CHAPTER 21
The brain is a never-ending source of fascination for me. It’s the organ that unites us as a species and distinguishes us from one another. It keeps us breathing and upright, makes us elated or anxious, and, not least, harbors our creativity. Here is a truly astonishing piece of evolutionary engineering, one that does so many things so much better than the most advanced computer, and yet we’re just scratching its surface.
The 1990s saw an explosion of new theories in genomics, informatics (the conversion of data into usable information), and molecular neurobiology. In February 2001, eleven years after it began, the Human Genome Project released a first draft of the roughly 3 billion base pairs that comprise our genes. The HGP confirmed that fewer than twenty-five thousand human genes were needed to create the brain’s 100 billion multifaceted nerve cells, all linked in intricate networks totaling a quadrillion neural connections. How could such a small genome serve as the blueprint for such a complex organ? And how might the HGP’s achievement be used to advance neuroscience?
I was meeting around that time with experts in early learning and linguistics, and their research was engaging, but I felt a pull to get inside the human brain, the ultimate machine. To think it through, I met with Jim Watson, the director of the Cold Spring Harbor Laboratory and codiscoverer of the double-helix structure of DNA. Then in his seventies, Watson was a confirmed iconoclast, always ready to venture off the beaten path. He proposed that I found a behavioral research center to focus on gene expression in the brain, the phenomenon of different genes “switching on” in different cells. The cell’s “expressed” genes direct the production of particular mixes of proteins, which in turn differentiate heart cells from skin cells (or tumor cells) and control how they function.
I also met with Steve Friend, the founder of a cutting-edge Seattle genome-analysis company. He, too, thought the time was ripe for a facility at the crossroads of human psychology, genomics, behavioral genetics, and brain biology. Advances in data storage and retrieval would enable us to compile and analyze the masses of new information we gathered.
“The more I read about the brain the more fascinated and interested I am,” I wrote in a December 2000 e-mail that included my first mention of a brain institute. “I am especially interested in how the genetic ‘blueprint’ for building the brain works.”
MOST NEUROSCIENCE RESEARCHERS are highly specialized, pursuing their questions in discrete areas of the brain as though they’re drilling into an orange with a needle. I wanted to cover the entire rind and help scientists locate the most promising spots to drill, to get them probing faster and deeper that much sooner. In March 2002, I invited twenty-one scientists, including four Nobel laureates, to join me at a three-day brainstorming session, or charrette. The scientists assembled at a dock in Nassau in the Bahamas and ferried over to our conference center for the weekend, my yacht, Tatoosh, a serene setting for an intensive discussion.
In addition to Watson and Friend, the guests included Richard Axel, the Nobel Prize–winning neuroscientist who’d advanced the understanding of our sense of smell; Steven Pinker, the Harvard psychologist and bestselling author of books on linguistics; Marc Tessier-Lavigne, who did pioneering work on the assembly of the embryonic and fetal brain; Lee Hartwell, who won his Nobel for discovering the genes that control cell division; and David Anderson, a Cal Tech neurobiologist who’d play an instrumental role in defining our mission.
I came to the charrette with a rough vision of an institute on the frontier of brain science. One expert suggested that I establish a top-tier research facility, on par with the Rockefeller Institute, to recruit the best and brightest researchers from around the world. The price tag: $1 billion, half to start up and half to endow.
Money aside, I was wary of the traditional academic model for research institutes. Scientists of stature pursue whatever they find most interesting and are not easily steered. I had seen the downside of a loosely defined organizational mission at Interval Research, which Vulcan had closed two years earlier, and I wasn’t eager to repeat it. The alternative was to concentrate on a single large-scale endeavor that might transform the field, a neuroscience equivalent to the Human Genome Project. We’d have concrete milestones en route to tangible results within a few years. I wanted a facility run on an industrial scale, with biotech urgency but without the profit motive.
My guests debated what exactly our institute should address. The discussions were lively, wide-ranging, and often competitive; great scientists are adept at putting forward their proposals. (It’s what they do to get their funding grants renewed.) All sorts of ideas were floated. Was there an underlying genetic basis for happiness, or for love? How could we improve brain-imaging technology? What single disease might be most usefully explored?
