How is a gene like a drug? The more there is of it, the bigger the effect. You have to be careful how you spoon it out. Of course, gene “doses” don’t come in teaspoons, they come in chromosomal copy numbers.

You typically have two copies of each gene – one on the chromosome dad gave you, and one on the chromosome you got from mom – although, it must be said, the “flavors” of these copies many not be identical (e.g., specifying blue versus brown eye color).

And sometimes – in fact, often – one copy of a gene is “turned off” altogether, its activation more or less blocked by biochemical stop-signs. That’s about the same as having only one copy, until and unless the light turns green at some point. A particularly pronounced case of single-dose-itis (my word) occurs on the sex chromosomes, designated either X (for female) or Y (for male) because if you view them under a microscope, that’s sort of what they look like. Unlike the other 22 pairs of paternally and maternally derived chromosomes contained in each human cell, X and Y chromosomes actually look noticeably different from one another even at the gross-inspection stage. “Viewed” closer up with the tools of molecular biology, the two versions of the sex chromosome turn out to have large numbers of lengthy stretches that really are different and indeed may be entirely absent on the Y chromosome. Those differences make every cell in a woman’s body different from every cell in a man’s, as UC-Berkeley biologist Art Arnold, PhD, once pointed out at a particularly lively Stanford symposium on gender differences last year.

Still, X and Y chromosomes share plenty of common regions. So a deviation from the usual double chromosome count, even when the extra or missing chromosome is an X or a Y, can make a big difference in the dosages for plenty of genes. One genetic defect called Klinefelter syndrome, characterized by the presence of a Y and two X chromosomes in each cell, leads to an excessive dose of many genes (three copies instead of two, to be specific). Another genetic defect, Turner syndrome, results in each cell containing only a solitary X chromosome – and only a single copy of numerous genes. Both Turner and Klinefelter syndromes are marked by characteristic cognitive deficits.

Allan Reiss, MD, PhD, director of Stanford’s Center for Interdisciplinary Brain Sciences Research, and his colleagues compared the brains of people with Klinefelter and Turner syndromes with those of individuals with normal sex-chromosome counts. They showed in this imaging study in the Journal of Neuroscience, that anatomical aberrations in particular brain regions among people with extra or absent copies of the sex chromosome closely track the neurological deviations associated with these syndromes – and, importantly, that these aberrations may be caused by the gene-dosage differences resulting from variant sex-chromosome counts.

Previously: Tomayto, tomahto: Separate genes exert control over differential male and female behaviors, Humor as a mate-selection strategy for women? and Brain imaging, and the image-management cells that make it possible
Photo by Naberacka

The RNA whisperer is at it again.

In a study just published in Nature, Stanford’s Howard Chang, MD, PhD – an expert in all things RNA – and his colleagues detail how they were able to translate from one language spoken by this versatile biomolecule to another, more obscure but important one.

RNA is best known as the intermediate material in classic protein production. A so-called “messenger RNA” molecule serves as a mobile, short-lived copy of its more durable lookalike, DNA, the stuff genes are made of. Gene-reading machines in a cell’s nucleus produce RNA copies of protein-coding genes. Unlike a gene, which is a sequence of chemical letters situated somewhere on a big, bulky chromosome, a messenger RNA molecule can float out of the nucleus to the cell’s watery cytoplasm where proteins get made, and transmit a gene’s instructions to the protein-making machinery.

But RNA does more than simply specify which proteins are going to get made. A messenger RNA molecule’s 3-dimensional shape, for example, conveys bountiful information telling the cell’s protein-producing proletariat where to bring it, what to do with it when it gets there, and when and and how much protein to make from it.

DNA is famously double-stranded. That’s because, of its four component chemical “letters,” two in particular share a strong mutual attraction, biophysically speaking. Happily, the other two letters have a chemical crush on one another as well. So, when the letters composing one DNA strand are complementary to those on a closely opposed strand (and they virtually always are), the two strands lock in a lasting embrace to form a stable double helix.

