I'm lost. What's my purpose in life?

I have a personal mission statement and constitution. I try to review it at least once a week to revise it and reflect on how well I've lived it the last week, and to plan on how I'll better live it.  In my constitution I have principles and values written out, such as "I will have fun at failing," and "I will not judge other people." Sometimes I succeed, sometimes it's like I've forgotten this list exists. What is perhaps more important than the constitution is the mission statement. I have not been very happy with the life purpose I've defined for myself. It's vague but it's the best one I've come up with. The only thing I'm really happy with is that I deliberately chose a purpose that I thought most other people wouldn't understand on any level (I'm weird- I embrace it). I'm told that reflecting on my life purpose should bring me to tears. That you can find your life purpose by sitting down and writing hundreds of "life purpose" statements until you find the one that makes you cry. I've tried that, but nothing gives me that emotional "umph." And I've been worried that I can't find it.

Sometimes I think, hey I just need to focus. #1 Work on finding a proper life goal everyday. #2 Have some flexible plan for advancing that life goal each and every day. #3 Make sure by the end of each day I've met some milestone and feel like I've made progress. Then things will work out.

Not only is this focus hard, I'm also not sure it's the best plan anymore. I've been worried that I don't have a satisfying life purpose, but I think now that the worrying is the real problem. It's occupying me with trying to find some "ideal" life path and so I feel like I don't have enough time to experiment with new things. 

Society teaches us to focus on the career progression (in science it's undergrad => grad student => post-doc => junior faculty => tenure), or the life progression significant other => married => family => house in suburbs. If you don't make progress, others are trained to ask you why you haven't. Some people are happy with it, but a lot of people aren't. Some people think it's necessary, and they don't want to wander off it because it's risky. But you know what? I think a lot of it has to do with life/career progressions being pre-defined for you.  If you find your own reason to get married and buy a house that you won't pay off for 10 years, a reason that is made for you and only you, you'll be a lot happier with it.

This pre-defined path through life can sometimes feel like a prison. So we rebel against it, and we often go overboard and rebel in unhealthy ways. People party a lot, do drugs, cheat on their significant others, quit their jobs without a plan. Most of the time people do this to a lesser extreme, where we might simply lose focus on our work and do our own thing for a while. We might grow in new ways, but then reality sets in and your boss yells at you and you realize your peers have published 3 papers while you have nothing to show. So you freak out and go back to the pre-defined path. You feel bad. Nothing you feel bad about can ever be maintained (omg I HAVE to do this or else my career tanks). So it starts to fail. You work long hours but your work doesn't go anywhere, and it's because you feel bad about it. It's a hell-on-earth prison. So you rebel against it, and it starts all over again.

These are meanderings. We have to deal with societal expectations, but we also have to find our own way. Finding a correct balance- no, the correct MIX of the two is critical. And what's the best way to address something that is critical? Find a way to make it fun. Then you'll do it each and every day, and you won't worry about it.

I recently served on a panel to discuss graduate and medical school with a group of high schoolers applying to college. Every other question was along the lines of "What should I be doing right now to make sure I get into medical school?" It didn't bother me so much that they already "knew" what they wanted to do right out of high school- sure, it's naive, but I have confidence that they'll properly re-evaluate once they are exposed to more life choices during college. What did bother me was that they thought they would be trapped in whatever career path they chose, so they were scared to death that if they didn't optimize everything in their education that they would be stuck in some unhappy mediocre position. That they had to choose their career path NOW so that they could do everything right in the pre-defined life progression. Society is pushing students to imagine some ideal path through life, and if you just follow that you'll be all set for life. I was sucked into this for way too long, until I really started to reflect on what I wanted to get out of life.

Over the past year, I've been focusing on internalizing the mantra "Don't think life is good vs. life is bad. Think about what you can do right now to make it better, regardless of whether it's subjectively good or bad." It's self-managing your own thoughts. But I've really only been applying it to the "what" and the "how" of life. Not the "why" quite yet, and I realized this month that this has been a constant source of distress that I haven't been able to really address until recently.