By the second day, the conversation kept circling back to the idea that had first surfaced in my talks with Watson and Friend. What neuroscience needed more than anything else, I kept hearing, was something very basic: a better map of the brain.
In existing maps relating to gene expression, the anatomic resolution was too coarse to be of much help in deciphering how the organ really worked. The National Institutes of Health had recently funded a Brain Molecular Anatomy Project, but the work was too fragmented for consistent quality control, and there was only enough funding to look at six hundred genes per year. At that rate, a complete atlas might take half a century. Brain mapping was stuck in a cottage-industry stage, like the one that hobbled genome sequencing before the HGP and Craig Venter’s Celera Genomics made the effort systematic.
By our closing session, the scientists were unanimous. A brain atlas was “an appropriate inaugural project for the Allen Institute because of the incalculable contribution the Atlas can make towards solving basic molecular and genetic questions about human behavior.” The atlas would link genetics and anatomy, with maps of switched-on genes overlying the brain’s three-dimensional structure. It would open new avenues of research into neurological and psychiatric disorders, as well as fundamental questions of brain science. Our initial effort, the scientists agreed, should map the adult mouse brain and focus on healthy specimens. (Most studies were then looking at embryonic brains, and NIH research emphasized diseases.)
A brain atlas of gene expression fit my main criterion, to go where important work lay undone. It was “big science” with obvious real-world utility. From Alzheimer’s and Parkinson’s to schizophrenia, brain disorders afflicted tens of millions of Americans. Once we mapped a normal “reference” brain, we’d be able to isolate the active genes that triggered these ailments. Scientists could begin to find ways to target them therapeutically. The potential was staggering.
And far down the path, I thought, our work might even help uncover the essence of memory, desire, compassion—of what makes us human.
I LOVE TO travel with close friends and family. My mother liked Tahiti and Japan, though she was less fond of Africa after a hippopotamus broke into the compound she was staying in and had to be rope-lifted out of the swimming pool. Her favorite trip was a plantation tour on the Mississippi, where she paused on people’s porches to share iced tea and listen to their stories, just as she’d once lingered with her neighbors on her way home from school in Anadarko. She was still the best listener I’d ever known.
Over the years, I had bought up land around my home on Mercer Island, adding houses for my mother and sister. My mom thrived there amid her fifteen thousand neatly shelved books, most of them bought for a quarter or less at a thrift store. Nothing gave her more pleasure than perusing her stacks, meticulously organized by authors’ last names, and finding an old friend.
My mother used to lead a book club for faculty wives from UW, choosing works by African authors one year, Eastern European novels the next. She took almost as much joy in selecting as in discussing. When she set out to compile a list of 100 favorites for me, she wound up with 165—as she’d often say, “What’s better than a good book?” But her days as a reader were numbered. In a late-night e-mail journal entry on January 21, 2003, I wrote, “My mother is struggling right now with an Alzheimer’s-like condition. (She was diagnosed in the last two weeks.) I’m sick at heart about this.”
Her dementia was subtle at first. One minute she’d finish a crossword puzzle with ease, and the next she’d forget what she’d told me minutes before. She was angry about her memory loss; she’d reached that wrenching phase in which she knew she was slipping but felt powerless to stop it. Then came a long, slow twilight with gathering darkness. I saw the horrors of Alzheimer’s up close, and I was devastated. If there was anything I could do to spare others a similar fate, I was determined to try.
I turned fifty the day I wrote that entry, the point in life where many of us begin to consider what we’ll be leaving behind. In September 2003, I launched the Allen Institute for Brain Science with a $100 million contribution. Its charter was ambitious: “We believe this is a historic opportunity to unite the genome and the brain, and use the data and technology to tackle the challenges of neurodevelopmental, neurodegenerative and psychiatric disease.”
We found a facility in Fremont, a peaceful Seattle neighborhood perched above a ship canal. There was space for our whole staff under one roof: process engineering, molecular biology, anatomy, software development, database creation. As president and chairman of the board, my sister would once again oversee my brainchild. A blue-ribbon group of scientists, including several strong voices from our charrette, would serve on an advisory board.
