It’s been very gratifying to listen to the conversation that’s been triggered by my essay in this Sunday’s New York Times on scientific self-correction. Here, for example, is an essay on the nature of errors in science by physicist Marcelo Gleiser at National Public Radio. Cognitive scientist Jon Brock muses on how to get null results published.

I also got an email from Eliot Smith, the editor of the Journal of Personality and Social Psychology who accepted the controversial clairvoyance paper I described in my essay. I wrote that three teams of scientists failed to replicate the results and that all three studies were rejected by the journal because they don’t accept simple replication studies.

Mr. Zimmer

Your recent Times column stated the following:

Best regards,
Eliot Smith

I’ve passed on Smith’s message to my editor at the Times, and I’ll also take this opporunity here to apologize for the error.

I’m not sure how meaningful it is in the context of my essay, since my point was that policies against publishing replication studies get in the way of science’s self-correction. But a mistake is a mistake.

In the late 1800s, prominent astronomers declared that Mars was criss-crossed by canals–evidence, they declared, of an advanced civilization. But in the early 1900s, astronomers gazed through more powerful telescopes and discovered that the canals were mirages.

The astronomer Percival Lowell, who had become the leading champion of the canals, scoffed at the new findings He declared that the criticism came “solely from those who without experience find it hard to believe or from lack of suitable conditions find it impossible to see.”

Although the new evidence led many astronomers to abandon Lowell’s position, he never retracted his claim. It wasn’t until five decades after his death in 1916 that space probes finally went into orbit around Mars and sent back close-up pictures of a canal-free Red Planet.

I’ve always been fascinated by the way science casts aside bad ideas. For most of us, it’s easy to assume that science shakes them off quickly, but the truth is that it can take quite a while for the process to play out. Recently I was invited to contribute a piece to the new “Sunday Review” section of the New York Times, which just debuted this week. I wrote an essay on this phenomenon, which has been dubbed  ”de-discovery.” I drew on three recent examples of high-profile research that many other scientists have declared to be wrong–arsenic life, clairvoyance, and a link from chronic fatigue syndrome to a virus called XMRV.

To keep my essay from exploding into a novella, I had to limit myself to just these three examples–but I could have picked many others. You just need to check out a blog like Retraction Watch to see how important this part of the scientific process is today. The first draft of my essay actually started out with a fourth example, which I decided to cut it in the end. It’s a peculiar case of a de-discovery of a de-discovery.

In 1981, the late Harvard paleontologist Stephen Jay Gould published an influential book about racism and science, called The Mismeasure of Man. Gould argued that social influences could lead scientists to misinterpret their data to suit their beliefs about European superiority. One of his key examples was the work of a nineteenth century anthropologist named Samuel George Morton.

Morton collected 1,000 human skulls from around the world and measured the size of their brain cavities with seeds or lead shot. Gould re-analyzed Morton’s data and published his results in 1978 in the journal Science. He declared that Morton fudged his measurements to ensure that Caucasians would end up with the biggest brains.

In 2000, a freshman at the University of Pennsylvania named Jason Lewis started to measure Morton’s skulls for a research project of his own. He was interested in the ways different human populations adapt to different climates—including changes in the shapes of their skulls. It was then that Lewis learned from his advisors about the controversies swirling around the skulls. (He was born a year after The Mismeasure of Man was published.)

As Lewis carried out his own measurements, he gradually realized that Gould had been wrong. He then set out to systematically investigate the matter—taking three years to measure Morton’s skulls, and then another five years to work through Gould’s claims.

Lewis, who just finished earning his Ph.D at Stanford University, wrote up the results with his colleagues and submitted a paper in 2008 to the journal Current Anthropology, which had published a less detailed critique of Gould’s paper in the 1980s. The journal rejected Lewis’s paper, eventually informing him that it was not important enough.

The researchers had better luck with PLOS Biology, which published their paper earlier this month. Lewis and his colleagues presented evidence that Morton did not bias his findings at all. Instead, the researchers conclude, it was Gould who used shoddy statistics. There are many sound scientific reasons to reject racist views of human biology, they argue, but an unfair trashing of Morton’s research isn’t one of them.

“Our analysis of Gould’s claims reveals that most of Gould’s criticisms are poorly supported or falsified,” they write.

When I was researching my essay, I asked Lewis about what he thought of science’s self-correcting process now that he’s finally done with his exploration of Gould and Morton. He has decidedly mixed feelings.

“We can come back thirty years later and get the story straight,” he told me. “But it takes thirty years.”

As I write in my essay in the Times, there are certainly ways to make dediscovery a smoother, faster process. But in an age of instant viral communication, I think we’re going to remain frustrated by inescapable lags.

[Image: Wikipedia. Thanks to folks on Twitter for pointing me to Martian canals as a textbook case of slow dediscovery]

The Economist reports from this year’s AAAS meeting about a fascinating lecture delivered by the historian of science Lawrence Principe about his quest to figure out the real history of alchemy. Principe has done some impressive work to brush away the Whig history of modern chemistry and understand alchemy on its own terms.

