The Human Brain Gets a New Map

A few years ago, I had the pleasure of writing about the Paul Allen Institute for Brain Science. At the time, the Institute was just beginning a fairly epic undertaking - constructing a precise map of gene expression for the entire human brain. I had a chance to observe the beginning of the process, as trained dissectors cut a bloody brain into slabs of meat:

I'm in the dissection room of the Allen Institute for Brain Science in Seattle, and the scientist next to me is in a hurry: His specimen—this fragile cortex—is falling apart. Dying, the gray matter turns acidic and begins to eat away at itself; nucleic acids unravel, cell membranes dissolve. He takes a thin, sterilized knife and slices into the tissue with disconcerting ease. I'm reminded of Jell-O and guillotines and the meat counter at the supermarket. He saws repeatedly until the brain is reduced to a series of thin slabs, which are then photographed and rushed to a freezer. All that remains is a pool of blood, like the scene of a crime.

Behind all the gore there's a profound purpose: The scientists here are mapping the brain. And while conventional brain maps describe distinct anatomical areas, like the frontal lobes and the hippocampus—many of which were first outlined in the 19th century—the Allen Brain Atlas seeks to describe the cortex at the level of specific genes and individual neurons. Slices of tissue containing billions of brain cells will be analyzed to see which snippets of DNA are turned on in each cell.

If the institute succeeds, its maps will help scientists decipher the function of the thousands of genes that help produce the human brain. (Although the Human Genome Project was completed more than five years ago, scientists still have little idea which genes are used to make the brain, let alone where in the brain they are expressed.) For the first time, it will be possible to understand how such a complex object is assembled from a basic four-letter code.

"The maps of the brain we currently have are like those antique maps people used to draw of the New World," says Allan Jones, chief scientific officer at the Allen Institute. "We can see the crude outlines of the structure, but we have no idea what's happening on the inside." Jones is in charge of making sure the atlas gets finished. He wears starched button-up shirts and crisply pleated khakis, and he looks like the kind of guy who has a drawer full of bow ties. "Studying the brain now is like trying to navigate a vast city without any driving instructions," he says. "You don't know where you are, and you have no idea how to find what you're looking for."

Yesterday, the Allen Institute announced that their human brain map is complete. Here, for instance, is a 3-D snapshot of all the locations in the brain where the Prozac's biochemical target is expressed. Researchers can click on each dot and see which genes are expressed in those specific areas, in addition to the underlying biochemistry:

Allan Jones, the CEO of the Institute, was kind enough to answer a few questions about how the map was created and what it means.

Lehrer: Let's begin with the basics. How did you make this map?

Jones: We work with medical examiners and existing brain banks on both coasts. The brains we obtain through these sources have to meet strict criteria for a normal brain (typically accidental death or one caused by something other than brain injury or disease, such as cardiac arrest) and there has to be enough time after time of death to collect, process and freeze the brain within a 24 hour window. After consent is obtained from next of kin, we first get an MRI of the brain. This serves as a “scaffolding” framework for us to ultimately hang the detailed gene expression data. The brain is then removed, and slabbed into 1 cm slabs and quickly frozen. The frozen slabs are shipped to the Institute, where we further process them: sectioning the large slabs and staining them with histological stains so that we can determine specific anatomic locations for sampling, then partitioning the slabs into more manageable sized 2” x 3” pieces, then taking these pieces and thinly slicing them to put on special microscope slides. The slides are then subjected to laser capture microdissection (LCM); technicians and expert anatomists work together to draw regions of interest on a computer screen connected to an LCM microscope, then a laser precisely cuts the delineated areas and these fall into a small plastic tube. RNA is extracted from this tissue, and a quantitative read-out from the RNA is obtained on a DNA micro-array that takes assays of the ~25,000 genes in the human genome. For each human brain we generated over 50 million gene expression data points across ~1,000 anatomic regions using this methodology.

Lehrer: Why is this map important? After all, most endowed institutes fund individual researchers or specific fields of inquiry. Why did the Allen Institute decide to build a publicly available database?

Jones: The Allen Institute operates on a different model than most research institutes, with a focus on creating catalytic resources for those other researchers around the world. Our mouse brain atlas, which was completed in 2006, has really proved to be an extraordinary resource for scientists and is used by approximately 10,000 unique users from around the globe every month. It represents for researchers a reference for new discovery, hypothesis generation and confirmation of their own data, and often saves them from having to do an experiment themselves in the lab, which it turn saves time and money.

For the Human Brain Atlas, the dataset is one that simply cannot be repeated in an individual lab: the millions of dollars in infrastructure and in the generation of the data aside, it is very hard to obtain high quality normal human brain tissue. Existing brain banks provide wonderful support for the research community, but usually for very specific regions of the brain that are requested. Model systems are fantastic tools for modern science, but we ultimately want to understand the human brain in its normal and disease context and a comprehensive human brain dataset certainly helps!

Lehrer: You found that these two brains reveal a 94 percent similarity in average gene expression. Were you surprised by that number? How does it compare to the mouse map data? It strikes me as somewhat sobering that all of our individuality can be compressed into a mere 6 percent of variation in gene expression. Finally, have you begun analyzing these differences?

Jones: Given that we are looking at a small number of brains, we chose to focus on the similarities rather than differences at this point. We are encouraged by the finding (basically, the number is the average across all structures of the percent of genes that are expressed in common for each structure across the first two brains). Indeed, it will be fascinating to start to dig into the areas of similarity and difference, both in structure and in functional class of gene. We are just starting to delve into this level of detail for analysis and will likely have more to say on it in the future.

Lehrer: Frankly, I was astonished that 82 percent of all human genes are expressed somewhere in the brain. This seems to me like yet another reminder that the brain is one awesomely complicated piece of meat.

Jones: This number is almost exactly what we found in the mouse, so that is good corroboration. When you think about the complexity of the functions of the brain, and the variety of different cell types found within the brain (there are blood cells, epithelial cells lining the blood vessels, pockets of dividing adult stem cells, plus all of the flavors of neurons and glia) it’s not quite as surprising to see how much of the genome is used to serve the brain.

Lehrer: What's next for the Allen Institute? And what do you think will be the first field of study within neuroscience to benefit from the brain map?

Jones: Next up for the Allen Institute is a project that focuses on the wiring of the brain in the mouse; we’ll again take our industrial approaches to build out a highway map of the brain. We’re also excited to have recently brought on board our new Chief Scientific Officer, Dr. Christof Koch. With him, we’re going to be figuring out some future strategies for tackling some of the really hard problems in neuroscience related to the encoding of information.

I think the first fields of study to see high yield from the Allen Human Brain Atlas will be drug discovery and human genetics. Drug discovery because researchers will now have a way to filter promising candidates and better understand the activity of existing compounds as they are able to match up expression of the drug target with the areas of the brain in which it is turned on. Human genetics because it adds additional information (where is the gene turned on?) to the ever-growing gene lists that are coming out of larger population studies, which is an essential step toward understanding the role these genes play in the biology of the disease.