What was special about Einstein's brain?

It is a question that nags anyone who has reflected upon the brain, be they professional looker-at or simple armchair neurophysiologist. Just what was it that made Einstein Einstein? If there is one brain that defines smart, Albert had it. If we're going to finger the spark, divine the wellspring, that's the noggin to look in. Yes we may hope to develop it in ourselves, but if not then just to know the answer. What was it? What was special?

Weight? Normal. Shape? Normal. Taste? Delicious!

Okay, I made up that last one. But it's true: Einstein's brain has been studied and found to be, well, unremarkable. One might imagine getting inside that haloed head and finding a munificent instrument -- a cathedral of gyri and sulci, eternal verities of the universe made flesh. Alas, postmortem examination of Einstein's brain found it to be largely indistinguishable from the pork chop the rest of us have rattling around between our ears.

With one exception.

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Area 39

Here's the skinny from Marian Diamond, a neuroanatomist who studied the great man's brain. She and her coworkers published their findings in the journal Experimental Neurology back in 1985 (Vol. 88, pp. 198-204). If you'll permit me to paraphrase a bit, they found that Einstein's brain exhibited:

...excess glial cells in Brodmann area 39.

Huh. Well how about that.

Call me cynical, but I can't help but think Dr. Brainy McBrain is going to come up with something to report given the opportunity to poke Albert's brain, lest the Einstein estate get testy about ponying it up. Because LabKitty knows a thing or two about a thing or two, and I find this finding to be, well, unremarkable.

For the moment, however, let's take Diamond's statement at face value. What does it mean? What's a glial cell? What does an excess of them portend? And what the heck is a Brodmann area 39?

All in good time, dear reader. All in good time.

First, a little history.

A Little History

It may surprise you to learn that Einstein's brain is not floating in a vat at some Institute of Important Brains where scientists can sign up for time on it like the Hubble telescope. Indeed, Einstein's brain is not floating in a vat at all.

Our story beings in 1955. Einstein dies in Princeton University Hospital. An autopsy is scheduled. Enter 43-year-old staff pathologist Thomas Harvey. He finds that Einstein died of a ruptured abdominal aorta, consistent with the nausea and other symptoms Albert had presented. Dr. Harvey weighs the internal organs, checks around for whatever a pathologist checks around for during an autopsy. Then he opens the skull.

Here's where things get weird.

Harvey absconded with Einstein's brain. Not in an overpower-the-guards kind of way; more in a dog-ate-my-homework kind of way. Just taking this home 4 2night. BRB, he would have texted. Except one night turned into indefinitely. When interested parties began pressing him for the return of the brain, Harvey did not relent. He insisted he was overseeing a study of the material and would publish his findings in due time.

A swirl of urban legends soon surrounded the event, some of which having a thin veneer of truth. Harvey hired a local artist to paint a portrait of the brain (true). Someone removed Einstein's eyes (alas, true) which were later sold to Michael Jackson (not true). The Israelis put out a hit on Harvey (not true) and sent armed agents to seize Einstein's papers from Princeton (true). Harvey is a patsy, and Einstein's brain is really in a Moscow basement where the KGB is using it to build an army of genius robots (probably not true).

Depending on whose story you believe, Harvey was either a dedicated pathologist or an opportunist mad scientist. What we know for sure is that Harvey soon left Princeton, taking the brain with him. This marked the beginning of a long downward spiral in his professional trajectory, eventually finding the former Yale graduate working the third shift in a Kansas plastics factory. It was as if possession of the brain consumed him, like Kate Bush's red shoes or a Stephen King Estes Park hotel.

For better or for worse, Harvey seems to have earnestly considered it his life's mission to identify the root of Einstein's genius. He cut the brain into more than 200 pieces, and over the next 40 years doled these out to scientists around the world to study. Most of these efforts came to naught, either because the recipient found nothing special to report or had no idea who Harvey was and whose brain is this really?

However, one sample reached noted Berkeley neuroanatomist Marian Diamond. She analyzed a portion of Einstein's cerebral cortex - the outer layer of the brain that is associated with abstract thinking (as might be involved in, say, doing physics). As noted above, Diamond and her coworkers observed something peculiar, something unusual: an excess of glia in a region of Einstein's cortex known as Brodmann area 39.