Alchemy is saddled with such a bad reputation that many people don’t appreciate  how it played an important role in the birth of modern sciences, such as biochemistry and neurology.

Here’s part of a blog post I wrote in 2006 on this surprising link:

Jan Baptist van Helmont, a sixteenth-century Belgian alchemist, carried out a classic experiment on biological growth. He put a five pound willow sapling in a tube of 200 pounds of earth. For five years he gave the tree nothing but water, and then weighed both tree and earth. The tree had grown to 169 pounds, while the earth had lost a few ounces. “Hence one hundred and sixty-four pounds of wood, bark, and roots have come up from water alone,” he announced. Van Helmont believed that the willow was nothing more than transmuted water, given form by the willow’s inner soul.

I first came to appreciate the importance of alchemy in the rise of biochemistry while working on my book Soul Made Flesh, on the history of neurology. Thomas Willis, the first neurologist, started out as an alchemist, deeply influenced by Van Helmont. He came into contact with Robert Boyle through their shared interest in alchemy. And his first important work was a book that used alchemy to reinterpret physiology. Instead of the four humours, Willis saw body being made up of corpuscles of different sorts, borrowing concepts of Van Helmont and other alchemists. These corpuscles interacted with one another to produce changes, just as ferments made bread rise and grape juice turn to wine.

Willis later did groundbreaking work on the anatomy and function of the brain, which until his time had generally been considered a pretty useless organ. Willis envisioned the brain as an alembic, the distilling container of alchemy, in which some of the corpuscles of the blood were distilled into the animal spirits, which then flowed through the nerves. While some of Willis’s language and concepts are now hopelessly old-fashioned, he set the study of the brain–and thus the soul–on a new foundation.

The intersection of alchemy and biology is just further evidence that science does not advance by simply wiping the slate clean and starting completely from scratch. Some of the most dramatic revolutions were born within systems of thought that today seem hopelessly backwards. I wonder how twenty-ninth cenutry historians will look back at our own revolutions today. Who will be cast aside as the new alchemists?

In honor of the tenth anniversary of the human genome project, here are a couple telling images, courtesy of Mihaela Pertea and Steven L Salzberg.

First: a visual history of the estimates of the number of genes in the human genome.
And second, a warning to anyone who believes in an iron law that the more protein-coding genes in a species, the more sophisticated/complex/cool/human that species is:

I for one welcome our grapey overlords.

[Update: Biochemist Larry Moran takes issue with the very high numbers for early gene number estimates. Steven Salzberg defends the graph. Read it all here!]

While perusing the latest issue of the  Journal of the History of Neurosciences, I was surprised to discover a review of my book Soul Made Flesh. It’s been six years since it came out. I guess the stack by their nightstand is pretty tall!

But I certainly don’t mind the wait when it’s a review like this:

This book is a joy to read. Zimmer has crafted a pleasant style, leveraging his talents that were cultivated during his time as a newspaper journalist. The texture of the pages and the typesetting suggest an old-fashioned printing and binding for the book; it’s pleasant to handle and easy reading. Several chapters are adorned with period illustrations by Christopher Wren. For anyone interested in the birth of contemporary medicine, social philosophy, and religion, this is a wonderland of enticing history. In fact, most people interested in this period of history will find the book is an entertaining read; one that is difficult to put down.

Fortunately, the book is also still in print six years later, so you can get yourself a copy if you’re interested. Since the book looks at the birth of neurology 350 years ago, it’s not out of date!

Winner of the 2010 Strange Quark!

The skull cap is thick and flat. It looks distinctively human, and yet its massive brow ridge, hanging over the eyes like a boney pair of goggles, is impossible to ignore. In 1857, an anatomist named Hermann Schaafhausen stared at the skull cap in his laboratory at the University of Bonn and tried to make sense of it. Quarry workers had found it the year before in a cave in a valley called Neander. A schoolteacher had saved the skull cap, along with a few other bones, from destruction and brought it to Schaafhausen to examine. And now Schaafhausen had to make the call. Was it human? Or was it some human-like ape?

Schaafhausen did not have much help to fall back on. At the time, archaeologists had only found faint hints that humans had coexisted with fossil animals, such as spears buried in caves near the bones of hyenas. Charles Darwin was still two years away from publishing the Origin of Species and providing a theory to make sense of human evolution. Naturalists tended to look at humanity as a collection of races arranged in a rank from savagery to civilization. The most savage races barely ranked above apes, while the naturalists themselves, of course, belonged to the race at the top of the ladder. When anatomists looked at human bodies, they found what they thought was a validation of this hierarchy: differences in the size of skulls, the slopes of brows, the width of noses. Yet all their attempts to neatly sort humanity were bedeviled by the tremendous variation in our species. Within a single so-called race, people varied in color, height, facial features–even in their brow ridges. Schaafhausen knew, for example, about a skull dug up from an ancient grave in Germany that “resembled that of a Negro,” as he later wrote.

