The Polarized Postdoc

Know your enemy

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Contrary to what the buzz says, new developments in the war against cancer are not that hard to come by, or that minor. Those important characteristics in anti-cancer advances (speed, abundance and relevance) are in direct correlation to the money and effort invested in research. Which is why we need to keep committing both to an unfaltering fight. Because even the smallest victory saves countless lives, present and future.

It is my personal experience that usually cancer research elicits respect, and often encouragement, from lay audiences understanding the fierceness of the fight on both sides. But for some reason, lately cancer research is under a heavy flak of criticism based on lack of progress and innovativeness.

I disagree with both claims as strongly and biasedly as I possibly can. And I could use my insider´s view to go on a really righteous and uptight diatribe about why and how, exactly, but in my best scientist behavior I am going to just let the facts speak for themselves.

Just recently, two new therapies have been announced, one of them stemming from a pretty revolutionary and novel approach called synthetic lethality. In an agile leap from ideas to cures, this new concept has already provided effective therapies for one of the most aggressive and poorly understood forms of breast cancer, the so-called triple negative tumors. This positive response represents not only a victory, but a spearhead propelling us ahead in the game, opening new possibilities for treating other forms of the disease.

Because contrary to the rules of engagement proposed initially when we declared this war against cancer, the enemy is neither one, nor static. Cancer is an ample term that fits in solid armies of tumors growing silent and morphing in many different organs, guerrillas of circulating tumor cells ready to invade new territories, dormant mutations that act like secret agents turning normal cells to the dark side, collaborationist immune system components, and many more wicked weapons yet to be uncovered.

It has been clear for a while that the most effective way of winning is by getting to know your enemies, in every terrific form they take, and fight them to the ground one by one. This logic is simple and powerful enough, on top of tried and true, and I am perplexed as to why mass media can´t seem to accept it. There is not going to be a single bullet solution for cancer, but we are sure going to keep winning battles, if only they let us fight in peace.

One of the most poignant ones is the ongoing quest to discover how tumor cells can leave their niche and, evading several layers of surveillance, infiltrate other organs spreading the disease and making it impossible to control by surgical methods. Last week I had the privilege to witness an outstanding scientist describing how his group has devised a novel system to observe in real time the sly tricks of invasive tumor cells, shedding some light about the initial steps of this deadly process called metastasis.

The group of John Condeelis managed to put a microscope video camera inside a mouse breast tumor, and monitored the movements of tumor cells. In their recordings, we are able to witness in awe the showdown between immune cells (the vigilant macrophages) and tumor cells, as they chase each other´s chemical scent while sliding down the tumor´s scaffold of collagen fibers. The tumor cells swiftly follow the macrophage signal, EGF, to the blood vessels, where they can extend cellular protrusions to break into the blood stream. Hence, the first step towards invasion has happened, silently and far from the tightly surveilled edges of the tumor.

tumor cells ambush a blood vessel, ready to go on a invasion mission

green tumor cells ambush a red blood vessel, ready to go on a invasion mission

Once they had gathered this valuable recon intel, the researchers were able to capture some of these rogue tumor cells, simply by luring them with the same chemical whiff into a trap, a collagen coated steel tube. The prisoners were subjected to exhaustive interrogation of their genomes, which allowed for the identification of the potent weapons they were using to dig into the blood vessel and escape.
One of the proteins thus identified, dubbed Mena invasion isoform, is a unique variant found in cancer cells that enables for efficient movement and rearrangement of the cytoskeleton when the cell is reaching and carving the vessel wall. Sort of like claws and fangs, except more scary.
This finding is of outstanding importance and lasting relevance, and it makes me proud to be a scientist working on cancer. For the skeptics out there, yes, it is still too early, but surely the identification of both the mechanism and the molecular player responsible will in time allow for the development of drugs that stop either, or both. Just like with anti-angiogenesis therapies that cut enemy supply lines, limiting tumor cell mobility may not kill the disease completely, but it blows a severe hit on its progression. And sometimes that is all you need to maintain people alive, so we can all keep fighting.

Written by polarizedpostdoc

July 2, 2009 at 15:57

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Fireflies

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We don´t have fireflies back home. But there are plenty here in the golden coast of LI, so many that people whisks them away like regular airflies. Me, I can´t get over them. And I am so grateful for it, cause it means that I have spent enough time of my life without them to ensure that from now on they will stay fresh and new forever, always. It is like getting a bit of your childhood back every time, a rebate.

The golden coast of LI makes me feel that way about science too, sometimes. If you are a local scientist, when the conference season comes by in the summer you are constantly stumbling upon outstanding talks that light up the dark auditoriums. Instead of just fizzing around your sleepy head, they warm up your heart making you feel the excitement of that first biology class, fresh and new again. And much like real fireflies, I don´t remember ever experiencing anything like that back home. So for a healthy daily dose of amazement, you usually just have to look the right way, and persistently keep your eyes open for wonders.

