October 2019

The Legend of Santiago Ramon Y Cajal

Enduring lessons from early 20th century neuroscience

“What a cruel irony of fate to pair, like Siameses twins united by the shoulders, scientific adversaries of such contrasting character”

- Santiago Ramon y Cajal on Camillo Golgi

Santiago Ramon y Cajal and Camillo Golgi were like two peas in a pod. These Nobel Prize sharing titans of neuroscientific history cast a shadow that stretches well into the 21st century. Without their work, early pictures of the nervous system would’ve looked like Rorschach inkblots. Without them, we wouldn’t have so quickly resolved the neuron doctrine, the idea that the brain is an assembly of discrete cells rather than a singular interconnected network.

Golgi came first, discovering a new method of staining brain tissue for microscopy. Cajal, nine years younger, applied the method, dissecting, sectioning, staining, microscoping, and finally, creating truly beautiful images of nervous tissue structure.

In his writings, Cajal recognized the titan whose shoulders he was standing on, “The Savant of Pavia” he called him. But the relationship wasn’t all roses. After winning a fifty percent share of the Nobel Prize for Physiology or Medicine, Golgi prepared to deliver his lecture on the Neuron Doctrine. Cajal and other neuroanatomists impatiently twirled their mustaches and lubricated their monocles in enthusiastic anticipation. However, as the lecture began, it was clear to Cajal that he and Golgi were not so similar as he once thought. In this lecture, Golgi’s exposed himself to be everything that Cajal considered wrong with how people communicate science.

So, what’s so bad about Camillo Golgi? Can a century-old scientific grudge enlighten us about what’s wrong with the communication of modern-day brain science? And, might Cajal have been making a bigger point about the importance of integrity in the way we talk about research?

Political skepticism feels like a defining feature of modern politics. Whether it’s right-wing talk-radio rants about corruption of the cultural elite, or left-wing pontifications on the abuses of financial influence - constituents from both major parties agree that existing power structures are betraying the people.

Scientists, especially those studying neuroscience, aren’t immune to this wave of skepticism. In the past decade, books with titles like Brainwashed: The Seductive Appeal of Modern Neuroscience have earned national attention by making clear what every neuroscientist was thinking, that brain imaging was not nearly as brain-solving as it was alleged to be. Critical bloggers like Neuroskeptic and Neurocritic have amassed audiences in the hundreds of thousands by speaking their mind to a technical audience that was starved for critical perspectives. Only recently, Twitter accounts like JustSaysInMice, who’ve made their name by complaining about exaggerated scientific headlines, have resonated with a deeply frustrated scientific following.

Ten years ago, the director of the National Institute of Health, Tom Insel, asserted what was becoming a trope in modern psychiatric criticism - that psychiatric labels are merely labels, not thoroughly validated scientific constructs. Even the American Psychiatric Association, creators of the current diagnostic framework, have acknowledged so much. Nonetheless, psychiatric constructs remain embedded in our modern consciousness as objective scientific realities.

Cajal’s rejection of Golgi is reflected in our modern political rejection of the status quo. It’s a story about a scientist standing up for righteousness and honesty within a system that rewards the pretense of a solution. And it’s a narrative whose thread can be picked up today in existing scientific culture, where grandiose narratives and the neglect of important limitations are fueling career advancement. This is an ode to Ramon Y Cajal, a rant about psychiatry, and an assertion that it’s possible to achieve great success, and many scientists continue to do so, without compromising their values.

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Cajal’s Frustration with Psychology

Santiago Ramon Y Cajal grew up in a town of Navarre in the Spanish countryside. His dad was ambitious and transmitted his hopes of glory onto his son. Young Santiago was smart enough, earning good grades in all his favorite STEM disciplines, but of his humanities courses, his philosophical and religious education, he was skeptical from an early age. He believed that promoting mental health was a lofty goal, but was frustrated by how readily his teachers uncritically accepted ancestral wisdom. Which brought him to the brain. To Cajal, knowing the brain was to know the material nature of psychology, a critical first step towards overcoming mental illness. But in Cajal’s professional life, he was quick to acknowledge that the technology just wasn’t there yet. Scientists had yet to develop a method capable of piercing the impenetrable thicket of the gray matter. Psychology was extremely important, and knowing the brain was our key to knowing psychology, but science wasn’t yet prepared to bridge that gap.

This skeptical opinion, however, was not shared by everyone.

Long before Cajal’s time, people like the theatrical Franz Gall had gained notoriety for the theory of phrenology - that skull shape could predict mental faculties. Semi-scientists like Franz Mesmer proposed a physical basis to psychology. For those attuned to psychic energies, who had experience in the science of energy transference, hand-holding and eye gazing were standard treatment paradigms. A direct heir of medieval witchcraft, Cajal declared. More contemporary ideas were developed in which the brain was divided into sections, each being assigned a unique psychological function. Sound familiar? To Cajal, these ideas failed to clarify our understanding of human consciousness - the wall between psychology and biology remained impenetrable.