To make sense of the “Neanderthal cranium,” as he called it, Schaafhausen tried to fit it into this confusing landscape of human variation. As peculiar as the bone was, he decided it must belong to a human. It was very much unlike the cranium of living Europeans, but Schaafhausen speculated that it belonged to an ancient forerunner. Yet for naturalists of Schaafhausen’s age, such a heavy brow ridge implied not the advanced refinement of European civilization, but wild savagery.

Well, Schaafhausen thought, Europeans were pretty savage back in the day. “Even of the Germans,” Schaafhausen wrote in his report on the Neanderthal cranium, “Caesar remarks that the Roman soldiers were unable to withstand their aspect and the flashing of their eyes, and that a sudden panic seized his army.” Schaafhausen found many other passages in classical history that suggested to him a pracitically monstrous past for Europe. “The Irish were voracious cannibals, and considered it praiseworthy to eat the bodies of their parents,” he wrote. Even in the 1200s, ancient tribes in Scandinavia still lived in the mountains and forests, wearing animal skins, “uttering sounds more like the cries of wild beasts than human speech.”

Surely this heavy-browed Neanderthal would have fit right in.

Some 150 years later, pieces of that original Neanderthal cranium now sit in another laboratory in Leipzig, just 230 miles away from Schaafhausen’s lab. Instead of calipers, it is filled with a different set of measuring tools: ones that can read out sequences of DNA that have been hiding in Neanderthal fossils for 50,000 years or more. And today a team of scientists based at the Max Planck Institute of Evolutionary Anthropology published a rough draft of the entire Neanderthal genome.

It is an historic day, but it reminds us, once again, that the publication of a genome does not automatically answer all the questions scientists have about the organism to whom the genome belongs. In fact, a careful look at the new report is a humbling experience. We gaze at the Neanderthal genome today as Schaafhausen gazed at the Neanderthal skull cap that first introduced us to these ambiguous humans.

Since Schaafhausen’s day, paleoanthropologists have discovered Neanderthals across a huge range stretching from Spain to Israel to Siberia. Their fossils range from about 400,000 years ago to about 28,000 years ago. Instead of a lone skull cap, scientists now have just about every bone from its skeleton. Neanderthals were stocky and strong, with a brain about the size of our own. The isotopes in their bones suggest a diet rich in meat, and their fractured bones suggest a rough time getting that food. There’s no evidence that Neanderthals could paint spectacular images of rhinos and deer on cave walls like humans did. But they still left behind many traces of very sophisticated behavior, from intricate tools to painted jewelry.

Ideas about our own kinship to Neanderthals have swung dramatically over the years. For many decades after their initial discovery, paleoanthropologists only found Neanderthal bones in Europe. Many researchers decided, like Schaafhausen, that Neanderthals were the ancestors of living Europeans. But they were also part of a much larger lineage of humans that spanned the Old World. Their peculiar features, like the heavy brow, were just a local variation. Over the past million years, the linked populations of humans in Africa, Europe, and Asia all evolved together into modern humans.

In the 1980s, a different view emerged. All living humans could trace their ancestry to a small population in Africa perhaps 150,000 years ago. They spread out across all of Africa, and then moved into Europe and Asia about 50,000 years ago. If they encountered other hominins in their way, such as the Neanderthals, they did not interbreed. Eventually, only our own species, the African-originating Homo sapiens, was left.

The evidence scientists marshalled for this “Out of Africa” view of human evolution took the form of both fossils and genes. The stocky, heavy browed Neanderthals did not evolve smoothly into slender, flat-faced Europeans, scientists argued. Instead, modern-looking Europeans just popped up about 40,000 years ago. What’s more, they argued, those modern-looking Europeans resembled older humans from Africa.

At the time, geneticists were learning how to sequence genes and compare different versions of the same genes among individuals. Some of the first genes that scientists sequenced were in the mitochondria, little blobs in our cells that generate energy. Mitochondria also carry DNA, and they have the added attraction of being passed down only from mothers to their children. The mitochondrial DNA of Europeans was much closer to that of Asians than either was to Africans. What’s more, the diversity of mitochondrial DNA among Africans was huge compared to the rest of the world. These sorts of results suggested that living humans shared a common ancestor in Africa. And the amount of mutations in each branch of the human tree suggested that that common ancestor lived about 150,000 years ago, not a million years ago.

Over the past 30 years, scientists have battled over which of these views–multi-regionalism versus Out of Africa–is right. And along the way, they’ve also developed more complex variations that fall in between the two extremes. Some have suggested, for example, that modern humans emerged out of Africa in a series of waves. Some have suggested that modern humans and other hominins interbred, leaving us with a mix of genetic material.

