The Ways and Means of the Immune System

Wanted: Dead or Alive

2011-06-24T21:52:00.000-07:00

It would be very useful for the immune system to be able to discriminate between live and dead bacteria.

Well, that's pretty obvious.

Immunologists have long known that live bacteria induce different, and better, adaptive immune responses than dead bacteria. Again, it may seem obvious, but is hard to reconcile with current thinking about how adaptive, or antigen-specific, immune responses develop. Robust adaptive immune responses need two things: the antigen that makes antigen-specific T and B cells expand, and inflammatory signals, which tell the immune system that something wrong or dangerous is around and that its okay to try and eliminate the sources of the antigens they recognize.

(This is not the whole story, but its a good starting point, and the whole point of this blog is to try and understand the point of immunology and not to get hung up on details.)

Anyway, seminal and beautiful work by many people, primarily Charles Janeway and Ruslan Medzhitov (you'll definitely hear more about him here, I really enjoy reading what he writes), found that those inflammatory signals could be triggered by specific components of microbes, called "patterns". In other words, when the immune system ( the innate immune system, have I mentioned how strange I find these categorizations? I digress) sees a molecule X, which is made by almost all bacteria of a certain kind, it responds because X is a pattern, characteristic of "bad" bacteria. So if you combine foreign antigens and pattern X, you should get nice robust responses to the antigens because you have both antigens and inflammation.

And you do get beautiful, strong responses to antigens this way. The only problem is that dead bacteria usually retain their patterns, like X. So there must be something else that sets live bacteria apart from their dead counterparts, something other than pattern X.

In a simple, elegant study published in Nature, Julie Blander's lab at Mount Sinai found a possible candidate-a pattern that is characteristic of bacterial life, a vita-PAMP they call it ( not my favorite term, but...). They show that ribonucleic acid, or RNA is rapidly lost from bacteria when they are killed, and that if you just add RNA back to dead bacteria, they become as good at inducing strong immune responses as live bacteria. Specifically, they found that messenger RNA (mRNA), so called because they carry the information coded by a gene in a message that is "translated" into a protein, is a vita-PAMP.

What is so strange, and so cool, about their findings is that they found that all bacteria had vita-PAMPs and the ability to induce certain immune responses. Not just pathogenic, or harmful bateria, but al bacteria, including the billions that live in our digestive tracts and at our mucosal surfaces, our commensal families. Why then do we not explode in a mass of inflammation and immune responses-after all we share body space with billions of bacteria? Is it because of strict specialization and compartmentalization: are the cells that recognize vita-PAMPs far away from our natural bacterial buddies, so that their detecting vita-PAMPs is a sign that bacteria are where they have no business being? Or do our immune systems keep responding to vita-PAMPs at a low level, and so get de-sensitized? Or, to get a little fanciful, is it good for us to keep responding to some levels of vita-PAMPs all the time-keep the immune muscles warm and in tone?

Much food for thought. And the nice thing? All this comes from such a simple question and an old observation-someone just asked "But, why?"

(Kind of like-why do ultra-tired babies cry their heads off instead of going to sleep? It's so obvious, you're tired, go to sleep. Don't sit up in bed, throw all your cuddly sleep toys out of your crib and howl to the high heavens. Apparently it is not that obvious. Sigh.)

It's been a while

2011-05-26T20:59:00.000-07:00

It's been a long time since I wrote here. I started blogging as a new postdoc, to vent about the frustrations, and to join the community of scientists on the web who describe the vagaries of the scientific life.

I haven't enjoyed being a postdoc very much, and I'm distinctly ambivalent about still having the same job. There are many ups to being a postdoc and many downs, but I' not going to talk about them anymore, there are so many people who say it better. Besides, all that talking blinded me to why I do it in the first place: I think the immune system is pretty damn awesome, and I find something interesting to read about it nearly every day.

A lot has changed since I last wrote here: I have an energetic toddler, I'm far more downbeat about my ambitions to cure disease, I'm tired, I feel guilty most of time, and I'm afraid I'm losing my spark, the zip that makes my mind interesting and unique. All of which said, I find that I'm still jazzed about immunology, and I'm going to just try and focus on that. The ideas, the innovations and the incredible pace with which our understanding of the immune system progresses.

So the next post will be about my new favorite idea. And will be posted in a time period less than three years.

Ending a Statement With a Question Mark?

2008-04-23T08:10:00.000-07:00

Have you ever conciliated your way through a scientific discussions by ending negative statements or disagreements with an implied question mark? I do it a lot, and I'm not sure I like the reason why.

As a woman (and maybe as a man too, though I have not had direct personal experience with this, any insight would be welcome), I tend to walk the fine line between directness and conciliation. I am naturally emphatic, and used to state my opinions strongly-maybe too strongly-carried along by the force of my convictions and the absolute determination not to give in to anybody. Some of this crazy certainty faded with age and some wisdom, but I still am pretty definite in what I believe and inclined to be forceful in what I say.

One big reason why I stopped being loud and emphatic and thumping my metaphorical fist on the table is because I realized I hated being at the receiving end of such treatment. I hate being steamrollered, its uncomfortable and puts me off the discussion. I also found that not thumping table meant I could hear other people, a nice change. So politeness and a genuine curiosity to hear other people's thoughts started me off on my path of less declaiming and more questioning. As an added bonus, people warm to gentle conciliation more than they do to vocal steamrollers.

That there is the rub: within the reasonable demands of courtesy, how much should one conciliate? It's a reflex now, I always take the diplomatic path rather than just say what I think outright. I like to think that I stand by my convictions-I'm just more mellow about them-but is that really true? Have I gone too far down the road of conciliation? In lab meeting particularly, or during seminars, I ask questions and challenge people almost apologetically. In some cases, it makes the questioned feel more comfortable, and in some cases it makes them more dismissive of your question. Is a reputation for being thoughtful and a disinclination to put people on the spot worth being dismissed?

Why so I have this need to instinctively subdue my challenges? The saddest thing is that I think I do it because I am a woman. There are men in my group who are distinctly less indirect, often outright rude and in-your-face with their challenges and it doesn't affect the esteem in which they are held. And in the most bitter of stereotypes, when other women do the same they are called aggressive, bitchy and unpleasant. I used to be against overt feminism because I thought it was loud, exclusionary and exhaustingly unproductive, not to mention bound to get you laughed at. It galls me though that the natural instinct of intelligent ambitious women of my generation is to tone it down, to try and not become one of those women who became PIs in the 1970s and -80s. While I am certainly not a fan of rudeness or putting someone else down out of a sense of your own superiority, I am so tired and fed up of ending every sentence with an implied question mark.

This post is my 50th on this blog(I'm slow), and its also for my mother, the kind of feminist I would like to be.

A Link Between Environemental Toxins and Autoimmunity?

2008-04-15T21:45:00.000-07:00

The title of a paper in the advanced online publication section of Nature refers to a possible link between environmental toxins and autoimmune disease: an irresistible hook, and of course I could not resist. So followed some excited perusal of Veldhoen et al (doi:10.1038/nature06881) and another paper on the same subject, Quintana et al (doi:10.1038/nature06880), also in the AOP section.

So is there a link between environmental toxins and autoimmunity? Well, maybe, though I am not entirely convinced of that aspect of things, and here is why. Both papers discuss the effect of triggering the aryl hydrocarbon receptor (AHR) on T cells (description in the sidebar, for those of you are interested). The AHR, to my chemistry-ignorant mind, is a protein that binds hydrocarbon molecules with aromatic rings. The AHR is a type of protein, called a transcription factor, that decides when genes are turned on. In tune with this known ability of the AHR, both studies find that triggering the AHR on a subset of T cells called helper T cells turns on genes that influence the function of these T cells.

Helper T cells can direct the immune response along different paths, towards a more allergic response, one that is better suited to the fighting of infection, or towards a more inflammatory response which can result in the immune system attacking oneself—“auto”immunity. Helper T cells work by producing cytokines, small proteins that zip around the body carrying messages from one cell to another. Helper T cells that produce the cytokine IL-17, called Th17 cells, play a large role in autoimmune diseases: for instance, blocking IL-17 in a mouse model of multiple sclerosis, experimental autoimmune encephalitis (EAE), protects mice from getting the disease. Other helper T cells—regulatory T cells or Tregs—combat autoimmunity by battening down active T cells, and giving mice Tregs can protect them from a variety of autoimmune diseases. So helper T cells can go either way, either promoting or suppressing autoimmune disease.

Veldhoen et al find that triggering the AHR on helper T cells through its ligand FICZ* enhances the generation of both mouse and human Th17 cells. Treating mice with FICZ also accelerates the progress of EAE, suggesting that triggering the AHR enhances autoimmunity. FICZ is generated by UV treatment of tryptophan, an essential amino acid, and the authors suggest that it may be generated by exposure of the skin to UV light, thereby connecting environmental factors to an autoimmune disease. A connection I find a bit tenuous, but the idea is interesting and novel, and I am very curious to know what they find next.

Quintana et al present a more detailed study, with results that suggest something different. They find that triggering the AHR through a more famous ligand, TCDD**, leads to the enhanced development of Tregs, the tranquilizers of the immune response. Now, TCDD is thought to be very toxic, and is found in the environment (most infamously, in Agent Orange), but it seems to actually counteract autoimmunity, because treating mice with TCDD considerably slows down their development of EAE. Qunitana et al also agree that FICZ treatment enhances the generation of Th17 cells, and simultaneously retards Treg formation.

Both compounds bind to the AHR with different affinities, and possibly in different ways, which might explain their opposing actions. In any case, aromatic hydrocarbons are capable of modulating the immune response and shaping its eventual outcome, an exciting and novel set of findings. That they have such strong effects (reversing or accelerating EAE is pretty strong) certainly suggests that they bear further study, and back up the idea that things in the environment can have an effect on our immune systems. After all, having too many Tregs because you were exposed to TCDD may save you form some autoimmunity, but too-tranquil T cells are not very good at fighting off infections. Similarly, too much sun can turn tryptophan—which we absolutely need—into FICZ, which can then diffuse off into our bodies and do something to exacerbate autoimmunity somewhere. Food for thought.

