National Geographic : 2014 Feb
Seeing the Brain 43 Complicated, but not random. Lichtman and Kasthuri discovered that every neuron made nearly all its connections with just one other one, scrupulously avoiding a connection with almost all the other neurons packed tightly around it. “They seem to care who they’re connected to,” Lichtman says. Lichtman can’t say yet whether this fastidious pattern is a general rule or a feature of just the tiny area of mouse brain he sampled. Even as they scale up the technology, he and his colleagues will need another two years to complete a scan of all 70 million neurons in a mouse. I ask about scanning an entire human brain, which contains a thousand times more neurons than a mouse’s. “I don’t dwell on that,” he says, with a laugh. “It’s too painful.” When and if Lichtman completes his three- dimensional portrait of the brain, it will reveal much—but it will still be only an exquisitely de- tailed sculpture. His imaged neurons are hollow models; real neurons are crammed with living DNA, proteins, and other molecules. Each type of neuron uses a distinct set of genes to build the molecular machinery it needs to do its own job. Light-sensitive neurons in the eyes produce photon-catching proteins, for example, and neurons in a region called the substantia nigra produce a protein called dopamine, crucial to our sense of reward. The geography of proteins is essential to understanding how the brain works— and how it goes awry. In Parkinson’s disease the substantia nigra neurons produce less dopamine than normal, for reasons that aren’t yet clear. Alzheimer’s disease scatters tangles of protein through the brain, although scientists have yet to firmly settle on how those tangles give rise to the devastating dementia the disease causes. A map of the brain’s molecular machinery called the Allen Brain Atlas has been generated at the Allen Institute for Brain Science in Seattle, founded ten years ago with funds from Micro- soft co-founder Paul Allen. Using the brains of recently deceased people, donated by their families, researchers there use a high-resolution magnetic resonance imaging (MRI) scan of each brain as a three-dimensional road map, then slice it into microscopically thin sections that are mounted on glass slides. They then douse the sections with chemicals that reveal the presence of active genes harbored in the neurons. So far the researchers have mapped the brains of six people, charting the activity of 20,000 protein-coding genes at 700 sites within each brain. It’s a colossal amount of data, and they’ve only begun to make sense of it. The scientists estimate that 84 percent of all the genes in our DNA become active somewhere in the adult brain. (A simpler organ like the heart or pan- creas requires far fewer genes to work.) In each of the 700 sites the scientists studied, the neurons switch on a distinct collection of genes. In a pre- liminary survey of two regions of the brain, the scientists compared a thousand genes that were already known to be important for neuron func- tion. From one person to the next, the areas of the brain where each of those genes was active were practically identical. It looks as if the brain has a finely grained genetic landscape, with spe- cial combinations of genes carrying out tasks in different locations. The secret to many diseases of the brain may be hiding in that landscape, as certain genes shut down or switch on abnormally. All the information from the Allen Brain At- las is posted online, where other scientists can navigate through the data with custom-made software. Already they’re making new discover- ies. A team of Brazilian scientists, for instance, has used it to study a devastating brain disor- der called Fahr’s disease, which calcifies regions deep inside the brain, leading to dementia. Some cases of Fahr’s disease had already been linked to a mutation in the gene SLC20A2. In the atlas the scientists found that SLC20A2 is most ac- tive in precisely the regions that are targeted by the disease. They also found a network of other genes that is most active in the same areas, and now they’re trying to find out whether they’re involved in Fahr’s disease as well. Of all the new ways of visualizing the brain, perhaps the most remarkable is one invented by Stanford neuroscientist and psychiatrist the secret to many diseases may be hiding in the brain’s genes, as they shut down or switch on abnormally.