The Polarized Postdoc

Archive for July 2009

The quest for the perfect muffin, part I: Screening

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Yes, lucky reader, you have heard well, there is not only another muffin post, but also a third one on the way. The truth is, of late my polarized life has been skewing dangerously towards the stay-at-home-and-bake side, neglecting the rave-around-the-city part I was so fond (and proud, given my years) of.

But I am convinced it´s not all the unstoppable decay of age, it´s also this intoxicating, dumbing suburbia I dwell in that is turning me into a domestic goddess. Nothing wrong with being one, as long as it is a personal choice and not the only choice.

Long Island can pass for a decent summer getaway, with nice beaches, the best of the city life in bloom close by, and interesting characters on display around its towns and villages. But it demands a good deal of imagination, or other chemical methods, to survive the dire boredom of the winter months. During the snow season, the hipster-clubber in me peacefully hibernates. Tried waiting for the train in the cold wee hours of January nights, scantily clad. It wasn´t my thing, my mediterranean genes concurred.

So I have developed a winter version of myself, that wears Uggs and cute aprons, and throws dinner parties. I am not yet into board games, but I feel them coming close. For entertainment, not happy with all the mixing and matching routinely performed at lab, winter me usually cooks and bake her way through the cold. Thankfully, there are plenty of other bored, cold, hungry scientists around on whom to bestow some baked goods (see sample in Figure 1). Otherwise, I would be rolling around like a barrel come March.

tried and true

Figure 1: The muffin musketeers

This last winter, we embarked in a very ambitious and potentially relevant culinary project, The Quest For The Perfect Muffin. Our initial approach was a high-throughput one, much in the vein of current biomedical research. We decided to adapt and test in the same experimental conditions selected muffin recipes previously reported in the literature (refs 1, 2, 3, and others). These are the muffin varieties we tested:

-B&W muffins (cream cheese and chocolate)

-Power Banana muffins (mocha-chocolate-nut streusel)

-Naughty Pumpkin muffins

-Blue on Blue (blue corn-blueberry)

-Peanut Butter and Jelly muffins

-White Chocolate Macadamia Muffins

-Triple Ch muffins (cherry, chile, chocolate)

-Ying/Yang muffins (banana-nutella surprise/nutella-banana surprise)

We tried to cover with these the most common muffin ingredients, and add on some offbeat ones, and survey most of the possible deliciousness sources.

Figure 2 illustrates a typical work-in progress experiment:

now, for the fun part of the experiment

now, for the fun part

The results? As expected, most muffin types studied caused grunting, smiling, and a hefty sugar rush response in the voluntary tasters. We observed that the banana-based muffins were consumed significantly faster (p<0.005) than the other types. Moreover, the presence of chocolate acted as a potent stimulant and gave muffin testers a second wind that was much appreciated. This response was observed to a certain extend also in people that consumed PB&J muffins, but nevertheless those were deemed “too intense”, suggesting that there is a feedback loop for muffin-driven activation. Thus, our preliminary data show that the perfect muffin must harmonize, but not mix banana, nuts and chocolate.

Taking this into account, we refined the next phase of our quest by undertaking a “candidate approach”. We sought to combine the components highlighted in our screen in the right amounts to deliver the best possible muffin experience. Were we able to create the perfect muffin? Is it reproducible? Do we have the right controls? Find out more in the next and final chapter of the perfect muffin quest.

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Written by polarizedpostdoc

July 27, 2009 at 18:51

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Karma muffins

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Hypothetically speaking, if one were to accidentally back into someone´s car´s door, and drive away in a hurry without leaving a note, and then some weeks later someone else would in turn back into your car´s door and scram (leisurely or hurriedly) without leaving a note, it must mean that the universe, using the active forces of karma, has just spun around enough to recover its equilibrium.

But rationally speaking, that universal balance cannot, possibly, be ever preserved still. The logic of supernatural forces implies that when you backed into someone´s car the first time, the owner probably deserved it somehow, and you were just a toy being brandished by karma´s hands. So the bad energy merely got transfered, or derived from good one. And so on, and so forth, ad infinitum, it follows that an endless chain of unfairness fuels the dynamic balance of the universe.