*6-Formylindolo[3,2-b]carbazole (FICZ)
**2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin)

The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins
Marc Veldhoen, Keiji Hirota, Astrid M. Westendorf, Jan Buer, Laure Dumoutier, Jean-Christophe Renauld & Brigitta Stockinger
doi:10.1038/nature06881

Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor
Francisco J. Quintana, Alexandre S. Basso, Antonio H. Iglesias, Thomas Korn, Mauricio F. Farez, Estelle Bettelli, Mario Caccamo, Mohamed Oukka & Howard L. Weiner
doi:10.1038/nature06880

Multi-tasking Madness

2008-04-12T08:27:00.000-07:00

"I hate running PCRs to type mice, because I could have been doing X experiment instead."

No I could not have done X experiment instead. I have two hands and one head and unless I can master the usage of my toes, its one thing at a time. The typing of mice (or testing of serum for tissue culture, restocking of boxes, running of FACS samples) is as essential as anything else, despite being boring as hell. This feeling of "I could have been doing something else, obviously more useful or constructive" is a fallacy, and a stressful one at that.

I feel such a strong impulse to multi-task all the time, but often its the multi-tasking that slows me down. I am naturally a quick mover and I tend to dart around doing things, keeping myself busy. This tendency goes to the extreme in lab, where I don't feel occupied unless I have three threads running. And guess what? I make mistakes and have to repeat things, which adds to my not-inconsiderable work load (I have a particular PCR jinx).

There is this drive today to get things done, faster and better, now instead of soon. Lab work is easier and research is more competitive, so it's easy to see how this has come about. Is it constructive though? If something takes a certain amount of time to do, what is the point of rushing it or wishing it along faster? Or, inserting other tasks into the gaps? One does get more done eventually, but at more cost to oneself. And is that really efficient in the end?

I have discovered that I do not like operating at full stretch all the time. Sometimes I really enjoy it, I am in the zone and buzzing. But the rest of the time, I think my research would be better served by my working with more discipline. Unfortunately, when one can work in the zone, one starts to expect it of oneself always, and that is just not realistic. So I am going to run PCRs and DNA gels, and only those, this Saturday and look out of my window at the sunny trees.

(I might reshuffle my papers, read a few, trackback a few references, no matter.)
(And yes, its Saturday, I know)

Postdoc as Domestic Goddess (or God)

2008-04-03T18:57:00.000-07:00

Skill 1: Combines ingredients with precision, follows instructions to the letter, but adds the occasional touch of improvisational flair with interesting outcomes. Occasionally works with the reagents at hand instead of what may be ideal, with perfectly acceptable results. Not afraid to use alcohol as necessary.

Skill 2: At the end of a process, puts everything away in its allotted space, wipes down all work surfaces, neatly collects trash. Surveys area, spots missed spots with the eagle eye trained by years of experience. Has no patience with others' sloppy work areas, is disgusted by ill-maintained and unclean surfaces. Is zealous about the weekly wipedown. Again alcohol accompanies as needed.

Skill 3: Monitors the health, diet and breeding habits of several small dependent creatures. Always has a mental map of which little creature is where.

Skill 4: Plans menus and processes days ahead. Has activities allotted to each day, to be carried out according to a strict schedule. Adheres to said schedule with admirable focus.

Skill 5: Does the shopping for supplies as needed. Prefers to do so on a regular schedule (schedule is important), but is willing to pop down to the shop when running short. Combines trips to shop with transport of laundry.

An alternative career maps itself out...

Blog List

2008-04-02T17:55:00.000-07:00

Oh I am so stoked by this new feature on blogger (Draft blogger for now), it imports blogs from my google reader and posts them in my blog list! That is so good because I could not figure out blogroll and have been feeling bad about being a lazy one who hasn't manually entered everyone yet.
Love it. Because you are all awesome bloggers, and I am so glad to have found you.

Paranoia and the Destruction of the Soul

2008-04-01T17:54:00.001-07:00

I wanted to write a happy post today since I'm in a really good life-mood (research mood is low-level fatalistic tending towards zen acceptance), but I've been thinking about paranoia a lot lately. A good friend and colleague is having a really hard time in lab because they feel like slices of their project are being given away without their consent. And they are right, the project is hard to partition in the first place, and there are three bright, invested individuals working on it at the same time. However my friend has made particular innovations, and is uniquely qualified to do some things, that they had suggested in the first place. This slicing and dicing has been going on for nearly two years now.

Enter full blown, pull out all the stops paranoia. Behaviour-altering, mind-bending paranoia. I won't share reagents, I'll never discuss a good idea in lab again paranoia. It's getting to the point where they are saying and doing things I don't think are characteristic or believable, and they are morphing into human jelly. And I just want to stand up and scream at them to stop it. I have tried to bring up the subject more gently and constructively than that, but an unavoidable side-effect of paranoia is that one perceives judgment and betrayal in what everyone says. So what do I do?

I think paranoia is the single most destructive emotion one can give in to. I know this regarding emotion from deep personal experiences; and regarding work from having been scooped three times in grad school. I have worked with many brilliant and paranoid people, and the one thing that always leaps out at me is the amount of energy they waste in spinning their paranoid wheels. It is such a waste of all that brilliance, all those (rapidly diminishing) neurons firing salvos of negative emotion. It drains you, makes you bitter, changes you in fundamental ways, alters your equation with everyone you work with, and is utterly pointless in the end.

It is both insulting and patronizing to tell someone they are being paranoid when they feel, legitimately or otherwise, that they are being deprived of what is rightfully theirs. However protecting one's territory can go too far, and when that line is crossed, it really messes things up. Academic research as it is today relies on the goodwill and respect of one's peers, and paranoia and its close companion suspicion, are the surest way to erode all goodwill and respect that anyone has for you. And in the end, it destroys your own self-respect, and no paper is worth that.

The Endgame

2008-03-29T13:00:00.000-07:00

I've been thinking about "the endgame" a lot these days.
(Style note: I swear not to begin anymore posts with "I've been thinking about..." anymore, it might be time for "It was a dark and stormy night...")

What is my endgame? With this postdoc and all that I am doing now, involving low-level politicking, writing etc. Let's say its an academic position in India, doing cutting edge research in infectious diseases. What then am I doing to go there? How specifically do I go about getting there, as opposed to just trying to do good research and sending up prayers to the gods of funding and publishing?

This is a novel way of thinking for me, and one that I think should have started a long time ago. I drifted into science because I was bright and academically-inclined. The drift wasn't aimless, it was influenced by the fact that I love talking to intelligent people about intelligent things, my mother is a scientist, and I thought science and scientists were so cool. I came to the US because it was kind of the done thing at my (competitive) college: my friends all wrote the GRE and sent out applications. Most of us did well, and nearly all of us went to good schools. I floated into biology because I liked both biology and chemistry, and biology incorporated elements of chemistry. I went where I did for grad school because they offered me a place, and it seemed really cool.

I don't mean to say that I just faffed through life and things happened to me. I think it was more that I hadn't found all the the dislikes and loves that I have now. I liked most things, I was interested in studying most things, and I looked on travelling as an adventure. I had no conception of the mind-bending cultural changes I was about to face, and I did not think for one second about how hard it would be to consider living and working in India after nearly ten years as an American scientist. I am pretty fortunate that things have turned out well, and I am very fortunate to have discovered both ambition and immunology. Fulfilling that ambition would be much easier if I had actually started thinking about my life and career choices more actively a long time ago. I didn't, though, and whether that was a function of culture, personality, upbringing, I can't say with certainty. But it is what it is, and I'm going to find out, soon enough.

Now I know better, its all about the endgame. Which includes immunology, India, a family, my large and extended family, writing, travelling and a faculty position.

Too ambitious?

One Week at a Time

2008-03-13T17:36:00.000-07:00

So my last post was about how charged up I am about an academic career.
With that in mind, let me describe my week:

Saturday: Transfected cells, let's say A cells, to use for experiments. Fed them, put them away, felt very good about the adventurousness of the experiment being undertaken.

Sunday: Realized while 40 miles away that I had completely forgotten to get another set of cells, call them B cells, ready for the experiment. B cells are needed for the final step of the experiment. Crap. Bummer. Well will just have to get them ready on Monday.

Monday: Got B cells, and third and final type of cells, called C, ready. A cells, of course are nice and confluent and ready to use, only I am not going to use them. F*cking A. Efficiently set up more of A cells to start the whole things again, but nested so I don't waste any time.

Tuesday: Set it all up, A cells, B cells and C cells. They are happy in the incubator, ready for me to read them tomorrow. Whew, that didn't work out too badly did it?
Transfected second batch of A cells.

Wednesday: Started off readings, all negative. Completely, and it doesn't even look like A cells make the protein I transfected into them (which is the whole entire point of transfection!). Double sh*t. No f*ck it, triple sh*t. Then the blinding realization dawns that I threw away my leftover B cells after using them yesterday, and I don't have any more going. There are no words, only anti-endorphins.

Thursday: Started round 2, with some alternative B cells. Also, smartly decided to check whether transfecting served any purpose this time, since I screwed up the previous time and let A cells go much longer than they should have. Turns out that transfecting A cells doesn't work when I do it (though it is routine procedure in my lab). Nothing, nothing at all. There's no point in doing the next step, with alternative or otherwise B cells. Now what? Blog, I suppose. Maybe some beer.

Friday: Strategize? Re-evaluate? Retire?

I am a shining example, I tell you.

I Like Being a Scientist?

2008-03-07T11:47:00.001-08:00

Something interesting happened to me recently. I've had a busy few months: I went to India, for a wedding (mine), came back to the US and to work. Pounded out a bunch of experiments before I left and few since I returned. Struggled badly with jetlag (it only gets worse!), cultural disaffection, being tired and ill, loads of pressure from the boss and truly pernicious lethargy.

