On vaccination.

On vaccination.

The shape of things determines what they can do. Or, as a molecular biologist would phrase it, “structure determines function.”

In most ways, forks and spoons are similar. They’re made from the same materials, they show up alongside each other in place settings. But a spoon has a curved, solid bowl – you’d use it for soup or ice cream. A fork has prongs and is better suited for stabbing.

In matters of self defense, I’d reach for the fork.

On a much smaller scale, the three-dimensional shapes of a protein determines what it can do.

Each molecule of hemoglobin has a spoon-like pocket that’s just the right size for carrying oxygen, while still allowing the oxygen to wriggle free wherever your cells need it. A developing fetus has hemoglobin that’s shaped differently – when the fetal hemoglobin grabs oxygen, it squeezes more tightly, causing oxygen to pass from a mother to her fetus.

Each “voltage-gated ion channel” in your neurons has a shape that lets it sense incoming electrical signals and pass them forward. Voltage-gated ion channels are like sliding doors. They occasionally open to let in a rush of salt. Because salts are electrically charged, this creates an electric current. The electrical current will cause the next set of doors to open.

Every protein is shaped differently, which lets each do a different job. But they’re all made from the same materials – a long chain of amino acids.

#

Your DNA holds the instructions for every protein in your body.

Your DNA is like a big, fancy cookbook – it holds all the recipes, but you might not want to bring it into the kitchen. You wouldn’t want to spill something on it, or get it wet, or otherwise wreck it.

Instead of bringing your nice big cookbook into the kitchen, you might copy a single recipe onto an index card. That way, you can be as messy as you like – if you spill something, you can always write out a new index card later.

And your cells do the same thing. When it’s time to make proteins, your cells copy the recipes. The original cookbook is made from DNA; the index-card-like copies are made from RNA. Then the index cards are shipped out of the nucleus – the library at the center of your cells – into the cytoplasm – the bustling kitchen where proteins are made and do their work.

#

When a protein is first made, it’s a long strand of amino acids. Imagine a long rope with assorted junk tied on every few inches. Look, here’s a swath of velcro! Here’s a magnet. Here’s another magnet. Here’s a big plastic knob. Here’s another magnet. Here’s another piece of velcro. And so on.

If you shake this long rope, jostling it the way that a molecule tumbling through our cells gets jostled, the magnets will eventually stick together, and the velcro bits will stick to together, and the big plastic knob will jut out because there’s not enough room for it to fit inside the jumble.

That’s what happens during protein folding. Some amino acids are good at being near water, and those often end up on the outside of the final shape. Some amino acids repel water – like the oil layer of an unshaken oil & vinegar salad dressing – and those often end up on the inside of the final shape.

Other amino acids glue the protein together. The amino acid cysteine will stick to other cysteines. Some amino acids have negatively-charged sidechains, some have positively-charged sidechains, and these attract each other like magnets.

Sounds easy enough!

Except, wait. If you had a long rope with dozens of magnets, dozens of patches of velcro, and then you shook it around … well, the magnets would stick to other magnets, but would they stick to the right magnets?

You might imagine that there are many ways the protein could fold. But there’s only a single final shape that would allow the protein to function correctly in a cell.

So your cells use little helpers to ensure that proteins fold correctly. Some of the helpers are called “molecular chaperones,” and they guard various parts of the long strand so that it won’t glom together incorrectly. Some helpers are called “glycosylation enzymes,” and these glue little bits and bobs to the surface of a protein, some of which seem to act like mailing addresses to send the protein to the right place in a cell, some of which change the way the protein folds.

Our cells have a bunch of ways to ensure that each protein folds into the right 3D shape. And even with all this help, something things go awry. Alzheimer’s disease is associated with amyloid plaques that form in the brain – these are big trash heaps of misfolded proteins. The Alzheimer’s protein is just very tricky to fold correctly, especially if there’s a bunch of the misfolded protein strewn about.

#

Many human proteins can be made by bacteria. Humans and bacteria are relatives, after all – if you look back in our family trees, you’ll find that humans and bacteria shared a great-great-great-grandmother a mere three billion years ago.

The cookbooks in our cells are written in the same language. Bacteria can read all our recipes.

Which is great news for biochemists, because bacteria are really cheap to grow.

