Epi-what?

A recent article in the New Yorker on epigenetics is drawing rage from scientists far and wide, because it apparently lacks a few key perspectives.  I decided to read the article and attempt to weigh in since this is an area I am particularly interested in and one that I follow pretty closely.  Before I comment though, I would like to acknowledge the excellent standing of the writer of the article, Siddhartha Mukaherjee, on account of the Pulitzer Prize he received for his wonderful book on cancer, The Emperor of All Maladies. This was a fine book and the recognition bestowed on the author seemed well placed to me, so what had gone wrong with the New Yorker article?

I read the article and for the most part enjoyed it.  Mukherjee weaves personal observations of his mother, a twin, with conversations on epigenetics with researchers  in the field.   These scientists have certain views, not all of which are accepted as mainstream.  One, for example, talks about an "epigenetic code"  which is not a broadly accepted concept. In the writing of the article, it seems Mukherjee down-played the role of transcription factors in the bigger epigenetics picture, and focused mainly on histone modification and methylation.  These terms are mumbo jumbo to most readers, but they are important to scientists. In the processes that modify the instructions of the genetic code there is a series of (sometimes unfortunate, sometimes not) events of which methylation and histone modification are rather downstream.  Transcription is nearer the top.  The fact that Mukherjee pretty much ignored transcription was what got him into hot water. Rather he waxed lyrical about the histones (because they are super interesting- little coils of DNA that expand and contract depending on how tightly they are bound), and about methylation.  He implied a stronger role for these elements than is currently accepted. Scientists from the field and a fair few outside of it called foul, and Mukherjee wrote rebuttals and explanations.  The article is an excerpt from a full book on genes that is yet to be published. He did not have time to go into all the details, he said, and quickly published an apology for omitting transcription factors and overextending speculations. However, reading his response to his critics it seems he wasn't so much sorry, as irritated.   And perhaps he had good reason.  As I read the complaints it seems like the critics all got together and decided on a response, then all said the same thing.  It seemed a bit witch-hunty to me but then I am not an epigenetics scientist.  I do think part of it had to do with what is extrapolation based on very early evidence, versus what the scientific establishment have accepted as fact. One critic even likened him to Deepak Chopra which seemed a bit excessive (I like Chopra for his edgy thinking, but obviously the Dawkins of the world do not share my affection).  I confess that I am way more comfortable with speculation than most scientists. I believe it is an essential part of the scientific process that gets us to eventual truth.

I would recommend you read the New Yorker article and decide for yourselves whether the author is scientifically accurate enough.  I felt he was, based on my limited understanding, but agree he over-emphasized some aspects over others. He also implied epigenetic changes can have lasting change which is a hotly debated area right now. My bigger interest though, is how easy it is for a writer to go from superstar to scourge of the earth; from Pulitzer Prize winner to scientific incompetent, in one fell swoop.  It happens very, very quickly, and I suspect Mukherjee will not recover easily from this experience. In the take downs there are also a fair few jabs at the New Yorker itself, for placing literacy juice over scientific fact.  Again, I have little beef with the New Yorker's style. I am a fan of the magazine and don't expect hard core science, but rather anecdotal tales with science in a supporting role.   Did Mukherjee take anecdote too far?  Read the article, and see for yourselves.  Let me know what you make of it.


References:

Same but Different

How epigenetics can blur the line between nature and nurture, by Suddharta Mukherjee

A couple of criticisms appear in these links:

https://whyevolutionistrue.wordpress.com/2016/05/05/the-new-yorker-screws-up-big-time-with-science-researchers-criticize-the-mukherjee-piece-on-epigenetics/ 

https://whyevolutionistrue.wordpress.com/2016/05/07/laffaire-mukherjee-the-last-word/

Little cancers and turtles

Very quick thoughts in follow up to the last blog on cancer metastasis.  In this article  ("Overkill: America's Epidemic of Unnecessary Care" from the 11th May New Yorker), Atul Gwande questions many medical procedures as unnecessary.  I loved the piece and I buy his arguments.  Referring to a recent book by Dr. H. Gilbert Welch, from Dartmouth Medical School ("Less Medicine, More Health," published by Beacon Press, 2015), he calls the cancers that don't appear to be doing much, and therefore may not need action,  'turtles' as opposed to the rabbits that race ahead and need to be stopped in their tracks. Turtles don't need the same level of diagnostic technology as the rabbits, but modern medicine tends to throw everything at everything, often at great cost and even detriment to the patient. 