My goal now is to be lost. And I'm going to have a ton of fun doing it.

Last-minute edit: Yesterday I found a life purpose statement that brings me to tears. But that just moves the bar up, and I bet tomorrow I will subjectively feel just as lost. Finally, this post was motivated by the first question in this Q&A by James Altucher. I have found his blog to one of the most thought-provoking ones out there, even if I don't agree with him. And his honesty is an inspiration to anyone who feels like they have hide their failures to prevent society from judging them- which is everyone.

Friday Links: eat your egg yolks, avoid antimicrobial soap

Most of this post will be about egg yolks, but I'll start with the following PSA: if a soap is labeled "antimicrobial," don't use it. Just don't use it.

http://cebulka26.wordpress.com/2012/08/16/triclosan-its-in-everything-but-is-it-warranted/

If I see antimicrobial soap at a restaurant, I don't use it. I just wash with hot water. This concise and informative blog post from Ania (fellow MD/PhD) reminded me of why I do this. The active ingredient is triclosan, but I doubt it's very active anymore because it's in a bazillion products. Many of the microbes that we would theoretically want to kill are probably already immune to it. Continued use will just give microbes more and more chances to evolve resistance to not just it but also all related antibiotics, resulting in antibiotic-resistant bacteria that could kill a lot of people. The Black Death wasn't much fun, so I hear.

The fact is, there's currently zero evidence that antimicrobial soap helps prevent infection compared to regular soap. And given the potential health risks that Ania outlines (triclosan could affect your hormones, muscles, cancer…), why the hell would you use it? You're better off not using soap at all.

Egg yolks OMG!!

http://www.dailymail.co.uk/health/article-2188265/Eating-egg-yolks-bad-smoking-speeding-coronary-artery-disease.html?ito=feeds-newsxml

For some reason, the least-significant studies seem to get the most publicity, and the media likes to create outrageous headlines like "eating eggs yolks as bad as smoking." Incredibly misleading and not at all implied by the paper- especially when you consider that the audience is the public-at-large. For some people cutting back on egg yolks is prudent (but not at all proven to be beneficial), but should average 25 year olds avoid egg yolks as they should avoid smoking? Absolutely not, and the lack of context in this article is irresponsible.

First, some conceptual background: when you drink a lot of water, do you get water intoxication? No, you pee it out. Guess what? You excrete cholesterol through your liver into your digestive tract, and you can simply make less cholesterol. Your body reacts to greater cholesterol intake by decreasing cholesterol synthesis, and you end up with the same amount in your blood. The cholesterol that your body makes on a daily basis is significantly greater (about 3-5 fold) than what is recommended in your diet. Thus, your body can easily handle twice as much cholesterol consumption as normal, and eating more cholesterol per se does not increase your blood cholesterol. Your body needs cholesterol, and it will handle it as needed.

If you don't eat this, your body will probably make it instead and you'll end up with the same blood cholesterol either way. OK, maybe not for this many egg yolks, but you get the idea.

Of course, if you drink TONS of water (>12L), you can get water intoxication (this happens to ill-informed marathon runners). So there's a point at which cholesterol intake will start adversely affecting your blood cholesterol, and yes high blood cholesterol is a huge risk factor for heart disease. Furthermore, individuals with kidney disease will not be able to deal with water overload. Similarly, if you already have cholesterol imbalances (due to genetics, age, obesity, microbiome perturbation, whatever) then you should start watching your cholesterol intake, because the mechanisms to keep your blood cholesterol in check have already been overwhelmed.