The highest hurdle for a brain atlas was the sheer amount of data to be collected and organized. Where the HGP’s data consisted of sequences of letters, ours would be high-resolution images, which needed far more storage space. The initial mouse brain atlas would involve 85 million images on 250,000 slides—600 terabytes of data (600,000 gigabytes, or 600 trillion bytes), or more than half as much as the total content of the Internet when we began.
Early on, we confronted a pivotal issue. Should we charge for access to our database? Revenue from users and royalties from commercial work could help expand our operation. On the other hand, the institute’s success had to be measured by the discoveries it sparked. The more widely the atlas was used, the greater the chance of a breakthrough. Charging for access might limit use to elite universities and the largest pharmaceutical firms, while shuting out some talented researcher in Johannesburg or Seoul who couldn’t come up with the fee. We decided to place our data in the public domain, with free Internet access and a powerful, user-friendly interface. No registration would be required.
POSTMORTEM HUMAN BRAINS are all very different. The donors vary in age, genetic backgrounds, and upbringing, all variables that shape the organ’s form and function. And so, like countless human-oriented studies before us, we opted to start with the ideal laboratory mammal, the mouse. The mouse brain is no larger than an almond, no heavier than a teaspoon of sugar. But it’s a terrific template for mapping. It closely resembles our own brain in both form and content, with 90 percent of a mouse’s genes having a human counterpart. Inbreeding would give us close-to-identical subjects at a uniform age of eight weeks, a near-perfect experimental system.
We chose a state-of-the-art hybridization technique developed at the Max Planck Institute in Germany and later implemented at Baylor College of Medicine. The mouse brains would be sliced north-to-south into hundreds of sections, then dunked into an RNA solution to probe for a specific active gene—one gene per slice, five or six genes per brain. All neurons expressing that gene would be revealed.
The scope of an all-gene atlas demanded an intensively choreographed, high-throughput approach to convert hundreds of thousands of slides into digital data. Modeling our work after Baylor’s, we organized laboratory robots in assembly-line fashion, staining slides around the clock (up to four thousand per week), photographing the sections under microscopes, and channeling the images to our database.
A year after we launched, I promoted Allan Jones, who had overseen the collaboration with Baylor and recruited much of our staff, to run the project. It was a big promotion, but Allan quickly proved up to the task. In December 2004, we released the first installment of the Allen Brain Atlas: visual data from nearly two thousand genes. David Anderson, the advisory board member who first proposed the atlas project, calculated that we’d accomplished over fourteen months what might have taken a solitary scientist seventy-seven years.
A database is only as good as its interactive search functions. If people can’t find and download what they’re looking for, it’s like a vast library with no call numbers. In structuring the mouse brain atlas database, we created software that answers both the “where is” and “what is” questions. Say, for example, you are looking at a gene that increases sensitivity to painkillers like morphine, and want to know just where it is switched on. First you’ll be taken to the high-resolution, two-dimensional data for that gene at the cellular level. Then a viewing application, the 3-D Brain Explorer, will show how the gene is distributed across the “consensus” brain of all mice used in the study. Or, if you prefer, you can type in amygdala (the region of the brain that governs fear and anticipation) and see which color-coded genes are active in that area. Either way, for the very first time, you will have access to gene-expression data at the cellular level.
The neuroscience community initially greeted our tool with some skepticism. The Allen Institute was the new kid on the block, funded by a technologist with no track record in the field. Our industrial-scale approach was unorthodox, and it took a while for people to believe that the data was really free, no strings attached.
Less than two years after our launch, in September 2006, the full set of data for the mouse brain atlas was released on schedule, three years after we’d begun. With our first database complete, we made public these findings:
The brain contains more genetic activity than we had thought. Scientists had previously estimated that two thirds of the genome was expressed somewhere in the brain. The Allen Brain Atlas shows that the proportion is closer to 80 percent, which helps explain why drug therapies designed for other organs often have side effects.