And now I want to work. I want to do experiments, read immunology, gossip about science. I even looked up job openings in India, because I think I want to start my own lab there. I want to keep being a scientist.

It's difficult, rarely rewarding, massively underpaid and a niche profession if I ever heard of one. My job prospects in my home country are limited, to say the least, aside from the fact that I have never actually worked in India. I have done all my research in the States and am, for all practical purposes, an American scientist. I have a new husband and our busy life together. I need some sexy papers, and some powerful, original ideas. I need to push and slog and labour till I can't stand it anymore and my family can't stand it anymore.

Why would I do this? I guess its because I really like being a scientist.
Who knew.

Managing Time

2007-11-21T08:50:00.000-08:00

Long blog absences generally mean that someone isn't doing a very good job of managing their time. Sighs. It's been a busy-postdoc phase, which is a good thing because it means that I actually have work to do on multiple projects. It also means, however, that I have really had to re-evaluate how I manage my time.

As an experimental scientist one's single greatest asset is the ability to manage time. I've always been a fan of schedules, I used make little timetables for my day even as a little kid. I don't make schedules because I like to, I do it because I am chronically lazy and unless I set myself concrete targets to meet (preferably in writing), I will waffle and procrastinate. As a young grad student I was high on "doing science", and thrilled with the maverick aspects of research and liked to "go with the flow", "see where my data lead me" etc etc. It didn't work out so well as you can imagine.

So, I started making monthly schedules with the invaluable help of iCal. First big roadblock: my work computer and home computer did not have the same calendar entries or alerts. I tried synchronizing them, then decided that the best possible way was to have a paper copy. And that system has served me extraordinarily well ever since. I print out a monthly calendar with standing meetings on it, and then add all my experiments and other things on it. In pencil, because I do chop and change my plan a lot. I post that schedule on the corkboard above my desk and it stares balefully at me all day.

That worked really well in grad school, where I usually had to plan my experiments up to three or four weeks in advance, coordinate cell sorting schedules, GM-CSF addition, FACS time (the bane of all immunologists) etc. Now I find that I need to plan three months ahead because of the nature of the experiments. Three months! It's crazy and more anal than I'd like, but the whole house of cards is distinctly precarious when I don't plan that far ahead.

It really irks me to have to map out so much so far ahead. I detest feeling circumscribed by my schedule. Seriously, I am now one of those people who has to check their calendar all the time. There aren't FACS time calendars printed for the time I need to use them. The plain truth is, however, that my productivity has shot up since I started planning so far ahead. And I can say now, with relative confidence, that we can go out of town at X time since I won't have a pressing cell commitment then. Along with the calendar, I make a list of objectives for the next two months. What are the questions that need to be addressed now, how can I prioritize them, and what should I do when to optimize the use of my time. Together with the calendar, I felt really on top of things, on top of my game and in charge of my science.

Then I find myself mentoring two rotation students (first year grad students checking out the lab) and all my carefully made plans crumble. I am here all the time, rushing rushing rushing, trying to perform mad feats of time-juggling and trying to keep four projects and three people on track. And I have to say, it's not going to happen. This has exposed the crucial flaw in my scheduling system: inflexibility. If you're just one person, you can organize your time perfectly, plan all you need to do and execute with all the precision your heart can desire. You can't do that when you're mentoring other people. So I suppose the choice is whether you mentor people or not, and I feel very strongly that one should mentor, having been the recipient of some kickass mentoring myself. I am forced to conclude therefore that while planning and time management and the key to being productive in lab, I must schedule some wiggle room.

Responsibility for Scientific Fraud

2007-10-31T14:09:00.000-07:00

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.

Thoughts?

D'yer Mak'r

2007-10-26T08:02:00.001-07:00

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.

The Battle of Evermore

2007-10-18T09:39:00.000-07:00

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…

Good Times Bad Times

2007-10-11T12:31:00.000-07:00

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?

What is and What Should Never Be

2007-10-05T11:09:00.000-07:00

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?

Hm.

Stairway to Heaven

2007-10-05T10:58:00.000-07:00

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

From Schmutzie

No Quarter

2007-10-03T09:15:00.000-07:00

(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.

When the Levee Breaks

2007-09-26T08:38:00.000-07:00

Plug it as best you can and keep going.

This is probably the best, and only advice I would have to give to an emerging scientist. This is also the most valuable lesson I have learned over the years from my various mentors. I don't think it was explicitly stated as such, and certainly not in the words of Led Zeppelin, but it was a strong message I got.

I did my Ph.D. in a fairly unusual situation. I was one of very very few students where I was, in a very postdoc-heavy environment. Some of the labs in Ph.D. place didn't had only postdocs and technicians. It was an intimidating environment in the beginning, especially when I was a mousy first-year. But what happened over they years is that I ended up having a plethora of mentors.

I learned how to do FACS from one postdoc, dissect mice from another, inject mice from yet another. I developed a deep respect for "bullshit detectors" and a strong seminar habit (which I really don't get enough of here), learned to ask "Why?" instead of "How?". I learned to think ahead, to plan for figures, to never run out of mice. I learned how to deflect tantrums, how to stand up for myself, how to speak at conferences, all from my Ph.D. advisor and various postdoc mentors. I didn't really have any interaction with student peers, didn't have a student milieu, but it turned out to be a phenomenal experience overall.

Not that it was all happy days and everybody being helpful. But when times were hard and feelings were hurt, the people I really admire kept going. They put their heads down, ignored their feelings of being neglected by the boss, ignored ridicule from other lab members (yes, ridicule) and kept working, and working smart. That's the best thing to do- let the work speak for itself. Don't let yourself drown when the levees break. Swim.

Some of the nicest people were the most useless as mentors and some of the most seemingly curmudgeonly the best mentors. The hard lessons are not learned easily. The mentors I have the most respect for now, in retrospect, are those who told it like it was. Directness can be unpalatable, but it is the only way to clarity, scientific and otherwise.

Another thing I feel strongly about is that you have to pass mentoring on. If you have been treated well, you have to treat people well. If you have not, you have to be extra vigilant not to take it out on people who you will be mentoring. Everyone starts somewhere and impatience is absolutely incompatible with mentoring. This may be seem obvious, yet it is surprisingly easy to forget.

Its easy to resent time taken away from experiments, its easy to be annoyed by constant interruptions, I certainly am. That doesn't mean that one should indulge that annoyance.

So as a mentor, I want to be direct, firm, hopefully gentle, accessible. But most of all, I would like to be constructively critical, and pass on the importance of a bullshit detector. Let's see.

scientiae-carnival

Communication Breakdown

2007-09-25T13:58:00.000-07:00

I'm having some writer's block, partly because I have resolved not to complain and partly because the postdoc work curve is on the upswing. Up up towards the ceiling, a good thing overall except for the constant ambivalence towards said work.

Anyway, to make this more fun, October is Led Zeppelin song titles month. I'm going post with Led Zeppelin song titles and incorporate the title into the post. It should serve to repair the communication breakdown (see?) of this past month. Oh, and did I mention that the posts will continue to be about postdoc-ing and Immunology? Let's see how it goes-I see vistas opening up. No quarter, Over the hills and far away, Rambling on, the Battle of Evermore... If you have a song you'd like to challenge me with, go ahead, leave me a comment.

So the major work upswing has been because my boss and I have somehow resolved a major communication breakdown. I have been miserable here because I have been feeling underappreciated and fundamentally not respected. By my boss. Also, said boss has also been dismissive of my ideas and has not been receptive to me branching off on my own or following my instinctive interests, which are in infectious diseases and has been pushing me to work on boss's own interests, which are classical and molecular.

Suddenly boss is listening to me. And seems ok with, even very mildly encouraging of my pursuing something at the juncture of infectious disease and classical immunology. Not too much improvement in the overt respect and appreciation department, but that may be a function of temperament. I am flabbergasted, and thrilled! It's a little sad what I consider an improvement, given the aforementioned lack or R&A. But I'll take anything!

What caused this? Is it because I stood up for myself? Mildly and politely, but I did. Is it because I was direct and stated (repeatedly) that while all the classical stuff was all very well but since it is the boss's thing I couldn't possibly take it with me to start my own lab (if and when)? Because I said that I was interested in this and would like to take it with me? Because what I am suggesting will be a hot thing to put in grants? Because the boss is happier with life and therefore finds it easier to interact with us?

A combination of these I think, with grants and mood probably higher on the list than the rest. Food for thought, complaining does not achieve much, communicating does. Hm.

Onwards...

The Rights of Native Indigenous Peoples

2007-09-13T11:23:00.000-07:00

The UN just passed a non-binding declaration supporting the rights of native indigenous peoples. 143 members of the general assembly voted for it, 11 abstained and 4 voted against: USA, Australia, Canada and New Zealand.

Wow.

Postdoc Carnival: What's up Postdoc? August 23rd

2007-08-23T10:07:00.000-07:00

Hello everyone,

It's always a joy to host a carnival where you read things written by your peers that are so insightful, truthful and enjoyable. Thank you everyone who wrote to me with posts and those who suggested posts, and without any further ado, the carnival.

Regrets Regrets

I wanted to know what all of you would have done differently if you could, and the spectrum of answers was fascinating. Dr. Brazen Hussy wouldn't change a thing, barring the occasional drunken quarrels with her advisor. Day by Day wouldn't change much either in the balance, she regrets only not spending enough time with her friends from grad school. Lou proposes that we all appreciate the here and now and learn from our pasts rather than regret them, and Propter Doc has a detailed and insightful analysis of what she would have changed given her current perspective. Katie at Minor Revisions has a frank and honest essay on regretting the time she has wasted and the questions she should have asked. And comes up with one the most memorable quotes I have heard in a while: "Post-docs are a renewable resource here." and goes on to compare postdocs to plankton. Fabulous and fabulously apt. Ragey One, Apparently and I do have some regrets, Ragey would not have accepted her current position knowing what she knows now, Apparently would have done her postdoc experience differently, and I would have interviewed more.