A Look Ahead

Not to spoil the punchline, but the response of the neuroscience community to Diamond's announcement can charitably be described as a giant meh. Nobody slapped their forehead upon hearing the news. Zut alors! Glia in area 39! It all makes sense now! I'm telling you this up front because I would feel bad if you read the rest of my tale expecting a grand denouement and instead discovered it to be something of a shaggy dog story.

Still, knowledge is never wasted, even knowledge of a shaggy dog story. Besides, the next time you overhear some stranger marveling over Einstein's glial cells, you will be prepared to roll your eyes and dismissively inform them that -- point of fact -- the response of the neuroscience community to Diamond's announcement could charitably be described as a giant meh. You're on your way to making a new friend!

To explain all this, though, we need to look at how anatomists explore the cellular structure of the brain, a field of study known as histology. One might imagine analysis of Einstein's brain was performed using cutting-edge technology. Ginormous state-of-the art equipment. Expensive machines that go ping. Sharks with frickin' laser beams mounted on their heads.

Not so. The techniques Professor Diamond used were invented over a century ago. You can do them in your kitchen (as long as your uppity Condo Association doesn't take offense. Don't ask).

Welcome to the wild world of histology.

The Wild World of Histology (Part I)

Serious study of the brain began only in the middle of the 19th century. Sure, the Greek physician Galen worked out that the brain was important for figgerin' back in antiquity, mostly by observing gladiators who got maimed in the noggin. But Galen didn't offer much in the way of illuminating detail, just like a real theory of physics would have to wait for Newton's calculus to supplant Aristotle's cocktail party talk about "things naturally seeking the center of the universe."

What changed? The 19th century saw application of the microscope to neuroanatomy for the first time. Although Leeuwenhoek's instrument had been around since the late 1600s, it took some time for the device to be useful in the study of the brain.

The first problem was that you must slice the tissue thin enough that light will pass through it. A fat chunk of brain under a microscope tells you nothing; you may as well be looking a Pop Tart (which, believe it or not, I have. A chunk of Pop Tart under a microscope indeed tells you nothing).

The slicing problem was solved by the invention of the microtome, a miniature version of the machine they use at the deli to wafer your prosciutto. A hunk of brain is glued to a chuck which can be advanced in a precise fashion - usually by twisting a screw - and a knife or razor blade is then guided through the tissue to carve off a thin slice. Slice-advance-repeat until your brain chunk is sliced up like miniature bologna.

An expert can thin-section fresh brain, however the tissue is usually pickled first (the technical term is "fixed") to make it easier to cut, most commonly using formaldehyde or one of its chemical cousins. After that, you stick your slices to a glass slide, scrounge up a microscope, and you're ready to make history.

But, alas, there is another problem.

The Wild World of Histology (Part II)

A thin slice of brain tissue is transparent. Stick one under a microscope and you will see nothing except perhaps a yellowish tinge. This brings us to the second problem in the microscopic study of brain: You must stain brain cells to see them.

Histologists have an arsenal of dyes and stains at their disposal, like artists working in different media. There are stains that label parts of neurons, like a particular protein stuck to its surface, and stains that completely fill individual neurons plucked from the thousands of cells in the tissue apparently at random. There are stains that stain the axons that make up a nerve and stains that color the myelin insulation that surrounds them. There are dyes you can inject in one area of the brain that will be slurped up and and stain all the neurons that project there. And there are dyes you can inject into a neuron that will stain all the neurons that neuron talks to. There are antibody labels and fluorescent viruses, genetically-engineered glowing neurons and radioactive tracers. Lions and tigers and bears.

But the histology technique used in our story is the humble Nissl stain, an easy-to-use technique developed by the physician Franz Nissl in the late 1800s. His technique stains a cell's "Nissl substance," early anatomist-speak for what was later established to be ribosomes of the endoplasmic reticulum (the technique also stains DNA in the cell nucleus. This turns out to be important later).