It seems like after some lackluster beginnings, last week we finally kick-started the summer, and I saw my first fireflies, both real and imagined. To fully appreciate the first ones, I am afraid you would have to move here one August, muddle through the hot wet air with a cold beer in a sweaty glass, and sit quietly near some bushes at sundown.

But for the second ones, you don´t need to leave your seat, just keep your eyes open and continue reading these posts. I am going to try and transmit the feeling of being mesmerized by summer science, time and time again. Cause as my friend Max just put it, there are a billion outlets for hard data, but there is only one outlet for me, and you are in it.

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July 2, 2009 at 11:55

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The shape of cells to come

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By now you are aware of the importance of polarity for the correct function of essential biological processes. And you are asking yourself, but where does it start? How does it work? What are the cues that help cells identify the external asymmetry, and translate it into an internal one? Well, those questions are still being actively pursued by many talented scientists, and also regular ones like me. And as in every good story, our quest started out by sheer chance, or its technical counterpart, serendipity.

But in order to grasp polarized organization in all its beauty, we first need to get acquainted with regular organization. The mechanisms and pathways that determine unpolarized cell shape comprise a common core that is going to carry out the polarity differentiation program. So let´s unveil them, briefly I promise.

Like the structure of a building, or even the bones in your body, cells are equipped with a microscopic skeleton, the cytoskeleton. It is a system of interconnected filaments and tubes that provides the physical support and scaffold for all the cellular organelles. The interior of a cell is little more than a container for different subcellular structures, that in turn subdivide ad infinitum into smaller structures. To orient you inside this fractal microcosmos, this is a depiction of how we scientists see the inside of a cell when we close our eyes (color choices may vary):

animal cell, from A Blog Around The Clock

animal cell, from A Blog Around The Clock

The cytoskeleton components not only keep everything in place, and give structural support to what is fundamentally a bag of liquid, but they also act like rails, or highways, through which cellular components can be shipped from one location to another. This shipping process usually goes from the cellular factories that assemble proteins and lipid structures, through the packing stations, round the energy central, to their target locations. For example, our cell may synthesize an adhesion protein to attach to its neighbor cell, and ship it to get polished and refined (usually by adding sugar and lipid tails and coats). Then the adhesion molecule will be directed through the cytoskeletal meshwork to its place at the plasma membrane, where it will insert itself and stretch out to grab on to an identical molecule from the adjoining cell. And just like that, life can go on.

Cytoskeleton networks and the sorting machinery, together with the membranous system of compartments, constitute the stable structural basis that enables the cell to function as such. But they represent a plastic arrangement that lends itself to multiple modifications and slight variations. It is thus exciting to think a step further about how this organization can be adapted to support not just a cell, but an asymmetric one. As usual, the answer to this is simpler, smarter, and far more beautiful than we could have imagined.

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June 16, 2009 at 20:40

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The fine lines

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And now, for something completely different.

Has it ever happened to you to find yourself too sick to do any work but not sick enough to stop doing everything else? I walked that fine line this weekend, often humming along in a haze.

I had tickets for one of my favorite musicians at one of my favorite venues in one of my favorite cities, John Vanderslice´s show at the Bowery ballroom in Manhattan. Bought by one of my favorite persons. So no persistent rain or incoming cold was about to stop me from going. And I am glad, cause it was an amazing evening. I wish I had more, better words to praise John Vanderslice´s music. He is such a talented songwriter and outstanding performer, incredibly professional and devoted, and also more kind and generous, down-to-earth than any renowned musician I have ever seen. He is both unassuming and overreaching, and his songs usually strike the right balance between universal and intimate feelings. A fine line to play by.

I think our favorite theme of the night was “Too much time”. Me and the ticker-buyer heard this song for the first time when he premiered it last year, also in NYC, in a heart warming show starring just him and his guitar. We still maintain that was the best version, but the rock-and-roll riff he did this weekend came very close. I have no recording of either, but you can decide about your favorite version also by checking these ones out, from sterogum and from this other live recording. There is also the official version, from his new album Romanian Names. All highly recommended!

The nightly city outing did not help my recovery, so I was not able to work on Sunday either and decided to work on our communal lab garden instead. And bake frantically. Surprisingly, I am still sick today!

Aside from my breast cancer research I have some ongoing baking and cooking projects that I work on sporadically (but not as sporadically as I should). My main quests are to find/produce the best-of-the-crop cornmeal, the morphing muffin and the perfect loaf. Because why go to a store when you can slave at home and come up with only slightly inferior results? These are collaborative projects that could not be possible without a team of very talented tasters and sous-chefs, often recruited from our seafood club.