Dealing with other diverse subjects, other postdoc or former-postdoc bloggers have some great things to say. Sunil at balancing life wonders why Ph.Ds are so long, Incoherently scattered ponderings has some advice for what not to have on a CV and YoungFemaleScientists discusses whether its easier for foreign postdocs to find jobs here as opposed to US postdocs looking elsewhere. Marianne at the Eternal Postdoc tells us why being a postdoc is so hard, and Chall at Dreams and Hopes of a Scientist believes that your PI will find it easier to believe in you when someone else does. Chris at Highly Allochthonous finds that the postdoc is willing but the equipment isn't and a group of postdocs formed the postdoc union (wonder how they are doing?). Also, no to be discriminatory, but I have to mention some lovely women in science, Micella Phoenix DeWhysse at Science Careers has a whole series on Educated Women, here's one, and women in science as always has cool things to say.

And finally, the utterly apt and necessary PostDoc Oath, from the Girl from Ipanema. Say it with me everyone, " I X postdoc, do solemnly swear that..."

What would I have done differently?

2007-08-23T07:25:00.000-07:00

Interviewed more.

I don't believe in regrets and hand-wringing. I am self-aware enough to know that I made an informed choice and I saw most of the red flags in my current lab when I interviewed. I didn't expect them all to be true, but that is a different matter.

I interviewed over one long weekend, in one area. I did restrict myself geographically for personal reasons, and that geographical restriction is turning out to be the best past of this experience. Anyway, over that weekend, I interviewed with five PIs and three labs. One experience was excellent, saw some potential problems, figured awareness was half the battle. One experience was really good, but I would have ended up being the senior person in the lab and the PI wasn't even directly offering me the job anyway. The other three were washouts. I was already pretty fed up with the process, because I had a few pre-screening rejections based on the tight funds at the time and my average but not sexy CV. So I didn't send out more applications and accepted offer from said excellent interview experience.

Red flags and all. And everything I thought might possibly go wrong did. Everything possible. Which really sucks, but I thought they were all possible. I also think that every lab has its, shall we say, quirks. I didn't expect the personality of the PI and the community of the lab to be this negative. I have some wonderful colleagues, so it makes it easier, but otherwise, not good. And the general research environment is not conducive to one's greater professional development.

So, I made an informed decision and took a chance, it didn't pan out. I'm dealing. But, in restrospect I should have interviewed more, seen more places, other labs, other dynamics and then decided.

Oh well.

The Damage Response Framework

2007-08-21T09:20:00.000-07:00

The Damage Response Framework of Microbial Pathogenesis is an idea, put forward by Liise Anne Pirofksi and Arturo Casadevall in 1999. I first heard of it when I heard Arturo Casadevall give a talk: and what a talk! If you ever get to see him speak, do so, its well worth it. The point of this idea, or framework of ideas, is to find a way to describe “pathogenesis” in the most universally applicable way.

What is pathogenesis?
It means the genesis and progress of disease. A pathogen (as described in the sidebar) is an organism that causes disease, a simple enough definition, and fairly all-inclusive one may think. Maybe not. What about an organism that doesn’t cause disease in a normal healthy “immunocompetent” host, but causes disease in hosts that have deficient immune system fro some reason? These normally harmless microbes cause harm only in immunocompromised individual (Immunocompromised: possessing a compromised immune system. A fine example of the immuno-rule, if you want to make a term immunologically relevant, add the prefix immuno to it). An extreme example from Casadevall and Pirofski: harmless useful baker’s yeast Saccharomyces cerevisiae is considered a non-pathogen most of the time, in fact we consume it with great gusto. However, in some severely immunocompromised people, it causes disease. So is it a pathogen?

The Damage Response Framework
The key words in the previous paragraph are immunocompetent and immunocompromised, words used to describe the host. As illustrated by the baker’s yeast example, a “non-pathogenic” microbe can cause disease depending on the immunocompetence of the host. So, the pathogenicity, or disease-causing potential of a microbe is partly determined by the immune state of the host it infects, and a disease is the outcome of the interaction between the host and the microbe. This is the (paraphrased) first tenet of the damage response framework. This may seem obvious, but it is a really novel way of looking at disease, as the interplay between the host and the microbe, with the microbe contributing virulence, and the host contributing either resistance or susceptibility. It is a fine balance in other words, with the occurrence of disease depending on the balance between said virulence and susceptibility at any given time.

The second tenet of the damage response framework refers to the definition of disease itself: that the degree of disease caused is determined by how much damage is caused to the host. If one accepts that individuals have different susceptibilities to a certain microbe, then is follows that they will be affected by it to different degrees. Some individuals will show no symptoms despite being infected, some will show moderate symptoms, and some will be felled. They are all infected, does that mean that they all have disease? Not if one uses the damage response framework to measure disease. It doesn’t matter if an individual is infected, i.e. the microbe has entered their body, it only matters if their body has suffered damage, and to what extent.

The third tenet of this framework is that the damage caused by infection with a microbe can be caused either by the host or the microbe. Microbes can cause damage in many ways: they can kill host tissues, they can form big aggregates that physically impede blood flow or digestion, they can alter the basic metabolic balance of the host. The immune system is fast, robust and precise for the most part, however, it works by sending cells and cytokines out into the body to whirl around and do their thing. Immune cells eliminate infection by killing host tissues that are infected; it stands to reason then that there will be some collateral damage. This collateral damage can be minimal and go unnoticed, or it can be measurable but worth it because the microbe is eliminated, or it can be so extensive that it causes most of the damage to the host. Tuberculosis is a good example of the third case, the granulomas that are such distinctive features of clinical tuberculosis are large collections of highly activated immune cells, raring to go and damaging large swathes of the host along the way.

The Practical Applications
The most useful direct application of the damage response framework is to eliminate the subjective classification of microbes as strong or weak pathogens, as opportunistic pathogens or non-pathogens. This is achieved by using a new system of classification (because everyone wants to be Linnaeus!). The damage causing ability of a pathogen is plotted on a damage response curve, and the pathogen is classified based on its characteristic curve. The curves plot host damage and benefit on positive and negative y-axes respectively and the host immune response on the x-axis, going from weak to strong. I don’t want to reproduce the figure from Nature Reviews here, but I’ll try and describe the curves. The most easily visualizable are Class 3 pathogens that have a U-shaped curve, with high damage caused when the host immune response is either too weak or too strong. The difference would be that the damage is caused by the microbe when the host response is too weak and by the host when the response is too strong.

These curves are really nice and interesting, but ironically, their main weakness is that they are too subjective. Strong and weak are relative terms, so these curves have limited application until we can quantify both damage and the host immune response in amore universal way. Another thing is the role of time. Infections take various courses over time, for example some viruses infect the host and become latent, hiding out in the host till they become activated upon which they cause damage. If the host immune response manages to overcome the activated virus the damage is limited and the virus reenters a state of latency, and has the potential to reactivate, propagating the cycle. A necessary component of the damage response curves is time then, on a third axis. This is probably pretty complicated computationally, also we I don’t really think there is enough data yet to make these for many pathogens. Especially since data needs to be collected with these curves in mind, a mindset change that yet needs to happen. Effectively, we would also need a massive though exercise in which we place all the data we have on microbes and the host responses they provoke together with the damage they cause are placed in a kind of giant multidimensional matrix and look for correlations and points of intersection. The biologist in me quakes at the scale, and the extremely rudimentary mathematics training I have had leaves me bug-eyed at the thought.

Extolling the coolness and a Summary
The Damage Response Framework of Microbial pathogenesis is incomplete and imperfect, but it is simple, clear, and phenomenally novel in its simplicity. It takes into account the interaction of both the host and the microbe, for after all they both affect each other constantly and while convenient, it makes little sense to treat them as separate independent entities while studying disease. I like to think of the host and microbe as trains on two separate but curving tracks. The host is headed towards a state of susceptibility and the microbe towards fitness to cause damage. At a given time, the curves of the tracks get close enough together and if the host train loses its balance on the track a little, becoming sufficiently susceptible, it collides with the microbe train and damage results. The extent of the damage depends on the angle of the collision (host susceptibility) and the momentum of travel. A limited and involved metaphor, but it helps me to visualize these interactions.

If you’d like to read about this idea in Pirofski and Casadevall’s own words, a great review is in Nature Reviews Microbiology in 2003, Volume 1, page 17. I’ve only skimmed the surface, there are so many implications and possible applications- not to mention caveats- that I haven’t gone into. It’s a seminal idea, and makes for very interesting reading and thinking.

Postdoc Carnival: (Renewed) Call for Posts

2007-08-20T19:03:00.000-07:00

Hello All,

We are definitely entering the plea category. If you have anything you'd like to say, or have already said, about postdoc-ing or postdocs, send me an e-mail with a link to

veoclaramente@gmail.com

by Wednesday night. For the Carnival to be posted on Thursday the 23rd.

Looking forward to it!

60 years

2007-08-15T08:58:00.000-07:00

SIXTY YEARS

Never feel bad anymore?

2007-08-14T13:56:00.000-07:00

The saddest happy song ever.
Island in the Sun by Weezer “..We’ll never feel bad anymore..”. Lovely fifties-sixties-ish chords. The “ hey hey”. Gets me every time.

“…We’ll run away together
We’ll spend some time forever
We’ll never feel bad anymore…”

Definitely not one of those days. Feels like I will be borderline bored forever. I know that’s not true, it’s a phase of the project, It’s all me really, I should plan better, I should be proactive, do more, fulfill my potential.

Don’t want to. Sighs.

Off to culture cells.

The Lab Wardrobe

2007-08-13T10:00:00.000-07:00

I played against type today, I am wearing a skirt, pretty shirt and cute shoes. To Lab. It's a good thing I have a lot of computer work planned!