If talk of DNA and endoplasmic reticulum makes you glaze over, fear not. For the details are less important than the effect: A Nissl stain transforms a slice of brain tissue from a semi-transparent wasteland into a sea of spots. Perhaps an example would be helpful.

An example Nissl-stained thin section is shown in the accompanying figure. Each purple spot is a brain cell (this example shows a slice of the hippocampus). Some of the spots are bigger and some are smaller. Some are round dots and some are triangularish splotches. These details provide information to the trained eye of the histologist. More later.

Professor Diamond used a Nissl stain to study Einstein's brain. What was she looking for? What can a bunch of spots tell you about a brain?

Enter Korbinian Brodmann.

Brodmann Areas

Early neuroanatomists begin to cast about for some way to make sense out of the depressing complexity their accumulating histological material was showing them. Perhaps most troubling of all was the cerebral cortex, for here there seemed to be no footholds whatsoever. Many parts of the brain have characteristic features discernible even to the naked eye, but beyond its various infolding the gross anatomy of the cortex provides few clues. Surely the cortex is not just one big slab of cells wrapped around the brainstem. There must be some principles that govern its organization. What are they?

In the early 1900s, Korbinian Brodmann and other anatomists working in Germany began to compare Nissl-stained sections from different parts of the cortex, looking for characteristic features. This they found not in the individual cells, but in how the cells were organized into layers.

Here's the idea.

Take a "core sample" of the cortex - from its surface down to the white matter underneath - and Nissl stain it. If you take a step back and squint a bit, you will notice the cells in your section are not distributed uniformly. Rather, they congregate into layers. Some of the layers are dense with cells; others are rather sparse. Some layers have big cells, others have small cells. And so on.

Three examples of what I am trying to describe are shown in the accompanying figure. Note how each section has its own characteristic appearance. The section on the left has three layers of small cells; a wide band near the top and two narrow bands further down. The center section has a tight band of small cells in the middle of the tissue and a diffuse band of small cells at the top. The section on the right does not exhibit much cell layering at all, but rather contains large cells spread throughout.

Using this sort of witchcraft, Brodmann and co-workers parceled out the human cortex into 47 distinct areas. I won't lie: Identifying Brodmann areas is often as much an art as it is science. Still, many of these areas were later confirmed to have functional significance using more sophisticated techniques. For example, Brodmann area 17 is now known to be primary visual cortex, the location in cortex where visual information first arrives. Brodmann area 4 is now known to be primary motor cortex, the region of cortex where voluntary movements originate.

As you are probably now wondering, where is Brodmann area 39? And what goes on there?

Brodmann Area 39

Wikipedia will tell you that Brodmann area 39 is located at the caudal pole of the left temporal gyrus. This tells most people not much, so here's what to do: Feel around at the base of the back of your head for a bump. Be not alarmed -- everybody has one (medicos call this the external occipital protuberance aka the inion). Press on your inion using the thumb of your left head and stick your pinky in your left ear. Your index finger is now pointing approximately at your Brodmann area 39.

Failing that, you could just take a gander at the accompanying figure.

What sort of mental gronkulations transpire at this location? Just as I mentioned that Brodmann area 17 is visual cortex and Brodmann area 4 is motor cortex, Brodmann area 39 is in something called association cortex. The idea is that "primary" cortex (visual, auditory, somatosensory, whatever) gets first crack at any incoming information. When they're done, they pass their results onto association cortex, which then, well, "associates." The image of a cat goes to visual cortex; the mewing goes to auditory cortex. Only when this information is combined in association cortex do you enjoy a single mental percept of, say, grumpy cat.

At least that's the story you'll find in textbooks. The truth of it is a different story. One of the dirty little secrets of neuroscience (and there are many) is that we have no idea what happens in association cortex. It is an enigma, as wide as a church door and as impenetrable as the icy silence of an angry girlfriend. Get a neuroscientist liquored-up at your next campus function and s/he may well spill the beans: ...if we don't know what it does, we call it "association cortex." Hahaha! Then s/he will throw up on your shoes.

