I wanted to talk about depression but first I have to talk about inflammation

Monday’s post was inspired by this paper on depression and inflammation.  Let’s dig in.

First question:  what is inflammation?  Allow me to translate the wikipedia article.

First, local cells detect that something is there that should not be.  Not every cell can do this.  Wiki’s list is:  macrophagesdendritic cellshistiocytesKupffer cells and mastocytes.  Every cell on that list is part of the immune system except for Kupffer cells, which are part of the liver.*  These cells all have pattern recognition receptors whose job is to identify molecules that represent a threat.  In a perfect world, they would recognize every threat and ignore every host molecule and harmless foreign matter.   In the real world, my body spent years convinced that tree pollen was a mortal threat and the only cure was blinding sinus pain.

When a particle activates the pattern recognition receptors they release mediators (the names, types, and specialities of these are easily a blog post in and of themselves) which cause blood vessels to increase in diameter (=vasodilation).  The most immediate obvious of this is increased blood flow, but the dilation also increases the permeability of the blood vessel walls, which allows fluid and protein to leak from the blood vessels into organ tissue.  With the help of a mediator, this also allows white blood cells, especially neutrophils ( the source of the best immune system chase scenes) into the organ tissue.  The additional fluid also increases flow to the lymph nodes, which is the in-body equivalent of getting a pathogen sample to the CDC: the lymph nodes study the fluid for pathogens in their tiny little lymph labs** and, having identified it, trigger the development of a counter-attack.    The mediators also increase the sensitivity of nerves to pain, to incentivize you not to re-injure the area.

And that’s how a physical insult becomes an acute inflammatory reaction.  If the insult is chronic, or if the inflammatory reaction becomes self reinforcing (e.g. inflammation makes an ingrown toenail more ingrown), it becomes chronic inflammation, which we will talk about on Friday, and hopefully get to the actual article on depression on Monday.

*If you’re me, you may have to remind yourself that dendritic cells != dendrites.

**Some day I’m going to learn how that process actually works and not pretend it’s a tiny reenactment of The Andromeda Strain, but the image will do for our purposes.

What I want to be when I grow up

Long ago, “fever” was considered an illness in and of itself, not a symptom.  Imagine yourself as an 18th century doctor with that mindset, but 21st century technology.  Sometimes people feel better after two days of rest and fluids, sometimes they die, sometimes they live but are permanently weakened.  Mostly it seems like the weaker people die, but not always.  Sometimes antibiotics help.  Sometimes they don’t.  Sometimes one antibiotic helps but another doesn’t.  Tylenol always seems to make people feel better initially, but sometimes the fever rebounds.  Sometimes interferon helps, sometimes it does nothing.  Some people who get a lot of fevers seem to benefit from anti-retrovirals (what we know now as the HIV cocktail), but lots of others don’t and they have pretty nasty side effects.  Vaccines don’t seem to affect lifetime fever numbers very much, but do reduce the occurrence of the fever with specific symptoms.  We can’t tell if working with animals makes you more or less likely to catch a fever.  You can make some guesses based on whether or not the person experienced recent trauma, associated symptoms, and the symptoms of people around them, but it’s essentially guess and check.

I think that’s where we are with depression and anxiety.  They’re real, just like fevers are real, but they are symptoms with many possible underlying pathologies.  We already know some of these: thyroid disorder, anemia, chronic abuse, vitamin D deficiency.  But we’re not even very good at screening for those, much less the fringier ones like sensory processing disorders or digestive disorders.*  And who knows what kind of neurological or developmental issues could produce.

It’s even trickier because depression/anxiety can cause a lot of physical problems.  It’s hard to eat well or exercise with a lead blanket on you.  The physical effects of stress are real and costly.  Whether the mental or the physical came first, they can rapidly form a self-reinforcing cycle.