Ah dressing like a scientist. The bleach-proof scruffy eternally dreary clothes. To be honest, there is something to be said for jeans, t-shirt and sneakers, after all that takes care of the general ick factor of exposed skin in the animal room or the slight overall scariness of working with radioactivity. But how long can one go on dressing "like a scientist"? Company t-shirts, jeans from six seasons ago. I'm tired of it, I have a whole wardrobe that doesn't get worn enough.

I think the true revolution is the ballet flat. They are great! Closed toes, flat, comfortable and go with everything. Practical and attractive, imagine that, whole new worlds have opened up. Bringing on the new wardrobe...

More on Illegal Immigration

2007-08-09T14:14:00.001-07:00

Something that concerns me a lot, as you can probably tell.

Today's Editorial in the New York Times

I could not agree more. Their basic thesis for those who may not be able to read it is that the US government's current policy about illegal immigrants is based on punishment and making people's lives miserable. I quote

Their one big idea is that harsh, unrelenting enforcement at the border, in the workplace and in homes and streets would dry up opportunities for illegal immigrants and eventually cause the human tide to flow backward. That would be true only if life for illegal immigrants in America could be made significantly more miserable than life in, say, rural Guatemala or the slums of Mexico City. That will take a lot of time and a lot of misery to pull that off in a country that has tolerated and profited from illegal labor for generations.

The American people cherish lawfulness but resist cruelty, and have supported reform that includes a reasonable path to earned citizenship. Their leaders have given them immigration reform as pest control.

The thing is that this article is such a great example of American generosity. How many countries would be so generous about this issue? Do I think that governmental policy should be more generous? Resoundingly, yes, partly due to a visceral and admittedly unfair feeling that this whole country is founded on immigration and therefore has more of a responsibility to immigrants now.

Its a nice article at any rate and a strong statement from an extremely influential media source.

edited to re-format link

Call for Posts: Postdoc Carnival August 23rd

2007-08-08T10:04:00.000-07:00

I am going to host the next What's Up Postdoc? carnival, and here is a call (appeal?) for posts.

The theme? What would you have done differently? If something, why and what? And if nothing (lucky you!), why?

Feel free to ignore the theme, and just write. Or send something from your archives. I'd really like to hear what you have to say.

E-mail posts to me at veoclaramente@gmail.com

Thanks and Happy Writing!

Stresses and Professionalism

2007-08-08T10:00:00.000-07:00

Dissatisfaction is a common theme these days, whether the speaker/writer is a postdoc, a student, a financial professional, a software engineer, a insert-what-you-will-here. Which begs the question why? Is it because as a generation we have had things relatively easy? The struggles that may have defined life in earlier times are certainly less relevant to our lives, but we have a different set of stresses to deal with. Some are unique to the growing phenomenon of immigration, or migration, some are a function of increasingly isolated living situations and more nuclear families, some are certainly due to the fact that the bar for success is higher these days, to list only a few.

The question then is to what extent should these stresses influence one's performance professionally?

An individual is only as effective as the the sum of the stresses they are under. Simply put, one's life influences one's work. Some are better at compartmentalizing than others, and the result is often that they are able to separate the stresses of not-work from those of work, what is often the key to professionalism. And, as I've said before, I believe that professionalism is absolutely essential, both to work well and to maintain a pleasant work environment. However, are there circumstances when the stresses so far outweigh one's wish or ability to remain professional? What then?

Some obvious examples (only for the purposes of illustration!) that come to mind are pregnancy, clinical depression, serious illness, the serious illness of a family member. Many women don't have any problem working as usual through a pregnancy, what of those that are cripplingly sick? Or have complications that require them to take a lot of time off? And depression? Depression has degrees, and there are degrees of depression that are paralyzing, what then? If a colleague is seriously ill, its easy to see a way to be understanding, what if its a parent or grandparent? Is sympathy limited then?

For that is what it comes down to in the end, the ability to relate to someone's difficulties in a certain situation. It is much easier to make allowances for a colleague when one has been in a similar situation, and much harder to do so when one has not. Men, and many women, can be less than understanding about pregnancy related problems, and depression is such an amorphous thing that is is often quite difficult to feel for it, let alone understand it. Specific examples aside, what may not seem as stressful to an outside observer may be unbearably intense pressure to the person going through it. And it will, absolutely will, affect their work.

Some people have better coping mechanisms, for whatever reasons, physiological, emotional, mental or physical. It is inherently unfair that people who can cope better get less of a break, but that is the way it is. They need fewer allowances made for them, and often can be more professional in their approach to work, but they should not have that same expectation of everyone else. People are quick to perceive an inequality or an injustice, and are often justified in feeling put upon. But that does not necessarily mean that the people who seek more refuge from their stresses through less involvement in their work are doing so deliberately or as a means towards getting favours.

So my contention is that compassion is as essential a part of being professional as drive or discipline. No, one does not have to be friends with or confidantes of one's colleagues, but a little compassion for their troubles does not hurt. There are some stresses that do justify the loss of some professionalism. Burnt out late stage grad students, overloaded working parents, utterly demoralized postdocs, disorganized PIs who have lost control of their labs, all of these are real, if regrettable. It is hard, if even possible, to be patient with these people, especially if one hasn't been through these experiences personally. That is no reason not to try. And there will always be people who abuse compassion, with endless excuses and complaints, but is that reason not to be compassionate to anyone?

"Illegal" Immigration

2007-08-07T21:23:00.000-07:00

A thoughtful adn though-provoking post by my dear Mincat, its a point of view, check it out.

http://damelo.blogspot.com/2007/08/illegal-immigration.html

Can a Life in Academia be Balanced?

2007-07-30T10:24:00.000-07:00

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.

scientiae-carnival

Back in Lab in Under 11 Hours

2007-07-26T09:22:00.000-07:00

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.

Harry...Tomorrow!

2007-07-20T08:41:00.000-07:00

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.

Tomorrow!

Then the discussions, which is even better!

How to Choose a Postdoc Lab

2007-07-19T10:28:00.002-07:00

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.

Informed Consent and Clinical Trials

2007-07-10T11:31:00.000-07:00

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.

TB slips out

2007-07-06T09:17:00.000-07:00

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.

Some people may have called it

2007-06-26T14:16:00.000-07:00

heh.

Your Score: Freak- INFJ

26% Extraversion, 73% Intuition, 33% Thinking, 80% Judging

Well, well, well. How did someone like you end up with the least common personality type of them all? In a group of 100 Americans, only 0.5 others would be just like you. You really are one of a kind... In fact, I do believe that that's one of the definitions for the word "FREAK."

Freak's not such a bad word to describe you actually.

You are deep, complex, secretive and extremely difficult to understand. If that doesn't scream "Freak!" I don't know what does. No-one actually knows the REAL you, do they?

You probably have deep interests in creative expression as well as issues of spirituality and human development.

You've probably even been called a "psychic" before, because of your uncanny knack to understand and "read" people without quite knowing how you do it. Don't fret. You're not actually psychic. That would make you special and you'll never accomplish that.

You're also quite possible the most emotional of them all, so don't take this all too hard. Nevertheless you most definitely have the strangest personality type and that's not necessarily a good thing.

*****************

If you want to learn more about your personality type in a slightly less negative way, check out this.

*****************

The other personality types are as follows...

Loner - Introverted Sensing Feeling Perceiving

Pushover - Introverted Sensing Feeling Judging

Criminal - Introverted Sensing Thinking Perceiving

Borefest - Introverted Sensing Thinking Judging

Almost Perfect - Introverted iNtuitive Feeling Perceiving

Loser - Introverted iNtuitive Thinking Perceiving

Crackpot - Introverted iNtuitive Thinking Judging

Clown - Extraverted Sensing Feeling Perceiving

Sap - Extraverted Sensing Feeling Judging

Commander - Extraverted Sensing Thinking Perceiving

Do Gooder - Extraverted Sensing Thinking Judging

Scumbag - Extraverted iNtuitive Feeling Perceiving

Busybody - Extraverted iNtuitive Feeling Judging

Prick - Extraverted iNtuitive Thinking Perceiving

Dictator - Extraverted iNtuitive Thinking Judging

Link: The Brutally Honest Personality Test written by UltimateMaster on OkCupid Free Online Dating, home of the The Dating Persona Test

Responsibility

2007-06-20T15:13:00.001-07:00

Sometimes responsibility is the only thing that keeps me going.
I was a good kid, a reasonable teenager, and a successful college student. I wasn't particularly virtuous or hard-working, I was just really responsible. I always felt responsibility weigh heavily.

Now I am a postdoc, and not too thrilled with the state of my professional life. I feel like I am pushed to work on something that just doesn't interest me, I do not enjoy the nitty gritty daily grind of the lab work I do, I fell that my abilities are not adequately appreciated let alone compensated, and I feel that I am not being given enough other opportunities, such as reviews and writing. Yet I keep going. Sometimes it is the small part of my project I enjoy, sometimes it is the thrill of research, of finding out something new, sometimes it is just ambition, visa status or inertia, but mostly what keeps me trudging onwards (and upwards? outwards?) is an over-developed sense of responsibility.

I feel a responsibility to my employer, despite what I think I do not get in return. I feel a responsibility to my Ph.D. boss and lab because my success reflects on them (and terrible guilt on behalf of all the mice that were sacrificed along the way). I feel responsible to my future husband because I rooted him out of a place he loved to move here. I don't want to let my family or my country (really) down. Most of all though, I feel this immense responsibility to myself. I have spent so much time working towards this, so much effort. I have heard to many times that I have potential, and dammit, I want to fulfill it. I owe myself that. I am responsible to myself for the person I am and the person I will become, and giving up is not a part of that person.

So I go responsibly on, and if it wasn't for that aggravating rational-state-that-shall-not-be named, I would have quit a while ago. At least I think so, who knows, maybe ambition and inertia are sufficient. In any case, my responsibilities are here to stay, and I am made that way. And maybe that's enough. After all research requires persistence and luck above all, and who cares what motivates the persistence. Does it matter that it is responsibility? In my case it appears to be enough, so why not. Its as good a way as any to keep going.