Be that as it may, we have arrived, finally, at Brodmann area 39 in Einstein's brain. You are almost at the end our tale, like San and Frondo slogging their final steps inside Mt. Death, into which they will cast the necklace, all the while evading the eye of Calgon as LabKitty might evade a copyright attorney of the Tolkien estate.

However, like the weakness of Frondo at the moment of truth, one final plot twist remains.

Glial Cells

Each dot in a Nissl stain is a brain cell. Note I write "brain cell" and not "neuron." For there is not one but two types of cells in the brain. Montagues and Capulets. Sharks and Jets. Stuffing and potatoes.

Neurons and glia.

This division was noted by the early anatomists, but its functional significance was only established a century later using techniques that could measure the electrical activity inside cells. These have confidently divided brain cells into two camps: (1) neurons, which carry out information processing, and (2) all the other cells, which don't. The latter are collectively called "glia" (or "glial cells" if you're not into the whole brevity thing).

What do glia do? The catch-all term is that they provide "support" for the neurons. Think of them as the pit crew, with neurons being the actual cars that go out and race.

Some examples: There are glia called astrocytes that buffer potassium in the brain, maintaining the proper ionic environment for neurons to do their thing. There are glia called microglia that eat neurons when they die. There are glia called oligodendrocytes that provide electrical insulation around nerve bundles. Many glia pull double duty, for example, providing scaffolding for the developing brain and changing jobs once everything is in place.

You can tell a neuron from a glia in Nissl-stained tissue if you know what to look for (I refer the interested reader to the technical note below for an explanation). Long story short: the little round dark spots? Glia. The big lighter splotches? Neurons.

You are now armed with everything you need to understand Professor Diamond's assessment of Einstein's brain.

Technical Note: Neurons and glia look different in Nissl for two reasons. First, neurons are larger than a typical glia; hence larger, yes, but also a neuron is chocked full of endoplasmic reticulum (ER). Glia? Not so much. Second, neurons do not undergo cell division. This means the DNA in a neuron is never condensed, so the nucleus is big. Glia do, so their nucleus is compact. The net result is that we obtain lighter staining of the ER + nucleus in a neuron, and darker staining of only the nucleus in glia.

An Excess of Glial cells in Brodmann Area 39

The chunk of brain tissue that Dr. Harvey sent Professor Diamond had been sitting in formaldehyde for decades so it was well-fixed. Diamond and colleagues cut the sample into thin sections using a microtome, then stained the sections using the Klüver-Barrera method, a cocktail of Nissl and myelin stains so popular with histologists that you can ask for it by name. The Nissl stain colors neurons and glia in purple; the myelin stain colors bundles of axons coursing through the tissue in light blue. Once the sections were mounted on glass sides, Diamond would have glued coverslips over the tissue. And once the glue had dried, she would have headed off to the microscope with her big collection of stained brain slices.

At the microscope, Professor Diamond counted neurons and glia in the various Brodmann areas of Einstein's cortex contained in the sample Dr. Harvey had provided. Upon examining Brodmann area 39, Professor Diamond discovered the ratio of glia-to-neurons there to be unusually high. How high? About 75% higher compared with brains taken from other individuals of a similar age.

Thus she reported her results: an excess of glial cells in Brodmann area 39.

No other Brodmann areas were reported as unusual, either because they weren't or Dr. Harvey did not provide them.

Epilogue

Scientists are killjoys by nature, if for no other reason that giving any one of us recognition makes it more likely they'll get funded and you won't. Great scientific discoveries tug at the purse strings as well as the heartstrings.

That being said, excess glial cells in Brodmann area 39 just don't get LabKitty's fur puffy. It could be a fluke. It could be related to non-physics thinking, like Albert's violin playing. Or it could be a chicken-and-egg dealio, with the true cause of bonus function elsewhere forcing a flowering of glia cells in area 39 to catch up. And, as I have noted, area 39 is smack dab in the middle of the no-cat's land called association cortex. It would be swell if we knew what area 39 does before we start making claims about what enhancing it does.