Genes are expressed in distinct areas. Most of them are switched on in very specific subsets of cells or particular regions of the brain. This discovery has unveiled how biochemistry varies in different parts of the brain and how it relates to their specialized functions. By understanding these variations, scientists will be better equipped to modulate biochemical activity in diseased brain structures.
Previous brain maps were sometimes inaccurate or incomplete, even on a gross anatomical level. As they defined gene expression patterns, our scientists came across previously unnoticed structural subdivisions. These findings have refined the understanding of how the brain is partitioned, a key to better diagnoses and therapies.
After announcing the completion of the mouse brain atlas in Washington, D.C., I met Francis Collins, the former head of the Human Genome Project and now director of the National Institutes of Health. Early on, we’d felt a certain tension radiating from his agency; some at the NIH may have viewed our institute as a competitor. But Collins congratulated me wholeheartedly that day, and our institutional relationship has grown ever since. (In 2009, the Allen Institute won a GO Grant through the NIH as part of President Obama’s stimulus package.)
Over time, any resistance to our work has dissolved. Susumu Tonegawa, a Nobel laureate and director of MIT’s Picower Center for Learning and Memory, called the mouse brain atlas “a breakthrough in neuroscience. It’s a new, extremely powerful approach to try to understand the brain. I would say it’s revolutionary.” Time said it was “a go-to source for researchers studying everything from multiple sclerosis to brain tumors.” In 2007, after Allan Jones coauthored a paper on the atlas in Nature, user hits on the Web site rose to record levels and are now up to a thousand visitors a day.
WHEN I TRAVEL to scientific institutions, I’m delighted to hear stories of how our atlas has helped the field. “We use it every day,” a Stanford neurology professor told the Associated Press after a brief Web site glitch sent worried graduate students pouring into his office. “We can’t imagine life without this tool anymore.” Like the genome sequence, the brain atlas can save grad students and postdocs years of grind-it-out preliminaries. Researchers can track expression patterns for their gene of interest from our database, and that becomes their starting point. It’s like handing prospectors a map of a region’s diamond reserves. They can concentrate on the digging, knowing they’ve been directed toward something of value.
One of the livelier topics at our charrette was breadth versus depth. Should we map the entire brain or focus on a single region? The wisdom of a whole-brain atlas is now clear. A Harvard researcher found a receptor gene expressed in the hypothalamus, in one of the few neurons in the brain linked to obesity; the atlas has accelerated his quest for a safe and effective drug therapy for appetite control. At the Seattle Swedish Neuroscience Institute at Swedish Medical Center, another researcher uses our data to zero in on genes with abnormal activity levels in glioblastomas, a lethal form of cerebral tumor. We’ve heard similar stories from researchers on Alzheimer’s, epilepsy, Down syndrome, and just about any other process or disease associated with the brain.
I’m especially excited about the institute’s role in what may be a landmark study on the origins of autism, the spectrum of brain disorders that impairs a person’s ability to communicate, express emotion, and form social bonds. The project began in 2008, when Autism Speaks funded an effort led by Eric Courchesne of the Autism Center of Excellence at the University of California–San Diego. Courchesne had already established that autism was characterized by excessive brain growth in infants and toddlers, notably in the cerebellum and frontal lobes, but his studies had been limited by low-resolution imaging. Meanwhile, other studies had identified dozens of suspect genes but couldn’t tell where they were located or what they might be doing. Courchesne wanted to pinpoint both the genes and their locations to understand what might be setting off the disorder on a molecular level. Fortunately, he had rare postmortem brain tissue from both autistic and normal children. (Previous autism studies had mostly used adult brains, a major drawback for work on a developmental disorder.)
That was where we came in. Our high-resolution techniques enabled us to look more deeply into cellular structure, and to focus in particular on genes that are normally expressed in cells in specific cortical layers. We could then tell if those cells were in the right places in autistic children or not. In essence, we could trace autism’s fingerprint.
We began by sectioning brain tissue from both the autistic and control cases. In each, we explored a part of the frontal lobe tied to attention, working memory, and “theory of mind”—the ability to understand that other people have their own perspectives on the surrounding environment. Our goal was to find out whether this area of the brain was organized differently in autistic children.