Reconstructing this history is important for many reasons, not the least of which is that scientists can use it to plot out the rise of the human mind. If Neanderthals could make their own jewelry 50,000 years ago, for example, they might well have had brains capable of recognizing themselves as both individuals and as members of a group. Humans are the only living animals with that package of cognitive skills. Perhaps that package had already evolved in the common ancestor of humans and Neanderthals. Or perhaps it evolved independently in both lineages.

In the 1990s, the geneticist Svante Pääbo led a team of scientists in search of a new kind of evidence to test these ideas: ancient DNA. They were able to extract bits of DNA from bones that were found along with Schaafhausen’s skull cap in the Neander valley cave. Despite being 42,000 years old, the fossils still retained some genetic material. But reading that DNA proved to be a collossal challenge. Over thousands of years, DNA breaks into tiny pieces, and some of the individual “letters” (or nucleotides) in the Neanderthal genes become damaged, effectively turning parts of its genome into gibberish. It’s also hard to isolate Neanderthal DNA from the far more abundant DNA of microbes that live in the fossils today. And the scientists themselves can contaminate the samples with their own DNA as well.

Over the years,Pääbo and his colleagues have found ways to overcome a lot of these problems. They’ve also taken advantage of the awesome leaps that genome-sequencing technology has taken since they started the project. They have been able to reconstruct bigger and bigger stretches of DNA. They’ve been able to fish them out of a number of Neanderthal fossils from many parts of the Old World. And today they can offer us a rough picture of all the DNA it takes to be a Neanderthal.

To create a rough draft of the Neanderthal genome, the scientists gathered DNA from the fossils of individual Neanderthals that lived in Croatia about 40,000 years ago. The scientists sequenced fragments of DNA totalling more than 4 billion nucleotides. To figure out what spot on which chromosome each fragment belonged, they lined up the Neanderthal DNA against the genomes of humans and chimpanzees. They are far from having a precise read on all 3 billion nucleotides in the Neanderthal genome. But they were able to zero in on many regions of the rough draft and get a much finer picture of interesting genes.

One of the big questions the scientists wanted to tackle was how those interesting genes evolved over the past six million years, since our ancestors split off from the ancestors of chimpanzees. So they compared the Neanderthal genome to the genome of chimpanzees, as well as to humans from different regions of the world, including Africa, Europe, Asia, and New Guinea.

This comparison is tricky because human DNA, like human skulls, is loaded with variations. The DNA of any two people can differ at millions of spots. Those differences may consist of as little a single nucleotide, or a long stretch of duplicated DNA. Each of us picks up a few dozen new mutations when we’re born, but most of the variations in our genome have been circulating in our species for centuries, millennia, and, in some cases, hundreds of thousands of years. Over the course of history these variants have gotten mixed and matched in different human populations. Some of them vary from continent to continent. It’s possible to tell someone from Nigeria from someone from China based on just a couple hundred genetic markers. But a lot of the same variations that Chinese people have also exist in Nigeria. That’s because Chinese people and Nigerians descend from an ancestral population. The gene variants first arose in that ancestral variation and then were all passed down from generation to generation, even as humans migrated and diverged across the planet. And when Paabo and his colleagues looked at the Neanderthal genome, they discovered that Neanderthals carried some of the same variants in their genome too.

The scientists compared the variants in the Neanderthal genome to those in humans to figure out when the two kinds of humans diverged. They estimate that the two populations became distinct between 270,000 and 440,000 years ago. After the split, our own ancestors continued to evolve. It’s possible that genes that evolved after that split helped to make us uniquely human. To identify some of those genes,Pääbo and his colleagues looked for genes that were identical in Neaderthals and chimpanzees, but had undergone a significant change in humans.

They didn’t find many. In one search, they looked for protein-coding genes. Genes give cells instructions for how to assemble amino acids into proteins. Some mutations don’t change the final recipe for a protein, while some do. Pääbo and his colleagues found that just 78 human genes have evolved to make a new kind of protein, differing from the ancestral form by one or more amino acids. (We have, bear in mind, 20,000 protein-coding genes.) Only five genes have more than one altered amino acid.

The scientists also found some potentially important changes in stretches of human DNA that doesn’t encode genes. Some of these non-coding stretches act as switches for neighboring genes. Others encode tiny pieces of single-stranded versions of DNA, called microRNAs. MicroRNAs can act as volume knobs for other genes, boosting or squelching the proteins they make.

Another way to look for uniquely human DNA is to search for stretches of genetic material that still retain the fingerprint of natural selection. In the case of many genes, several variants of the same gene have coexisted for hundreds of thousands of years. Some variants found in living humans also turn up in the Neanderthal genome. But there are some cases in which natural selection has strongly favored humans with one variant of a gene over others. The selection has been so strong sometimes that all the other variants have vanished. Today, living humans all share one successful variant, while the Neanderthal genome contains one that no longer exists in our species. The scientists discovered 212 regions of the human genome that have experienced this so-called “selective sweep.”

