What do we know? That there's a lot we don't know. It'll take a detailed map to sort it all out.
Today the cover of Nature, the prestigious scientific journal, is dedicated to a paper that outlines the first findings of the map of the human brain being created by the Allen Institute For Brain Science, the neuroscience Manhattan project being funded by Microsoft co-founder Paul Allen.
The new publication comes out of the Allen Institute’s effort to create a map of which genes are turned on and off in the human brain, a feat the Institute accomplished a half decade ago in the mouse. Already, the mouse map has become a standard tool for neuroscientists, and the hope is that the human brain atlas will be as well. (For more on the institute’s overall effort, see: Inside Paul Allen’s Quest To Reverse Engineer The Brain, from the current issue of Forbes magazine.)
An animal’s genes are contained in its DNA, locked in the center of its cells; to access the genetic code, the DNA must be transcribed into a related chemical called RNA, which can take messages to the parts of the cell that make the chemicals that comprise most of the body. The Allen Institute’s atlases are measures of what RNA transcripts are in the cell – this is a bit like monitoring what information is being read off the body’s hard disk.
The Nature paper unveils data from the first two human brains completely analyzed by the Allen Institute, with a bit of analysis from a third. There are several surprises – and it’s not clear what they all mean. “At the moment we’re making descriptions,” says Ed Lein, a neuroscientist who is one of the paper’s co-authors. “A key role for the neuroscience community is to understand how these differences relate to the unique properties of the human brain. ”
- Cells in the “thinking” part of the brain look a lot more similar than scientists had expected. The thinking we do, including the experience we have of being us, is generated in the cortex, the most well-developed part of the brain. You might expect, then, that the cortex would be accessing the DNA code in all sorts of different ways. But the Allen Institute researchers found remarkably little difference between one neuron in the cortex and the next. In terms of how they use their genetic hard drives, these cells are very much the same.
- Your left brain and right brain are using your DNA in the same way. Another surprising difference: the left and right sides of the brain tend to have different functions. But on the level of gene expression that the atlas measures, these are again hard to detect. The two hemispheres of the brain look very much alike.
- The differences that do exist are important. There’s not a lot of genetic variation in the landscape of the brain, but what there is is apparently important. The Allen Institute researchers found that they could accurately predict where a neuron would be in the cortex by what genes it was expressing. So these tiny differences apparently matter. One interesting distinction: the neurons involved in getting sensory impressions, like sight, sound, and touch, are similar to one another and different from the rest of the brain.
- The differences are not where you’d expect. When we think of a brain cell (if we think about brain cells at all), we think of neurons, the spindly nerve cells that transmit signals to each other and make up the circuits of our brains and bodies. But there’s another type of cell in the brain, called a glial cell, that creates the sheaths that protect neurons and the matrices in which they sit. And there is more variation in what genes are expressed in the glia than in the regular neurons. That could mean they are more important than we thought, accounting for the differences between people – or it could mean that variation in glial cells doesn’t matter much, so there’s a lot of it.
- We are not mice, or monkeys. One of the most important uses of the Allen Atlas will be to figure out how the human brain is different from the brains of the experimental animals scientists can test in their labs. Big drug companies such as Eli Lilly, AstraZeneca, and Pfizer have been struggling to create new medicines for diseases like schizophrenia and Alzheimer’s, largely without success, and the difference between lab mice and people may be one key reason. In one tantalizing clue, the Allen Institute researchers point to differences in a gene called CALB1, which is used to move around calcium ions, which are key chemical messengers for the nervous system. In rhesus macaques and mice, this gene is expressed throughout the hippocampus, the brain region that plays a key role in the creation of memories. But in humans, CALB1 is expressed only in the dentate gyrus, pointing to a potential difference between the brains of these other mammals and ours. It’s not known what this difference means.
One important result of the lack of variation between cells and between different brains is that the Allen Atlas will be completed with just six brains, not the 10 researchers thought they would need when the project started in 2008. The institute is moving on, with a new $300 million investment from Allen, to try to do new experiments to create circuit diagrams of the mouse visual cortex and to understand all the cell types that exist in the human brain.
Allen himself, when I met him this summer at the Allen Institute in Seattle, is prepared for this to be a long, hard slog. He told me that the brain is “hideously complex” and that it’s going to take “decades and decades” of more research to understand. “We are talking about dozens and dozens of Nobel Prizes,” he said, “that have yet to be won to understand how the brain works.” (For more, see Inside Paul Allen’s Quest To Reverse Engineer The Brain.)