can make, everyone wants postdocs, they are cheap, smart and young. Its important to spend some energy on this choice because it impacts where you end up next, not to mention your general mental health.

In the end though, a job is a job is a job (next post), and wherever you end up, if you don't work at the job for whatever reason, it won't go very well. So good luck, congratulations on graduating and welcome to mad wonderful world of postdocs.

Tuesday, July 10, 2007

Informed Consent and Clinical Trials

This is an issue that has been bothering me for a long time, and I've decided to post about it after reading an article in Nature Medicine about a lawsuit the Nigerian government has brought against Pfizer.

There are a few main points that comprise the main issue, as I see it.

1. We need drugs for many diseases, and these drugs have to eventually undergo clinical trials in humans.

2. Many drugs being brought out now target diseases, such as HIV, that have a large number of sufferers in developing countries (the term Third World is a throwback to cold war terms and I think it is distinctly inappropriate in today's world).

3. Clinical trials need large cohorts of people, both those who have the disease and those who don't.

4. Drug companies want to save money on clinical trials.

All these parts of the problem are linked and interdependent and none can be cited alone as the reason for the increasingly popular practice of conduction clinical trials in developing countries.

I am not against the practice, in fact I am more or less in favour of it. For many years "developing country diseases" have been neglected in the drug development process largely because the countries that suffer the most often have the least resources to support the expensive process of drug development. As a consequence of that expense, many people in developing countries do not have access to many drugs. So, if clinical trials are actually held in these countries, it may make access to the drugs being tested easier in these countries. Also, the fact that the trials are conducted in these countries mean that drugmakers have to consider factors that they would not have otherwise, such as heat-stability of drugs in hot equatorial countries; cultural factors that may influence the taking of medicines with meals etc. That the drug companies are moving south and east purely in search of greater profits doesn't bother me so much, as long as the outcome is beneficial.

Anyway, I digress. The two core tenets of conducting clinical trials are informed consent and that no harm should be caused. Informed consent is obvious, the people making up the cohorts of the clinical trial should know what they are getting into. They should know that they face potentially lethal side effects, that the drug may not work, and that they may be in control groups where they receive only placebos. They should know all of these things, and should sign documents attesting that they know and understand these things and choose to participate in the trial willingly and with full awareness of possible consequences.

No harm gets a little more involved. Clearly, if the drug starts to show bad side effects during the trial, it should be stopped. All drugs have side effects, one has to weigh the relative benefits against the side effects, and call a halt when the the relative benefits are far outweighed by the negative effects. Also, if the drug works, then one cannot, by any ethical moral or human standard, continue to withhold the drug from ill people in the placebo group. Once you start to treat your control group, interpreting the results automatically become much harder to interpret. And how do you determine what has caused harm, the drug or the disease? Most people participating in clinical trials are very ill, its hard to say what makes them worse, diseases progression or treatment. Its a very tough call.

Informed consent is a much clearer issue. You just have to have it. Informed consent is valid when it is solicited from prosperous educated people who have resources and are willing and able to analyze the issue objectively. Is it valid when it is obtained from poor illiterate desperate people? Is it valid when sick, frightened people are offered the vague potential of a medicine that they would not be able to afford otherwise? Are they able to make the decision to participate in the clinical trial objectively and with a full appreciation of the consequences? Illness makes even the most coldly analytical personal more prone to emotional choices, what of people with no other recourse? Poor and desperate, the prospect of a cure is offered you, what would you do?

It is in these situations that drug companies should be especially vigilant about their practices regards obtaining informed consent. Sympathetic counselors, fluency in the local language and a clear unhurried explanation of all the consequences are absolutely vital. If there is any question at all as to how informed consent was sought and got, then the conductors of the clinical trial risk crossing the line between recruitment and outright exploitation. And that is what worries me about the conduct of clinical trials in developing countries. Huge numbers of sick people, less stringent regulations, less enforcement of what regulations exist: these are all the reasons that make developing countries such "desirable" places to conduct clinical trials, but these are all reasons that makes the conduct of the trials in these places prone to misconduct. Conductors of trials have to be extraordinarily vigilant to avoid abuse, my questions is are they always so?

I don't know and I don't pretend to know much about clinical trials and the ins and outs of the daily conduct of these trials. I am a lay person, but I am concerned. I want very much for my country and other developing countries to have access to valuable drugs and I can see the huge advantages of having drug trials conducted in these countries, as a scientist and a human being. I think that all of us who think about these things should be concerned and should ask the hard questions, so that drug companies and the governments of these countries feel the pressure of accountability.