If you need a whole bunch of some human protein, you start by trying to make it in bacteria. First you copy down the recipe – which means using things called “restriction enzymes” to move a sequence of DNA into a plasmid, which is something like a bacterial index card – then you punch holes in some bacteria and let your instructions drift in for them to read.

The bacteria churn out copies of your human protein. Bacteria almost always make the right long rope of amino acids.

But human proteins sometimes fold into the wrong shapes inside bacteria. Bacteria don’t have all the same helper molecules that we do,.

If a protein doesn’t fold into the right shape, it won’t do the right things.

If you were working in a laboratory, and you found out that the protein you’d asked bacteria to make was getting folded wrong … well, you’d probably start to sigh a lot. Instead of making the correctly-folded human protein, your bacteria gave you useless goo.

Shucks.

But fear not!

Yeast can’t be grown as cheaply as bacteria, but they’re still reasonably inexpensive. And yeast are closer relatives – instead of three billion years ago, the most recent great-great-grandmother shared between humans and yeast lived about one billion years ago.

Yeast have a few of the same helper proteins that we do. Some human proteins that can’t be made in bacteria will fold correctly in yeast.

So, you take some yeast, genetically modify it to produce a human protein, then grow a whole bunch of it. This is called “fermentation.” It’s like you’re making beer, almost. Genetically modified beer.

Then you spin your beer inside a centrifuge. This collects all the solid stuff at the bottom of the flask. Then you’ll try to purify the protein that you want away from all the other gunk. Like the yeast itself, and all the proteins that yeast normally make.

If you’re lucky, the human protein you were after will have folded correctly!

If you’re unlucky, the protein will have folded wrong. Your yeast might produce a bunch of useless goo. And then you do more sighing.

There’s another option, but it’s expensive. You can make your human protein inside human cells.

Normally, human cells are hesitant to do too much growing and dividing and replicating. After all, the instructions in our DNA are supposed to produce a body that looks just so – two arms, two eyes, a smile. Once we have cells in the right places, cell division is just supposed to replace the parts of you that have worn out.

Dead skin cells steadily flake from our bodies. New cells constantly replace them.

But sometimes a cell gets too eager to grow. If its DNA loses certain instructions, like the “contact inhibition” that tells cells to stop growing when they get too crowded, a human cell might make many, many copies of itself.

Which is unhelpful. Potentially lethal. A cell that’s too eager to grow is cancer.

Although it’s really, really unhelpful to have cancer cells growing in your body, in a laboratory, cancer cells are prized. Cancer cells are so eager to grow that we might be able to raise them in petri dishes.

Maybe you’ve heard of HeLa cells – this is a cancer cell line that was taken from a Black woman’s body without her consent, and then this cell line was used to produce innumerable medical discoveries, including many that were patented and have brought in huge sums of money, and this woman’s family was not compensated at all, and they’ve suffered huge invasions of their privacy because a lot of their genetic information has been published, again without their consent …

HeLa cells are probably the easiest human cells to grow. And it’s possible to flood them with instructions to make a particular human protein. You can feel quite confident that your human protein will fold correctly.

But it’s way more expensive to grow HeLa cells than yeast. You have to grow them in a single layer in a petri dish. You have to feed them the blood of a baby calf. You have to be very careful while you work or else the cells will get contaminated with bacteria or yeast and die.

If you really must have a whole lot of a human protein, and you can’t make it in bacteria or yeast, then you can do it. But it’ll cost you.

#

Vaccination is perhaps the safest, most effective thing that physicians do.

Your immune system quells disease, but it has to learn which shapes inside your body represent danger. Antibodies and immunological memory arise in a process like evolution – random genetic recombination until our defenses can bind to the surface of an intruder. By letting our immune system train in a relatively safe encounter, we boost our odds of later survival.

The molecular workings of our immune systems are still being studied, but the basic principles of inoculation were independently discovered centuries ago by scientists in Africa, India, and China. These scientists’ descendants practiced inoculation against smallpox for hundreds of years before their techniques were adapted by Edward Jenner to create his smallpox vaccine.

If you put a virus into somebody’s body, that person might get sick. So what you want is to put something that looks a lot like the virus into somebody’s body.