Getting to the study, I have many objections:

1. Glaring source of recall bias. Egg yolk intake is self-reported in a questionnaire. But how many people actually keep track of their egg yolks? I'm guessing extremely few- and any variable that people do not consciously track is subject to huge memory bias. Furthermore, egg yolk intake is really hard to estimate, because eggs are used in all sorts of foods (bakery items, etc). I certainly would not trust my own estimation. And there is a huge source of memory bias in this study: people with the worst heart disease (regardless of the cause) are far more likely to "remember" that they ate a lot of egg yolks. We know that people's memories are heavily biased by their situation, and there is a pre-conceived notion out there that egg yolks are "supposed" to clog your arteries. People naturally look for an explanation for their disease, and if they find an easy explanation (eg egg yolks), then they will sub-consciously alter their memories to believe that they ate more egg-yolks. The memory effect should get stronger with greater severity of disease, and so all of the results of this paper could be explained by recall bias. Furthermore, the study itself can influence people's memories. You're going around a clinic full of worried people asking them how many eggs they eat. At least subconsciously, people are going to start blaming eggs for their health, even if they ate the same # of eggs as the next person.
2. The study population is heavily biased. The patients are already attending a vascular clinic! As I mentioned, there are likely sub-populations for whom cholesterol intake will increase their blood cholesterol (morbidly obese individuals, patients with familial hypercholesterolemia who are genetically unable to regulate their own cholesterol, etc). Those are the sub-populations whose cholesterol homeostasis mechanisms are already out of whack, and they are the ones most likely to be attending the clinic.
3. The data is nothing but correlative. Eating egg yolks (self-reported, again) is shown to be correlated with artery blockage. Sure, they use some statistical analysis to show that the effect is still present after you adjust for "coronary risk factors" but many risk factors are still unknown (yay science!), so you can't adjust for everything. The problem is that there are thousands of variables out there, and they are all correlated with each other to different degrees. People who live in a certain part of the country might eat foods rich in cholesterol, but guess what- that might also be the most polluted part of the country. Or there is a virus circulating in warm climates that increases your risk. Or people in that part of the country might be older, etc. If you look at 1000 variables, eventually you'll find one that fits simply by chance.
4. Simplistic clinical endpoint. Small point, but they just looked at neck artery blockage. Artery blockage, even if systemic, does not translate to disease. It's a risk factor like any other, and like all risk factors it doesn't affect all individuals in the same way.

Plant Zen

http://www.disneyresearch.com/research/projects/hci_botanicus_drp.htm

http://www.benchfly.com/blog/forget-wireless-keyboards-and-touch-your-plant-instead/

Finally, I have no idea what to make of this. You can hook up a plant (any plant, like a potted plant) to your computer, and somehow an electrode in the soil can tell what part of the plant you're holding. So you can control your computer by touching a plant. Is this a hoax?

I predict that eventually we'll be able to hook up anything to computers. But I think it will take a little more than just sticking an electrode into the soil.

wtf?

Alzheimer's: commentary on treatment strategies

My goal is that any reader can take something away from this Alzheimer's post, regardless of their experience in medicine or science. It's Friday Links-driven, but with far more of my own commentary/explanation than normal.

First up: an article about a clinical trial for Alzheimer's treatment that appears to have failed. While I don't research Alzheimer's, I'm going to argue in this blog post that 1) single "magic bullet" treatments are unlikely to ever work for a chronic complex disease that develops over many decades like Alzheimer's (once the disease has actually manifested symptomatically), but 2) single "magic bullet" prevention methods might work for specific patient sub-populations. In this case, different prevention methods would work for different sub-populations. Meanwhile 3) Broad, non-specific treatments that target multiple biological processes are better for stabilizing Alzheimer's after it's been diagnosed (discussed in the second link). Note that this is NOT the same as combination therapy.

http://www.technologyreview.com/view/428592/pfizer-disappointed-with-first-results-for/?ref=rss

Bapineuzamab is an antibody that recognizes and binds to beta-amyloid, one of the molecules involved in the pathogenesis of Alzheimer's (note that I don't say it's the cause or even a significant cause). For my non-biomedical readers, this is a common treatment strategy nowadays. Say protein X causing disease Y is floating around in the space between cells in your body. Specific antibodies can be made to bind specifically to protein X which physically blocks protein X from damaging other things ("neutralization"). Furthermore immune cells are then able to recognize the antibody bound to protein X, and clear protein X from the body. This strategy is used in treatment of diseases like rheumatoid arthritis and lymphoma, and it works wonders.