What stuck with me about this article though, was the reference to a "microcarcinoma" in a patient's thyroid.  He explains that as many as a full third of the population has microcarcinomas in their thyroids but only 1 in 1000 die from thyroid cancer each year.  Since it is only the relatively rare microcarcinoma that takes off like a rabbit and becomes deadly, some experts suggest that microcarcinomas not be called cancers at all and currently, guidelines do not recommend treatment.  This reminds me of a study I read a few years ago that found breast cancer cells to be highly prevalent in women over 65 ( it could have been 60- I don't remember exactly), with relatively few turning into actively progressing cancer.   These are not discovered until autopsy when the patient has died of something unrelated.
So if these observations are correct-and I have no reason to suspect they are not- then we are all potentially walking around with cancer in situ, with most of these cheeky little cells not doing much more than scaring the pants of the pathologist (and eventually the patient) that comes across them.  The procedures to remove some of these microcarcinomas are more risky that the cancer cells themselves, as Dr. Gwande points out. So why not leave them alone until they start to act up and show signs of causing trouble?  The answer is obvious; because we don't know if or when that will happen, and by the time we find out, it may be too late.  We can see why there is a tendency to act versus not act, when these characters are found.  To change the paradigm we would have to find a means to non-invasively monitor these cells for signs of growth and movement.

In order to do this we need to answer a few questions:

• How does a micro cancer cell 'decide' to take off and grow? What are the stimuli and how does the transition begin? How long does it take to become a fully fledged, rapidly dividing menace?
• Are there plasma factors that can be measured when this happens?
• How does a cell ' decide' to metastasize. How long does it take to create the mechanism to do so?
• Once the pieces are in place, and the cancer cells leave the primary site, how do they decide where to settle, and how long does it take to successfully seed the new site?

It seems there is a temporal aspect to this (remember in the last blog, the metastatic seeding seemed to occur in waves).  I know there are some very big brains working on these questions and I am scraping the surface only.  This blog is really me thinking-out-loud on my own journey to stake out the heart of cancer and it's wily ways.  

Moveable feasts: How cancer takes the party on the road

A few years ago I wrote a brief blog about the importance of metastasis to cancer's lethality.  About 90% of cancers deaths are due to metastasis. Metastasis is the process that leads to secondary cancers that arise in areas of the body that are remote to the primary tumor.  Cancer is at its most vicious once it's on the road and looking for new sites to settle, so research into the mechanisms of metastasis are crucial to finding potential new treatments.

In this week's Nature magazine there are a couple of very interesting articles that describe how complex this metastasis process appears to be.  One is about how breast cancer cells escape from the primary tumor in the first place, and the other is about the 'seeding' process that allows the roving cancer cells to set up shop in remote tissue in lethal metastatic prostate cancer. A third article by Hong et al, in Nature Communications also demonstrates the complexity of metastasis in prostate cancer using a similar analysis. What follows is my take-away from the articles. This particular Nature issue has other interesting cancer articles so I recommend looking at the whole thing (may require a subscription for the main papers though).

