This article was taken from the July 2012 issue of Wired magazine. Be the first to read Wired's articles in print before they're posted online, and get your hands on loads of additional content by subscribing online.
No road, no trail can penetrate this forest. The long and delicate branches of its trees lie everywhere, choking space with their exuberant growth. No sunbeam can fly a path tortuous enough to navigate the narrow spaces between these entangled branches. All the trees of this dark forest grew from 100 billion seeds planted together. And, all in one day, every tree is destined to die.
This forest is majestic, but also comic and even tragic. It is all of these things. Indeed, sometimes I think it is everything. Every novel and every symphony, every cruel murder and every act of mercy, every love affair and every quarrel, every joke and every sorrow -- all these things come from the forest.
You may be surprised to hear that it fits in a container less than 30 centimetres in diameter. And that there are seven billion on this Earth. You happen to be the caretaker of one, the forest that lives inside your skull. The trees of which I speak are those special cells called neurons. The mission of neuroscience is to explore their enchanted branches -- to tame the jungle of the mind. Neuroscientists have eavesdropped on its sounds, the electrical signals inside the brain. They have revealed its fantastic shapes with meticulous drawings and photos of neurons. But from just a few scattered trees, can we hope to comprehend the totality of the forest?
In the 17th century, the French philosopher Blaise Pascal confessed that he was terrified by the vastness of the universe. Pascal meditated upon outer space, but we need only turn our thoughts inward to feel his dread. Inside every one of us lies an organ so vast in its complexity that it might as well be infinite.
As a neuroscientist I have come to know first-hand Pascal's dread. I have also felt embarrassment.
Sometimes I speak to the public about the state of our field. After one such talk I was pummelled with questions. What causes depression and schizophrenia? What is special about the brain of an Einstein or a Beethoven? How can my child learn to read better? As I failed to give satisfying answers, I could see faces fall. I finally apologised. "I'm sorry," I said. "You thought I'm a professor because I know the answers. Actually I'm a professor because I know how much I don't know."
Studying an object as complex as the brain may seem almost futile. The brain's billions of neurons resemble trees of many species and come in many fantastic shapes.
Only the most determined explorers can hope to capture a glimpse of this forest's interior, and even they see little, and see it poorly. It's no wonder that the brain remains an enigma. My audience was curious about brains that malfunction or excel, but even the humdrum lacks explanation. Every day we recall the past, perceive the present, and imagine the future. How do our brains accomplish these feats? It's safe to say that nobody really knows.
Daunted by the brain's complexity, many neuroscientists have chosen to study animals with drastically fewer neurons than humans. The worm lacks what we'd call a brain.
Its neurons are scattered throughout its body rather than centralised in a single organ. Together they form a nervous system containing a mere 300 neurons. That sounds manageable. Every neuron in this worm has been given a unique name and has a characteristic location and shape. Worms are like precision machines mass-produced in a factory: each one has a nervous system built from the same set of parts, and the parts are always arranged in the same way.
What's more, this standardised nervous system has been mapped completely. The result is something like the flight maps we see in the back pages of airline magazines. The four-letter name of each neuron is like the three-letter code for each of the world's airports. The lines represent connections between neurons, just as lines on a flight map represent routes between cities. We say that two neurons are "connected" if there is a small junction, called a synapse, at a point where the neurons touch. Through the synapse one neuron sends messages to the other.
Engineers know that a radio is constructed by wiring together electronic components like resistors, capacitors and transistors. A nervous system is likewise an assembly of neurons, "wired" together by their slender branches. That's why the map was originally called a wiring diagram. More recently, a new term has been introduced -- connectome.
This word invokes not electrical engineering but the field of genomics. DNA is a long molecule resembling a chain. The individual links of the chain are small molecules called nucleotides, which come in four types denoted by the letters A, C, G and T. Your genome is the entire sequence of nucleotides in your DNA, or equivalently a long string of letters drawn from this four-letter alphabet. With three billion letters it would be a million pages long if printed as a book. In the same way, a connectome is the totality of connections between the neurons in a nervous system. The term, like genome, implies completeness. A connectome is not one connection, nor even many. It is all of them. In principle, your brain could also be summarised by a diagram that is like the worm's, though much more complex.
Would your connectome reveal anything interesting about you?
The first thing it would reveal is that you are unique. You know this, of course, but it has been surprisingly difficult to pinpoint where, precisely, your uniqueness resides.