You can see the full list of all these promising pieces of DNA in the paper Pääbo and his colleagues published today. If you’re looking for a revelation of what it means to be human, be prepared to be disappointed by a dreary catalog of sterile names like RPTN and GREB1 and OR1K1. You may find yourself with a case of Yet Another Genome Syndrome. In all fairness, the scientists do take a crack at finding meaning in their catalog. They note that a number of evolved genes are active in skin cells. But does that mean that we evolved a new kind of skin color? A new way of sweating? A better ability to heal wounds? At this point, nobody really knows.

If you believe the difference between humans and Neanderthals is primarily in the way we think, then you may be intrigued by the strongly selected genes that have been linked to the brain. These genes got their links to the brain thanks to the mental disorders that they can help produce when they mutate. For exampe, one gene, called AUTS2, gets its name from its link to autism. Another strongly-selected human gene, NRG3, has been linked to schizophrenia. Unfortunately, these disease associations just tell scientists what happens when these genes go awry, not what they do in normal brains.

The most satisfying hypothesis the scientists offer is also the one with the deepest historical resonance. It has to do with the brow ridge that so puzzled Schaafhausen back in 1857. One of the strongly selected genes in humans, known as RUNX2, has been linked to a condition known as cleiodocranial dysplasia. People who suffer from this condition have a bell-shaped rib cage, deformed shoulder bones, and a thick brow ridge. All three traits distinguish Neanderthals from humans.

Pääbo and his colleagues then turned to the debate over what happened when humans emerged from Africa. Scientists have debated for years what happened when our ancestors encountered Neanderthals and other extinct hominin populations. Some have argued that they kept their distance and never interbred. Others have scoffed that any human could show such self-restraint. After all, humans have been known to have sex with all sorts of mammals when given the opportunity, so why should they have been so scrupulous about a very human-like mammal?

The evidence that scientists have gathered up till now has been very confusing. If you just look at mitochondria, for example, all the Neanderthal form tiny twigs on a branch that’s distant from the human branch. If Neanderthals and humans had interbred often enough, then some people today might be carrying mitochondrial DNA that was more like that of Neanderthals than like other humans.

On the other hand, some scientists looking at other genes have found what they claim to be evidence of interbreeding. They would find gene variants in living humans that had evolved from an ancestral gene about a million years ago. One way to explain this pattern was to propose that modern humans interbred with Neanderthals or other hominins. Some of their DNA then entered our gene pool and has survived till today. In one case, a team of scientists proposed that a gene variant called Microcephalin D hopped into our species from Neanderthals and then spread very quickly, driven perhaps by natural selection. Making this hypothesis even more intriguing was the fact that the gene is involved in building the brain.

Pääbo and his colleagues looked for pieces of the Neanderthal genome scattered in the genomes of living humans. The scientists found that on average, the Neanderthal genome is a little more similar to the genomes of people in Europe, China, and New Guinea, than it is to the genomes of people from Africa. After carefully comparing the most similar segments of the genomes, the scientists propose that Neanderthals interbred with the first immigrants out of Africa–perhaps in the Middle East, where the bones of both early humans and Neanderthals have been found.

Today, the people of Europe and Asia have genomes that are 1 to 4 percent Neanderthal.That interbreeding doesn’t seem to have meant much to us, in any biological sense. None of the segments our species picked up from Neanderthals was favored by natural selection. (Microcephalin D turns out to have been nothing special.)

While working on this post, I contacted two experts who have been critical of some earlier studies on hominin interbreeding, Laurence Excoffier of the University of Bern and Nick Barton of the University of Edinburgh. Both scientist gave the Neanderthal genome paper high marks and agree in particular that the interbreeding hypothesis is a good one. But they do think some alternative hypotheses have to be tested. For example, interbreeding is not the only way that some living humans might have ended up with Neanderthal-like pieces of DNA. Cast your mind back 500,000 years, before the populations of humans and Neanderthals had diverged. Imagine that those ancestral Africans were not trading genes freely. Instead imagine that some kind of barrier emerged to keep some gene variants in one part of Africa and other variants in another part.

Now imagine that the ancestors of Neanderthals leave Africa, and then much later the ancestors of Europeans and Asians leave Africa. It’s possible that both sets of immigrants came from the same part of Africa. They might have both taken some gene variants with them did not exist in other parts of Africa. Today, some living Africans still lack those variants. This scenario could lead to Europeans and Asians with Neanderthal-like pieces of DNA without a single hybrid baby ever being born.