As I’ve mentioned before, my hypochlorhydria was diagnosed when I went to a psychiatrist for anxiety.  It turns out a well founded subliminal fear of starving to death makes you antsy. I have a friend who had been diagnosed with dysthemia (mild depression) for years before she developed an eye thing and finally got diagnosed with adult onset, type 1 diabetes.  One possibility is that all the symptoms of depression were caused by insufficient insulin.  Another is that the anti-depressants damaged her pancreas and caused the diabetes.  This is why I want to be a psychiatric NP.  Therapists don’t get to do the physical side, medical generalists and other specialists don’t get to deal with the mind enough, and MD specialties are too isolated.  The idea of taking apart those vicious cycles and helping people rearrange the parts into what works for them is incredibly powerful to me.

Learning how to learn.

 My brother was a mathematical protege.  You know those kids who teach themselves to read as babies, and by the time anyone thinks to ask them to look at a letter flash card they’re already reading chapter books?  He was the mathematical equivalent.  He looked at problems and just knew what the answer was.  Sometime in elementary school he took at IQ test (a real one, administered by trained professionals) and scored perfect on the math section.  Meanwhile, I remember math as the only subject in elementary school I was bad at (it wasn’t- I also struggled with whatever foreign language they pretended to teach us that year.  But it was the only subject I was bad at that my parents cared about).

By age 18, I had finished three semesters of calculus and another of differential equations at community college, and I went on to take more when I matriculated at college for real.  I was very into computational biology, which involves very high level calculus. My brother got to pre-calc, maybe calculus, at high school, and never took any in college.  His first stumbling block was teachers that marked him off for not showing his work, even though his answer was correct.  They never understood that for him, there was no intermediate step.  The second stumbling block was when he met problems hard enough he stopped seeing the answer.  When I faced the same level of problems, I had toolkit of how to approach problems and derive answers, painfully derived from all the other, easier problems I’d seen but couldn’t solve.  He had nothing.  And so I eventually went much further in math.  Originally it was just because my parents insisted on a math class every semester and I wasn’t going to rock the not-going-to-high-school boat, but I eventually came to enjoy it because it was so easy and everyone else found it so hard.  I got a severe case of mono while taking differential equations and still got an A+, because the class simply wasn’t hard enough to measure the change.

I saw a miniature version of this playing Portal 2 with a friend (we were playing co-op after we’d each finished the individual campaign).  At lower levels he saw the solution before I’d even oriented myself in the room.  At higher levels he’d sit there stuck while I said things like “that’s the only piece of portalable wall, and clearly we need to use that wall paint for something, so let’s portal the paint over to there and see what happens.”  Translation for those of you who haven’t played Portal:  we have a bunch of parts, they can only connect in so many ways, let’s connect some likely looking ones and see what presents itself.  

I have several points I want to make about this.  First, I think we as a society tend to conflate the following: initial skill at a subject, speed of learning a subject, ceiling of ability in a subject.  My brother’s and friend’s initial abilities were higher than mine, but their ceilings appeared to be lower, in part because my initial skill level led me to develop skills we weren’t directly measuring.

The second one is more personal, more speculative, and will require more stories.  In a nutshell, I think math was the only thing I ever learned how to learn.

I mentioned I also struggled with languages.  When I struggled with math my parents put me down and painstakingly walked me through my homework until I got it right.  When I struggled with Spanish they said “yup, foreign languages are hard.”  I loved and love reading and writing, but when I started to get graded for them, and felt the grades were more about ability to fit the teacher’s conceptions than anything I enjoyed about reading or writing, I swore off all but the most mandatory English classes, and more generally anything “subjective.” I fell in love with behavioral biology at age 12 and took a staggering number of mandatory prerequisites in order to pursue it (seven semesters of chemistry, two of physics, plus all the biology you have to take before they let you get to behavioral*.)  But I don’t feel like I ever mastered any of the parts except those I was interested in.  I have this nasty tendency to just skim textbooks and fill in the complicated parts from context.  This worked way better than it has any right to- I graduated cum laude from Cornell University with a double major in computer science and biology- but not well enough.  I could have done better.  Not necessarily on anything Cornell was measuring, but better nonetheless.  

I was originally considering math for my second major at Cornell.  That died my first semester, when I was suddenly taught theory by people hired for their research rather than applications taught by people hired for their teaching.  Suddenly class was nothing but proofs, and I hated them.  Except that my eventual second major, computer science, also required proofs.  I hated them there too, for one semester, but they started to grow on me the second, and I went on to take multiple 600 level theory classes.  I loved the little logic puzzles.