Whenever I start thinking like that my heart gets dizzy. I have to admit that I am not much of a believer. It´s not personal, you gods and goddesses and earth energies, it´s just that I have trouble with the idea of believing itself. Of choosing to accept instead of to proof, or discover. In absolute terms, though, a life of faith sounds much more relaxing than endlessly trying to answer all the “whys” and “hows” and wtfs” around you.

battering heights

battering heights

This weekend, as a mental vacation from worry, and to make up for some recent bad energy transfers, I decided to give karma a try, scientifically speaking. I always picture karma like a molding water mill wheel, Ignatius Reilly-style. So my premise is that if karma is some sort energy cycle, not created or destroyed but just transformed by human actions and consequences, it must be amenable to measurement. It has to have a quantifiable unit, kJs perhaps (karma-joules, not kilo joules, thank you).

And if we have our units, we can devise a system to calculate how many KJs are there in a hug, a kind salute, a ride to the airport. But as we don´t know either the exact parameters of the energy conversion reaction (is it exotermic? explosive? catalyzed?), save for that sometimes it includes a kinetic intermediary in the form of car crashes, we need to create good energy, from scratch. More accurately, from our very own chemical potential. AKA, the wheel of life.

top o´ the muffin

top o´ the muffin

To do so, and establish a proper standard that we can apply to daily life, I figured I could make a well-known vehicle of good energy, that comes already aliquoted in individual doses. So instead of worrying, I adapted a warm looking muffin recipe to my non-dairy, berry-crazy standards. Then proceeded to bake them and spread them amongst my friends and folks, who received different doses of the sugary vibes. Now, I plan to just sit back, hang out and observe how the good karma expands and extends from my oven, into the hostile world, perhaps in waves of good luck or strikes of love. If we apply some simple exponential amplification rules, it is likely that this experiment might keep me busy for a while. So for now, worrying will have to wait for the next wheel´s turn.

(Good) Karma Muffins

Procure:

-1/2 cup margarine

-1+1/4 cup granulated sugar

-1/2 tsp salt

-1+1/2 cup all-purpose flour

-1/2 cup cake flour (optional, you can use AP)

-2 large eggs

-2 heaping tsp baking powder

-1/2 cup soy milk

-1 tsp vanilla extract

-6 ounces each of raspberries, blackberries, and blueberries, fresh or unthawed, sprinkled with:

-1 tsp sugar

-1 tsp cinnamon

-1 oven at 385F

-1 hand mixer

Perform:

-Sift flour and baking powder together and set aside.

-Cream margarine, sugar and salt with until soft (one day we must discuss the scientific value of baking terms such as this, or “until just combined”, “fluffy” or “just moist”)

-Add eggs and beat until fluffy, to your best judgement.

-Pat berries dry on a paper owel.

-Into the liquid mixture, fold alternatively one thir of flour, one third of milk, repeat until just combined. Add vanilla.

-Sprinkle berries with sugar and cinnamon, fold into batter.

-Pour 1+1/2 tbs of batter into greased muffin cups. I always have trouble calculating how much to aliquot, and can never seem to avoid putting too much. This measure seems to produce some handsome, pointy doses of good energy to share.

-Incubate in the oven for 20 minutes, or until golden and dry according to the international toothpick standard.

-Cool for 10 minutes on a rack, invite friends over, have them with hot chocolate, and rate your muffinity according to the width of the smiles and volume of grunts elicited. Good luck, and good karma.

Written by polarizedpostdoc

July 27, 2009 at 17:54

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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

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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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Empanada

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“Empanada” is a Spanish word with poignant connotations for my life right now. Literally, it means “breaded” or “tucked inside bread” and usually refers to a traditional dish from the north-west of Spain. This region delimited by mountain ranges and crooked coast lines is the home of velvety, furry grassed hills and the rich silver stretch of the Atlantic ocean that we call Cantabric sea.

In slang, to be “empanada” refers to that distracted state in between spirited away and absent-minded that can be experienced when you have many loose ends slashing out all over your brain. Which is exactly how I feel these days. Tucked between the dough of fate, in a cloudy haze, at times dizzy or giddy with fear or excitement. A true case of empanada.

