There is a macabre brilliance to the machine in Jeff Lichtman’s laboratory at Harvard University that is worthy of a Wallace and Gromit film. Brain goes into one end and out the other comes sliced brain, courtesy of an automated arm that wields a diamond knife. The slivers of tissue drop one after another onto a conveyor belt that zips along with the merry whirr of a movie projector.
Lichtman’s machine is an automated tape-collecting lathe ultramicrotome (ATLUM). It produces long strips of sticky tape with brain slices attached, all ready to be photographed through a powerful electron microscope. When these pictures are combined into 3D images, they reveal the inner wiring of the organ, a tangled mass of nervous spaghetti. The research by Lichtman and his co-workers has a goal that is so ambitious it is almost unthinkable.
If we are ever to fully understand the brain, they say, we must know how every neuron inside is wired up.
Though fanciful, the payoff could be profound. Map out our “connectome” — following other major “ome” projects such as the genome and transcriptome — and we will lay bare the biological code of our personalities, memories, skills and susceptibilities. Somewhere in our brains is who we are.
To use an understatement often made by scientists: The job at hand is not trivial. Lichtman’s machine slices brain tissue into exquisitely thin wafers. To turn a 1mm thick slice of brain into neural salami takes six days in a process that yields about 30,000 slices, and chopping up the brain is the easy part.
When Lichtman began this work several years ago, he calculated how long it might take to image every slice of a 1cm mouse brain. The answer was 7,000 years. The human brain is another story.
There are 85 billion neurons in the 1.4kg of flesh between our ears. Each has a cell body (gray matter) and long, thin extensions called dendrites and axons (white matter) that reach out and link to other cells. Most neurons have lots of dendrites that receive information from other nerve cells, and one axon that branches on to other cells and sends information out. On average, each neuron forms 10,000 connections, through synapses with other nerve cells. Altogether, Lichtman estimates there are between 100 trillion and 1,000 trillion connections between neurons.
Unlike the lung, or the kidney, where the whole organ can be more or less understood by grasping the role of a handful of repeating physiological structures, the brain is made of thousands of specific types of brain cells that each look and behave differently. Their names — Golgi, Betz, Renshaw, Purkinje — read like a roll call of the pioneers of neuroscience.
Lichtman, who is fond of calculations that expose the magnitude of the task he has taken on, once worked out how much computer memory would be needed to store a detailed human connectome.
“To map the human brain at the cellular level, we’re talking about 1 million petabytes of information. Most people think that is more than the digital content of the world right now,” Lichtman said. “I’d settle for a mouse brain, but we’re not even ready to do that. We’re still working on how to do one cubic millimeter.”
He says he is about to submit a paper on mapping a minuscule volume of the mouse connectome and is working with a German company on building a multbeam microscope to speed up imaging.