In the past century, technical neuroscientific advances have offered us the prospect of a newfound biological basis of the mind, and with that, a potential cure for mental illness. Today, we confidently assign psychological functions to brain regions or neurotransmitter deficiencies or network disturbances.

What we have today is not Gall’s phrenology or Mesmer’s animal magnetism. For the most part, neuroscience isn’t pseudoscience. But to Cajal, and many modern neuroscientists, to understand biological psychiatry is to know why we are the way we are, and more importantly, know how to help people in need. If modern neuroscience has begun discovering the truth, why are psychiatric diagnoses still designated based on expert consensus rather than biological fact? Why are one in five adults still struggling with a mental illness?

Part of the answer is that people don’t seek treatment, and modern social networks are frail and fickle things. But another part of the answer is that we maybe haven’t yet penetrated the thicket. As confident as we are in our understanding of neurobiology, our scientific attempts to cure psychiatry by treating the brain have often fallen flat.

On Cajal’s Rejection of Theory and the Skepticism Void

In the early 1900s, now in Valencia, Santiago Ramon Y Cajal revolutionized the way we conceptualized brain-structure. He created spectacular drawings of cellular neuroanatomy - transcribing microscopic observations of silver-stained brain tissue into black ink on brown parchment. Spindly fibrous neurons came in all shapes and sizes, some had thousands of branches, some formed complex and mysterious networks. His drawings were works of enormous scientific achievement that had the aesthetic merit to stand on their own.

Which is why it’s so surprising to learn that when Cajal first published his findings, he was met with silence. If he were giving a lecture today, graduate students would be scrolling through Instagram’s Science & Tech channel, MD’s would be finishing up patient notes, professors would be corresponding with grants officers and journal editors. The scientific community in the early 1900s turned a blind eye to the images that would become burned in every 21st-century neuroscientist's consciousness. Why was Cajal ignored? Does it speak to a larger systematic problem? How did he go from the anonymous neuroanatomy savant to a titan of neuroscientific history?

Cajal’s answer was fairly simple, theories pass while facts remain. Hard-work and patience is all it takes. Put your head down, do the work, and maybe one day you can start to define the narrative. While many of his contemporaries proposed biological models of cognition or grandiose narratives about brain structure, Cajal was at his microscope, collecting facts. When the time was right, but no sooner, Cajal injected himself into theoretical debates. Like many of his contemporaries, he was fully convinced by the Neuron Doctrine, brain cells were discrete things. But until then, he remained neutral, presenting the facts without any elaborate theorizing on the structure of the brain, and more importantly, its relation to the structure of the mind.

Maybe because of this rejection, or his frustration with the prevalence of 19th-century neuro-pseudoscience, Cajal’s antipathy towards theory was intense. In fact, he formalized his curmudgeonry in a document he called “Illnesses of the Will”. It’s a sort of antique listicle, a Seven Ways Scientists Are Ruining Science 👨‍🔬. By modern standards, the piece is unbearably moralizing, second only to anything written by Tolstoy; but to the 19th century, there’s a compelling social critique. He notes that talking about theory, rather than collecting facts, is fundamentally lazy. A strain of this attitude persists today, where critiquing a field of research from the “sidelines” is a faux pas. More importantly to Cajal, however, is that theorists care more about telling a good story than giving it to us straight. When the current state of knowledge is disorganized and uninteresting, according to Cajal, that’s exactly what we should be saying.

From one perspective, talking about theory isn’t a benign activity. It shapes policy decisions, guides funding priorities, and influences the questions scientists are asking. Theory trickles its way into the popular media, shaping lifestyle choices and medical expectations. Today, scientific papers are available to anyone in an instant (summaries are, at least). If a scientist doesn’t properly contextualize their research, university press offices and social media will. Many argue that a scientist today has an obligation not to bury their heads in the gritty facts they’ve discovered.

But the reality about discussion sections in scientific papers is that they are plagued with misrepresentation. Given the substantial power of a beautiful narrative, there’s an opportunity for abuse. For example, scientists may selectively cite studies that agree with their theory, or they may neglect to mention (or neglect to adequately discuss) key experimental limitations. Scientists may have an ethical obligation to honestly contextualize their findings, but the lack of tangible incentives to do so has created an environment where the validity and importance of a study’s findings are often overstated.

The modern scientist is faced with a difficult calculation. They could follow Cajal’s heroic example of emphasizing the careful collection of facts. Thinking long-term, maybe Cajal was right when he said that theories are ephemeral while facts remain. Alternatively, a pragmatist may think that obtaining research funding (and therefore a job) requires compelling narratives, and that the path to tenure is paved with notoriety. Even if one wants to contribute to humanity's scientific understanding, salesmanship is an important part of existing in the modern academic environment.

The consequences of pragmatism are becoming more clear. We’ve created a dichotomy where some scientists are willing to make grand assertions, and some remain, like Cajal, neutral. But without the incentive for a vocal opposition, pride- or career-driven scientists have created a vacuum in which a growing mass of un-expressed skeptical perspectives is festering. Perhaps there’s nothing new about modern times, but it seems the vacuum is reaching a critical mass. Aided by gate-keeperless web platforms, atomic nuclei in the super-massive interior are beginning to fuse, exotic new elements are forming, and strangely skeptical narratives are sputtering into the digital universe.