Your connectome and mine are very different. They are not standardised like those of worms. That's consistent with the idea that every human is unique in a way that a worm is not.
Differences fascinate us. When we ask how the brain works, what mostly interests us is why the brains of people work so differently. Why can't I be more outgoing, like my extroverted friend? Why does my son find reading more difficult than his classmates do? Why is my teenage cousin starting to hear imaginary voices? Why is my mother losing her memory? Why can't my spouse (or I) be more compassionate and understanding?
I propose a simple theory: minds differ because connectomes differ. Personality and IQ might also be explained by connectomes. Perhaps even your memories, the most idiosyncratic aspect of your personal identity, could be encoded in your connectome.
Although this theory has been around a long time, neuroscientists still don't know whether it's true.
But clearly the implications are enormous. If it's true, then curing mental disorders is ultimately about repairing connectomes.
In fact, any kind of personal change -- educating yourself, drinking less, saving your marriage -- is about changing your connectome.
But let's consider an alternative theory: minds differ because genomes differ. In effect, we are who we are because of our genes. The new age of the personal genome is dawning. Soon we will be able to find our own DNA sequences quickly and cheaply. We know that genes play a role in mental disorders and contribute to normal variation in personality and IQ. Why study connectomes if genomics is already so powerful?
The reason is simple: genes alone cannot explain how your brain got to be the way it is. As you lay nestled in your mother's womb, you already possessed your genome but not yet the memory of your first kiss. Your memories were acquired during your lifetime, not before. Some of you can play the piano; some can ride a bicycle. These are learned abilities rather than instincts programmed by the genes.
Unlike your genome, which is fixed from the moment of conception, your connectome changes throughout life. Neuroscientists have already identified the basic kinds of change. Neurons adjust, or "reweight", their connections by strengthening or weakening them. Neurons reconnect by creating and eliminating synapses, and they rewire by growing and retracting branches. Finally, entirely new neurons are created and existing ones eliminated, through regeneration.
We don't know exactly how life events -- your parents' divorce, your fabulous year abroad -- change your connectome. But there is good evidence that all four Rs -- reweighting, reconnection, rewiring and regeneration -- are affected by your experiences. At the same time, the four Rs are also guided by genes. Minds are indeed influenced by genes, especially when the brain is "wiring" itself up during infancy and childhood.
Both genes and experiences have shaped your connectome. We must consider both historical influences if we want to explain how your brain got to be the way it is. The connectome theory of mental differences is compatible with the genetic theory, but it is far richer and more complex because it includes the effects of living in the world. The connectome theory is also less deterministic. There is reason to believe that we shape our own connectomes by the actions we take, even by the things we think. Brain wiring may make us who we are, but we play an important role in wiring up our brains.
To restate the theory more simply:
*You are more than your genes.
You are your connectome.*
If this theory is correct, the most important goal of neuroscience is to harness the power of the four Rs. We must learn what changes in the connectome are required for us to make the behavioural changes we hope for, and then we must develop the means to bring these changes about. If we succeed, neuroscience will play a profound role in the effort to cure mental disorders, heal brain injuries and improve ourselves.
Given the complexity of connectomes, however, this challenge is truly formidable. Mapping the roundworm's nervous system took over a dozen years, though it contains only 7,000 connections. Your connectome is 100 billion times larger, with a million times more connections than your genome has letters. Genomes are child's play compared with connectomes.
Today our technologies are finally becoming powerful enough that we can take on the challenge. By controlling sophisticated microscopes, our computers can now collect and store huge databases of brain images. They can also help us analyse the torrential flow of data to map the connections between neurons. With the aid of machine intelligence, we will finally see the connectomes that have eluded us for so long.
I am convinced that it will become possible to find human connectomes before the end of the 21st century. First we'll move from worms to flies. Later we'll tackle mice, then monkeys. And finally we'll take on the ultimate challenge: an entire human brain. Our descendants will look back on these achievements as nothing less than a scientific revolution.
Do we really have to wait decades before connectomes tell us something about the human brain?
Fortunately, no. Our technologies are already powerful enough to see the connections in small chunks of brain, and even this partial knowledge will be useful. In addition, we can learn a great deal from mice and rats, our close evolutionary cousins. Their brains are quite similar to ours and are governed by some of the same principles of operation. Examining their connectomes will shed new light on our brains as well as theirs.
