Update: 2013 Reading Goal

It is now January 10. I am 10 days into my goal of reading 52 books in 2013. Last night I finished Happiness: A Guide to Developing Life's Most Important Skill, which was decent. I already agreed with the author that happiness is a skill (see prior blog post), and many of the chapters seemed redundant. If you're looking for a better and more succinct version, read 7 Habits of Highly Effective People. I did however enjoy the science chapter where they use fMRI and EEG to understand the physical basis of happiness. The author is a scientist-turned-monk, after all. Before that I finished The 4-Hour Chef, which gave me a lot of ideas on how to learn to read more effectively (it's a book about learning, not cooking per se). I have lots of ideas for holding myself accountable, making the project interesting, and deliberately improving my reading skills.

For the rest of the month, I intend to read two of the following:
The Emotion Machine
To End All Wars: A Story of Loyalty and Rebellion
Catching Fire
The Universe Within: Discovering the Common History of Rocks, Planets, and People
So Good They Can't Ignore You. I hear this one is a good read if you're trying to "Find your passion" and are getting nowhere.

If I find a book is very long, I may give myself two weeks to read it. And then I will make that up by reading 2 short books in 1 week.

I've been pretty busy between research and teaching, so I haven't been able to write up a post on the specifics of my goal plan. But it'll come. I promise!

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.

The scale of neurology is larger than the observable universe

This week, I am happy to report that I am pretty much back on track in terms of my work routine, and productivity is once again through the roof. Spelling out and publicizing my exact strategy for not wasting time on the computer definitely motivated me to adhere to it- which is the entire point of writing a blog! But I also have another motivating factor working in my favor this week- a new undergraduate just joined the lab! When I teach, I feel like I learn more than when I'm just trying to learn. Like writing, teaching someone forces me to spell out my logic as clearly as possible, which both clarifies my thinking and uncovers hidden assumptions I had been making that may be wrong. Furthermore, the best way to teach is to ask the student questions that stimulate the student's thought and lets the student figure out the answer. That means I need to put myself in the position of a beginner, so I learn more about my own field and gain insights that I might have missed. It's true that until you can teach a subject, you haven't mastered it. But what is often overlooked is that the very act of teaching something is the METHOD by which one masters something.

Yesterday, I attended the Life Sciences Institute symposium, and this year's focus was on Neuroscience. The speakers were amazing (most were HHMI), and it reminded me why I want to go into neurology. Let's just examine some of the highly attractive intellectual aspects of neurosciences

Brain-specific systems: Molecular and cellular mechanisms that are unique to the brain and, in many cases, unique to the human brain. Non-coding DNA seems to be one of the biggest things that separates us from chimpanzees- why? A lot of it might be transposons that are specifically activated in the brain to jump around and disrupt genes, so that every brain cell has different DNA- thus creating a diversity not seen in any other organ system, other than the immune system. Another thing, which I just learned from Robert Darnell, MD, PhD (Rockefeller) is that the brain has its own splicing system (Nova proteins, etc) allowing the generation of novel isoforms not seen anywhere else in the body. 20,000 genes becomes 100 or 1000 times that number because the brain can generate far more unique proteins than the rest of the body due to novel mechanisms of splicing. Furthermore, different parts of the brain have different splicing systems, and in fact different parts of the same brain cell have different splicing machinery- possibly explaining some aspects of memory assuming these are stable states. And so it also makes sense that certain cancers would co-opt the Nova system to drastically change their gene expression profiles and give them a proliferative advantage, despite the immunological risk it puts the cancer at (spontaneous regression of Nova+ cancers have been observed due to the immune response).

Combinatorial complexity: This point can be best illustrated using one of the simplest examples in neuroscience (even though really it's not simple at all). The problem is recognizing self vs. non-self. Neurons don't want to synapse onto themselves because otherwise they inhibit themselves and become useless, or they hyper-activate themselves and end up killing themselves. But how does a highly branching neuron figure out that the neuron it has reached is another neuron or another part of itself? Larry Zipursky, PhD (UCLA) has discovered how this is accomplished in the Drosophila fruit fly. The Dscam class of molecules have alternative exons at four positions. Combinatorial complexity means that 12 x 48 x 33 x 2 = 38,000 unique Dscam molecules. Furthermore, each neuron expresses a random combination of about 50 different Dscam molecules. How many different profiles thus are possible in the brain? 

38,000^50 = 10^229. That is far greater than the number of particles in the entire universe. In fact, if every particle in the universe had an entire universe inside of it, and every particle in that universe had a entire universe inside of it, 10^229 is still far larger. Now, when a Dscam group on one neuron encounters a Dscam group on either the same or another neuron, it only binds if they match sufficiently. If it binds, they inhibit each other and cause the synapse to fail. So essentially, the likelihood that two different neurons will have profiles similar enough to inhibit each other is essentially non-existent. Thus, every neuron has a unique barcode that allows its dendrites to recognize other dendrites on itself. Even cooler, the Zipursky lab systematically deleted alternative exons until they figured out how many unique Dscam molecules are required to prevent inappropriate self-synapsing and inappropriate avoidance of non-self.

Region-specific features: Let's not forget that the brain is huge. Really huge. The human brain should not be thought of as one organ system. A single brain's complexity is more on the order of the entire rest of Earth's biosphere. So one part of the brain might act under totally differently principles than its neighboring part, even though the majority of proteins are the same. So when you treat the brain with a single simple drug, it may have really awesome effects in one part, but it's going to affect everything else too, possibly adversely. Let's take dopamine as an extremely simple example. Insufficient dopamine is a cause of some Parkinson's symptoms, so dopamine therapy can have massive benefit in terms of quality of life for Parkinson's patients. But dopamine is also inappropriately elevated in an entirely different part of the brain in schizophrenia, so a potential side effect is schizophrenic-like symptoms. Conversely, treating schizophrenic patients with dopamine antagonists can have Parkinsonian side effects. 