RNA molecules are strings of four different chemical letters almost identical to those constituting DNA. But unlike DNA, an RNA molecule typically travels solo, as a single-stranded chain of those four chemical letters. It is thus a rather playful, floppy molecule. Nonetheless, the same alphabetical affinities that produce DNA’s double helix are at work in an RNA molecule, albeit in a more fleeting form: Small sequences of chemical letters along an RNA molecule find themselves attracted to complementary sequences elsewhere on the same molecule, causing it to fold into so-called secondary structures featuring pinched double-stranded sections alternating with bulges and loops, hairpins and hinges.

Chang’s gang has figured out how to predict, based on an RNA molecule’s linear chemical sequence, the way it will fold up into its secondary structure. They were able to do this for  thousands of differently shaped RNA molecules found in one type of human cell – about a thousandfold increase over the number of such structures that had been laboriously determined to date, Chang told me. That has consequences for understanding disease mechanisms and, potentially, for drug discovery as well.

Looks like RNA research is shaping up.

Previously: Night of the living dead gene: Pseudogene wakes up, puts chill on inflammation, New job description for RNA, oldest professional biomolecule and iPhone app shows 2D structures of thousands of RNA molecules
Photo by OliBac

Pulmonary hypertension, a dangerous increase in the pressure of blood vessels in the lung, is one nasty disease, as I wrote in a Stanford Medicine article a few years ago. As many as three times as many women – many of them quite young – as men are diagnosed with the spontaneous form of PH (which can also arise from scleroderma or bad pharmaceuticals). While an increasing number of pharmaceutical treatments and advocacy groups have made the diagnosis more palatable, there is still no outright cure. Largely, this is because the molecular mechanisms of pulmonary hypertension have remained mysterious.

But recent work has strongly implicated inflammation in pushing predisposed tissues over the edge into the diseased state. And this week, a Journal of Experimental Medicine study led by PH specialist Marlene Rabinovitch, MD, and her colleagues at Stanford’s PH-focused Vera Moulton Wall Center plunks a potentially pivotal piece of the puzzle into place. Rabinovitch and her associates showed that levels of a pro-inflammatory growth factor usually designated by the acronym GM-CSF (if you really must know, it’s “granulocyte-macrophage colony stimulating factor”) rise substantially when a cell-surface receptor with a heavyweight acronym of its own, BMPR2 (for “bone morphogenic protein receptor”) isn’t functioning properly. That can be due to mutations in the gene that codes for the receptor (as occurs in familial versions of PH), to various environmental causes, or the interaction of the two.

Elevated GM-CSF levels in pulmonary tissue work like a siren to call various hot-tempered inflammatory cells to the vasculature of the lung, resulting in thickened vessel walls and commensurately narrowed blood vessels. Conversely, by finding ways to compensate for BMPR2 under-performance, perhaps researchers will be able to develop therapeutics that keep GM-CSF levels within safe limits, modifying the course of incipient PH or even arresting it.

Several million actual and potential sufferers await that Big If with bated breath.

Previously: Researchers reverse pulmonary hypertension in rats by blocking inflammation-producing pathway, New arterial insights portend potential treatments for life-threatening diseases, and Man receives life-saving transplant thanks to health-care reform and a truck
Photo by ePublicist

Men have deeper voices and tons more facial and body hair than women. They are (usually) bigger, stronger, and much more likely to risk their lives on a whim. I, for example, have been known to bite a full-sized salami in half with a single snap of my jaws when hungry, angry or threatened. Or just for the hell of it.

But when it comes to immune response, men are wimps. It’s well documented that, for reasons that aren’t clear, men are more susceptible to bacterial, viral, fungal and parasitic infection than women are and that men’s immune systems don’t respond as strongly as women’s to vaccinations against influenza, yellow fever, measles, hepatitis and many other infectious diseases.