I usually parse by several online recipes to use as starting points to devise my own take. Lately I have been staying away from fancy websites that used to lure me with glorious shinny pictures, as they made my deflated efforts look dull and scruffy. But I could not resist giving this outlandish cornbread a try, out of scientific curiosity I guess. An important member of the team is allergic to dairy, and I don´t want to kill him (well, most of the time I don´t), so I adapt all the recipes to non-dairy friendly. I also try to shy away from overly complicated and specialized ingredients that you can only use sparingly. My budget and pantry are not that big. Oh and I always put more fruit/chocolate/nuts than they ask for. Same reasons plus gluttony. Here is the resulting protocol:

Cowless lemon blueberry basil corncake

Reagents

1 cup all-purpose flour

1/2 cup coarse ground cornmeal

1/2 cup finely ground cornmeal

1/2 cup granulated sugar

1 tbs baking powder

1/4 tsp baking soda

3/4 tsp salt

2 tbs margarine melted and cooled

2 tbs basil-flavored olive oil

1 cup home made non-dairy buttermilk (soy milk with 2 tbs lemon juice stirred in 5-10 minutes before)

2 eggs lightly beaten

2 tbs lemon juice

1/4 tsp lemon zest

almost 1 cup blueberries dusted with flour.

2 tbs basil herb mix (comes refrigerated in a tube, and handy when your garden herbs are just starting to take off)

Protocol.

1 Preheat oven to 375F (for cooking purposes temperature is NOT in Celsius. Everywhere else it should be).

2 Grease loaf pan, 9×5 inches (see above for measuring system cooking exceptions)

3 Sift in the solids in a big bowl and mix.

4 In a separate bowl whisk oil, butter, buttermilk, eggs, lemon juice and lemon zest.

5 Add liquids to solids and mix quickly. With a rubber spatula fold in blueberries and basil.

6 Pour and bake for 40 minutes. Cool on rack.

Although my pictures are not as good as the original blog´s, I hope you can tell that the result was similar. As a die-hard scientist, I am always very pleased when you follow the instructions and get exactly to where you are supposed to.

lemon blueberry basil cornbread

IMG_3278_2

The on-site cornmeal experts consensus was that this had a surprisingly lightness to it, and that it merged warmth and freshness quite astonishingly. A deliciously fine line.

And yes, you have guessed right, I am a girl!

Written by polarizedpostdoc

June 15, 2009 at 13:03

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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.

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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.

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June 14, 2009 at 17:58

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That´s it, I am doing it

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I never pegged myself for a blog writer, never even been much of a blog reader. I lack the right amounts of voyeurism and narcissism, the online skills, and the secret conviction of having something important to say. To everybody, no less! I have neither an extraordinary life, outstanding abilities, or unique opinions to share, nor the flame of youth to thrust me forward, but I do like to write. So I am going to write to you, and hopefully we will find we have things to learn from each other.

What I mostly do when I am not writing and beating myself up is try to figure out why and how breast tumors develop, with the ulterior aim of stopping them, or better yet, killing them altogether. One of the ways I do this is by diving down inside my microscope and surveying tumor samples for early changes in the tissue organization that may mark the beginning of a tumor. Diving down to the cellular level does give you that little pang in the stomach, if done properly. So hold your breath and come on down as we dive into the magnifying lenses!

Slide5Slide6Slide17

Dizzy? Sorry, soon I will try to explain the wonders of that multicolor microscopic world I spend my days in. But I also invest a significant chunk of my time reading like a maniac, cooking like the world´s ending, baking in a sugar rush, learning about music as if they´d quizzed me on it, growing oddly-shaped vegetables, stretching my yoga mind and strengthening my pilates body, knitting as if the winter was upon me, running my miles best when they are across the streets of Manhattan, and generally doing most ordinary things my own unique way. You may find yourself jumping from molecules to edible, hearable, wearable posts, but I promise to try and always follow the most rigorous scientific approach to the most outrageous matters. And I hope through that we both grow better, wiser, happier.

I am counting down my days as a researcher, the only thing I really know how to do well. Lab work has been my life for more than ten years, all of my adulthood, and it is mighty hard to put it all away and start from scratch. So I thought it could be helpful if instead of funneling the hindsight, and the insights, into my friends inboxes as accustomed, I posted them here. Maybe this way my experience (one might even boldly call it expertise) would not feel so wasted. I have never written in public, or for an invisible omniscient screen, so please bear with me. But also bear on me. I believe there is a good chance that your comments will be more merciful that the spinning wheel of my internal criticism. Without trying, in the end, I would have remained a self-taught failure.

I always thought that starting a blog was like emptying your warm mug of water in the ocean. But now that the “publish” button is upon me it feels more like switching on your own star in the velvet silence of the night sky. Almost everybody will never know, or care, oblivious through their lives of city lights and roofed evenings. But it will shine anyway, unperturbed, with no purpose but the beauty and not use but to brighten your life, should you stumble upon it while chasing a furtive galaxy away. So goodnight to you astronomer, here´s to always looking up.

Written by polarizedpostdoc

June 12, 2009 at 16:55

Posted in personal, science