I think.

scientiae-carnival

Consolidation

2007-06-19T21:54:00.000-07:00

Reunification, A joining, whatever. Clarity has been merged with this blog, and I've re-posted some of my favourite Clarity posts over here. Since blogger will not let you merge two blogs that you own under the same account. Because that would be too easy.

Anyway, here I am and here we go.

On Race and Being a Scientist

2007-06-19T21:50:00.003-07:00

Skookumchick over at Rants of a Feminist Engineer had posted on the subject of race in science. Taking my cue from her, here I go.

I have to say that because of my nationality, race and nationality are rather inextricably linked in my thinking, so I will declare right now that I use the two to refer to the same thing. Sorry.

I am Indian, as may have become obvious to those of you who read my blog and notice my stubborn use of -ou- spelling. I grew up in India and came to the US to do my Ph.D., now I am a post-doc. I've been a foreign student, a non-resident alien, then a resident alien and now am a temporary worker.

There are so many stereotypes associated with various races and their work ethic/abilities/social skills. I'm not trying to offend anyone, but here's a list of some I have heard: Indians are bright and lazy, lack social skills and speak English with a funny accent; Chinese people are incredibly hard-working, paranoid and competitive and do not speak English well at all; Japanese people are eternally polite to your face but do exactly whatever they please anyway, the French are clubby and snobbish, the Germans are correct, humorless and boring, Americans are crazy workaholics with an alien literal sense of humour.

My accent in English could easily be American, in fact I get judged for that quite a lot in the Indian community. One of the two most paranoid, competitive people I have met was indeed Chinese, the other was American. However, the single most helpful technician I have ever known is Chinese, she is a darling. Two of the most intelligent-and yes, sarcastic- people I know are American and I enjoy and respect their insights and judgment tremendously. One of my dearest mentors in grad school was Japanese and he was always communicative and sharing with me. Many of my friends and my best colleagues have been, and are, French. Based on friends again, I think Germans are the most modest, open-minded people I know and amazing friends in the bargain.

I think that it is important to discuss issues of race and representation but one always risks falling into the trap of letting stereotypes do the deciding. However hard one tries, if one makes race a central issue one will end up classifying people one meets based on one's perception of their countrymen's qualities. If one is lucky and honest, one may overcome these stereotypes and make real connections to people despite all, but how often is one lucky or honest?

I resist concentrating on race for many reasons, a big one, and possibly an ignoble one, is because I do not want to be associated with the stereotype. I have known incredibly lazy Indian people, I have also had Indian colleagues who shamelessly made use of a boss's niceness and took way too much advantage. I am not like that, and it galls me no end to have colleagues who "have given my countrymen a bad name". I have also met hard-working like-minded Indians whom it is a privilege to associate myself with. However, I do not speak to Indians at work in our native tongue, if it is the same, or the national language because I think it is wholly inappropriate to use a language that other people do not understand in a workplace. It makes people hostile, which is completely understandable. Over coffee, I'd love to gab in Hindi, but in lab? No. I won't do it.

I resist emphasizing my race for another reason: I have worked so hard to be thought of as "just" a scientist, not an "Indian scientist", or the "Indian girl in that lab". People have actually called me by another, very different, name because there was another Indian in our lab with that name. The foreign student, the foreign post-doc...I think I have managed to shed all these labels, not because I am not proud of being Indian or because I am embarrassed to be considered foreign, but because I want to be thought of primarily as a scientist. I don't want Indian to be my defining professional label, just like woman is not my primary label of choice, more on that later. I feel that as a foreign post-doc, race and nationality are such dominant issues in the rest of my life- getting fingerprinted upon entry into the US, needing authorization to travel, my boyfriend shaving off his beard because he is Indian and will probably have trouble flying with a beard because of what he looks like. I don't want my race or nationality to be a central issue in my professional life as well.

I am joyously Indian and fiercely proud to be so. I am also a scientist and proud of that. I am not necessarily an Indian scientist is all.

I was a Happy Postdoc that week

2007-06-19T21:50:00.001-07:00

I started writing this last week, so the title should actually read last week, but since there is still some residual happiness, the title stands.

The experiment worked!!!!! It worked!!! The one that really sets up the whole project, the one that indicates that I just may be on the right track...that one worked! I may yet be wrong, and hundreds of controls and repeats have yet to be done, but it worked! (Mad happy dancing) That's the feeling, that's the feeling I work for. That is why I do research. That is why I worked hard, that is why I swallowed disappointment after disappointment and kept on plodding. It's a great feeling.

It's an ephemeral one. It will last till the next one doesn't work. Or, the next experiment will work and the next and the paper will go out. Then the happiness dulls or is replaced by other happinesses-it had better, otherwise you're the person who is always talking about "My Science paper.." (I don't have one, I'm just saying). The happiness can make you drunk with success and eventually flushed with arrogance. Or it will fade leaving something worse, the memory of exhilaration. Or, if you're really lucky and balanced, it will even out into something you can sustain in the longer term. However, if you're lucky and balanced, you wouldn't care so much that results would exhilarate you...and so on.

Is it worth it, to work for such transient highs and more persistent lows? I don't have the energy to sustain such high ups and such low downs for so many years. Soaring is great, crashing sucks and repeating the cycle is even worse. Or am I one of the less common hyper-emotional ones who is far too affected by her work? It is not because I am a woman, in fact the most emotional scientists I have met were men, but I digress into trivializations. Do I want to work for those elusive high moments? Do I want to deal with all the pits and self-doubt? To borrow from Rusted Root, am I hooked on a feeling? Am I high on believing that I will succeed? Do I need to be that way to be a successful scientist?

Don't really know, and dude, when the experiment works I don't know if I really care to think about it. Doubts can wait.

"I can't stop this feeling
Deep inside of me..
....
I'm hooked on a feeling
I am high on believing.."

-Rusted Root, The Ooga Chaga song, adapted to Postdoc-hood

Professionalism or the Lack Thereof

2007-06-19T21:49:00.001-07:00

One of the things that bothers me the most about the scientific establishment these days is the pervasive lack of professionalism I see at every level. From department heads and PIs to postdocs, lab managers and lab technicians. The only people who might be excused for not having learnt some professionalism are early grad students, but as they move onwards through grad school it should really be something they learn. Given the nature of many labs today though, they are not going to learn the value of being professional and will go on to be unprofessional postdocs, then PIs, then department heads.

What do I mean when I say professionalism? I mean that you have a job, therefore do your job, whinge if you will but do not make a career out of emotion and insularity. One's boss does not have to be one's friend. Their moods should not be a cause of great concern to their employees. Tantrums, hissy fits, concealment, bitching, sabotage, paranoid delusions, prestige issues, ego hassles, ignorance and just plain idiocy shouldn't have to be a normal part of one's day. I don't claim these as problems unique to a laboratory setting, I am sure these issues affect many workers in many walks of life (I know they affect publishers and engineers for example). But am I wrong in thinking that these problems are overrepresented in academic research settings?

Research is a hard job, it is completely self-driven, there are no benchmarks, no signposts that mark significant achievements other than peer-reviewed publications that go through an incredibly subjective evaluation process. You don't get much pay, praise or publicity. You work on an arcane subject in dimly-lit surroundings (maybe not always) and set yourself up for pillory by your peers every so often. Maybe 0.1% of us will find a cure for AIDS. Or even discover what AIDS is. I don't, however, think that the difficulty of what we do makes a lack of professionalism okay.

In fact being a professional would make life easier, at least it would according to me. Detachment from drama, perspective about achievement, calm in the workplace, hell, I want all these things! I am a better scientist when I don't want to curl up in a ball of stress every time I sit down at my desk. The experiment didn't work? Oh well, troubleshoot it and do it again. It did? Awesome, go get a drink. It's a job, life goes on. The boss didn't say hello? Forget it, as long as he or she discusses your data with you constructively and with an open mind. Go in, do your job, make some friends as a bonus, leave at the end of the day, go on with your life. Courtesy and respect (Propter Doc has put this very well) should be the cornerstones of the lab not precedence and credit-mongering. I don't know how we came to be a generation of scientists and mentors who are so caught up in the cult of scientific personality that an egregious tyrant with Cell papers in their CV is worshiped while a fair-minded collaborative mentor with less famous papers is followed by condescension and pitying whispers. It saddens me.

I really believe that increased professionalism, which also involves better treatment of employees and better compensation of exceptional talent, is the only way to better research. The question is, is unprofessional behaviour too institutionalized to root out? I don't

Anonymity

2007-06-19T21:47:00.000-07:00

The paradox of anonymity is that you can be more yourself.

Anonymity enables us bloggers. Intimacy, truthfulness, genuine feeling, none of these would be possible without being anonymous. One expresses frustrations with lab, with particular people, one shares one's stories-be they funny, sad, outrageous or mundane. We all do these things under the comforting cover of anonymity. the first post about one's lab is made with trepidation, will someone see me? What if they find out? Then gradually, acquisition of a blog-persona emboldens you, you become Veo Claramente when you're typing, not Dr. Postdoc. You say the things that you have always thought and only told Postdoc Parents, Postdoc siblings, Mr. Postdoc-to-be or those always lovely and amazing Fellow Postdoc friends. Writing comes pouring out and suddenly people are reading! Someone comments, and you're on your way. You have this different life, almost, and you feel free to talk about the things that bother you. And then some.

Anonymity also shields some truly repellent people, who stalk and threaten. Trolls who lurk and comment. Malicious bloggers who use also their anonymity to liberate themselves, but to liberate their bad sides (maybe I shouldn't assume these people have good sides, but) and let it hang out in all its stinking glory. Freedom is universal after all, and can be used in any way. Your personal code is the only thing that prevents its misuse. The protection of anonymity is offered to everyone.