A new study just published in the Proceedings of the National Academy of Sciences by immunologist Mark Davis, PhD, who directs Stanford’s Institute for Immunity, Transplantation and Infection, and his colleagues may explain why. The same steroid hormone that makes a man’s beard, bones and muscles grow operates – albeit it in a slightly indirect way – to shrink immune responsiveness. Yep, we’re talking about (sigh…) that much-maligned male molecule, testosterone. In a nutshell, high circulating testosterone levels boost the activity of a clutch of genes that, among other things, dial down the aggressiveness with which our immune systems fight back against invading pathogens.

Now why, we ask ourselves, would evolution be so perverse as to have designed a hormone that on the one hand enhances classic male secondary sexual characteristics such as muscle strength, beard growth (or antler size, as the case may be) and risk-taking propensity – the very hallmarks of the alpha male – but on the other hand wussifies men’s immune systems?

Here’s what I got from talking at length (and, I admit, in an uncharacteristically high-pitched voice) to Davis in preparation for the news release I wrote about the study:

The evolutionary selection pressure for male characteristics ranging from peacocks’ plumage to deer’s antlers to fighter pilots’ heroism is pretty obvious: Females, especially at mating-cycle peaks, prefer males with prodigious testosterone-driven traits. Davis speculates that high testosterone may provide another, less obvious evolutionary advantage… Men are prone to suffer wounds from their competitive encounters, not to mention from their traditional roles in hunting, defending kin and hauling things around, increasing their infection risk. While it’s good to have a decent immune response to pathogens, an overreaction to them — as occurs in highly virulent influenza strains, SARS, dengue and many other diseases — can be more damaging than the pathogen itself. Women, with their robust immune responses, are twice as susceptible as men to death from the systemic inflammatory overdrive called sepsis. So perhaps, Davis suggests, having a somewhat weakened (but not too weak) immune system can prove more lifesaving than life-threatening for a dominant male in the prime of life.

Previously: Best thing since sliced bread? A (potential) new diagnostic for celiac disease, Deja Vu: Adults’ immune systems “remember” microscopic monsters they’ve seen before, Immunology escapes from the mouse trap and Immunology meets infotech
Photo by Craig Sunter *Click-64*

I hail from the so-called Ashkenazi branch of Jews, who account for the great majority of all Jews in the world today. Ashkenazis are distinguished by the historical fact that, over the last couple of thousand years or so, they propagated throughout Europe, generating and maintaining tens of thousands of distinctly Jewish communities in diverse countries spanning the entire continent. My dad was born in Lithuania; my mom’s mom came from an Eastern European region that has belonged to any one of about a half-dozen countries, depending on what particular year you happen to be talking about; and my mom’s dad grew up in Russia, near the Black Sea.

Tradition holds, though, that Ashkenazi Jews ultimately trace their origins straight back to ancient Israel, whence most Jews were expelled en masse in 70 CE by their Roman conquerors and sent skittering to all parts of the globe. (Jews who initially fled to Spain and Portugal are referred to as Sephardic. Those who took up residence in Iran, Turkey, Iraq and Northern Africa, are designated as Mizrahi.)

But in the late 1970s I read what was then a recent book titled The Thirteenth Tribe, written by polymath Arthur Koestler, advancing a theory that today’s Ashkenazis descend not from the Holy Land but, rather, from Khazaria, a medieval Turkic empire in the Causasus region whose royals, caught between the rock of Islam and the hard place of Christendom, chose the politically expedient course of converting to Judaism. That hypothesis has become highly politicized, with some groups holding that Ashkenazis, who constitute half of Israel’s current population, are colonialist interlopers with zero historical claim to the land of Israel.

Plausible at the time, the Khazar-origin premise has crumbled under the onslaught of modern molecular genetics. The latest volley: a study published this week in Nature Communications. The study’s senior author, Stanford geneticist Peter Underhill, PhD, works in the lab of  Carlos Bustamante, PhD, whose high-resolution techniques have highlighted the historical hopscotch of other migratory peoples.

Underhill, Bustamante and their co-authors analyzed the Y chromosome – a piece of the human genome invariably handed down father-to-son – of a set of Ashkenazi men claiming descent from Levi,  the founder of one of the Twelve Tribes of Israel. (Names such as Levy, Levine and Levitt, for example, bespeak a Levite heritage.)