Aside from the human version, there is also the bite size one, empanadillas, that are pretty much the local take on dumplings. They look like puffy dough balls, and are filled with an assortment of the seasonal earth and sea goodies at hand. Much like this:

As much fun as empanadillas are to make and eat, my family used to favor the bigger scale version, probably because it is more high throughput- friendly. To produce a bona-fide empanada, women folk would sit around and chop, simmer and chat, in an unspoken and informal ritual. The flow of tradition that shaped me ran deep and strongly through moments like those, and only after I fled away from home I realized the warmth and spiritual nourishment I was exiling myself from. For this, and for the flavorful bliss tightly packed in each bite, empanadas have always been high on my homesickness list.
So, to try to fight of my baker´s block and quell my existential anxiety, I decided to adapt my heirloom empanada recipe to American standards, and present it here (with experimental data) for your enjoyment. Here, take a slice of Northern Spanish heaven.
Somewhat Distracted Spanish Tuna Pie

Reagents

2 Frozen or hand-made puff pastry sheets, thawed
Salt, pepper
Thyme
Olive oil (Spanish if you can)
2 Big sweet onions (Spanish if you can)
3-4 Cloves of garlic
1 Red/orange pepper
1 Sweet green pepper
3/4 cup of canned peas
1 can whole peeled tomatoes
2 Eggs, hardboiled, plus 1 for washing
3-4 cans of tuna* (Spanish** if you can, or albacore)
*you can also change it up a bit and used 2-3 chicken breasts, seared.
**I usually find cans of Ortiz tuna at most higher-end supermarkets like Whole Foods or Fairways. It is expensive so you can mix it with regular albacore.
Protocol
Before you commence chopping mayhem, please do remember to:
-thaw the pastry
-warm your oven to 400-425 F
-start hardboiling the eggs
-heat up olive oil covering the bottom of a wide and deep skillet
Then, chop up the onion, garlic and peppers and start simmering them at medium heat. Add salt, pepper, and herbs, but do not stress about it, you can correct the flavor later once everything else is in.

veggies ready to take it to the next step

veggies ready to take it to the next step

Cook for 10-15 minutes until vegetables are soft.
In the meantime, take the eggs out of the boiling water and cool them.
Drain and stir the peas and the tuna into the skillet, mixing well.
With you hands, crush in the tomatoes so that they are chunky, and cook them in until the liquid has reduced visibly.
Meanwhile, the dough should be ready to roll. On a lightly floured surface, roll the dough from the center into two rectangles that fit your oven pan.
Cover it over a baking sheet and chill it in the fridge until it is ready to bake.
feeling the filling

feeling the filling

Peel and dice the hard boiled eggs and add them to the filling, stirring them in and incorporating everything. Now is a good time for a taste, and to correct the salt and spice. If you don´t want to overdo the herbs, but still want a bit more aroma, add on some thyme instead of the whole Provence mix.
Turn the heat down a little and continue cooking for ten more minutes to bring out the flavors.
Take the pastry out of the fridge and extend it over some parchment paper on the bottom of an oven pan.
Carefully transfer the filling with a slotted spoon to the pan. Try to leave behind as much liquid as possible, otherwise the dough will be soggy.
Once you have around 1 inch or 1 1/2 inches of filling in, cover with the remaining pastry. Push down the edges into the bottom pastry to seal and trim it all around. With the leftover dough, you can write your name on top, or the name or your loved ones. I find that swear words are also exceptionally tasty.
Beat up the remaining egg and brush it evenly on top of the pie. Bake for 20 minutes, turning down the oven or covering with tin foil if the top starts burning. Typical results are a crusty, golden top layer and a flaky dough that candidly melts in contact with the hot filling, swamping your mouth with its delicate and flavorful texture. If the first bite makes you strangely homesick and brings memories of your mother´s kitchen, you know you have successfully recreated a true empanada. Better eat one that become one, so… enjoy!
one, two, three... empanada

one, two, three... empanada

Written by polarizedpostdoc

July 10, 2009 at 14:21

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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

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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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