Here's the rub, It really bothers me that we should should we need it. The need to hide bad behaviour is obvious, the need to hide frustration less so. Why do we have to be careful about voicing our frustrations as long as we are reasonably polite and resort to only limited name-calling? Why is it that we face the possibility of reprisals for expressing opinions and telling it as we see it? I do have a quixotic sense of justice and what the world should be, but even so. Something is not right if so many people are out there, blogging about being grad students, postdocs or faculty, all staying anonymous and guarding that anonymity intensely. Hey, I'm not "coming out". I feel like I should be able to without the fear of destructive consequences. However, if I was guaranteed no bad consequences, would I turn Veo Claramente into a pseudonym? I don't know. My conscience and my sense of what is right would be satisfied, but I don't know if I want all the things I say to be attributable to me. I really don't know.

What would you do if you could out yourself without negative consequences?

Awesome blog

2007-04-24T08:42:00.000-07:00

On Nature Medicine's website. She writes really well and deals with just my kind of subject matter.
Love it! And love the title.

A Spoonful of Medicine

Nice article in this week's issue of Science

2007-04-18T14:16:00.000-07:00

There's a really cool article in the News Focus section of Science magazine this week, it's called "The Education of T cells" if you'd like to check it out. The author interviews several of the people who are really active in the field right now, and some of the people who's work I have discussed earlier. It's a nice article, I found it easy to read, but I don't know if it might be too technical for the non-technical reader. Let me know, I'm always curious to hear how technical is too technical.

Some of the things predicted by the scientists interviewed in this article are cool, but seem a bit far-fetched to me. Informed skepticism or lack of vision? I don't know, and time will tell.

Enjoy reading!

The Hygiene Hypothesis

2007-03-29T21:00:00.000-07:00

The Hygiene Hypothesis: Probably the one idea in Immunology that annoys me the most. It bugs me, drives me nuts, nevertheless it has held and persevered for nearly twenty years. So there must be something to it, and I must shelve my prejudices and look into it.

Let me get my complaints out of the way first, so that you can treat my point of view with the necessary skepticism. On the other hand, maybe I am good person to look into this idea since I am the ultimate skeptic and totally disinclined to believe. Hopefully not too prejudiced, but I’ll leave you to be the judge of that. My biggest peeve with the Hygiene Hypothesis is irrational, it is the name- it is pejorative. There is no nice way to think of it. It is meant to explain the increased incidence of allergic diseases in countries with a “Western” lifestyle, and postulates that decreasing family size and improved hygiene in these countries has led to the increased prevalence of allergic disease. Why? How? Let me try and explain.

At the core of the ideas that eventually constitute the Hygiene Hypothesis and attendant years of research is a set of apparently contradictory observations, best exemplified by this one: farmers have a much lower incidence of hay fever than the rest of the population. Intuitively perhaps, this seems odd. Farmers and people who live on farms are exposed to pollen and other things that give rise to hay fever far more than people who live in cities, so if the tendency to get hay fever was evenly distributed in the population, there should be a similar percentage of farmers who get it as, say, bus drivers. This is not the case, however and the whys and hows have been hotly debated these many years.

There is a really important immunological idea that needs explaining at this point, it is the phenomenon of Th1 and Th2 T cells (which expand as Type 1 helper T cells and type 2 helper T cells, but that is not really necessary to know). Th1 and Th2 T cells as a concept have been around for donkey’s years, and anyone who has ever worked in immunology has brushed up against it. It describes two different subsets of T cells (ha, you would never have figured that one out) and it is a separation into subsets based on function. Specifically, that function is the production of certain small molecules called cytokines.

Cytokines are the e-mail messages of the immune system. Whenever a cell is activated, and this applies to nearly all immune cells, it sends out the message that it is activated by dumping cytokines into its milieu. The particular cytokine- or set of cytokines since immune cells can often produce a whole bunch of cytokines at the same time- dumped out depends on the way in which the cell has become activated. So, if you read about something horribly unjust on the news, you’re activated to be indignant and send indignant activist e-mail to your friends. Inflammatory even. On the other hand, if you’re really annoyed with a colleague’s carping or unprofessional behaviour, you send insistent annoyed e-mail to friends or family. You are irritated in fact. And then a friend sends you seven increasingly frantic messages about the date that didn’t call back and you see a need and send out an instant, powerful, soothing message. A dampening, or regulatory message. These messages have effects on other people, some intended and others unanticipated. These messages also affect people who are near and those who are far; those who are directly involved or hapless bystanders. Cytokines send out messages that initiate war upon an enemy infection, or those that irritate one’s own body to the point of itching or sneezing, or messages of cessation and calm. As required, and as far as blood can circulate. Sometimes they are just sparks, and other things form the flame, of fever for example, but that’s for another day. You get the picture.

Th cells are really good cytokine producers. Th1 cells make so-called Th1 cytokines, which are generally more of the sound-the-charge type. Th2 cells make, well, Th2 cytokines that belong more to the irritant family. The view has been long held that Th1 cytokines are needed to fight infections, and when they go out of control, they cause autoimmune diseases, such as Crohn’s disease. Th2 cytokines on the other hand are thought to be the ones that cause allergic types of reactions, but they are very necessary to clear parasitic infections, like worms living in your gut. Of course the longer something is studied the more ambiguous it becomes and that is not the whole story. Anyway, the key thing is that Th1 cytokines can block the production of Th2 cytokines and vice versa, which is why I have been discussing them as opposites. Depending on the order or amount (or both) in which they are made, either Th1 or Th2 cytokines end up dominating an immune response.

Back to the Hygiene Hypothesis. The idea builds up as follows:
Th2 cytokines are among the primary causes (actually effectors) of allergic disease,
Th1 cytokines suppress the production of Th2 cytokines,
Various microbes in the air, soil, water and environment cause the production of Th1 cytokines
Clean environments contain less microbial “challenges”, therefore less Th1 cytokines are made
Ergo, the Th2 cytokines run amok and you have a higher incidence of allergic disease.

There is a lot of evidence in favour of the hypothesis and a fair amount against it. The interesting thing about the Hygiene Hypothesis is that most of the data for or against comes from epidemiological studies. Epidemiology is the statistical study of diseases in populations, and is by its nature observational while Immunology is the mechanistic study of disease and is primarily an experimental science. The reason for this strong reliance on epidemiological methods, in my opinion, is that it has been tremendously hard to show experimentally that normal every day environmental stimuli induce Th1 cytokines. Exceptions exist, such a group that has collected stable dust in Switzerland and is going to use that to determine if there is any immunologic response to it. (Stable dust! There’s also a study that compares the effects of cats and dogs as opposed to farm animals during pregnancy.) Most of the data come, however, from observations of large cohorts of people in different environments.

Some of these studies have come out with really cool results. One idea that seems to have a lot of validity is that persistent, heavy worm infections protect you from developing asthma, or more precisely atopic disease, which is more or less allergic skin irritations. This is graded however, and you need to have a really massive worm infection to get this protection. Heavy but not massive worm infections do not really protect, but they do not harm (as far as asthma is concerned anyway) and light worm infections, as might be found under hygienic conditions, actually mean you may get more asthma. Worms induce strong Th2 responses, so this may seem like we’re really on to something. Here’s the rub: the same societies that have a higher incidence of Th2-type allergic diseases also have a higher incidence of Th1-mediated autoimmune diseases like Crohn’s disease.

There is a lot more data for or against, but this example is clear and well-characterized, so I'll just stick to the case of the worms.

So Th1 and Th2 do not provide the entire explanation. Here’s one that I found a lot more satisfying. Take the case of massive worm infections; a person with a massive worm infection has usually mounted an intensely strong immune response to it (Th2, but that isn’t really material). The body has very effective mechanisms in place to ensure precisely that immune responses don’t run amok and eventually destroy everything in their paths. These mechanisms, dampening or regulatory mechanisms, kick in when there is a really strong immune response and turn it off irrespective of the nature or outcome of the immune response. So highly worm-infected people have probably turned down their immune response quite a bit, and since allergy is an immune response, it is turned down as well. Therefore people who have much less worm infections have revved up and ready immune systems and may therefore be more prone to develop allergies or autoimmune diseases. This mechanism feels very plausible to me. Does that mean I have been converted to the Hygiene Hypothesis? Not entirely, and these are my reasons.

Allergic diseases abound in less hygienic environments, South Asians and Africans do get asthma, eczema etc. Of course, the hygiene hypothesis doesn’t claim to explain all asthma incidence, merely increased incidence in certain societies.

The other objection is a technical one. Most of the epidemiological studies use “atopy” or skin irritation (oversimplified, but) as their readout since asthma may take a long time to come up as actual wheezing symptomatic asthma. And asthma patients are usually heavily medicated, so all observation are much more difficult to interpret. However, atopy is not asthma, and may not even be a prelude to asthma, so in a way, they are all using apples to measure orange growth. There are some studies that go much deeper though, but in general, with epidemiological data, one need many many numbers of people and much statistical significance before one can have confidence in the data. Time will tell.

This is linked to the one above: For every study that has a certain result, there is one that has the opposite. That worries me, because I wonder if we are not inventing a correlation when there isn’t one?

And one can go on, genetics, economics etc. I think the crux of the matter is that it is not as simple as the original Th1 vs. Th2 idea, nor is it an explanation of all relevant phenomena. However the Hygiene Hypothesis does seem to have some validity and one needs to wait and see. And change the name!

Papers read (All reviews I’m afraid):

Yazdanbaksh M., et al Allergy, Parasites and the Hygiene Hypothesis. 2002. Science. Volume 296. p 490.

Vercelli D., Mechanisms of the Hygiene Hypothesis-Molecular or Otherwise. 2006. Current Opinion in Immunology. Volume 18. p 733.

Liu AH., and Leung DYM., Renaissance of the Hygiene Hypothesis. 2006. Journal of Allergy and Clinical Immunology. Volume 117. p 1063.

Ramsey CD., and Celedon JC., The Hygiene Hypothesis and Asthma. 2005. Current Opinion in Pulmonary Medicine. Volume 11. p 14.