The view of cancer as just cells gone wild is changing to one of cells behaving badly in a somewhat organized way. The party contains cells that are just like the first cancer cells in the tumor (clonal cells), but also other cells that represent 'sub-clones',  derived from the primary cancer cells but with subtly different, and often competing, personalities.  The distribution of these personalities at the primary cancer site may well determine its fate. Some of these characters appear to be particularly good at evading chemotherapy. Others are good at creating the environment that allows them to escape from the primary tumor, and set out for new pastures through the bloodstream or the lymphatic system.  The Nature article by Wagenblast et al, shows that these Houdini cells (my term), are aided and abetted in their escape by two proteins called Serpine2 and Slpi that they express on their surface.  In breast cancer cells at least, these proteins cause the cells to acquire characteristics of endothelial cells (the cells that line the blood vessels) which means they can form connections between the tumor and blood vessels, thus providing the escape route. As such, they are potential target for new cancer treatments.  The proteins are also anticoagulants which may help keep the blood flowing and the escape hatch open. These so-called vascular mimics are very aggressive cells with what appears to be a focussed mission to get the team on the move. As Mary Hendrix points out in her review of the paper, their presence is a clear advantage for the tumor, but not so much for the patient- those people who show vascular mimicry in their cancers tend to have a poorer clinical outcome.  While the study used breast cancer cells in mice, the same proteins have been found on metastatic lung cells in humans.  Whether the current findings will apply to metastasis more broadly across other tumor types is not known, but it's a good hypothesis that deserves more attention in my view.

The second study of interest in this issue is by Gundem et al and this looks at the evolution of the remote metastatic sites in patients with lethal metastatic prostate cancer.  While prostate cancer is common, associated metastasis is much less common. Using whole-genome sequencing, the studies showed both clonal and subclonal cells to be present in the primary tumor. Hypothetically, the subclones may compete for dominance and in the presence of chemotherapy, those who have the resistance personalities may be able to prevail, changing the composition and fate of the overall tumor.  The studies also showed that at least two subclones were able to seed one metastatic site meaning that is is not only the primary tumor clones that seed the distant sites, but rather clusters of diverse cells. The diversity of these cluster may determine whether the seeding is successful or not. There are many circulating tumor cells but successful metastatic is relatively rare which suggests that the subclasses may cooperate during seeding process by leveraging distinct properties that at the moment are not understood. Michael Shen in his review of the current studies, suggested that disseminated single cells could settle in a remote site and remain dormant until cooperative metastatic cells arrive to help them take hold.  It was also interesting that some of the secondary tumor cells may have come from other secondary tumors as well as the primary tumor meaning that metastases could be reseeded several times from the both the primary and metastatic sites.  

A separate study by Hong et al, found similar results to Gundem et al, and also showed metastatic seeding occurs in temporal waves.  They also found that cells from the primary prostate tumor, can persist in the circulation in the long term, even after the primary tumor has been surgically removed.  This is wildly interesting to me and I am going to research this further for a future blog.  I've always felt understanding temporality is a major key to understanding disease.  This is all groundbreaking stuff and opens up new areas of research that could result in new treatments.   I am left wondering if the temporal waves, or the subclonal signatures could be influenced by epigenetic changes from environmental impacts?  I am off to explore!

 Nature. 16th April 2015. 

Personalized medicine starts to hit its stride

The flexible genome [pic from nature.com]

I recently attended a conference at Harvard Medical School on big data and translational medicine.  Translational medicine is the discipline that links scientific discovery (bench insights) to patient care (at the bedside, hence the term that is sometimes used..."bench to bedside").  The general idea is that we never have a truly clean slate of health.  We are conceived, born, live our lives and eventually die.  During this time, we are in a constant state of change. While we have  a solid set of genes in our personal genetic code, they are under considerable pressure from other elements such as regulatory genes and epigenetic signals that are influenced by an individual's internal and external environment.  Some of the changes wrought by these elements are permanent and others are transient but either way, they affect the expression of the our genes in real time throughout our lives and constantly nudge us towards disease.  Add to the mix DNA repair mechanisms that also become less effective as we age, and the scene is set for our gradual demise from before we are even born. At any given time, we have a number of mutations and damaged physiological systems that do not constitute enough for overt disease.  Over time, these effects multiple and at some point we will experience a symptom or two and eventually, a diagnosis.  By the time the symptoms appear, the disease has become quite complex and pervasive, and because of this it is much more difficult to treat. If it could be caught in the earlier stages where there are fewer factors involved, and fewer compensatory systems triggered, it could potentially be nipped in the bud. This is one major goal of translational medicine- to identify the unique signals that show disease or disease risk at a stage where treatment is likely to be more targeted and more successful.