I’ve been scared about nursing school because it’s a lot of physiology, which I did everything I could to avoid when I was studying biology.  I know I find it more interesting now than I did then, but that’s because everything I’ve done since is researching my own medical problems, at my own pace.  How will I handle having to learn what other people tell me to, on a timetable they set?

My first solution was a combination of denial, Trying Really Hard, and cramming all the knowledge I could into my head ahead of time.  This was not going to work.  But this kind of learning is a learnable skill, and that skill is something I can learn ahead of of time.


The implicit promise of good luck

Last summer, five year old Rebecca Meyers was diagnosed with brain cancer.   It was one of those bizarre situations where, aside from the malignant mass growing in her brain, she seemed to be really lucky.  Her family was vacationing far from home but near one of the best hospital she could hope to go to, and multiple family members and family friends were vacationing close enough to support her parents during the first few weeks.  The tumor extraction was a miracle of modern medicine.

Seven months later her brain is lighting up with new tumors.  She may not live long enough to have her Make-a-Wish Foundation wish granted.

I’ve been reading her father’s updates since she was diagnosed.  I have no connection to the family, but he’s a good writer and it’s a naturally dramatic story.  I didn’t realize till I read that she was definitely going to die that I had taken the initial luck as some sort of promise.  Subconsciously I believed that someone/thing must have arranged things so that she could receive such good care, and they wouldn’t bother unless they knew they could manage to pull her out on the other side.  I feel betrayed, and it’s definitely because of the initial good fortune, not the intervening positive results.

Maybe being by Children’s Hospital of Philidelphia was random chance.  Maybe there really was something magic taking care of her, but it ran out of juice or was given a higher priority or just screwed up.  And now a little girl is going to die and it just feels so unfair.

Flu Week/Book Review: Flu, by Gina Kolata

Flu‘s full title is Flu: The Story of the Great Influenza Pandemic of 1918.  It does not deliver what it promises, but what it does deliver is pretty neat.

From the title, I expected it to be about the biology and/or social effects of the 1918 flu pandemic.  I would have been perfectly fascinated by either of these.  The 1918 pandemic is one of very few plagues that was more deadly to healthy young adults than children and the elderly.  The only other disease I can think of that does that is HIV, and in that case it’s caused by the mechanism of transmission.  Both children and the elderly breathe, so that’s not the issue with the flu.  On a sociological level, the 1918 flu killed 3-5% of the world’s population, wiped entire villages off the map, and complicated the logistics of WW1.  How did people react to that?  How did it change society?  Flu talks a lot about how little the pandemic was talked about in the early aftermath, but nothing about how it affected society.

On the biological level, Flu raises several interesting mysteries. One, how did infections go from 0 to everyone so fast?  Even accounting for rapid transit, the disease seemed to spontaneously generate in multiple cities simultaneously.  Two, why did most of the victims suffer from an additional bacterial infection.  Was in opportunistic?  A co-infection that led to especially devastating outcomes?  She even hints that the answers may be related, but never returns to either.  My inner epidemiologist was heartbroken.

What Flu does talk about is how scientists have investigated these questions.  The anti-body work to demonstrate it was probably pig flu.  The ingenious methods of finding samples from a disease that died out 30-80 years ago.  Some of the politics of handling potential modern epidemics.  These are all fascinating, and important, and really hard to do well.  Demonstrating how science progresses is in many ways more valuable than any given scientific fact, which has a 50% chance of being proven wrong   I do wish Kolata hadn’t gotten my hopes up so high with the medical mysteries, but I would have happily read a book that promised exactly what this one delivered.


Flu week: herd immunity

Vaccinations are one of the wonders of the modern world.  Most people think primarily of the first order benefits- I got a vaccination, therefor I don’t get sick.  Hurray!  Then there are the second order benefits- I got a vaccination, therefor I don’t get sick, therefor I can’t infect anyone else.  Hurray!    If enough people are vaccinated, this culminates in  a third order effect, herd immunity.