Cajal Rejects Golgi’s Character and a Reflection on Modern Neuroscience

In 1906, The Nobel Prize in Physiology or Medicine was jointly awarded to Camillo Golgi and Ramon y Cajal "in recognition of their work on the structure of the nervous system." As was their duty, both scientists gave a lecture on their life’s work. As Cajal describes it, to this point, Golgi was an idol. He was The Savant of Pavia, the titan who laid the groundwork for his life-ambitions. At the Nobel ceremony and festivities in Stockholm, Cajal finally was introduced to his eminent colleague.

Contrary to Cajal’s ideas, and the growing neuroscientific consensus, Golgi decided to give his lecture repudiating the idea that neurons, as discrete cellular units, formed the basis of the brain. Despite what his contemporaries would think, Golgi maintained his position that the Neuron Doctrine wasn’t true. Instead, Golgi would discuss, as he had proposed long ago, it may be that the brain is a single interconnected network, a monolithic mass.

What followed, from Cajal’s perspective, was the prideful or lazy pontifications from a scientist who remained dogmatically adherent to a narrative that he himself had first popularized. In his lecture, Golgi selectively cited research that supported his theory, neglected key pieces of contradictory data, and allegedly, went so far as to physically alter anatomical drawings. Later, reflecting on the event, Cajal laments Golgi’s ego-worship, his immunity to new data and ideas, and more so, how lowly Golgi must have thought of his fellow scientists to think that they’d fall for his deceit. In Cajal’s mind, Golgi prioritized a beautiful theory, his beautiful theory, over intellectual balance and humility.

Golgi’s lecture was by no means sensational. It was 29 typed pages of a nuanced consideration for a hypothetically-wrongly-discarded scientific theory. Which makes me wonder whether Cajal applied a double standard, because after all, Golgi was rejecting a theory that Cajal had stood behind. At the same time, history proved Golgi wrong. Neurons are genetically and anatomically discrete units, derived from a singular embryonic cell. Using more sophisticated microscopy and detailed genetic labelling approaches, modern scientists can confirm what most recognized over a century ago. The question that remains is the truth about Golgi’s character. Was he the manipulative, closed-minded, reputation-obsessed scientist that Cajal accused him of, or instead, was he a brilliant scientist-inventor who made a mistake interpreting the data?

For the past century, neuro-technologists have been building on Cajal and Golgi’s early work. Transporting Cajal into the 21st century, he’d stare wide-eyed at modern electron microscopy, a technique incomproby more detailed than his microscopy methods. He’d be awed by our MRI-based, non-invasive brain recording technologies. He wouldn’t be able to deny that neurotechnology has made incredible advancements.

But it’s one thing for science to have advanced beyond where we were, and another to have advanced far enough to begin bridging the gap between psychology and biology. How would he evaluate the grand theoretical narratives that dominate neuroscience’s conception of the human mind? Would he welcome the view that discrete brain regions underlie discrete psychological functions? Or would he be prepared to accept that “connectivity”, as measured in our crude modern way, reveals the biological basis of consciousness?

In my view, Cajal would maintain his skeptical distance from biological psychology. Perhaps he would materialize in the form of Sebastian Seung, a modern day neuroanatomical revolutionary who remains insulated from theoretical or psychological speculation. But again, neurotechnology has come a long way. Maybe we’ve hacked away enough of the thicket that Cajal would be ready to join the search for the neural correlates of mental illness.

As much as Cajal railed on scientists who embody the moral weakness of “theorization”, it’s clear that Cajal doesn’t outright reject the interpretation of results, and his frustration with Golgi illustrates this point. Nowhere in Cajal’s writing on this event does he express his frustration that Golgi speculated beyond his data. Instead, Cajal laments, the data was in, the controversy was resolved; in his Nobel speech, Golgi was either willfully naive, or transparently manipulative.

The set of ethical challenges faced by science is familiar. Purists remain united in their frustration with things like the selective publishing of positive results, the deceptive communication of statistical procedures, and the selective incorporation of facts as it suits a scientist’s reputational agenda.

We can’t forget that Golgi still invented a truly revolutionary staining method, and according to Cajal, it’s facts that remain, while theories are ephemeral. At the same time, there’s enormous opportunity to spin research in an attempt to sway public opinion, including scientific opinions. Insofar as a cultural change has the capacity to make a difference, Cajal may represent a beacon of hope, an affirmation that it is possible to achieve great success, and many scientists continue to do so, without compromising their integrity.

Post-script: The writer of this article is also the founder of the science communications company Golgi Productions. In preparing this piece, there may have been a slight feeling of regret, and a hope that the name of the business would not be taken as an endorsement for Camillo Golgi himself.

Sources

Golgi, Camillo (1906) The Neuron Doctrine - Theory and Facts https://www.nobelprize.org/prizes/medicine/1906/golgi/lecture/
Ramón y Cajal, Santiago, and Juan Cano. Recollections of my life. Vol. 8. MIT press, 1989.