One way to make something that looks like the virus, but isn’t, is to take the actual virus and whack it with a hammer. You break it a little. Not so much that it’s unrecognizable, but enough so that it can’t work. Can’t make somebody sick. This is often done with “heat inactivation.”

Heat inactivation can be dangerous, though. If you cook a virus too long, it might fall apart and your immune system learns nothing. If you don’t cook a virus long enough, it might make you sick.

In some of the early smallpox vaccine trials, the “heat inactivated” viruses still made a lot of people very, very sick.

Fewer people got very sick than if they’d been exposed to smallpox virus naturally, but it feels different when you’re injecting something right into somebody’s arm.

We hold vaccines to high standards. Even when we’re vaccinating people against deadly diseases, we expect our vaccines to be very, very safe.

#

It’s safer to vaccinate people with things that look like a virus but can’t possibly infect them.

This is why you might want to produce a whole bunch of some specific protein. Why you’d go through that whole rigamarole of testing protein folding in bacteria, yeast, and HeLa cells. Because you’re trying to make a bunch of protein that looks like a virus.

Each virus is a little protein shell. They’re basically delivery drones for nasty bits of genetic material.

If you can make pieces of this protein shell inside bacteria, or in yeast, and then inject those into people, then the people can’t possibly be infected. You’re not injecting people with a whole virus – the delivery drone with its awful recipes inside. Instead, you’re injecting people with just the propeller blades from the drone, or just its empty cargo hold.

These vaccine are missing the genetic material that allow viruses to make copies of themselves. Unlike with a heat inactivated virus, we can’t possibly contract the illness from these vaccines.

This is roughly the strategy used for the HPV vaccine that my father helped develop. Merck’s “Gardasil” uses viral proteins made by yeast, which is a fancy way of saying that Merck purifies part of the virus’s delivery drone away from big batches of genetically-modified beer.

#

We have a lot of practice making vaccines from purified protein.

Even so, it’s a long, difficult, expensive process. You have to identify which part of the virus is often recognized by our immune systems. You have to find a way to produce a lot of this correctly-folded protein. You have to purify this protein away from everything else made by your bacteria or yeast or HeLa cells.

The Covid-19 vaccines bypass all that.

In a way, these are vaccines for lazy people. Instead of finding a way to make a whole bunch of viral protein, then purify it, then put it into somebody’s arm … well, what if we just asked the patient’s arm to make the viral protein on its own?

#

Several of the Covid-19 vaccines are made with mRNA molecules.

These mRNA molecules are the index cards that we use for recipes in our cells’ kitchens, so the only trick is to deliver a bunch of mRNA with a recipe for part of the Covid-19 virus. Then our immune system can learn that anything with that particular shape is bad and ought to be destroyed.

After learning to recognize one part of the virus delivery drone, we’ll be able to stop the real thing.

We can’t vaccinate people by injecting just the mRNA, though, because our bodies have lots of ways to destroy RNA molecules. After all, you wouldn’t want to cook from the recipe from any old index card that you’d found in the street. Maybe somebody copied a recipe from The Anarchist Cookbook – you’d accidentally whip up a bomb instead of a delicious cake.

I used to share laboratory space with people who studied RNA, and they were intensely paranoid about cleaning. They’d always wear gloves, they’d wipe down every surface many times each day. Not to protect themselves, but to ensure that all the RNA-destroying enzymes that our bodies naturally produce wouldn’t ruin their experiments.

mRNA is finicky and unstable. And our bodies intentionally destroy stray recipes.

So to make a vaccine, you have to wrap the mRNA in a little envelope. That way, your cells might receive the recipe before it’s destroyed. In this case, the envelope is called a “lipid nanoparticle,” but you could also call a fat bubble. Not a bubble that’s rotund – a tiny sphere made of fat.

Fat bubbles are used throughout cells. When the neurons in your brain communicate, they burst open fat bubbles full of neurotransmitters and scatter the contents. When stuff found outside a cell needs to be destroyed, it’s bundled into fat bubbles and sent to a cellular trash factories called lysosomes.

For my Ph.D. thesis, I studied the postmarking system for fat bubbles. How fat bubbles get addressed in order to be sent to the right places.

Sure, I made my work sound fancier when I gave my thesis defense, but that’s really what I was doing.

Anyway, after we inject someone with an mRNA vaccine, the fat bubble with the mRNA gets bundled up and taken into some of their cells, and this tricks those cells into following the mRNA recipe and making a protein from the Covid-19 virus.