Using our catalog from the mouse brain atlas and the narrower Allen Human Cortex Study, alongside data from two normal control brains, we identified about twenty genes that were strongly and consistently expressed in the target area. Of those twenty, five had already been implicated in autism. We then studied more than two thousand slides to compare those genes’ expression in the autistic and normal brains. We expected to find abnormalities throughout the subregion, and we did. But we were surprised by the form they took: small, self-contained areas that were unusually dense with neurons yet showed a sharp decrease in the expression of most of the target genes. These pathological patches, as our scientists called them, existed in all of the autistic subjects. The brain tissue surrounding them appeared completely normal.
Here was powerful evidence that autism might be a focal disorder in self-contained local areas in the brain. Most of the pathological patches were measured in millimeters and were easy to overlook in the tight mesh of neurons unless you examined one layer of cortex at a time. Decades of experiments with lower-resolution MRIs had failed to detect them.
The UCSD–Allen Institute study represents a new and powerful way of doing large-scale neuropathological research at the molecular level. Beyond confirming that vaccines cannot possibly cause autism, it reveals clues that may clarify the disorder’s developmental origins and help explain why children vary across its spectrum. By understanding the cellular basis for autism, scientists may be able to devise new interventions, from early diagnostic testing to drug and other therapies. It now even seems possible that we might establish the root causes of autism, along with schizophrenia and other diseases, within our lifetimes.
OUR AMBITIONS HAVE continued to grow. The Allen Human Brain Atlas, a four-year project scheduled for completion in 2012, represents a leap in scale and complexity. (The human brain is two thousand times as large as its mouse counterpart; flatten out the human cortex, and it’s the size of a seventeen-inch pizza.) The challenges begin with finding suitable tissue. We need brains from “normal” adults between twenty and sixty-eight years old, with no local injuries, drug addictions, or history of neurological or psychiatric disease. (Suicides are ruled out by definition.) And because brain tissue deteriorates within twenty-four hours of death, it can be challenging to get it in time. Thanks to the institute’s relationships with NIH-funded brain tissue repositories on both coasts, we have received three brains so far and hope to get ten to complete the initial atlas. That might seem like a small sample for building a reference brain map, but only a small percentage of human genes vary in their pattern of expression across individuals.
Given the amount of staining and scanning involved, it would be impractical to submit the entire human brain to analysis. Following the recommendation of our advisory council, we compromised. As a first step, we’re building a comprehensive 3-D atlas that will cover all expressed genes in all areas and offer something for every specialty. Because this first 3-D cut can’t get down to the cellular level, we’ll also provide a finer-resolution database for up to five hundred genes of especially high value to researchers in each of the major brain structures. Together, these two approaches will furnish unparalleled information about the normal human brain.
Our second game-changing project is the Allen Mouse Brain Connectivity Atlas. At our charrette, Richard Axel pointed out that human behavior is primarily controlled not just by the expression of individual genes, but even more so by the physical and biochemical pathways that excite or inhibit billions of interdependent neurons. Most current research in this area is limited to efforts to define cell-to-cell or region-to-region connections. Our goal is to tackle the brain as a whole and to illustrate in detail how neurons are wired throughout.
A comprehensive brain circuit map demands new techniques for tracing connections, and the complete data set could run as large as several quadrillions of bytes. But if we succeed, this kind of diagram could dramatically expand our knowledge of how nerve cell communications are altered by disease and how new therapies might most effectively intervene.
DURING MY FIRST flush of excitement over the mouse brain atlas, I met Eric Kandel, the Columbia University neuroscientist who won the Nobel Prize in Physiology or Medicine for his work on memory storage in neurons. I told him, “We’re going to know so much more about the brain in the next ten years.”
Dr. Kandel gently applied the brakes. “I’ve been working in this field for fifty years,” he said, “and not in my lifetime—and probably not in yours—will we understand the brain.”
I was reminded of a question I’d put to the assembled luminaries at our charrette: “How many Nobel Prizes will need to be won in neuroscience before we really know how the brain works?” Their responses ranged between twenty-five and fifty.
That’s a long, long way from here. In the meantime, I’m confident that our atlases will help those future laureates and speed them on their way.