Everything above is old news, but the conference revealed exciting new directions for translational medicine.  For the first time, I have hope that personalized medicine is really starting to become a reality.  Large data sets are being collected, not by physicians or pharmaceutical companies, but by patients.  Over 95% of these patients are allowing their data to be used for massive projects that will attempt to connect early signs and symptoms with the risk of various chronic diseases.  Linking seemingly insignificant phenotypic changes to chronic disease development will eventually allow serious diseases to be detected before they become fully fledged and more entrenched.  For instance, already we know that slow blink rate is related to Parkinson's Disease and this can be used as a flag to look for additional symptoms in patients who are at risk of  Parkinson's.  Whether medicines can be developed and given to patients at these very early stages remains to be seen, but a critical step is incorporating some of these phenotypic or 'patient-reported-outcomes' (PROs) into clinical trials so that the more subtle signs associated with disease can be used to monitor effectiveness of treatments in early stages.  Big data is crucial here, and that patients are willing to share their data at such an unprecedented rate is remarkable.  I have had ideas about epigenetic disease triggers, PROs as trial endpoints, and very early disease intervention for many years, and to see it start to come together as translational medicine is absolutely thrilling to me.
I believe we are on the edge of a precipice and that this science will now begin to accelerate on a logarithmic scale.  Astra Zeneca just signed a nice deal with PatientsLikeMe, which is a strong indication that personalized medicine is about to go mainstream.  I can't image a more exciting time to be in healthcare.  Now, if we can also figure out the economics of the system and make that work in favor of the patient versus the insurers, we would be firmly on the path to better health for all.

The probiotic...glow?

I have pondered the validity of probiotics many times over the past couple of years, wrestling with the boundless enthusiasm of Jamie Lee Curtis versus the seeming lack of solid scientific data.  I learned at the Digestive Disease Week conference in San Diego last year, that one would have to eat about 6 probiotic yogurts a day to get enough of the beneficial little beasties within to make much of a difference to the symptoms of, say, irritable bowel syndrome (IBS).  At the conference there were several vendors hawking probiotics and even a 'Probiotics for Dummies' booklet.  I remained sceptical.
Since that conference I have read quite a bit on gut bugs, more correctly known as the gastrointestinal microbiome.  Overall, we have ten times more bacteria in our bodies that we have actual cells, and a hefty chunk of those are in our lower intestines.  So what difference would adding a few more possibly make?
Well, aside from the assertions regarding internal effects, a new paper has suggested probiotics may have a more visible benefit that may even confer an evolutionary benefit.  Researchers from Greece, Canada and MIT in the US, noticed that the fur of mice being fed probiotic yoghurt for studies on intestinal effects became unusually lustrous as the experiments progressed.  They followed up with a separate study on the effects of the probiotic yoghurt on the fur and indeed found daily consumption of the yoghurt with the probiotic microorganism Lacotobacillu reuteri (L. reuteri)  resulted in thicker skin and more lustrous fur, that was in part related to an effect on the immune system. To be sure it wasn't the yoghurt itself that was responsible, in a separate group of mice the investigators supplemented the diet  with the L. reuteri bug in drinking and found the same effect.  What's more, they also found increased acidity in the mucous membranes of the animals which they associated with increased fertility. The investigators thus concluded that the 'healthful glow' imparted on the animals from eating the probiotic yoghurt ( or drinking the 'good bug' in water) was an external display of fertility. Studies in humans are sure to follow, faster than you can say Activia. In the meantime, I am off to see what's in the 'fridge....