This mRNA recipe won’t teach the cells how to make a whole virus — that would be dangerous! That’s what happens during a Covid-19 infection – your cells get the virus’s whole damn cookbook and they make the entire delivery drone and more cookbooks to put inside and then these spread through your body and pull the same trick on more and more of your cells. A single unstopped delivery drone can trick your cells into building a whole fleet of them and infecting cells throughout your body.

Instead, the mRNA recipe we use for the vaccine has only a small portion of the Covid-19 genome, just enough for your cells to make part of the delivery drone and learn to recognize it as a threat.

And this recipe never visits the nucleus, which is the main library in your cells that holds your DNA, the master cookbook with recipes for every protein in your body. Your cells are tricked into following recipes scribbled onto the vaccine’s index cards, but your master cookbook remains unchanged. And, just like all the mRNA index cards that our bodies normally produce, the mRNA from the vaccine soon gets destroyed. All those stray index cards, chucked unceremoniously into the recycling bin.

#

The Johnson & Johnson vaccine also tricks our cells into making a piece of the Covid-19 virus.

This vaccine uses a different virus’s delivery drone to send the recipe for a piece of Covid-19 into your cells. The vaccine’s delivery drone isn’t a real virus – the recipe it holds doesn’t include the instructions on how to make copies of itself. But the vaccine’s delivery drone looks an awful lot like a virus, which means it’s easier to work with than the mRNA vaccines.

Those little engineered fat bubbles are finicky. And mRNA is finicky. But the Johnson & Johnson vaccine uses a delivery drone that was optimized through natural selection out in the real world. It evolved to be stable enough to make us sick.

Now we can steal its design in an effort to keep people well.

#

Lots of people received the Johnson & Johnson vaccine without incident, but we’ve temporarily stopped giving it to people. Blood clots are really scary.

You might want to read Alexandra Lahav’s excellent essay, “Medicine Is Made for Men.” Lahav describes the many ways in which a lack of diversity in science, technology, and engineering fields can cause harm.

Cars are designed to protect men: for many years, we used only crash test dummies that were shaped like men to determine whether cars were safe. In equivalent accidents, women are more likely to die, because, lo and behold, their bodies are often shaped differently.

Women are also more likely to be killed by medication. Safety testing often fails to account for women’s hormonal cycles, or complications from contraceptives, or differences in metabolism, or several other important features of women’s bodies.

White male bodies are considered to be human bodies, and any deviation is considered an abnormal case. Medication tested in white men can be approved for everyone; medication tested in Black patients was approved only for use in other Black patients.

Although more than half our population are women, their bodies are treated as bizarre.

For most people, the Johnson & Johnson vaccine is safe. But this is a sort of tragedy that occurs too often – causing harm to women because we’re inattentive to the unique features of their bodies.

#

I haven’t been vaccinated yet, but I registered as soon as I was able – my first dose will be on April 26th. Although I’ve almost certainly already had Covid-19 before, and am unlikely to get severely ill the next time I contract it, I’m getting the vaccine to protect my friends and neighbors.

So should you.

On ethics and Luke Dittrich’s “Patient H.M.”

On ethics and Luke Dittrich’s “Patient H.M.”

The scientific method is the best way to investigate the world.

Do you want to know how something works?  Start by making a guess, consider the implications of your guess, and then take action.  Muck something up and see if it responds the way you expect it to.  If not, make a new guess and repeat the whole process.

4587547291_34689fa739_z.jpg
Image by Derek K. Miller on Flickr.

This is slow and arduous, however.  If your goal is not to understand the world, but rather to convince other people that you do, the scientific method is a bad bet.  Instead you should muck something up, see how it responds, and then make your guess.  When you know the outcome in advance, you can appear to be much more clever.

A large proportion of biomedical science publications are inaccurate because researchers follow the second strategy.  Given our incentives, this is reasonable.  Yes, it’s nice to be right.  It’d be cool to understand all the nuances of how cells work, for instance.  But it’s more urgent to build a career.

Both labs I worked in at Stanford cheerfully published bad science.  Unfortunately, it would be nearly impossible for an outsider to notice the flaws because primary data aren’t published.

