The Polarized Postdoc

Posts Tagged ‘science

Resistance

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The fight with cancer is a battle of endurance, and persistence. In the end, for each individual and for the science community, the last one standing will be the winner. Until then, all tricks, dirty and otherwise, are justified.

The same way that wars can be studied as strategic games by compartimentalizing away all their horror, it is sometimes fascinating to be at the front lines and get a glimpse of the progress of the cancer battle, in real time. A good example is this book about the development of herceptin, a novel about the process of developing a successful drug against breast cancer. Far from an sterilized science report, it is an enthralling tale of hope and human bravery. But wait, don´t run out to buy the book just yet, please, first finish reading the post!

The basis of any anti-cancer attack lies on the fact that cancer cells don´t form an isolated army, but instead hide guerrilla-style amongst the normal cells in your body. So we have to identify them, and get rid of them either by resecting the tumor mass or by applying somehow selective chemical weapons.

Not so long ago, we witnessed the raise of targeted therapies as effective chemical treatments of many tumor types. The rationale of this approach resides in classifying tumors according to their molecular profile, instead of organ or histological type, and targeting the underlying genetic lesions that generates or sustains tumor growth.

There are different ways to do this, such as using small molecule inhibitors (TKIs) that stop the pernicious activity of the oncogenic kinases. Antibodies that block the proteins responsible for the aberrant properties (uncontrolled growth, invasion, dedifferentiation) are currently effective therapies against breast cancer too. Wider in scope, anti mitotic agents kill cells when they try to divide and expand. Normal cells are usual quiescent so they can dodge the killer drug, except from the parts of our bodies that undergo active turnover such as our hair, mucosas, and immune systems. Which explains the sometimes terrible side effects.

Recently, yet another smart gun has been devised, taking advantage of the unique aspects of cancer biology. Once of the reasons why tumor cells roam free and divide in a fast and uncontrolled manner is the fact that they have over-ridden part of the exquisite control mechanisms that ensure genetic integrity during cell division. These mechanisms are like will executors, making sure that the daughter cells receive one each an accurate and faithful copy of their mother genetic material. Then they can read and interpret it to build all their cellular structures in their progenitor´s image. This is of utter importance for the survival and correct function of the organism and is often the bottom line alteration triggering carcinogenic events. For this reason, many redundant mechanisms simultaneously oversee cell division in this manner and although loss of one of them can be tolerated, and even beneficial for cancer cells, complete lost is programmed to inevitably lead to system failure and death. Tumor cells live on the edge, escaping surveillance to be able to divide even if they carry severe genetic aberrations, just barely enough to avoid programmed cell death.

Researchers have just released a new drug, olaparib, that inhibits the function of one of the control mechanisms that dictates if cells survive aberrant division or commit suicide, and have shown that it can be used to selectively kill tumor cells. Now, other concerns regarding short-term and long-term toxicity will have to be addressed, but this does not obscure this brilliant victory for our side.

Sadly, even in the midst of success, there is a fast turnaround for the good news, and no long after some these drugs prove efficiency, the first signs of resistance are reported. The rough, fast-paced tumor cells have a high rate of mutation that allows them to adapt to adverse environments. So soon after seemingly succumbing to the TKI drugs, tumors resprout having developed new ways of surviving and thriving that lend the pathways targeted by the drugs obsolete.

Seldom prey of discouragement, there you find the scientists again, running back to their labs to design and test new drugs. The next battle starts studying how the resistance appears, following the process in the test tubes or tissue culture plates. Many great researchers like Dr. Sordella are currently working on coming up with new strategies that will kill the resistant tumors, and eventually unravel the basis of resistance itself to stop it before it develops.

The urgency, relevance and exciting nature of this type of work can be strongly addictive, as I can personally atest. Sometimes it is hard to find a reason to leave the lab, at all, which is dangerous enough for obvious reasons. But to keep the fight alive we need more motivated researchers, more inventive minds and brave patients, and if you are neither of those, you can still go ahead and chip in some money for the many fundraising initiatives.

But no matter how neatly and thoroughly we swim over it, the horror is still there. The crude reality of the cancer disease is everywhere around us. A few days ago I learned of the terrible disease affecting a dear professor of mine. He is fighting lung cancer with erlotinib, the same drug whose improvement I was just helping write a grant to fund. I wish him all the best, with all my heart. But my mind also knows the side effects, the probabilities, the uncertain waiting time and the failure rate he is facing.