But Bapineuzamab failed to have any effect on Alzheimer's progression in this Pfizer trial. Why? I'm going to use my extraordinary powers of hindsight (dig deep- you probably have this ability too!) and say that it probably has far more to do with the fact that beta-amyloid is just a tiny piece of the puzzle for Alzheimer's than any problem with the drug. Bapineuzamab probably recognizes beta-amyloid just fine, and it might even clear beta-amyloid from the body. But I doubt that clearance of beta-amyloid would have any effect on Alzheimer's. Why? Because it's too late.

The trial looked at treatment of early-to-moderate Alzheimer's, but Alzheimer's develops over decades. For a while, it's just Mild Cognitive Impairment (MCI), but lots of people get MCI and never progress to Alzheimer's. So figuring out a way to predict Alzheimer's progression through things like blood tests and brain imaging is all the rage now (see third link). And that's why the trial focused on Alzheimer's rather than pre-Alzheimer's. But in the patients that do progress, what's going on?

The length of time that it takes for Alzheimer's to develop means that, even if beta-amyloid were to be the ultimate cause, then beta-amyloid can trigger numerous other biological processes that are themselves damaging to the brain. By the time someone has Alzheimer's symptoms, these "secondary processes" are already robust so more damage is occurring independent of beta-amyloid, and a lot of neurons are already malfunctioning or dead. This fundamentally alters the biology of the brain so that treatments are unlikely to reverse anything, and multiple causes of degeneration make it unlikely that single treatment would slow the progression of the disease. I won't review the ginormous body of literature implicating all sorts of things in Alzheimer's pathogenesis, but I'll take a couple as an example.

One way to abstract Alzheimer's (see picture below) is that everything causes everything else. It's a complicated feedback loop (or feedback web) where a bunch of biological processes all cause and worsen each other over a period of many years. For example (highlighting a tiny portion of the feedback web), extracellular amyloid or intracellular tau (hallmarks of protein misfolding) acting on one subset of neurons might interfere with normal breakdown of neurotransmitters, as well as directly causing neurons to fire inappropriately. Too much excitation of nearby neurons results in excitotoxicity (killing those cells) or in inappropriate activation. The brain might remodel in reaction, forming new synapses that result in electrical feedback loops that reinforce each other. The resultant clinical and subclinical seizures might interfere with brain function long after the damage is done. As neurotransmitters start to diffuse inappropriately due to synaptic dysfunction, they start affecting other cells indiscriminately, and damage may occur to brain's extensive blood system. This allows in immune cells that further alter the blood vessels to essentially break down the blood-brain barrier.  This lets in various molecules that again might cause excitotoxicity or protein misfolding, and maybe it even lets in bacteria. So damage leads to biological response that causes more damage, leading to further responses etc.

All of these processes cause each other, and all of them cause disease. Targeting a single initiating factor (which varies from patient to patient) might work for prevention, but not for treatment.

Importantly, many of the damaging processes are variations of normal brain biology. For example, microglia (kind of like the brain's immune system) see damaged neurons and eat them up. If you remove the source of damage, it is perfectly possible they continue eating up neurons instead of letting the neurons recover after the damage. There are medical examples where a disease has manifested for so long that cells that normally act to ameliorate a disease are "locked in" to their action even when it's no longer necessary, and they end up causing damage themselves (for example tertiary hyperparathyroidism). I think of this as part of the more general inflammatory response that occurs whenever there is damage- all sorts of immune cells react to initial damage and can end up causing more damage than the original insult (if you think that makes no evolutionary sense, it actually does. I might expand on that in a future post).