In the year AD79, Mount Vesuvius erupted with terrifying fury, burying the Roman town of Pompeii under tons of volcanic ash and lava. Frozen in time, Pompeii lay waiting for almost two millennia until it was accidentally rediscovered by construction workers. When archaeologists began to excavate the city in the 18th century, they discovered to their amazement a detailed snapshot of the life of a Roman town -- luxurious holiday villas of the wealthy, street fountains and public baths, bars and brothels, a bakery and a market, a gymnasium and theatre, frescoes depicting daily life, and phallic graffiti everywhere. The dead city was a revelation to historians, giving insight into the minutiae of Roman life.
Today we can conceive of finding connectomes only by analysing images of dead brains. You could think of this as brain archaeology, but it's more conventionally known as neuroanatomy. Generations of neuroanatomists have gazed at the cold corpses of neurons in their microscopes and tried to imagine the past. A dead brain, its molecules fastened in place by embalming fluid, is a monument to the thoughts and feelings that once lived inside. Until now, neuroanatomy resembled the act of reconstructing an ancient civilisation from the fragmentary evidence of coins and tombs and pottery shards. But connectomes will be detailed snapshots of entire brains, like Pompeii stopped in its tracks. These snapshots will revolutionise the neuroanatomist's ability to reconstruct the functioning of the living brain.
But why study dead brains when there are technologies for studying live ones? Wouldn't we learn more if we could travel back in time and study a living Pompeii? Not necessarily. To see why not, imagine some limitations on our ability to observe the living town. Let's say we could watch the actions of a single citizen but would be blind to all other inhabitants. Or, let's say we could look at infrared satellite images revealing the average temperature of each neighbourhood, but could not see finer details. With such constraints, studying the living town might turn out to be less illuminating than we'd hoped.
Our methods for studying living brains have similar limitations. If we open up the skull, we can see the shapes of individual neurons and measure their electrical signals, but what's revealed is only a tiny fraction of the billions of neurons in the brain. If we use non-invasive imaging methods for penetrating the skull and showing us the brain's interior, we can't see individual neurons; we must settle for coarse information about the shape and activity of brain regions. We can't rule out the possibility that some advanced technology of the future will remove these limitations and enable us to measure the properties of every single neuron inside a living brain, but for now it's just a fantasy.
Measurements of living and dead brains are complementary, and the most powerful approach, in my view, combines them.
Many neuroscientists don't agree with the idea that dead brains can be informative and useful, however. Studying living brains is the only true way of doing neuroscience, they say, because:
You are the activity of your neurons.
Here "activity" refers to the electrical signalling of neurons. Measurements of these signals have provided ample evidence that the neural activity in your brain at any given moment encodes your thoughts, feelings and perceptions in that instant.
How does the idea that you are the activity of your neurons square with the notion that you are your connectome?
Although the two claims might at first glance seem contradictory, they are in fact compatible, because they refer to two different notions of the self. One self changes rapidly from moment to moment, becoming angry and then cheering up, thinking about the meaning of life and then the household chores, watching the leaves fall outside and then the football match on television. This self is the one intertwined with consciousness. Its protean nature derives from the rapidly changing patterns of neural activity in the brain.
The other self is much more stable.
It retains memories from childhood over an entire lifetime. Its nature -- what we think of as personality --is largely constant, a fact that comforts family and friends. The properties of this self are expressed while you are conscious, but they continue to exist during unconscious states like sleep. This self, like the connectome, changes only slowly over time. This is the self invoked by the idea that you are your connectome.
Historically, the conscious self is the one that has attracted the most attention. In the 19th century, the American psychologist William James wrote eloquently of the stream of consciousness, the continuous flow of thoughts through the mind. But James failed to note that every stream has a bed. Without this groove in the earth, the water would not know in which direction to flow. Since the connectome defines the pathways along which neural activity can flow, we might regard it as the stream bed of consciousness.
The metaphor is a powerful one. Over a long period, in the same way that the water of the stream slowly shapes the bed, neural activity changes the connectome. The two notions of the self -- as both the fast-moving, ever-changing stream and the more stable but slowly transforming stream bed -- are thus inextricably linked and suggest a new field of science: connectomics.