My thoughts also go to the many people proud to be working hard to give, if not him, other future patients a better chance. One of them, another dear friend, has gotten sick as well, cause cancer spares nobody. And takes down civilians and enemy soldiers alike.

Sometimes the implications of this job just sneak up on you, sometimes they make you choke, reminding you of just how impotent we are when facing the enemy one on one. That is why we need an army, and a well-equipped one at that.

I promise I will stop bothering you with gloomy posts, and put up soon more joyful and delicious experiments, but I had to say that I can´t think of much better ways to put your money to good use than throwing some bucks here and there to help cancer research, or any research for that matter. We will try to use it wisely, and will be thankful for it. Because in the end, statistics non-withstanding, every day that we are still standing is a triumph against the disease.

To all those fighting, know that even if everything else fails you will still have our love and support. We will be rooting for you. Resist, my braves!

Written by polarizedpostdoc

July 23, 2009 at 12:59

Posted in personal, science

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Monkey Business

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While some of us are scooping summer bliss out of ice cream cones, the on-shift scientists continue their quest for the secrets of life. In this case, of eternal life. But of course, their proposed recipe for extended youth has major catch.

Life-prolonging phenomena are harder to come by that life-ending ones, but nevertheless some thirty years back it was discovered that caloric restriction diets effectively prolonged life span. For those of us who make our pies with lard, there was the consolation that those results came from studies in mice. Arguably of limited relevance for human biology, mice, with their intense three years average lives, were still he model organism of choice until know. They are a useful albeit imperfect system to study longevity, given the obvious drawbacks of setting up experiments likely to last longer than the researcher´s life span.

But eventually, curiosity and rigor prevailed and a group from Wisconsin stared thirty years ago to test whether caloric restriction had an effect on longevity. To this aim they used the closest non-human primate, the rhesus monkey. 30 males and 30 females were placed on either on a control or a low- calorie diet for 30 years. For those of you interested in those things, the low diet contained 15% protein and 10% fat.

During the course of the study, the investigators examined aging-related parameters, namely mortality and onset of related conditions such as cardiovascular disease, brain atrophy, cancer and diabetes. The results, contrary to non-conclusive previous studies, unequivocally show that a lower calorie intake expands life for an average of ten years. Moreover, leaner monkeys seem to display a healthier condition overall, with delayed onset of the diseases studies.

When compared to their take-out dinner mates (left) they look like this:

drop those cupcakes!

drop those cupcakes!

These pictures are striking, and gave raise to a very healthy, amusing debate amongst my fellow scientists. Of note, though, these data compare “normal” to “low” calories, and we can not extrapolate on the negative effects of a high calorie diet on the life span, a subject still under heavy debate.

Looking at this compelling evidence, we can reflect on quantity vs. quality. There are no standarized measurements for a good life, but I still spent a long time staring into the monkeys´ eyes. Trying to decipher if, beyond all those physiological readouts, there were other differences. Other than physical appearance, the paper does not comment on the quality of the macaques lives. Are the low-calorie diet monkeys more active, more creative, do they socialize more? Are they smarter, funnier, can they dance and sing better?

I don´t care, just give me a burger

I don´t care, just give me a burger

While those questions are irrelevant in the context of the presented research, they might be of interest for you as they are for me. In fact, the end point count of travels and stories, parties and midnight swims and hikes and dinners with friends and cakes in the oven may be more important to you than scoring those extra years.

To date, science can´t help you evaluate that, and the question is only yours to ask. Is a life of lyophilized broccoli worth getting 30% more years? Or living at all? If the answer is yes, now you have that option, just have to keep following science´s advice. If the answer is no, on the other hand, you might want to navigate in a different direction.

Whatever your choice may be, happiness is still not a monkey business. So however long and flavorful you decide to make your life, hope you make the most of it!