What about prevention? Note that things like excitotoxicity, brain remodeling, and breakdown of the blood-brain barrier can in turn cause beta-amyloid buildup. So there's no reason why beta-amyloid had to be the initial insult- in many (most?) patients beta-amyloid is probably secondary to another biological process. In these cases, drugs targeting beta-amyloid production and degradation probably would not have any preventative effect, because beta-amyloid was not the initial cause. However, there are subsets of patients where beta-amyloid is implicated as a major genetic cause (mutations that affect beta-amyloid production like in Down's syndrome, ApoE4, and presenilin). Prevention using Bapineuzamab is conceivable in those patients, as it would stop the secondary processes from occurring in the first place. However, if we found in another sub-population that inappropriate inflammation due to immune system malfunction (kind of like an autoimmune disease), then prevention would involve anti-inflammatory drugs (Aspirin? IVIg? Prednisone?). Thus, preventative measures for Alzheimer's would be specific to the patient's initial cause(s) of degeneration, which can vary widely depending on the patient.

http://www.technologyreview.com/news/428546/study-suggests-alzheimers-disease-can-be/?ref=rss

On the bright side, a very small trial showed stabilization of Alzheimer's with treatment with IVIg (intravenous immunoglobulin). IVIg is simply the mix of the collection of antibodies isolated from multiple human volunteers. There are antibodies against everything- bacteria, toxins, some human proteins, etc. The authors here speculate that there is an antibody targeting amyloid-beta, tau, or some other molecule. While this might be part of the picture, I worry that researchers might go after specific antibodies (which is just like the above Bapineuzamab trial). I challenge the notion that IVIg's broad and non-specific effects are a disadvantage. While one might think it's not 'optimized' for Alzheimer's treatment, the very fact that Alzheimer's involve a complicated web of numerous biological processes means that we need to target them all at the same time. Thus, a non-specific treatment with numerous antibodies doing many different things might in fact be the key to IVIg's efficacy.

For example, IVIg is used in the treatment of autoimmune disease, dampening down immune responses. How it accomplishes that is unclear (and is a bit counter-intuitivee since antibodies MEDIATE the immune response), but it is believed that it both interferes with the specific endogenous antibody that causes disease, as well as flooding the system with so many antibodies that it diverts the immune system from inflammation. Perhaps IVIg is dealing with the inflammatory component of Alzheimer's? Perhaps it interferes with the endogenous cells/antibodies that are damaging the brain? Thus, trying to narrow down the treatment to a single antibody or a few antibodies would eliminate some of the broad effects of IVIg that would be critical for influencing the numerous biological processes. This is different from combination therapy because we're looking for one or two treatments to influence many things (100+) things at once, rather than multiple (3-5) treatments for multiple (3-5) things.

Also note that IVIg only stabilized the disease, it didn't reverse anything. That's because the damage is done- the neurons are dead and the brain has remodeled itself. At this point, Alzheimer's could only be reversed by making new neurons by stem cell therapy. Because many of those dead neuronal circuits likely encoded specific memories and personality traits, we would need to find a way to program those back into the new neurons. Those would be Sci-Fi technologies that haven't even been imagined yet.

http://www.technologyreview.com/news/428480/an-alzheimers-warning-25-years-before-symptoms/?ref=rss

More on prevention: you need to be able to predict who is going to get the disease in order for a prevention to fulfill a cost-benefit analysis (since preventative treatments might have their own side effects, and you don't want to expose people who will never get the disease to unnecessary risk). This brain imaging study suggests that this is possible, at least in one inherited subtype of the disease.

http://www.newscientist.com/article/dn22128-alzheimers-villain-cures-multiple-sclerosis-in-mice.html

I'll just leave with you an interesting tidbit- they used beta-amyloid injected into the body cavity of mice to reverse multiple sclerosis (MS). What? Isn't beta-amyloid bad? But this sort of goes with my idea that injecting IVIg "distracts" the immune system from attacking brain cells, just like beta-amyloid might "distract" the immune system from attacking myelin sheaths in MS. I think the lesson here is: We need to think outside of the box and consider counter-intuitive treatments to deal with these complex diseases.

August goals; capturing your thoughts on paper

20th post! Not doing any special post to celebrate- I'm just noting it. I considered an epic, deep post (yeah, right) but today is going to have to be quick- it's a busy week as usual.