Another example: yesterday Luis Parada, PhD (MIT) discussed his work on SSRI anti-depressant therapy. He found that the reason why SSRIs take months to work even though they cause immediate serotonin changes is that SSRIs enhance hippocampal neurogenesis over time. New neurons need to form for SSRIs to work. More interestingly, exercise seems to have the same effect- explaining why I'm always happier after exercising consistently. Furthermore, activating hippocampal neurogenesis is sufficient to reverse depression and anxiety-like symptoms in mice, and blocking neurogenesis can block the positive effects of anti-depressants and exercise. This has major implications for depression therapy, since SSRIs currently affect serotonin all of the brain, resulting in all sorts of changes that may have all sorts of adverse effects. So if we develop a drug that specifically activates hippocampal neurogenesis, we can treat depression without the side effects. Exercise should also be incorporated as a mainstay of depression therapy. Lastly, I'd like to point out that this strategy can be used for cognitive enhancement in healthy people. Meanwhile, I'm going to keep on exercising.

One reason I want to go into neurology is that there are few good therapies for any of the major neurological disorders. But I have little doubt, based on what I've heard at research talks, that major neurological therapies will reach the clinic right around the time that I start residency. Right now there are some crazy flowcharts for figuring out which patients receive which therapies. But the brain is an entirely different animal. Figuring out which patients will benefit from neurological therapies (and cognitive enhancement) will require a fundamental understanding of these intellectually challenging topics such as combinatorial complexity. Thus neurology will provide me with intellectual challenge for my entire life. My prediction that most of the diseases of other organ systems will be cured within 100 years, and medicine will become tediously boring and trivial. I doubt that neurology will be solved for another 500.

I like my prefrontal cortex but it naps too often

Hello blog readers! It's a busy week, so this will have to be a shorter blog entry than normal, and I'm going to split it into two parts- one for today and one for the weekend.

I thought I'd write about something I've been very pleased about in the last 2 months. Today's entry will be about the problem I've been frustrated with for years, and the weekend's entry will be about the solution I discovered (I promise). For the last 5 years or so I always knew that I was wasting a ton of time on the Internet, often on mind-numbing things like stupid Youtube videos and memes. Amusing myself for a few minutes is a good thing, but doing it for hours is just silly. It doesn't have to be that way- if I can stay focused, the Internet becomes a great resource for educating myself, completing my goals, developing skills, and staying in touch with friends. Even the totally random stuff that is completely unrelated to my work can be useful if it stimulates my brain. In fact the Internet is sometimes my only resource, because I often don't need anything else to get stuff done. However, what happens in practice is that I will think, "Oh I'll just check this one page," and soon enough I've lost 2 hours and I don't feel like anything I did was interesting or useful. Those 2 hours are like a black hole, but I postulate that what's happening on the other side of the event horizon is that I actually lose my biological ability to make a conscious choice to shift gears and actually get some work done.

Sure, you can say, oh that's just an excuse. But really, there are a few things about the Internet that can create a perfect storm that, in my opinion, can rob you of your free will. And this is key- IMHO, the Internet is the best thing in the world if you control it. It's the worst if it controls you. So how might it actually rob you of your free will in practice? Mind-numbing Internet material, by definition I suppose, doesn't take much active thought to process. You plop yourself down and you are entertained- and your lower brain regions (the ones that evolved before the sapience of the frontal cortex) love those reward mechanisms to death, so it is perfectly happy performing it on auto-loop. It's a lot like TV. Your basal metabolic rate sitting and watching TV is lower than when you're just sitting, and that's because your brain goes into some sort of auto-hibernate mode and burns fewer calories. The seat of your free will- your frontal cortex- is forced to take a nap by the rest of the brain.

And then every page is littered with distractions. Every link and every image on the page can catch your attention and present you with a new page that is equally filled with links and images designed to distract you. Wasting time on the Internet is a habit that's hard to break because of the constant reinforcement. But of course, is this all bad? Doesn't everyone need some R&R? The average American watches like 6 hours of TV per day, so should I really be so concerned about losing my evenings to wasting time on the Internet? But in actuality, even though the Internet is activating reward circuits, it is not relaxing at all. The entire time, I'm anxious because I know I'm capable of getting my work done at a computer, and I feel guilty. And the computer offers LOTS of opportunities to get stuff done, which both makes me feel more guilty, and overwhelms me with work choices at a time when my frontal cortex is inactive, so I'm less likely to actually go do work.

So we're left with the fact that doing mind-numbing things on the Internet is unproductive, addicting, and provokes anxiety. It can be relaxing at the start, which is probably why we all chose to do it, but then it easily spirals out of control. Again, I will present something that's helped me with a lot of these issues in my next blog entry.

I'd just like to leave you with an observation. When I started this blog, I got a lot of comments along the lines of "how the heck do you have time to write a blog?" Simply put, I'm just shifting time away from mind-numbing R&R (which is not even so relaxing) in favor of creative and intellectually satisfying R&R (like online courses, Skyping, etc). And that is the type of rejuvenating activity that makes me more productive at work the next day because 1) I don't need to wake up my conscious mind again when I'm done (because it never shut off) and 2) it gives me a chance to reflect on my life goals so that I am more committed to my work.


Keep reading Part 2.