Written by polarizedpostdoc

July 17, 2009 at 11:02

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Evolutionary noise

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This year I celebrated America´s birthday in style, sitting around with my friends in our beer and burger filled bellies playing the evolution game. Basically, a hand-waving exercise to entertain ourselves whilst fireworks do their natural selection bit around the neighborhood. It consists in picking a natural feature or trait around you (from blue eyes to curved finches), and by applying simple evolutionary rules decide how and why it was preserved to be witnessed by us today. When asked about the rules by the significant non-scientist present, we were able to distill all the beauty and wisdom of Darwin´s theory in a few simple parameters: traits are selected-for, in a given environment, if they confer an advantage for either survival or procreation.

Everything else that comes along for the ride can be considered evolutionary noise. The term defines seemingly useless traits such as the ability to twist your tongue or move your ears. Unless you can do either in a really sexy way that can help guarantee your reproductive success, that is. Unfortunately for me, when I think about evolutionary noise I can not dodge this mental thumbnail of a low deep humming caused by our tail bones retracting and our skulls expanding. But I still love the game.

Of course, when played on a 4th of July evening, fireflies are the first thing to come up.

caught in mid-courtship by the National Geographic

caught in mid-courtship by the National Geographic

We were all pretty close to accurate in speculating that light production, in all its refinement and uniqueness, cannot be a by-product of insect species divergence. The green sparks are, far from noise, a well-tuned performance by the summer dusk orchestra. Our best, almost-educated guess was that flashes play a role in mating and/or prey attraction. This turned out to be true, albeit in a sleek and refined way: flash patterns actually differ from one firefly species to another, allowing the similar looking bugs to recognize a suitable partner. Which is definitely useful, and could even come in handy in some dark human shindigs I know. Moreover, some firefly females use their flash patterns to attract males from other species and eat them. Much like in the aforementioned shindigs, romance is a risky business in the mid summer nights.

From the evolution perspective, firefly light is all quiet, except from the smooching and chewing. The firefly take on “better living through chemistry” fits the profile of a selected-for advantageous adaptation. So maybe to hear the noise one has to come closer, and stare at recent evolution instead of long-hauled characteristics. For that I proposed an example recently learned from population genetics, one of the coolest scientific disciplines. Some weeks ago I had the pleasure to become acquainted with the work of GS Atwal. Simply put, Dr. Atwal uses overly complex statistical tools to dissect the distribution of genetic variants (aka allelles or SNPs in their multiple forms) in different human populations.

It has been known for a while that the genetic background determines susceptibility to certain diseases, including cancer. Population genetic studies are aimed at describing how the different variants appear, often linked to more trackable traits. The population distribution of some faulty variants of tumor suppressor genes correlates with the respective incidence of cancers that stem from the malfunction of the protein encoded by those defective genes. Confronted with this, the question that Atwal asked to climb to the next level of knowledge was how and why, even if they are obviously harmful, do these variants get fixed and stay in the population. Sort of a formal version of the evolution game, without fireworks or fireflies.

At a glance, it would seem like those cancer-prone variants (polymorphisms) are just lousy evolutionary noise. If you apply the rules, these variants do not affect survival of the individual until well after the peak of reproductive age (which is still in the prime of our twenties, biologically speaking). But in collaboration with some eminent geneticists and systems biology experts, Atwal determined that in some cases, the cancerous polymorphisms correlated with a better reproductive success, by increasing fertility rates and facilitating embryonic implantation. These studies in mice reveal an interesting aspect of cancer genetics, the antagonistic pleitropy of some of the genes involved in cancer protection pathways. This concept, while extremely stimulating for future cancer research purposes, is definitely not indicative of evolutionary noise, but of a complex symphony of form and function, shaping the way we perceive natural selection as we grow able to interfere with it. So even when cancer is in play, in the end is Evolution 1, Noise 0.

The score remained tight as well around the dinner table, as we continued to seek out other examples in the warmth of the quieting darkness, and together we lengthy discussed biological sounds of the kind of thumbs and tears and hair and appendixes, with moderate success and plenty of laughter, feeling loved, amused and content. And looking around to capture that moment of sheer perfection, I wondered at the unlikeness of it all, the infinite permutations along the invisible road that led to here, now. It occurred to me right there that the noise might be part of the music of change, entwined with the melody, and that only if they are inextricably blended chance can have a direction.

And I could not help but whisper, trying to entreat the swift moment,

Tarry a while! You are so fair!