If Ashkenazis were the spawn of Khazar royals, their DNA would show it. But those Y chromosomes were as Levantine as a levant sandwich. The same genetic “signature” popped up on every Levite sampled (as well as a significant number of non-Levite Ashkenazis), strongly implying descent from a single common ancestor who lived in the Fertile Crescent between 1,500 and 2,500 years ago. That signature is absent in the Y chromosomes of modern European non-Jewish men, and in male inhabitants of what was once Khazaria.

Yes, 2,000 years is a long time, and a fellow gets lonely. Genetic studies of mitochrondria – tiny intracellular power packs that have their own dollop of DNA and are always inherited matrilineally – have conflicted (contrast this with this) but, in combination with broader studies of entire genomes, suggest that a bit of canoodling transpired between Ashkenazi men and local European women, in particular Italian women, early in that two-millenia European sojourn.

I can relate. My wife is 100 percent Italian by heritage, and my daughter by my first marriage is half-Italian.

Previously: Caribbean genetic diversity explored by Stanford/University of Miami researchers, Stanford study investigates our most-recent common ancestors and Stanford study identifies molecular mechanism that triggers Parkinson’s
Photo by cod_gabriel

A posse led by Stanford microbe sleuth and microbiologist David Relman, MD, has apprehended Staphylococcus aureus, one of the most notorious sources of serious infections, lurking in formerly unsuspected nasal hideaways. The discovery may explain why attempts to expunge S. aureus from the bodies of hospitalized patients being readied for surgery often meet with less than perfect results.

About one in three of us are persistent S. aureus carriers, and another third of us are occasional carriers. This bacterial shadow, which abounds on skin (especially the groin and armpits) and is quite at home in the nose, does us no harm most of the time. But if it gets into the bloodstream or internal organs, it can cause life-threatening problems such as sepsis, pneumonia and endocarditis (infection of heart valves). That makes S. aureus not such a good thing to be coated with if you’re about to have your skin punctured by a catheter or pierced by a scalpel.

This is exacerbated by the all-too-frequent presence, particularly in hospital settings, of S. aureus strains resistant to an entire family of antibiotics related to methicillin. In 2011, more than 80,000 severe methicillin-resistant S. aureus infections and more than 11,000 related deaths occurred in the U.S. alone, along with a much higher number of less-severe such infections.

In a study just published in Cell Host & Microbe, Relman – who pioneered the use of ultra-high-volume gene-sequencing techniques to sort out the thousands of species of microbes that communally inhabit our skin, orifices and innards – and his team used this method to show that mucosal sites way up high in our nose, where standard S. aureus-elimination techniques may not reach, can serve as reservoirs for S. aureus. That may, at least in part, explain why efforts to rid patients of this potentially nasty bug have so often fallen short of the mark, as I noted in my news release about the new findings:

Rigorous and somewhat tedious regimens for eliminating S. aureus residing on people’s skin or in their noses do exist, but it’s typically a matter of weeks or months before the bacteria repopulate those who are susceptible. The new study offers a possible reason why this is the case.

Previously: Cultivating the human microbiome, Anti-plaque bacteria: Coming soon to your toothpaste? and Eat a germ, fight an allergy
Photo by OakleyOriginals

Mark down October 30 and November 20, 2013, as medical mileposts.

On Oct. 30, a Stanford surgical team led by neurosurgeon Jaimie Henderson, MD, implanted a next-generation deep-brain-stimulation (or DBS) device into a Parkinson’s disease patient’s brain. On the order of 100,000 nearly but not quite identical procedures have been performed worldwide in the past decade or so, to relieve symptoms of not only Parkinson’s but epilepsy, chronic pain and more. Making what took place just over a month ago unique wasn’t the surgery itself but, rather, the nature of the device that was implanted – the first time ever in the United States. (In August, a patient in Germany received such a next-generation DBS device, although for a different indication.)