"The Three Es" Hypothesis of Tumor Immune Surveillance

2007-03-06T20:50:00.000-08:00

Cancer Immunoediting: The three Es Hypothesis

Okay, here is post number two, and I am truly sorry for the delay, I have been working (yes really!). Also, in response to comments from dearly valued readers, I am going to try and make this less technical. Which should be easy, considering that I am going to try and explain the concept I read in an amazing review. So, no data parsing. Whew.

Cancer and the immune system have been co-existing for centuries, which is one of the most remarkable-and challenging-aspects of cancer biology. Basically, cancers occur when some cells in the body transform (that is the technical term) and become malignant, upon which they are no longer subject to the basic social rules that govern other, normal or untransformed, cells. Such as, stick to your own tissues, stop growing when told to, do not invade the rest of the body, do not divert the body’s blood vessels to give yourself nourishment and so on. Transformation of normal cells into cancerous ones can occur for a variety of reasons, such as radiation, carcinogenic chemicals, infection with an “oncogenic” virus that specializes in transformation of cells or a random, spontaneous mutation that results in a transformed cell with its attendant anti-social behaviour. This is really simplified and I but brush the surface, but you get the picture: a random event, often a mutation in the body’s own cells can lead to cancer, as both radiation and many carcinogenic chemicals cause cancer by causing mutations.

Here’s the rub: mutations occur frequently. Frequently! When cells divide, they duplicate their DNA and make mistakes while doing so, resulting in mutations. DNA damaging agents, like chemicals and radiation, cause hundreds of mutations, many of which are not productive, in that the cell’s DNA repair machinery kicks in and fixes it (That awesome machinery is the subject of a whole new discussion some day, immunology or not). Even so, transforming events are not rare, and that means we should get cancers more often that we do, and the fact that we don’t has led to much speculation on why. One of the earliest hypotheses on the role of the immune system in cancer, the “immunosurveillance” hypothesis proposed that, in immunocompetent hosts, the immunes system is patrolling the body for sign of transformed cells and eliminates them upon detection, and its only rare ones that get free to cause cancer.

Side note: Immunology, more than other fields of Biology, has the habit of coining terms that are more than likely to send you spell check into a hopeless tizzy. It’s a simple strategy really, just add the prefix immuno- to any English word and you have a whole new term. Immunosurveillance therefore means “surveillance by the immune system” and immunocompetent means “in possession of a competent immune system”.

The biggest problem with the idea of immunosurveillance is that it is, in the words of its proponent Lewis Thomas, “it cannot be shown to exist in experimental animals”. To quote the authors of the review I refer to below, “…how could such an invisible process be experimentally revealed?” If the immune system does actually patrol at steady state and eliminate transformed cells, how do you demonstrate it? The short answer is, using immunodeficient (see!) mice, made possible by sophisticated modern genetic techniques. These immunodeficient mice developed tumors much more frequently than their immunocompetent counterparts. In the interests of full disclosure, there was one study that directly contradicted this one but was then refuted by four groups. Anyway, so Robert Schreiber’s group found evidence for immunosurveillance.

The “three Es hypothesis” comes from this idea, and has been proposed by Schreiber and colleagues. They extend the concept of immunosurveillance to one of immunoediting, which is not the most intuitive title, but bear with me. The idea is that immunosurveillance is one phase of a more comprehensive process-immunoediting-which can be broken up into three component phases: elimination, equilibrium and escape. In the elimination phase, immune cells recognize and eliminate transformed cells. Generally, this is sufficient. After, or simultaneous with, the elimination phase, is the equilibrium phase in which the tumor cells and the immune system exist in an equilibrium of inaction: the tumor doesn’t grow and the immune system doesn’t attack it. This can continue for years, and the individual remains cancer free. Then, some tumors escape. This last phase occurs when a tumor mutates sufficiently to evade elimination by the immune system and grows out. The interesting thing that Schreiber and colleagues propose is that the cues the tumor receives during the elimination and equilibrium phases drive the evolution of escapes: that if the immune system fires bullets, tumor cells learn to make Kevlar and escape. The result is cancer.

This was a really good paper to read, and it is a really interesting idea. There is good data to support the existence of the elimination and escape phases, but the equilibrium phase remains hypothetical and will be hard to demonstrate. The basic idea is logical; at least it seems so to me, neat and believable. However, it unlikely to be the whole story. The hugest caveat with studying tumor immunology is the fact that tumor cells or basically ones own cells that have gone berserk. The immune system has extensive, elaborate machinery in place to ensure precisely that it doesn’t attack its own host body. How then is it supposed to tell that tumor cells are foreign? This is the million-dollar question in tumor immunology and for all the promise that tumor immunotherapy has- after all what could be better than using one’s own cells to combat cancer? -It is unanswered.

Paper referred to:

Dunn G.P., et al. The Immunobiology of Cancer Immunosurveillance and Immunoediting. Immunity. 2004. Volume 21, p137-148.

Directing Cells: Vitamins instruct the Immune System

2007-02-21T09:21:00.001-08:00

The topic I want to discuss today is the cues that T cells follow when they travel to various parts of the body. Normally, most T cells that are in the circulation do just that: they circulate. They go round and round the body following the bloodstream. But, there are a significant portion of T cells that reside in specific organs, organs that are not considered a part of the immune system per se, such as the skin, the liver and the intestine. Then how do these T cells decide to go to these organs, and then take up residence there? It appears to be a highly ordered process, during which T cells get specific signals that direct them to one organ or another. These directing signals also influence their function in their target organs and help specialize these T cells for their functions. T cells in the skin, for example, require the ability to react to different things than T cells in the intestine.

There are many molecules that can give T cells (or other cells, but I don't want to try to cover too many things at once) the guidance cues they need. One major class of molecules that do this are called chemokines and they do this by a process called chemotaxis. Chemotaxis is the movement of a cell in response to an increasing concentration of chemical, in this case a chemokine. Chemoattraction occurs when the movement is towards the higher concentration of the chemical. Chemokines are very small proteins that regulate cell homing, and are secreted by cells in specific organs. T cells that express the correct chemokine receptor then migrate to the organ where the chemokine is made. In particular, CCL27 is a chemokine made by skin cells, and CCR10 is the receptor on T cells that enables them to respond to CCL27.
CCR10 is not found on all T cells by default, it has to be induced or brought out on to the surface. A study in a recent issue of Nature Immunology (see below) finds that CCR10 can be brought to the surface of human T cells by the active form of Vitamin D.
In short, when T cells are exposed to the active form of Vitamin D, they start to express CCR10 on their surface. Previously activated T cells, that have already seen an antigen, are better that naive T cells at making CCR10 in response to active Vitamin D. Vitamin D is not active right off the blocks, it has to undergo three chemical modifications to become its final active form, called 1,25(OH)2D3. The first step is the conversion of an inactive precursor into Vitamin D3 by UVB rays if sunlight, this step occurs in the skin. Vitamin D3 is still not active. The second step is the conversion of Vitamin D3 into 25(OH)D3, in which form it can induce some CCR10 on T cells. The final step is the conversion into 1,25(OH)2D3, in which form it is most effective at inducing CCR10, and therefore migration to the skin.
The really cool thing about the paper is not only the idea that a vitamin can make T cells go to the skin, because that has been suggested before for vitamin A and the intestine (which I will come to in a minute). It is the demonstration that the T cells can themselves convert 25(OH)D3 into the active form to some extent, thereby making themselves able to migrate to the skin. even better, special antigen presenting cells called dendritic cells, can also do this, and can also accomplish the previous step, of converting Vitamin D3 into the 25 (OH)D3 form. The idea is then that dendritic cells activate T cells by presenting antigen to them, and while doing so also metabolize sunlight induced vitamin D3 and induce CCR10 expression on the T cells they are activating and therefore send them skinwards. The paper also shows that skin-derived dendritic cells are really good at converting vitamin D3 into the active form, and therefore can presumably induce better migration of T cells to the skin.
This is called "imprinting", and refers to the idea that T cells can be instructed by organ-specific cues to become organ-resident T cells. So, as an earlier study showed (see below), the vitamin A metabolite retinoic acid, is produced with greater efficiency by dendritic cells in the gut and induces T cells to home to the gut. Similarly, Vitamin D3 formed in the skin (Vitamin D2, the primary dietary form, is not as effective) can be metabolized by dendritic cells, presumably in the skin, and induces T cell homing to the skin. So cool! the organ itself "calls" T cells over, with whatever it has available.
This brings up so many things to think about, not the least of which is how much every system of the body is linked to the others. As a researcher, one tends to view one's own system in isolation, to study immunity alone or nutrition alone, whereas a truly healthy functional individual is the product of effective immunity and adequate nutrition. Superspecialization doesn't really seem to exist: one cell's vitamin is another cell's guidance cue.

Anyway, i though that was a nice study and a really nice idea, what do you think?

Papers referred to:

Sigmundsdottir H, Pan J et al. DCs metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine CCL27. 2007. Nature Immunology Volume 8 pp285-293

Iwata M et al. Retinoic Acid Imprints Gut-Homing Specificity on T Cells. 2004. Immunity Volume 21 pp527-538

The Immune System

2007-02-21T09:10:00.000-08:00

Hello...

I don't know why one is so often tempted to address an audience, particularly one that is invisible and possibly imaginary. Anyway. Hello all of you out there who are attracted by the title. I am a scientist studying the immune system, and while i may have issues with life in science and the conduct of it, not to mention the establishment, I find the immune system fascinating. So I've decided to write about it. I read a lot of papers (at least I should) published in the immunology journals of today, and often I find things that are so interesting that I just want to discuss them. So I plan to summarize, try to explain and wonder about some of the coool things I read about in immunology. Here. On this blog, coolimmunology.

I do take requests, let me know if there's something you'd like me to post about in the comments. Always, I am NOT a medical professional, these are just my personal opinions, formed by the reading of published journal papers. They are not representative of anything other than my private personal opinions. They are shaped by my background in research, and my specialties. I am not omniscient, so I do not know or understand everything.

That said, let the immunology begin!