A colleague of mine obtained data by varying several parameters simultaneously, but then graphed his findings against only one of these.  As it happens, his observations were caused by the variable he left out of his charts.  Whoops!

(Nobel laureate Arieh Warshel quickly responded that my colleague’s conclusions probably weren’t correct.  Unfortunately, Warshel’s argument was based on unrealistic simulations – in his model, a key molecule spins in unnatural ways.  This next sentence is pretty wonky, so feel free to skip it, but … to show the error in my colleague’s paper, Warshel should have modeled multiple molecules entering the enzyme active site, not molecules entering backward.  Whoops!)

Another colleague of mine published his findings about unusual behavior from a human protein.  But then his collaborator realized that they’d accidentally purified and studied a similarly-sized bacterial protein, and were attempting to map its location in cells with an antibody that didn’t work.  Whoops!

No apologies or corrections were ever given.  They rarely are, especially not from researchers at our nation’s fanciest universities.  When somebody with impressive credentials claims a thing is true, people often feel ready to believe.

antibodies.JPGIndeed, for my own thesis work, we wanted to test whether two proteins are in the same place inside cells.  You can do this by staining with light-up antibodies for each.  If one antibody is green and the other is red, you’ll know how often the proteins are in the same place based on how much yellow light you see.

Before conducting the experiment, I wrote a computer program that would assess the data.  My program could identify various cellular structures and check the fraction that were each color.

As it happened, I didn’t get the results we wanted.  My data suggested that our guess was wrong.

But we couldn’t publish that.  And so my advisor told me to count again, by hand, claiming that I should be counting things of a different size.  And then she continued to revise her instructions until we could plausibly claim that we’d seen what we expected.  We made a graph and published the paper.

This is crummy.  It’s falsehood with the veneer of truth.  But it’s also tragically routine.

#

41B1pZkOwmL._SX329_BO1,204,203,200_Luke Dittrich intertwines two horror stories about scientific ethics in Patient H.M.: A Story of Memory, Madness, and Family Secrets.

One of these nightmares is driven by the perverse incentives facing early neurosurgeons.  Perhaps you noticed, above, that an essential step of the scientific method involves mucking things up.  You can’t tell whether your guesses are correct until you perform an experiment.  Dittrich provides a lovely summary of this idea:

The broken illuminate the unbroken.

An underdeveloped dwarf with misfiring adrenal glands might shine a light on the functional purpose of these glands.  An impulsive man with rod-obliterated frontal lobes [Phineas Gage] might provide clues to what intact frontal lobes do.

This history of modern brain science has been particularly reliant on broken brains, and almost every significant step forward in our understanding of cerebral localization – that is, discovering what functions rely on which parts of the brain – has relied on breakthroughs provided by the study of individuals who lacked some portion of their gray matter.

. . .

While the therapeutic value of the lobotomy remained murky, its scientific potential was clear: Human beings were no longer off-limits as test subjects in brain-lesioning experiments.  This was a fundamental shift.  Broken men like Phineas Gage and Monsieur Tan may have always illuminated the unbroken, but in the past they had always become broken by accident.  No longer.  By the middle of the twentieth century, the breaking of human brains was intentional, premeditated, clinical.

Dittrich was dismayed to learn that his own grandfather had participated in this sort of research, intentionally wrecking at least one human brain in order to study the effects of his meddling.

Lacking a specific target in a specific hemisphere of Henry’s medial temporal lobes, my grandfather had decided to destroy both.

This decision was the riskiest possible one for Henry.  Whatever the functions of the medial temporal lobe structures were – and, again, nobody at the time had any idea what they were – my grandfather would be eliminating them.  The risks to Henry were as inarguable as they were unimaginable.

The risks to my grandfather, on the other hand, were not.

At that moment, the riskiest possible option for his patient was the one with the most potential rewards for him.

Turning_the_Mind_Inside_Out_Saturday_Evening_Post_24_May_1941_a_detail_1

By destroying part of a brain, Dittrich’s grandfather could create a valuable research subject.  Yes, there was a chance of curing the patient – Henry agreed to surgery because he was suffering from epileptic seizures.  But Henry didn’t understand what the proposed “cure” would be.  This cure was very likely to be devastating.

At other times, devastation was the intent.  During an interview with one of his grandfather’s former colleagues, Dittrich is told that his grandmother was strapped to the operating table as well.