With current DBS technology, a fine, insulated wire is threaded into the brain so that its lead, containing four electrodes, impinges on the relevant brain area. (In Parkinson’s, for instance, the targeted area would be key brain regions that participate in the generation of spontaneous involuntary tremors characteristic of that disease). In a second procedure, a pacemaker-like device called a neurostimulator is placed under the skin, typically near the collarbone. The neurotransmitter transmits signals – at frequencies, amplitudes and durations programmed by a neurologist – to the leads, which accordingly fire electrical impulses counteracting the aberrant brain signals producing the physical symptoms in question. Over time, the neurostimulator’s impulse-transmission pattern is optimized via a trial-and-error process involving extensive patient-neurologist interaction.

Stanford neurologist and Parkinson’s specialist Helen Bronte-Stewart, MD, routinely sees patients a few weeks after their DBS devices have been implanted. They come in having not taken their medications for a while, so she can observe their symptoms and watch how they respond to different DBS frequencies and intensities.

But the new device, manufactured by the same company (Medtronic, Inc.) that makes the existing one, has an additional capability. It can not only transmit signals to the brain but, in addition, monitor and record the brain region of interest’s electrical output.

This will let Bronte-Stewart remotely capture vast amounts of information about a particular patient’s brain-firing patterns to discern that patient’s “neural signature” – and ultimately, it is hoped, be able to develop algorithms for automating the device’s signaling program so that it changes in response to changes in brain activity. (The goal, in engineering vocabulary, is a “real-time negative-feedback loop.”)

On Nov. 20, after recovering from the surgery, the patient and Bronte-Stewart, a noted expert in movement disorders, embarked on the first of a series of groundbreaking sessions during which Bronte-Stewart will download data from the implanted device for thorough analysis. While brain-activity data has been downloaded from Parkinson’s patients while they’re lying still on the operating table after the initial electronic-lead implantation, the recorded data has by necessity reflected only activity in the brain while the patient is at rest. Now Bronte-Stewart will be able to identify the neural signatures of not only the resting state but also voluntary movement, task performance and the tremor itself, and to see how those neural signatures change in response to her manipulations of DBS frequency and voltage output.

Stanford has received 10 of the new “two-way” DBS devices from Medtronic, and is recruiting Parkinson’s patients who, while they may not benefit directly from the ongoing study, wish to make a difference in how this disease’s symptoms are treated.

Previously: Revealed: The likely role of Parkinson’s protein in the healthy brain, Mind-reading in real life: Study shows it can be done (but they’ll have to catch you first), Positive results for deep-brain stimulation trial for epilepsy and Stanford neurologist discusses advances in research on movement disorders
Photo courtesy of Jaimie Henderson

Perhaps the most famous name associated with Huntington’s disease is that of populist folk singer Woody Guthrie, who died of it at age 52 in 1967. Guthrie’s mom had died of it, too, when Woody was a teenager. So, it’s believed, did his mom’s dad. Two of Woody’s children by his first wife, Mary, died at age 41 of Huntington’s. (In 1968, his second wife, Marjorie, founded the Huntington’s Disease Society of America.)

A person first diagnosed with Huntington’s disease, an ultimately lethal genetic neurodegenerative disorder characterized by jerky movement as well as cognitive and psychiatric problems, can on average expect to live another 20 years – but not without heartache. There are drugs to alleviate some symptoms of Huntington’s, which most often manifests in the fourth and fifth decades of life, but none that delay its onset or slow its progression.

Work by Stanford neuroscientist Frank Longo, MD, PhD, may change that. As described in a study just published in The Journal of Neuroscience, Longo and his colleagues have shown that a drug that mimics some aspects of a key brain protein was able to reduce degeneration and movement deficits associated with Huntington’s disease in two different mouse models of the disorder. The findings add to a growing body of evidence that protecting or boosting neurotrophins — bulky proteinaceous molecules that support the survival and function of nerve cells — may slow the progression of Huntington’s disease and other neurodegenerative conditions.