If humans and Neanderthals did indeed interbreed, Excoffier thinks there’s huge puzzle to be solved. The new paper suggests that genes flowed from Neanderthals to humans only at some point between 50,000 and 80,000 years ago–before Europeans and Asians diverged. Yet we know that humans and Neanderthals coexisted for another 20,000 years in Europe, and probably about as long in Asia. If humans and Neanderthals interbred during that later period, Excoffier argues, the evidence should be sitting in the genomes of Europeans or Asians. The fact that the evidence is not there means that somehow humans really did find the self-restraint not to mate with Neanderthals.

Because interbreeding involves sex, it dominates the headlines about Pääbo’s research. But I’m left wondering about the Neanderthals themselves. We now have a rough draft of the operating instructions for a kind of human that has been gone from the planet for 28,000 years, which had its own kind of culture, its own way of making its way through the world. Yet I found very little in the paper about what the Neanderthal genome tells us about their owners. It’s wonderful to use the Neanderthal genome as a tool for subtracting away our ancestral DNA and figure out what makes us uniquely human. But it would also be great to know what made Neanderthals uniquely Neanderthal.

[Image from Project Gutenberg]

In tomorrow’s New York Times I have an essay about the art of seeing Nature’s unseen–from the bestiaries of the Middle Ages to today’s images of feathered dinosaurs and upright apes. Check it out, and also check out the accompanying slide show about Conrad Gessner, a Renaissance naturalist who assembled the greatest zoological encyclopedia of his day–which included unicorns.

As a science writer, I often find it sobering to read scientific history. Science works slowly, even though we wish it would work in nanosecond breakthroughs.

In 1913, for example, a Russian scientist named Nikolai Anichkov ran an experiment in which he had egg yolks fed to rabbits. On this cholesterol-heavy diet the rabbits developed atherosclerosis. The more cholesterol the rabbits ate, the bigger the deposits on their blood vessels became. It was a tremendous discovery, considered by some one of the greatest in medical history.

But it did not lead overnight to a treatment for heart disease. In fact, it did not even lead, on its own, to a clear understanding of how cholesterol ends up in the blood vessels. Instead, it focused the attention of later scientists on the question of cholesterol. It took many years for scientists to figure out the steps by which enzymes produce cholesterol molecules. Then scientists began searching for drugs that might interfere with those enzymes.

In 1971, six decades after Anichkov ran his egg-yolk experiments, Akira Endo of Tokyo Noko University and his colleagues, decided to see if microbes made natural cholesterol-fighting compounds (free pdf). They reasoned that such a compound would be a potent weapon against microbial competitors, since cholesterol and related molecules are essential for building cells. In 1973 they found a fungus that blocks a key enzyme in the cholesterol pathway. It took more than another decade before drugs based on Endo’s explorations, known as statins, reached the market. Today drugs like Lipitor are prescribed to millions of people.

If a journalist wrote an article on Anchikov’s intial research, the most accurate headline would have been something like: “RUSSIAN SCIENTIST DISCOVERS LINK BETWEEN MOLECULE AND HEART DISEASE. WILL LEAD TO POWERFUL NEW MEDICINE IN EIGHTY YEARS.”

Of course, it would be a rare journalist who would be able to see eighty years in the future like that. And headlines about events readers won’t be alive to see can seem awfully remote. Anchikov’s discovery did not change the lives of the people who could have read about it at the time. Their grandchildren, yes.

I’ve been thinking about Anchikov recently, after having read a letter to the New England Journal of Medicine. It’s by Joel Hirschhorn of Harvard, on the subject of genomes.

A decade ago a complete sequence of the human genome was still a dream, although a dream close to becoming real. In a typical article from 1999, a reporter wrote that “scientists hope to treat diseases in much the same way that software engineers fix faulty computer programs, by isolating flaws in the code.” Once we could read the entire human genome, the article promised, nothing would be the same: “By identifying the genetic roots of illnesses like cancer and heart disease, some experts say, the science of the genome, or genomics, may make it possible for a child born today to live to 150–or, some say, much longer.”

What a difference a decade makes. Scientists have been finding many genetic markers for common diseases like heart disease and diabetes, but they’re not pointing the way to obvious treatments. The falling cost of DNA is letting scientists sequence genomes left and right–not just people’s genomes, but the genomes of their cancer cells and their microbes. And for now, scientists are drowning in data rather than plucking out new cures.

Hirschhorn wants the growing number of skeptics to keep history in mind. In his NEJM letter he writes,

New biologic insights do not guarantee a rapid translation into clinical practice; the latter will require great effort by basic, translational, and clinical researchers. The difficulty in translation is not unique to genetic discoveries: nearly a century and three Nobel Prizes separate the determination of the chemical composition of cholesterol from the development of statins. Each discovery of a biologically relevant locus is a potential first step in a translational journey, and some journeys will be shorter than others. With a more complete collection of relevant genes and pathways, we can hope to shorten the interval between biologic knowledge and improved patient care. 

In the next issue of Newsweek, I consider the near-term and the long-term future of genomes. My essay is called “The Gene Puzzle.” Check it out.