Friday, July 6, 2007

TB slips out

I read a really cool paper in Cell last week, about the bacterium that causes TB, Mycobacterium tuberculosis (M.tb.). This bacterium is unique for many reasons, but I’ll mention only one here. M.tb. is well known for its unusual ability to live a long and productive life inside the cells it infects, macrophages. Macrophages are important cells of the immune system, and are necessary for both the early innate immune response and the later adaptive immune response.

M.tb is really good at evading both these responses, and it does so partly because it manages to take up residence within a special sub-compartment of the cell, called the phagolysosome. One could think of these sub-compartments, or organelles, as rooms within the cell. The phagosome is like an entryway, where stuff goes when it is first swallowed up by the cell. The lysosome is the place where all material goes to be degraded and recycled back to use. The interior of a lysosome is very acidic, which promotes its function but makes it very difficult for proteins or bacteria to survive for long inside. The phagolysosome is a fusion of both, a special organelle that only forms in cells like macrophages and is a distinctly inhospitable place, but M.tb. manages to hang on pretty well.

The absolute dogma through many years of M.tb. research has been that the bacterium lives inside the phagolysosome and doesn’t come out. It is thought to cleverly subvert other intracellular transport and delivery systems to obtain its nutrients while never leaving its den. That M.tb. lives in this “privileged” niche is the reason that is commonly cited for its ability to evade recognition by the immune system. Specifically, one arm of the adaptive immune system, cytotoxic CD8 T cells. Briefly, CD8 T cells have T cell receptors that recognize small fragments of proteins, called peptides, carried on the cell surface by MHC class I proteins (MHC expands to major histocompatibility complex, the main determinants of transplant rejection, another time!). CD8 T cells kill the cells that “present” antigen to them in this fashion, and are, as you can imagine, very useful in protection against many a pathogen.

Here’s the catch, as far as M.tb. is concerned anyway. Peptides that are presented to CD8 T cells are generated by chopping up proteins in the cytosol, the living room of the cell. The chopped up pieces of proteins are then moved into the ER (endoplasmic reticulum, the kitchen-cum-pantry), where they undergo some fine-tuning and latch on to the MHC class I molecules that will take them to the surface. If M.tb. is as good at hiding in the phagolysosome as it seems and never comes out into the cytosol, it is hard to see how M.tb. proteins come into the orbit of MHC class I.

And many years of research have said just that: M.tb. stays in the phagolysosome and doesn’t enter the cytosol. Good research too, extensive, well done and detailed and using diverse approaches. However, Nicole van der Wel and her colleagues have refined their detection techniques (essentially sophisticated microscopy, electron and fluorescent) to the point where they see something different. They find that while M.tb. does enter the phagolysosome very shortly after infecting and entering the cell, 48 hours after infection it is out and about in the cytosol. Some of the bacterium does stay in the phagolysosome, but much of it escapes, and eventually causes the host cell to die. Also, they find that it is the disease causing Mycobacterium tuberculosis and Mycobacterium leprae (leprosy) that can escape into the cytosol while attenuated vaccine strains like Bacille Calmette-Guerin (BCG, do you have the scar to show for it?) cannot do so. To tie the whole thing up nicely, the authors find that certain bacterial genes are necessary for this property and when these genes are deleted form the bacterium, it cannot move into the cytosol and cannot kill the host cell anymore.

So, to summarize, van der Wel et al show that contrary to widely believed dogma, M.tb. can escape into the host cell cytosol. This means that the bacterium may not be as able to evade immunity as thought previously. Also, given that only disease-causing mycobacteria can do this and that BCG does not, it brings into question the relevance of BCG as a vaccine, or even a model for studying TB. It is now much easier to visualize how M.tb. provokes a CD8 T cell immune response now that it has been shown to enter the cytosol. This is a really essential point, as the immune response to M.tb. is what causes the infamous granulomas, or patches, that one sees on the X-rays. Finally the observation that M.tb. that invades into the cytosol more often than not ends up killing the host cell goes some way towards beginning to explain the mysterious latency of the bug. M.tb. is latent in more people than it manifests as a disease in, and often it needs some kind of trigger for a latent M.tb. infection to become full blown TB. Maybe its because the bacterium lives in uneasy equilibrium with its host, killing its hosts when it gets too invasive otherwise just existing, and only becomes really infective when an external event disturbs the equilibrium. Time will tell.

Fantastic paper, just fantastic.

M. tuberculosis and M. leprae Translocate from the Phagolysosome to the Cytosol in Myeloid Cells

Nicole van der Wel, David Hava, Diane Houben, Donna Fluitsma, Maaike van Zon, Jason Pierson, Michael Brenner and Peter J. Peters Cell 129 1287-1298.