You all know that I was a little obsessed for a while with setting goals and tracking them. I developed a single system in Evernote and stuck with it. The rigidity was definitely worth it- I developed a lot of discipline and I got used to reminding myself of my goals frequently. Furthermore, I really liked having just a few primary goals for the month that I stick by, not letting myself get so excited about other ideas that I lose focus. What I've found is that this really makes me feel like I have a "theme of the month" which is great motivation. But now I've moved into an experimental phase, playing with incentives and expanding my thoughts on what I truly want to accomplish. You know, the "why" rather than the "what." Recently I've tried two new systems, one of which is described below in my August goals. I think I'll save the other for a post in the near future (it's a web + smartphone app).

My August goals are:

1) Make tally marks each time I lose focus at work. This is a neat trick and it's helped me a lot in the last week. Essentially I have a sticky note on my laptop keyboard that says "Focus." I catch myself every time I feel like I'm about to do something unrelated to the task at hand (such as randomly checking Facebook or the news for no reason), unless I explicitly give myself permission to do it. I make a tally mark, remind myself of why the task I was performing was important, and get back to work. If I actually get to the point of checking Facebook and getting distracted, then I make two tally marks. During breaks, I may explicitly give myself permission to visit a particular website, and even then I make sure I don't continue clicking on links forever.

1a) Make tally marks each time I find myself having negative thoughts. This is auxiliary to the first point, and is accomplished in the exact same way. There's no point to worrying incessantly about something. Whether something is going badly or not is useless information to me- in fact it will just distract me from doing what I need to do. If something is worrying me, then I should ask myself "Can I do anything about it? Right now?" If the answer is no, I stop worrying and focus on something I can actually influence. If the answer is yes, I either do it or make plans to do it. This is a game I've been playing in my head for a while, and I found that having an object (piece of paper) to dump this on helps me push away the thoughts that are bothering me. That brings me to my next goal.

2) Keep a pocket Moleskine journal. I've resisted keeping a dedicated paper journal for many months now. I figured- I have Evernote to record all my thoughts! Everything backed up in one place! But it's just too clunky on my iPhone while I'm on the go, and I really need to be able to draw diagrams and integrate them with the text. Accessing a stickied page in a paper journal is so much faster than pulling up the relevant note on my computer. I tried a Hipster PDA for a bit but it didn't work out. Anyways, I've used this for the past week to develop my thought processes on my values, my short- and long-term goals, my ideas, etc. Putting it on paper (or Evernote) helps you pare down the bazillion things going on in your head to just the most important things. I originally disliked the lack of structure in the Moleskine (and you can't copy/paste templates like in Evernote)- but I've come to understand that forcing yourself create a system from scratch for organizing your thoughts is important for, well, personalizing your personal development. By the way, if you haven't started recording your thoughts and goals in any way, I highly recommend you start. If time is a worry, just know that it will save you time. Here's a wealth of productivity systems you can implement in a Moleskine.

My red Moleskine. On my computer for size comparison- it fits neatly into my pocket.

A page from my Moleskine. I made a thought process flowchart in response to feeling guilty about not getting enough done in lab. I asked myself a couple of key questions that completely modified my perceptions and put the work I did that day in context. In the end I concluded that my other priorities were more pressing and so I was at peace with myself. Those key questions are labeled 1, 2, 3, and 4 in the flowchart and lead to specific actions I should take (eg not worry or find a specific way to fix it). Then I solidified it in a Moleskine flowchart- so I can refer back to it in the future so I don't stress myself out in the future unnecessarily.

3) Be productive in the evenings learning information or a new skill that is unrelated to labwork. I don't think I have time this month to keep a consistent side project up on top of my Moleskine experimentation, so I figure why not just keep my mind fresh. I'm reading a book about dishonesty (thanks Dale!), learning some coding, learning some memory tricks, doing logic puzzles, and whatever else. The primary reason I'm keeping busy at night is that I've found it helps me sleep a lot better than if I just watch 30 YouTube videos.

Finally, I have started using a productivity web app for my goal tracking. I'm using it to remind myself of a bunch of other goals that I'd ideally like to accomplish a few times a week. Because of the way the website works, I don't need to think about them as much as my primary goals, so I don't have the focus issue that arises when I have too many goals. I will share after I explore it a bit more.