[Animation: Wikipedia]

My mother, on whom I depend for all my New Jersey history, passed on a delightful tale of George Washington, Tom Paine, and their passion for chemistry experiments. In early November 1783, Tom Paine paid a visit to George Washington in Rockingham, New Jersey, where Washington was waiting for news of the end of the revolutionary war.  One night Paine and Washington got to talking with two colonels about the will-o-the-wisp, the fiery globe that people sometimes claimed to see floating over marshes.

They came up with two plausible hypotheses. The colonels thought that they were produced from some kind of matter in the marches, such as turpentine. Washington and Paine thought it was a gas.

So the next night, they got in a scow with some soliders and set out on the Millstone River to conduct an experiment. The soliders poked poles into the mud, and Washington and Paine held torches close. They saw bubbles rise, and then a flash of light broke out across the water. Washington and Paine were right. The gas would turn out to be methane, produced by the microbes in the mud.

There will be a reenactment of that presidential hands-on science in celebration of its 225th anniversary on November 5 at dusk on the Millstone River, Rocky Hill, NJ at the junction of Routes 518 and 603. You can watch from the north side of the Rt. 518 Bridge as it crosses the Millstone River.

Before 1833 there were no scientists.

It was in that year that William Whewell, a British philosopher, geologist, and all-around bright bulb, coined the word scientist. His mentor, the poet Samuel Coleridge, thought the English language needed a term for someone who studied the natural world but who did not inhabit the lofty heights of philosophy (like Coleridge).

There are plenty of people who lived before 1833 that most of us would call scientists–Isaac Newton, Antoine Lavoisier, Edmund Halley, Carol Linnaeus to name just a few. But the word would have been meaningless to them. The closest term they might use was “natural philosopher.” Their work and ideas were still deeply rooted in medieval ways of thinking about the world, and about the work they did.

Science did not emerge suddenly in a sudden onslaught of Modern Reason crushing Old Ignorance. Its rise was much slower and much more interesting. One of the most important parts of science as we know it is a way for people to share their observations and experiments. Today peer-reviewed journals are at the core of the scientific process. But until the seventeenth century, nothing like them existed. Natural philosophers generally were more interested in what the ancient Greeks and Romans had to say about medicine, physics, and biology, than what they might observe for themselves. In 1665, a group of natural philosophers in England got together and decided to publish what is arguably the first scientific journal: the Philosophical Transactions of the Royal Society of London.

It’s still going strong today, putting out a lot of important papers. And for the next couple months, the Royal Society is making the entire archive–all the way back to 1665–available for free.

In a press release, the Royal Society pointed to some particularly neat papers, such as Ben Franklin’s 1752 description of flying a kite in a thunderstorm. But I immediately looked up a much older paper about lightning from 1666, entitled “A relation of an accident by thunder and lightning, at Oxford.”

I first came across this paper a couple years ago while working on my book Soul Made Flesh. In the book, I describe how scientists natural philosophers discovered how the brain works in the 1600s. I focus mainly on Thomas Willis, widely considered the first neurologist. Willis did astonishing work, recognizing some of the fundamental features of the brain–that the flesh of the brain itself was the seat of thought, for example, rather than the spaces around it, known as ventricles. Willis published the first accurate pictures of the brain, in the first book about the brain. He argued that melancholy, epilepsy, and nightmares were all chemical disturbances in the brain. He even coined the word neurology.

For all that, however, Willis was still floundering in the dark. He had no idea of how the brain communicated with the rest of the body. He laid out an elaborate theory about how particles (“spirits”) moved around in the brain and then traveled down the nerves. But he had no actual evidence for this idea. And he knew nothing about electricity.

The communication recounts how Willis and his colleagues dissected a man killed by lightning. The bolt had thrown its victim, an Oxford scholar, out of the boat he had been rowing. When the scholar’s body was brought back to town, Thomas Willis came to see it along with his assistant Richard Lower and the mathematician John Wallis, who later wrote the . They picked up the man’s hat and put their fists through the hole the lightning had torn. His doublet had been ripped open and his buttons knocked off. Willis and his friends found spots and streaks across the torso where the skin seemed to be seared and hard, “like Leather burnt with the fire,” Wallis later wrote to the Royal Society.

The following night Willis and company returned, along with a crowd of onlookers, to cut the man open. “The whole Body was, by night, very much swell’d,” Wallis wrote. The stench that rose from the body was unbearable, but they soldiered on because such an opportunity might not come again in their lives. “There appear’d no sign of contusion,” Wallis wrote, “the brain full and in good order; the nerves whole and sound, the vessels of the brain pretty full of blood.” They opened the man’s chest and found that the burns did not reach below the skin. “The Lungs and Heart appear’d all well, and well-colour’d without any disorder,” Wallis wrote. The heavens had struck the man dead, and yet the natural philosophers could find nothing changed inside the body.