Longo’s team used a compound called LM22A-4, unearthed by Longo a couple of years ago in a computer search in collaboration with University of California-San Francisco neurologist Steven Massa, MD, PhD. LM22A-4 is a small molecule with less than 1/70 the bulk of the particular protein it mimics: brain-derived neurotrophic factor or BDNF, which has been studied in depth by many researchers and is known to be critical during the development of the nervous system and involved in important brain functions including memory and learning.

But unlike BDNF, LM22A-4 binds to and activates only one of two major cell-surface receptors for BDNF found in nerve cells. That’s a good thing, because the receptor LM22A-4 activates is associated with BDNF’s long-known ability to foster the survival of newborn nerve cells, while the receptor it doesn’t activate has been shown to respond to BDNF stimulation by inducing the death of nerve cells. This is helpful, perhaps, during early development when the brain needs to prune redundant nerve circuitry produced in a series of growth spurts, but it’s presumably going to be counterproductive in the treatment of a neuron-destroying disorder like Huntington’s.

Longo’s group examined the effects of LM22A-4 treatment in mice that were predisposed to develop symptoms of Huntington’s disease rapidly (within weeks) or gradually (within months). LM22A-4 treatment reduced the accumulation of abnormal proteins in the striatum and cortex — brain regions affected in Huntington’s disease. Motor behaviors (downward climbing and grip strength) also improved in the mice that received daily LM22A-4 treatments.

LM22A-4 has also shown promise in the treatment of stroke and other brain conditions. Because it was already commercially available when Longo and his colleagues’ computer stumbled on it, it also promises to be relatively cheap – kind of a “folk drug” – should any of its potential applications pan out. That would make Woody proud.

Previously: Newly identified protein helps explain how exercise boosts brain health,  Stanford neuroscientists uncover potential drug treatment for stroke and Stanford neuroscientist discusses the coming dementia epidemic
Photo courtesy of the Library of Congress

A healthy person’s brain has thousands, or maybe millions, of times as many synapses – contact points that relay signals from one nerve cell, or neuron, to the next – as there are stars in the Milky Way. In a blog entry not so long ago, I wrote:

In a sense, “you” are your synapses. They’re the defining features of the brain circuits that fire up or chill out to generate every thought that passes through your mind and every flicker of emotion or glimmer of recollection you experience. You wouldn’t want to leave home without them. Some of us get no choice. Massive synapse loss accompanies neurodegenerative diseases from Alzheimer’s to Parkinson’s to multiple sclerosis.

In a paradigm-shifting discovery just published in Nature, Stanford researchers found that a common but mysterious class of non-neuronal brain cells, called astrocytes because of their star-like shape, actively refine nerve-cell circuits throughout life by selectively eliminating synapses. much as a sculptor chisels away excess bits of rock to create an artwork.

Astrocytes, which account for between one-third and half of all the cells in our brains, belong to a general category of brain cells collectively called “glia,” from the Greek term for glue. That’s because until not long ago, neuroscientists (note the bias in that term) figured that these seemingly passive cells weren’t much more than packing peanuts for the “really cool” cells, neurons, that hog the lion’s share of attention.

Neurons, which compose merely 10 percent of all the cells in a healthy human brain, are so celebrated they’ve lent their name to brain science: neurology. But a team led by pioneering Stanford gliologist (I made that term up) Ben Barres, MD, PhD, has shown in the new study that astrocytes play a starring role in sculpting the very synaptic connections that are central to consciousness, cognition, motion and emotion.

As I once noted:

[Barres] – who trained as a practicing neurologist before circling back for his PhD – couldn’t help noticing, in autopsies, that the brains of people with “neurological” disorders invariably showed obvious signs of glial disarray. So he resolved to devote his career to the study of glial cells…

Thus began a decades-long efforts to unveil the manifold functions of astrocytes and their glial comrades-in-arms (described in detail in this Stanford Medicine article).  Barres and his colleagues have already shown that astrocytes in particular (there are two other glial cell types) play a critical role in determining exactly where and when new synapses are generated. With the finding that astrocytes also single out outmoded or downright counterproductive synapses and gobble them up, it’s increasingly certain that substantial remodeling of brain circuits takes place in the adult brain and that astrocytes are master sculptors of its constantly evolving synaptic architecture. This holds huge implications, according to my press release on the new study:

The findings also raise the question of whether deficits and excesses in this astrocytic function could underlie, respectively, the loss of this remodeling capacity in old age or the wholesale destruction of synapses that erupts in neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease.