Reference 
Levkovich et al. Probiotic Bacteria Induce a ‘Glow of Health’. PLoS One. 2013; 8(1): e53867.Published online 2013 January 16. doi:  10.1371/journal.pone.0053867

That was 2012.

A new year, a new resolution to blog more.  Of course, it never translates into me being more productive.   However, I am starting with a new blog post to kick off the year and as part of it I thought I would review what I learned in 2012 and what I am excited about for the coming year.  My major discovery last year was the world of epigenetics, acquired through a writing opportunity to cover the COST conference on Personalized Medicine that took place in Cyprus last June.  The conference was definitely the highlight of my work year and I hope to do it again this coming year if the follow-up goes ahead. The conference was designed to bring together practitioners of diverse disciplines to discuss personalized medicine from a number of perspectives and I was lucky enough to interview many of the participants and write up the summary of the conference.  Physicians, physiologists, engineers and philosophers were just a smattering of the perspectives represented. The field of epigenetics (the study of heritable influences on the genome, caused directly or indirectly by  environment and experience) was new to me, and I talked to as many 'experts' as I could about it and I came away convinced that the next major breakthroughs in medicine will be in epigenetics.  I also came away feeling that the most significant current hurdle we must address as scientists and physicians is overcoming our inability to put the complexity of our current health environment into manageable and communicable frameworks. We will only be able to do this if we start to think about problems holistically and top down, rather than from a reductionist perspective which by definition, is bottom up. The Parmenides Institute in Munich is at the forefront of this quest and on my wish list for 2013 is a visit to see Prof Albrect von Mueller at the institute to learn about the work and the tools being developed to expand cognitive reach in children and adults.
In mid 2012, I started a new job as scientific director of a medical communications agency; while I loved freelancing, I needed a regular income to pay for college and for health insurance.  I miss the freelancing lifestyle, but the new job is fun too.  I traveled quite a bit and already have much more planned for 2013. I also learned more than any normal person ever needs to know about the GI system. This coming year we have plenty of other areas of interest in the offing, including my favorite, neuroscience.   I am also exploring new business opportunities with a few friends, and I'll have more on that over the next few months.
In August last year, I wrote an invited editorial for the Personalized Medicine journal on crowdsourcing science and am following up with something similar in a cancer journal in the first quarter of 2013.  Crowdsourcing has its place in research but I think it needs to be used carefully. I'm looking for good examples in cancer at the moment if anyone has anything they'd like to share.  I will place a link on the blog when this one is published later in the year.

I'm always positive about the new year even though I don't much care for New Year's Evening festivities.  I like to look forward, and this year is no different. This year I'm going to work towards a few more publications as well as getting some of my less nerdy works published.  I hope to explore some academic connections and play my role to get the new business going.  With some luck and hard work, I might even finish the book I started 18 months ago. 

Overall, I plan to write much more this year (as I do every year!), but this year, I MEAN it.  Ha, ha. We'll see

Smart parents raise smart kids-right?