Happy 4th of July, everybody.

Written by polarizedpostdoc

July 6, 2009 at 15:15

Posted in personal, science

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Monday Mayhems in Lab

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Apart from feeding into the romantic notion of the single-minded (read: absent-minded), dedicated sage, there is a good practical reason why scientists usually work through their weekends, and that is to avoid turning Mondays into doomsdays. Which can easily happen if you stay away from your bench and/or email for too long. Say, a day or two. For your enlightenment, and as a cautionary tale for budding researchers, here is a list of the most common things that can go south when you decide that you “deserve a weekend off”. Ha. Famous last words.

-The hangover is not over. You were so happy to have some time off that you probably celebrated too hard, thinking you would have time to recover. But you have been secluded in lab for so long that you have neither the endurance nor the youth to party anymore, and you are so out of practice that you wake up Monday morning feeling like death. Chances are that when you manage to crawl back to lab you will thoroughly ruin all your month-long ongoing experiments by the end of the day. And still feel like death. But wait, it still can get worse…

-You forgot you had a 10 AM meeting to attend to. The reminder was sent last night but you were out drinking and did not think of checking the email when you came home and went straight to bed. So now you are hungover and late.

-You forgot you had a 10 AM meeting in which you were the speaker. This is one of the worst lab nightmares, but shockingly still an all too common occurrence. Why scientists tend to drink themselves to oblivion the moment they have some time off lab, is beyond the scope of this post. But would certainty merit some further investigation.

-Your boss had insomnia and/or personal problems during the weekend. Which he of course decided to take out on you, by bombarding your inbox with requests, questions and queries, first about past data that you had given him and he had forgotten about. Then about the experiment you talked about doing last week, and that according to his timeline should have produced brilliant results already. Then about why are you not around answering your emails. Obviously you are not required to check your email on the weekend, but why haven´t you? No wonder those experiments are taking too long. Get a coffee, you have to write a long apologetic email to the boss. That will probably end with some more or less overt form of “will never do this again”.

-You forgot to split your cells, or generally set up the overnight starter for the week´s experiment. By the time you realize this, your cells are overconfluent (and therefore deemed useless) or you don´t have any material to work with. This means that you cannot do any work today, even though you are in bright and early for a change. Moreover, this usually also means that you will have to do the bulk of the experiment next Saturday, instead of Friday. Blimey, if is it not THE Saturday you had those precious game tickets for. Oh, misery.

-In those limited hours you managed to stay away from lab, some crucial piece of equipment broke or got taken away. The latter will require countless and awkward hours of tracking and inquiries (what are those log books for, you wonder). The first one can bring by ripples of additional misery. Depending on the type of deceased equipment, there is an increasing range of irreversibility:

  • Power outage: that stopped all the PCR machines, shakers and temperature-regulated devices you had your experiments running, being shaken or incubated on. Wait, you did not have any experiments going this weekend so you have been spared! Hooray! Unless the power loss also lead to…
  • Incubator malfunction: you lost all the cells you were routinely maintaining for ongoing experiments. Depending on what part failed, your cells died of asphyxia or cold. You will have to thaw new stocks and grow them up before you can do any experiment again. Thankfully you made stocks, or didn´t you?
  • Freezer/fridge meltdown: a lab usually has four different types of cold storage: 4, -20, -80 freezers and -196 liquid nitrogen tanks. The first two are for reagents and short term storage. If and when they stop working they melt away with them the experiments you were storing for the weekend, along with considerable sums of money in antibodies, kits, chemicals, that will of course have to be replaced at an inordinately slow pace. Or never. This particular mayhem can be readily detected upon arrival to lab cause warm bacterial cultures and animal serums have a characteristic sweet rotten smell. Enjoy your morning!
  • Deep freezer failure: the thought of this makes me shiver. You just lost your clones, virus and cell line stocks. Plus the most valuable reagents. You could have been sitting at home scratching your armpit for the past three years, and would find yourself at this very same point. There is nothing left of your work to show. Nada. You also lost the work of the very talented people that worked here before you. Which can probably never be reproduced. If you had been here you could have noticed the freezer malfunction and salvage the contents. But you “needed time off”. Well, you are going to have plenty of that now. Get a coffee and sit down, you need to call your boss.