It was a different era,” he said.  “And he did what at the time he thought was okay: He lobotomized his wife.  And she became much more tractable.  And so he succeeded in getting what he wanted: a tractable wife.”

#

Compared to slicing up a brain so that its bearer might better conform to our society’s misogynistic expectations of female behavior, a bit of scientific fraud probably doesn’t sound so bad.  Which is a shame.  I love science.  I’ve written previously about the manifold virtues of the scientific method.  And we need truth to save the world.

Which is precisely why those who purport to search for truth need to live clean.  In the cut-throat world of modern academia, they often don’t.

Dittrich investigated the rest of Henry’s life: after part of his brain was destroyed, Henry became a famous study subject.  He unwittingly enabled the career of a striving scientist, Suzanne Corkin.

Dittrich writes that

Unlike Teuber’s patients, most of the research subjects Corkin had worked with were not “accidents of nature” [a bullet to the brain, for instance] but instead the willful products of surgery, and one of them, Patient H.M., was already clearly among the most important lesion patients in history.  There was a word that scientists had begun using to describe him.  They called him pure.  The purity in question didn’t have anything to do with morals or hygiene.  It was entirely anatomical.  My grandfather’s resection had produced a living, breathing test subject whose lesioned brain provided an opportunity to probe the neurological underpinnings of memory in unprecedented ways.  The unlikelihood that a patient like Henry could ever have come to be without an act of surgery was important.

. . .

By hiring Corkin, Teuber was acquiring not only a first-rate scientist practiced in his beloved lesion method but also by extension the world’s premier lesion patient.

. . .

According to [Howard] Eichenbaum, [a colleague at MIT,] Corkin’s fierceness as a gatekeeper was understandable.  After all, he said, “her career is based on having that exclusive access.”

Because Corkin had (coercively) gained exclusive access to this patient, most of her claims about the workings of memory would be difficult to contradict.  No one could conduct the experiments needed to rebut her.

Which makes me very skeptical of her claims.

Like most scientists, Corkin stumbled across occasional data that seemed to contradict the models she’d built her career around.  And so she reacted in the same was as the professors I’ve worked with: she hid the data.

Dittrich: Right.  And what’s going to happen to the files themselves?

She paused for several seconds.

Corkin: Shredded

Dittrich: Shredded?  Why would they be shredded?

Corkin: Nobody’s gonna look at them.

Dittrich: Really?  I can’t imagine shredding the files of the most important research subject in history.  Why would you do that?

. . .

Corkin: Well, the things that aren’t published are, you know, experiments that just didn’t … [another long pause] go right.

shredder-779850_1280.jpg

On stuttering.

On stuttering.

CaptureDuring his first year of graduate school at Harvard, a friend of mine was trying to pick a research advisor.  This is a pretty big deal — barring disaster, whoever you choose will have a great deal of control over your life for the next five to eight years.

My friend found someone who seemed reasonable.  The dude was conducting research in an exciting field.  He seemed personable.  Or, well, he seemed human, which can be what passes for personable among research professors at top-tier universities.  But while my friend and the putative advisor-to-be were talking, they got onto the topic of molecular dynamics simulations.

My friend mentioned that his schoolmate’s father studies simulations of cellular membranes.  And that guy, the father, is incredibly intelligent and very friendly — when I showed up at a wedding too broke for a hotel, he let me sleep on the floor of the room he’d booked for himself and his wife.

But the putative advisor corrected my friend when he mentioned the guy’s name.  “Oh, you mean duh, duh, duh, duh, Doctor ________.”  And smiled, as though my friend was going to chuckle too.

stutter_by_visualtextproject-d49ak0vThat’s when my friend realized, okay, I don’t wanna talk to you no more.  He found a different advisor.  He never regretted his choice.

Well, no, that’s not true.  All graduate students regret their choice of advisor sometimes.  But my friend never wished he’d worked for the jerk.

Yes, some people, with a huge amount of effort and probably an equal measure of luck, are able to get over stuttering.  But most can’t.  So it’s crummy that even well-educated, ostensibly sophisticated people would feel entitled to mock somebody for a stutter.  Presumably even that jerk would’ve refrained from an equivalent comment if my friend’s schoolmate’s father was blind or confined to a wheelchair.