Smart parents raise smart kids, but not for the reasons we all might think.  Making them do their homework, impressing on them the importance of reading, studying, paying attention in class, and generally being committed students, all give our kids the best chance at being smart-right?  Well, it turns out yes, and no.  While all the tricks we parents think we must teach our kids help them make the most of what they've got, what they end up having appears to be as much to do with what we gave them at conception, than whatever we've done for them since.
A large group of scientists running a project with the intriguingly mysterious name, Project ENIGMA, have discover that intelligence is probably affected by our genes to a greater degree than previously thought.  The researchers, from all across the globe pooled their resources and their data to look for correlations between DNA and specific brain disorders (the usual- dementia, depression, Parkinson's, schizophrenia, etc).  While they came up with some interesting data on the diseased brain, what they inadvertently uncovered was a connection between DNA and brain size, and even more curiously, between DNA and intelligence as measured by standardize IQ tests.  IQ tests look for a certain type of intelligence so the data has to be viewed with that in mind, but it appeared that a variant in a gene called HMGA2 may be able to explain differences in individual intelligence.  The difference in the HMGA2 was in one DNA letter only; at one point in the gene, the base thymine (usually represented as T), was replaced by a cytosine base (C).   People that had the letter C instead of T at a certain location on the gene were more likely to have a larger brain and score higher on the IQ tests.
This finding isn't really an answer to the question of inherited intelligence, but rather the starting point for many questions.  Correlation is not the same as causation and the size of the brain, the high IQ score and the genetic change, may all be linked by something else in the brain not yet found.  However, the association is interested and the methodology used by Project ENIGMA even more interesting.  Because it is difficult to obtain enough tissues in any one lab, to conduct thoroughly sound statistical analysis on genetic variations that only occur in a certain percent of the population, the researchers banded together to pool their brains, literally.  All the brain samples and data from each of the participating labs were used to look for associations between genes, brain size, disease risk and IQ test ability.  Without the collaboration, the project would not have been possible. The nature of the work and the extent of the collaboration has attracted hundreds of financial contributors that has ensured the success of the work.
So does this mean we should kick back as parents and let nature take its course?   Not at all.  Intelligence is only useful when harnessed appropriately, and usually (with notable exceptions), that happens through the cultivation of good study habits and the development of some level of self- discipline. When I was doing my PhD, someone told me that it would require one third pure hard work, one third organizational skills and one third smarts.  I never forgot that, and found it to be just about spot on not only for my PhD, but for pretty much every piece of work I've done since. Intelligence is only part of the picture.

[JOURNAL REFERENCE-Jason L Stein et al. Identification of common variants associated with human hippocampal and intracranial volumes. Nature Genetics, 2012; DOI: 10.1038/ng.2250]

NCI infographic on the use of social media in healthcare

Worth a look.  How social media is impacting healthcare from the National Cancer Institute:



Via: PowerDMS

Another slice of cake?

I'm watching CBS 60 minutes with Dr Sanjay Gupta telling us how sugar is poisonous and speaking to a doctor who is recommending that men eat less that 150 calories worth of added sugar per day, while women eat less than 100.  The report is interesting; the effects of just s sip of soda stimulates the same part of the brain as hard drugs like cocaine, and continued consumption of sugar lead to a tolerance similar to that experienced by drug addicts. In other words, the more  you eat, the more you are driven to eat.  The chemical at the heart of this is not picky.  However we get dopamine to release from brain cells, be in sex, drugs or rock and roll or now... sugar, we are driven to need more.   OK, so we eat a lot of sugar. So what?  As long as we reduce our fats, red meats, bacon, chips etc, we are basically OK- correct?  As long as we control our weight somewhat, and lay off the chips we should be fine- right? Not even remotely.  A study being discussed on the show, took young adults and carefully controlled their diets for a period of time while monitoring their physiology and biochemistry.  They had blood drawn and were scanned throughout the study period which had them eating a non-added-sugar diet for the first few days of the study, followed by a diet with 25% of their calories in the form of sugar; still a relatively low amount of sugar by American standards (on average we consume about a third of a pound a day).  Blood samples were drawn every 30 minutes and the added- sugar consumers showed significant increases in small dense LDL cholesterol (the bad kind that clogs the arteries) within two weeks of eating the diet with 25% sugar.   For those old enough, you might remember that in the 70s the government restricted fat in the diet.
There was a short term benefit, likely due to increased awareness of dietary causes of disease and the number of people who reduced their intake of saturated fates.  However, the effect was not sustained.  Doctors not he show suggested we have replaced that fat with carbohydrates, and refined sugar in particular.  As one researcher pointed out, food without fat tastes like cardboard, so the food industry upped the sugar content to keeps palates satisfied.  Now, cardiovascular disease is back on the increase and our children may be the first generation to have a lower life expectancy that their parents.