I hope this did not scare you away from lab too much already! I should mention that Monday Mayhems, though definitely a documented reality, are thankfully not that frequent. And other types of mayhems are infrequent also. Mostly Mondays are just uphill and long if you took the weekend off, and that is sometimes enough to make you wish you hadn´t. However, in my lab we sometimes experience once-in-a-labtime “Special F” Monday Mayhems that can lead to widespread panic. So far, we have had Floods, Fires and Fungal infestations. Those Mondays make you wish that, like me today, you had been too sick to come to work at all.

Written by polarizedpostdoc

June 15, 2009 at 11:06

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Now what?

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Well, now that I made it this far, I guess I can look back and start from the beginning.

There are two main biological phenomena responsible for me writing this from my bed today. One, a viral infection, has unabashedly succeeded on its first attack on my body and has me prostrated and almost convinced that my head is big balloon full of snot swiftly flying away from coherent reality. But that biological process has been thoroughly discussed elsewhere, so I will not dwell on it. Before I drift into mucous bliss, though, let me tell you about apical-basal polarity, the nifty property of some eukaryotic cells responsible for me being the polarized postdoc you read today.

Eukaryotic cells are the ones you and me and most complex organisms down to the border with bacteria are made of. One of their defining features is their lipid plasma membrane that encircles and protects all the rest of cellular components. But far from an inert fence, the membrane fulfills many important functions: it communicates with the external world via specialized receptors, regulates cell shape and volume by pumping ions and water in and out the plasma, anchors the cell to the extracellular matrix (the soil of the organ, so to speak), and allows for cell movement and protrusions, as well as diverse secretions such as the snot currently filling my respiratory system.

Plasma membranes are the cellular components that better differentiate between unpolarized and polarized cells. In the microscopic breasts from the previous post I labeled three membrane proteins that can be present in the cells with fluorescent red, green and pink dyes (the nucleus in the interior of the cell has been stained in blue, for reference). Non-polarized cells to the left only express the red protein, a sticky adhesion molecule that keeps cells glued to their neighbors. But to the right you can see how our polarized cells not only possess the whole spectrum of membrane proteins analyzed, but they are also localized exclusively to non-overlapping sections of the cell surface. That´s right, you are watching polarity in action.

unpolarized

polarized

“Polarity” in general is a property that implies directionality, asymmetry, intentional separation into opposite poles. At the cellular level, it refers to the asymmetrical organization that some types of eukaryotic cells develop as they differentiate, and that provides the structural framework for their biological function. Polarized cells are mature, sophisticated individuals that display an elaborated architecture in the context of an asymmetric organ. Which means that they usually face or bridge two dissimilar surfaces and have adapted their membranes to perform segregated roles in each one. For example, a cell from the intestinal epithelium faces on one side the interior of the tissue that forms the tube, and on the other, the lumen of the intestinal cavity. Actually, make that three surfaces, as our gut cell is also scrunched in between her neighbors that tightly rub her so-called lateral surfaces. But for simplicity, polarized cell membranes are usually divided into basal-lateral (facing the interior of the organ) and apical (facing the external cavity, conduit or surface)

An extreme example of this is the outermost layer of your skin, which faces both the big, cruel world and the warm, cozy interior of your body. Of course, you are telling yourself, the skin cells and the intestinal epithelium must have a way of recognizing this asymmetry and making sure that they have the proper receptors, pumps, and adhesion molecules on each side. This is essential in order to maintain a working vectorial exchange that will allow you to stay warm and cozy inside, as well as nourished, detoxified, tanned, lubricated, and able to see and read this post. Sometimes it also fills our heads with snot, but I am told that is just a side effect of the fight against resilient virus like mine. At least I sure hope so.

That, plain and simple, is what cell polarity is about, keeping the differences, generating asymmetry, and believe me it is such an elegant, ordered, smart process in all its beauty! But because of its complexity, we know very little about how it actually works, and that is why discovering its inner mechanisms has kept me enthralled for the best part of the past ten years of my life. The best ten years of my life.

Now I hope you will enjoy sharing this discovery journey with me, if I happen to win the war with this virus and recover to post more about it. Survival of the fittest, here I come.

Written by polarizedpostdoc

June 14, 2009 at 17:58

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