Most diseases are only infectious for a short period of time.  If they don’t infect at least one other person while you’re contagious, that line dies out.*  If a disease’s average transmission rate falls below one because there are so few infectable individuals, it will be impossible for the disease to sustain itself.  This is called herd immunity, and it means even vulnerable people (such as those with compromised immune systems) are safe.  If the population is “the entire world”, you can eradicate a disease entirely  This is what we did with smallpox.

This is why refusing to vaccinate your child didn’t have many consequences for the early adopters.  As long as vaccination levels in your local population (e.g. school) were high enough to provide herd immunity, and you didn’t travel to an area where the disease was endemic, you were safe.  But when enough people in the same population forego vaccines, the disease is able to get a foothold, with disastrous consequences.

The idea that vaccines cause autism is conclusively disproven, but I don’t find it unimaginable that some vaccines have some subtle negative side effects, or rarely trigger massive negative reactions  in unpredictable individuals.  But the cost of the vaccine only exceeds the cost of not getting the vaccine when everyone else is getting vaccinated.  If you’re in a population without herd immunity, the MMR vaccine is waaaay better for you than measles or mumps.**

This concept can extend beyond vaccinations to anything that lowers transmission rate, including hand washing, face masks, condoms, and HIV pre-exposure prophylaxis.  This why “what makes sense for an individual?” and “what is best for the population?” often have very different answers.


*You might be asking “But won’t they run out of people eventually?  How does any disease persist?”.  That is the subject of my undergraduate thesis, and also decades of work by hundreds if not thousands of brilliant people.  We have only a fraction of the answer.

**Rubella is actually not very dangerous at all, except for being absolutely devastating to the fetus if the mother catches it in a certain stage of pregnancy.  We vaccinate for it to protect those fetuses, not the vaccine recipients.

Flu week: why the flu is special.

Your immune system is faster to respond to pathogens similar to those that have infected you previously than it is to respond to completely novel pathogens, because it holds a memory of past infections.  I have read many descriptions of this process and they always read like magic to me.  I don’t know if I’m dense for not getting it, or if I correctly recognize the explanations as oversimplified.  Immunizations are designed to give your immune system that memory without the negative effects of an actual infection.  The common ways to do this are to kill the pathogen before it’s injected, or to use a weakened form of the pathogen that can reproduce but has fewer side effects.

The magic that allows the immune system to recognize pathogens is generally based on recognizing surface proteins.  If a pathogen’s surface proteins change too much, the past immunity is useless.  This is why it is so hard to fight HIV: it mutates so rapidly that the immune system can’t keep up.  It is also why flu immunity (natural or induced) rarely carries over from year to year: the virus’s surface proteins vary too much.

Variability can come from many sources.  One is a spontaneous mutation within a viral particle.  Another is when two similar viruses co-infect the same cell and exchange genetic material.    All viruses follow the same very basic pattern: they infect a cell with their own genetic material (either DNA or RNA), hijack the cellular machinery to copy that genetic material and to produce the proteins those genes encode for, and package up the DNA or RNA in those proteins into a new viral particle and escape the cell.  While the DNA/RNA is floating around, it may cross over.  In order to exchange alleles, two strands have to line up at equivalent points to cross over (e.g. the same position on the same gene).  If the DNA/RNA is circular, they must cross over twice, at equivalent positions, or the DNA/RNA strand is nonviable.  This is statistically very rare, but a single host cell can produce millions of new viral particles, so it still happens enough to be a concern.

The flu is special.  Most viruses have one long strand of DNA or RNA, which may be linear or circular.  Influenza has 8 strands, each of which carry one gene.  They are not actually chromosomes, but for our purposes they’re pretty equivalent.  When a flu particle is manufactured, the assembly machinery grabs 8 strands and packages them up.  If memory serves, the grab is random, but that gives only a (1/8)^8 chance of given viral package being viable, so I suspect I am wrong.

Either way, when a cell is co-infected by two different strains of flu, the viral assemblers will naturally mix and match from all available strains.  This makes it much easier to exchange genes between  different flu strains.

Tomorrow: it gets worse.