But we cannot chart the neuroscience of the future until we understand where we came from. What do we already know, and where are we stuck? The brain contains 100 billion neurons, a fact that has overwhelmed even the most fearless explorers. One solution to the problem of these kinds of overwhelming numbers is to forget about neurons and instead divide the brain into a small number of regions. Neurologists have learned much about the functions of these regions by interpreting the symptoms of brain damage. In developing this method, they were inspired by the 19th century school of thought known as phrenology.
Phrenologists explained mental differences as arising from variations in the sizes of the brain and its regions. By imaging the brains of many human subjects, modern researchers have confirmed this idea, using it to explain variations in levels of intelligence as well as mental disorders such as autism and schizophrenia. They have found some of the strongest evidence we have for the idea that minds differ because brains differ. The evidence is statistical, however -- the results revealed only by averages over populations. The size of the brain and its regions remain almost useless for predicting the mental properties of an individual.
This limitation is no mere technicality. It is fundamental. Although phrenology assigns functions to brain regions, it does not attempt to explain how each region performs its function. Without that, we cannot explain in a satisfying way why the region might function especially well in some people and malfunction in others. We can, and must, find a less superficial answer than size.
There is an alternative to phrenology -- connectionism -- that also dates back to the 19th century. This approach is more ambitious because it attempts to explain how regions of the brain actually work. Connectionists view a brain region not as an elementary unit but as a complex network composed of many neurons. The connections of the network are organised so that its neurons can collectively generate the intricate patterns of activity that underlie our perceptions and thoughts. The organisation of connections can be altered by experience, which allows us to learn and remember. The organisation is also shaped by genes so that genetic influences on the mind can also be explained.
These ideas may sound powerful, but there is a catch: they have never been subjected to conclusive experimental tests. Connectionism, despite its intellectual appeal, has never managed to become real science, because neuroscientists have lacked good techniques for mapping the connections between neurons. In a nutshell, neuroscience has been -saddled with a dilemma: the ideas of phrenology can be empirically tested but are simplistic. Connectionism is far more sophisticated, but its ideas cannot be evaluated experimentally. How do we break out of this impasse? The answer is to find connectomes and learn how to use them.
We are already starting to develop technologies for finding connectomes. But once we find them, what will we do with them? First, we'll use them to carve the brain into regions, aiding the work of neo-phrenologists. And we'll divide the enormous number of neurons into types, much as botanists classify trees into species. This will dovetail with the genomic approach to neuroscience, because genes exert much of their influence on the brain by controlling how neuron types wire up with each other.
Connectomes are like vast books written in letters that we barely see, in a language that we do not yet comprehend.
Once our technologies make the writing visible, the next challenge will be to understand what it means. We'll learn to decode what is written in connectomes by attempting to read memories from them.
This endeavour will at long last provide a conclusive test of connectionist theories. But it won't be enough to find a single connectome. We will want to find many connectomes and compare them, to understand why one mind differs from another, and why a single mind changes over time. We'll hunt for connectopathies, abnormal patterns of neural connectivity that might underlie mental disorders such as autism and schizophrenia. And we'll look for the effects of learning on connectomes.
Armed with this knowledge, we will develop new methods of changing connectomes. The most effective way at present is the traditional one: training our behaviours and thoughts. But learning regimens will become more powerful when supplemented by molecular interventions that promote the four Rs of connectome change. The new science of connectomics will not be established overnight. Today we can only see the beginning, and the many barriers that lie in the way. Nevertheless, over the coming decades, the march of our technologies and the understanding that they enable will be inexorable.
Connectomes will dominate thinking about what it means to be human. The transhumanism movement has developed elaborate schemes for transcending the human condition, but are the odds in their favour? Does the ambition of cryonics to freeze the dead and eventually resurrect them have any chance of success? And what about the ultimate fantasy of uploading, of living happily ever after as a computer simulation, unencumbered by a body or a brain? Using connectomics we should be able to test these claims empirically.
But before questions of the afterlife are investigated, fundamental questions about this life must be addressed. In particular: why are people different?
Connectomics may offer us an answer to this, and other, mysteries of the human condition.
*Extracted from Connectome: How the Brain's Wiring Makes Us Who We Are by Sebastian Seung, published by Allen Lane on June 7 at £20. Copyright Sebastian Seung <span class="s5">2012. penguin.co.uk.
Imagery from humanconnectomeproject.org*
This article was originally published by WIRED UK