It would take Benjamin Franklin and other eighteenth century scientists to begin working out the nature of electricity, and to recognize its role in the nervous system. But I still like to picture Willis puzzling over a cadaver, not realizing that the man had been killed by the same thing that made thought possible.

Here are some other landmark papers you can find in the archives…get them while you can.

The Complementary Structure of Deoxyribonucleic Acid
F.H.C Crick and J.D Watson – 1954

On the Hoyle-Narlikar Theory of Gravitation
S. W. Hawking – 1965

An Account of an Experiment Made by Mr. Hook, of Preserving Animals Alive by Blowing through Their Lungs with Bellows
Robert Hooke – 1667

An Account of a Very Odd Monstrous Calf
Robert Boyle – 1665

Observables upon a Monstrous Head
Robert Boyle – 1666

Account of a very remarkable young musician (Mozart)
Daines Barrington – 1770

Alexander Fleming (Paper describing early stages of penicillin discoveries) – 1922

Arthur Eddington’s solar eclipse observations, confirming Einstein’s general theory of relativity (Phil Trans 1919)

John Noble Wilford has a long, interesting article in today’s New York Times on the rehabilitation of the alchemist. Once the icon of the bad old days before the scientific revolution, alchemy has been emerging in recent years as more of a proto-science. Indeed, a fair number of the heroes of the scientific revolution were dyed-in-the-wool alchemists. Robert Boyle, one of the founders of chemistry, wanted to reform alchemy, not destroy it. He chased after the philsopher’s stone for his whole life. Many of his papers were destroyed in the eighteenth century because they were loaded with discussions of alchemy–which by then had acquired its bad reputation. Boyle’s legacy had to be protected.

Wilford reported from a recent meeting of historians of chemistry in Philadelphia. From his report (as well as this one from the New York Sun and this one from Chemical and Engineering News), it seems as if the meeting neglected one of the most interesting sides of alchemy: its role in the history of bio-chemistry. Alchemists believed that the life was the greatest transmutation of all, and they believed that the philsopher’s stone would serve as the ultimate medicine. While a lot of alchemists dealt in Kevin-Trudeau-style hogwash, some did important work.

Jan Baptist van Helmont, a sixteenth-century Belgian alchemist, carried out a classic experiment on biological growth. He put a five pound willow sapling in a tube of 200 pounds of earth. For five years he gave the tree nothing but water, and then weighed both tree and earth. The tree had grown to 169 pounds, while the earth had lost a few ounces. “Hence one hundred and sixty-four pounds of wood, bark, and roots have come up from water alone,” he announced. Van Helmont believed that the willow was nothing more than transmuted water, given form by the willow’s inner soul.

I first came to appreciate the importance of alchemy in the rise of biochemistry while working on my book Soul Made Flesh, on the history of neurology. Thomas Willis, the first neurologist, started out as an alchemist, deeply influenced by Van Helmont. He came into contact with Robert Boyle through their shared interest in alchemy. And his first important work was a book that used alchemy to reinterpret physiology. Instead of the four humours, Willis saw body being made up of corpuscles of different sorts, borrowing concepts of Van Helmont and other alchemists. These corpuscles interacted with one another to produce changes, just as ferments made bread rise and grape juice turn to wine.

Willis later did groundbreaking work on the anatomy and function of the brain, which until his time had generally been considered a pretty useless organ. Willis envisioned the brain as an alembic, the distilling container of alchemy, in which some of the corpuscles of the blood were distilled into the animal spirits, which then flowed through the nerves. While some of Willis’s language and concepts are now hopelessly old-fashioned, he set the study of the brain–and thus the soul–on a new foundation.

The intersection of alchemy and biology is just further evidence that science does not advance by simply wiping the slate clean and starting completely from scratch. Some of the most dramatic revolutions were born within systems of thought that today seem hopelessly backwards. I wonder how twenty-ninth cenutry historians will look back at our own revolutions today. Who will be cast aside as the new alchemists?

It’s always great to hear senior scientists talk about the bad old days, when one computer could fill an entire room and no one could say what genes were made of. Eric Kandel of Columbia has been studying memory since the 1950s, and won the Nobel Prize in 2000 for his work. These days he’s observing genes switching on and off at the junctions between neurons. But when he started out, he had to content himself with sticking electrodes into crayfish (chosen for their fat neurons). To observe their neurons, scientists would hook up the electrodes to amplifiers and loudspeakers, and the crackle of nerves would fill the room. With hindsight, we can cluck at the primitiveness of it all. But for Kandel, it was a new world. He had wanted to find Freud’s ego and the rest in the brain, and quickly discovered that it was a futile task. But being able to hear a crayfish’s neurons was, to him, the ultimate psychoanalysis.

For more on Kandel, you can read my new profile. The article is in the New York Academy of Science’s webzine (as well as the hard-copy version). They’ve also got a link to a recent lecture Kandel gave at NYAS that was the spur for the article.