So the sugar in our diet does as least as much harm to our cardiovascular health as fat, and maybe more. But the story doesn't end there.  Obvious effects of increased sugar are obesity, metabolic syndrome, and diabetes, and all of these diseases have peripheral effects.  Less obvious is the effect of sugar on some cancers. Because sugar stimulates increases in insulin, it also catalyzed the growth of certain types of cancers.  Almost a third of common human cancers contain insulin receptors that circulating sugar latches onto and triggers the tumor cells to take up the glucose to use for cell growth.  Basically the tumor cells highjack our blood sugar and uses it to feed itself and grow.  Exactly whether the sugars in the blood cause the tumor to begin or just nudge it along once it has become established makes no difference.  Sugar is good news for cancer, and bad news for us.

There is much more to the sugar story that I'll save for other blogs but as we think about how to balance our diets, it's worth thinking about the role of the food industry in our food choices.  Since I still have the TV on, I'm catching a few ads I haven't seen before.  In one, Con Agra is encouraging us to buy their products and is promising one meal for a hungry child for ever specially marked package we buy.  This sounds incredible and I am sure there is good will behind the gesture. Certainly, there are too many hungry kids in America today. However, the foods that Con Agra is asking us to buy includes Snack Paks, frozen chicken nuggets, Chef Boyardee and others, all of which are high in sugar.  We buy and eat a package of processed food that will go a little way towards poisoning us (some might think that's too strong a word but based on what I have read and hear, I don't think so) and in return Con Agra will feed a child.  Does this make anyone wonder exactly how they will be feeing that child?

And finally, as I complete this blog, I just saw a fantastic commercial on the TV with a diverse group of vibrant people stripping open their coats and cardigans to unveil bright red shirts with 'I'm unique', I'm A Vailable, I'm a dreamer....etc, as they run, walk, dance, around some city. It seemed like such a positive commercial, celebrating all that is good in the world- courage, difference, creativity.  Imagine my disappointment when I realized what the ad was for.   Dr Pepper.  Ugh.

Staying sane in the world today

Fish House play against a moving back wall at The Workshop in Mystic, CT

After reading this in Fast Company I think I may be a Genfluxer.   I usually dislike labels but I"m happy to adopt this one.  Genfluxers are comfortable with ambiguity, recognize that the future is inherently unstable, and wallow in chaos like pigs in muck.  That describes me pretty well and according to the article I am in good company.  Pete Cashmore, who runs Mashable is in there- he is a hero of mine.  Beth Comstock and Susan Peters  are shaking it up at GE. Baratunde Thurston is digital editor at The Onion and is a quintessential GenFluxer according to the article.   Social media and the Internet have created a fast-changing world that challenges many traditional notions of how work gets done. Knowledge Management (KM) was a discipline of sorts that grew up in the same time frame of Fast Company magazine and as I read the article I reflected on what it means to know what you need to know in the current environment.   Never before has it been so easy to gather information.  Just typing in a term into a search engine will get you a plethora of hits and comprehensive overview of your topic.  Some have suggested that the ease of information gathering has a down side in that you get what you ask for. And little else.  Serendipity is more elusive when you look for something directly, versus scanning through a magazine shelf and happening upon an interesting snippet that sheds new light on a particular problem.  A recent article in Intelligent Life magazine on the loss of serendipity in the digital sums it up nicely. Knowing what we know and don't know has perhaps never been easier, but the challenge now lies in asking the right questions and in not being too comfortable with your answers.  What seems right one day, may indeed be quite wrong on another depending on context.  Being open-minded and ready to shift perception based on emerging information is critical in today's environment.  For better or worse, we can no longer sit back and feel accomplished in our understanding.  I, for one, am comfortable with that although sometimes it feels easy to get left behind. Really, though, it may not be being left behind that is important thing to worry about. Rather, being too caught up with every changing view and losing sight of the big picture may be the greater danger.  That seems to me to be a recipe for burnout.  For individuals and companies wishing to keep their footing in the rapidly swirling environment, it seems that cultivating an open mind, getting comfortable with ambiguity, and being somewhat brave, may be the best approach to staying sane and, with luck (yes luck), finding success.