These objections (and worse) have been registered by big-shot neuroanatomists who have scrutinized Diamond's findings, albeit in more sober language. In the end, we are left with an inversion of Shakespeare. O nature, what hadst thou to do on earth; When thou didst bower the spirit of an angel; In mortal paradise of such ordinary flesh? We should be glad some first-rate neuroanatomists got a look at Einstein's brain, but Diamond's findings provide us more questions than answers.

Alas, I suspect had the brain slices not been labeled "A.E." the results would have never seen the light of day.

Postscript

And so we come to the end of our tale, Einstein's brain in hundreds of pieces scattered around the globe and not much to show for it. The secret is still locked inside; the combined labors of Franz Nissl, Korbinian Brodmann, Thomas Harvey, and Marian Diamond could not coax it out. A few other studies have since appeared, such as the 1999 Lancet article by McMaster University anatomist Sandra Witelson who reported Einstein's association cortex was plumper than the average bear's, a result consistent with Diamond's cellular observations but not proving their significance. Witelson's announcement generated considerable hoopla in the lay press, earning her a spread in People magazine and a fair amount of ire in the scientific community. Down here in the salt mines, media-darling scientists are viewed more like Stanley Pons than Tony Stark.

These days Marian Diamond is retired, having made a distinguished career of studying the effects of enriched environment on cognitive development, the structural differences between the male and female brain, and connections between the brain and the immune system. The study of Einstein's brain was for her, oddly enough, something of a minor side show.

Thomas Harvey practiced medicine until 1989. But in some sense his career was derailed one April morning in 1955, when a glimpse of the eternal verities of the universe made flesh enticed him to his fateful decision. A siren song he could not resist. Whatever Harvey had hoped to discover we will never know. He returned what was left of Einstein's brain to Princeton Hospital in 1998. His autopsy photographs and notes, including a map of how the 240 pieces he made of Einstein's brain fit back together, have been acquired by the National Museum of Health and Medicine in Washington. Perhaps one day a comprehensive study of Einstein's brain will be undertaken, a wish apparently expressed by Einstein himself, although quick to demand that his office, his sailboat, his house at 112 Mercer street not become freakish museum pieces.

Harvey died in 2007.

What made Albert's mind special? I suspect a great intellect is not generated by any one thing but rather a combination of many. Genes. Upbringing. Training. Motivation. Perhaps a little luck. Genius isn't contained in a Brodmann area; you can't point to a cluster of cells and shout Eureka! As Stephen Jay Gould once wrote:

I am, somehow, less interested in the weight and convolutions of Einstein's brain than in the near certainty that people of equal talent have lived and died in cotton fields and sweatshops.

It is not the genius locked away in one brain that is important, but rather the genius locked away in all. We cannot accept that the world is anatomically divided into two camps, that one camp is suited for great intellectual accomplishment and the other is forever outside looking in, that fortune doesn't matter, that hard work doesn't play as much a role as talent. Imagination may be more important than knowledge, but Albert's imagination would have taken him nowhere had he not buckled down and learned calculus.

The last word I give to Albert himself:

It strikes me as unfair, and even in bad taste, to select a few for boundless admiration, attributing super-human powers of mind and character to them. This has been my fate, and the contrast between the popular estimate of my powers and achievements and the reality is simply grotesque.

Old Timey Cortex T-Shirt
by LabKitty

Image Credits: Watercolor of Cleveland tower (Princeton University) by Magneticcarpet and appears under terms of the GNU Free Documentation License (v. 1.2). Image of Cajal in his laboratory is in the public domain. Microscope with stained slide by Alex Degarate and appears under terms of the Creative Commons Atrribution-Share Alike 3.0 Unported license. Nissl stain of rat hippocampus from the National Institutes of Health and is the public domain because it was created by a government employee as part of his or her normal job duties. Drawings of comparative cortical architectonics by Santiago Ramón y Cajal is in the public domain. Cytoarchitectual map showing Brodmann area 39 by Wasabee and released into the pubic domain. Image of Einstein at the blackboard is in the public domain.

Read more about the curious intersection of Thomas Harvey and Einstein's brain in Possessing Genius : The Bizarre Odyssey of Einstein's Brain by Carolyn Abraham and Michael Paterniti's Driving Mr. Albert : A Trip Across America with Einstein's Brain.