But stuttering, along with a few other conditions like depression and obsessive compulsive disorder, still gets treated like a moral failing.  Like a sufferer should be able to try harder and just get over it.

That attitude is especially bad as regards stuttering, because mockery and castigation seems to make the condition worse.  There are genetic factors that confer a predilection toward stuttering, but (unpublished, evil) work from Dr. Wendell Johnson showed that sufficiently vituperative abuse can cause children of any genetic background to become stutterers.

CaptureYou’ve read about the “monster” study, right?  Dr. Johnson stuttered, and he had a theory that his stuttering had been exacerbated by people’s well-meaning attempts to cure him.  His parents would correct his speech, draw attention to his mistakes, exhort him to be more mindful when talking.  Dr. Johnson thought that the undue attention placed on his speech patterns made him more likely to freeze up and stutter.  And, once that cycle had begun, his brain dug itself into a rut.  He began to castigate himself for his mistakes, perpetuating the condition.

Of course, that was just a theory.  To test it, you’d want to show two things.  First, that by not paying attention to the mistakes of an incipient stutterer, you can help that person evade or cure the condition.  And, second, that you could cause well-spoken people to develop stutters by convincing them and their interlocutors that they already were stuttering, and castigating them for it.

It’s totally ethical to conduct the first experiment.  The process itself would cause no harm, and the intention is to improve someone’s life.  If you can help someone get over a stutter, you’ll smooth future social interactions.  Stave off some mockery from colleagues at Harvard.  That sort of thing.

But the second experiment?  The process is miserable for the study subjects — you’re cutting them off all the time, criticizing them, forcing them to say things over and over until their thoughts are expressed perfectly.  And, worse, if you succeed, you’ve saddled them with burdens they’ll have to deal with for the rest of their lives.  Let the mockery commence!

CaptureDr. Johnson made one of his students conduct that second experiment on six orphaned children.  In the end, none of the children developed the syllabic repetition typical of most stutterers, but they became extremely self-conscious and reluctant to speak — symptoms that stayed with them for the rest of their lives.

Indeed, the symptoms triggered in those children are equivalent to the symptoms monitored for a stuttering model in mice.  One of the genetic factors associated with stuttering was recreated in mice, and those mice exhibited a condition somewhat analogous to human stuttering.

Dr. Dolittle did not participate in this new study, which made matters much more difficult for Barnes & colleagues.  If you don’t know what a mouse is saying, how do you know whether it’s studying?  They did measure variance from one vocalization to the next — in humans, repeating the initial syllable of a word lowers total syllabic variance — and saw that their mice with the stuttering gene repeated sounds more often.

Their best measurements, though, were the rate of squeaking, and the length of pauses between squeaks.  Like an oft-badgered child, the mice with the stuttering gene talked less and spent more time waiting, maybe thinking, between statements.

And it pleases me, given my pre-existing biases, to see more data showing that, if somebody stutters, it’s not that person’s fault.  Genetic predilection certainly isn’t the same thing as destiny, but it’s a nice corrective to the mocking jerks.  Sure, you can speak fine, Mister Mockingpants, but are you fighting against the current of a lysosomal targeting mutation?

(Oh, right, sorry, my mistake. Doctor Mockingpants. You jerk.)

*************

Capturep.s. As it happens, the mutation Barnes et al. introduced into mice is involved in the pathway I studied for my thesis work.  They introduced a mutation in the Gnptab gene (trust me, you don’t want me to write out the full name that Gnptab stands for), which is supposed to produce a protein that links a targeting signal onto lysosomal enzymes.  In less formal terms, Gnptab is supposed to slap shipping labels onto machinery destined for the cell’s recycling plants.  Without Gnptab function, bottles & cans & old televisions pile up in the recycling plant. The machinery to process them never arrives.

Which does seem a little strange to me… stuttering is a very specific phenotype, and that is such a general cellular function.  Lysosomal targeting is needed for all cells, not just neurons in speech areas of the brain.  It’s a sufficiently common function that biologists often refer to Gnptab as a “housekeeping” gene.  And proper lysosome function is sufficiently important that problems typically cause major neurodegeneration, seizures, blindness, and death, typically at a very young age.  Compared to that litany of disasters, stuttering doesn’t sound so bad.