Previously: Protein known for initiating immune response may set our brains up for neurodegenerative disorders, Unsung brain-cell population implicated in variety of autism and Brain imaging, and the ‘image management’ cells that make it possible
Photo by Ed Bierman

A few weeks ago, I blogged about the past half-century’s startling advances in computer competence. Referring obliquely to the Turing test, I mused, “Makes me wonder: Just how long will it be before we can no longer tell our computers from ourselves?”

A week later, as fate would have it, I showed up in a classroom on Stanford’s quad for a discussion between UC-Berkeley philosopher John Searle, PhD, and Stanford artificial-intelligence expert Terry Winograd, PhD, concerning a similar-sounding but subtly deeper question: “Can a computer have a mind?”

Failed philosophy major that I am (see confession), I refrained from raising my hand while Searle recapped his famous “Chinese room” argument. “I don’t understand a word of Chinese,” he told the audience. But were you to arm him with sufficient instructions for responding to myriad character combinations with counterpart character-combination outputs, he claimed, he might be able to fool a remote observer into concluding otherwise. (Philosophers are always “claiming” something or other. How nostalgic!)

Sure, machines might be able to “think” in the sense of manipulating symbols, said Searle. But when it comes to consciousness, such “thoughts” do not a mind make. Syntax (the manipulation of symbols – nothing but ones and zeroes, in this case) isn’t the equivalent of semantics (the effects of those manipulations on our consciousness: in a word, “meaning.)

“We still don’t know how the brain creates consciousness,” Searle said, arguing that to fully understand subjectivity, it will be necessary not merely to simulate brain function but to duplicate it. (A street map is not the same as the city it’s a map of.) That’s a comforting constraint for carbon-based throwbacks such as myself, who would like to feel our dominance is assured, at least for a while, by the excruciating nested complexity of the biological components-within-components-within-components of the human brain.

Aha! The Devil is in the details. (The Tom Südhofs of the world are busily working those out as I write this). Score one for biology: A ones-and-zeroes-based gizmo, which can’t even sprout body hair, may never acquire that precious thing called “consciousness.” At least, not on its own.

But what if nanotech and biotech team up?

Once upon a time before coming to Stanford , I wrote an article titled “The 21st Century Meets the Tin Woodsman” and subtitled: “Can Joe Six-Pack compete with Sid Cyborg?” Consider a scenario wherein computation- and communication-enabled nanoparticles, ingested in a pill, float through the blood-brain barrier and seat themselves at each of the quadrillion or so nerve-cell to nerve-cell contact points in a person’s central nervous system:

With nanobots monitoring every critical neural connection’s involvement in a thought or emotion or experience, you’ll be able to back up your brain – or even try on someone else’s – by plugging into a virtual-reality jack. The brain bots feed your synapses the appropriate electrical signals and you’re off and running, without necessarily moving. If nanotechnology gets traction, all bets are off, because whoever’s packing those brain bots will be infinitely more intelligent than mortal meat puppets like me … I hope our sleek semiconducting successors like pets, because, while the mammalian herding instinct ensures that many of us will go along for the ride, characteristic human obstinacy ensures that many will not.

Call me obstinate. To the best of my knowledge, I’m still 100 percent human. But in ten or twenty years, at the rate things are going, how will I be able to be sure you are, too?

Previously: Step by step, Sudhof stalk the devil in the details, snagged a Nobel, Half-century climb in computer’s competence colloquially captured by Nobelist Michael Levitt and Brains of different people listening to the same piece of music actually respond in the same way
Photo by Javi