Famous amnesic launches a bold, new brain project at UCSD
As best he could remember, Henry Gustav Molaison never visited San Diego, spending his entire life on the East Coast. When he died late last year at the age of 82, Molaison was a man almost entirely unknown except by his initials H.M. and the fact that experimental brain surgery had erased his ability to form new memories.
He forgot names, places, events and faces almost immediately. Half an hour after lunch, he couldn’t recall what he had eaten, or that he had eaten at all. His face in the mirror was a constant surprise because he remembered only what he looked like as a young man. Every question was new, even those asked just minutes before.
Yet Molaison bore this strange and unimaginable burden with grace and stoicism, allowing scores of scientists to study, probe and ponder his condition for decades, each seeking to better understand the mysteries of the human brain, memory and personal identity.
“H.M. started a revolution in the study of memory,” said Dr. Vilayanur S. Ramachandran, a professor of psychology and neuroscience and director of the Center for Brain and Cognition at UCSD at the time of Molaison’s death. “His was an unforgettable contribution.”
Molaison died of respiratory failure on Dec. 2, 2008, but his story — and his legacy — does not end in that Connecticut nursing home. Within hours of death, Molaison’s brain would be scanned, removed and placed in the preservative formalin, the first steps on a journey to San Diego and a new kind of immortality.
On a cold night in mid-February, Jacopo Annese returned to San Diego, arriving on Jet Blue Flight 411 from Boston. With him was the brain of H.M. They had flown coach: Annese in the aisle seat, H.M.’s brain in a 19-quart white plastic cooler strapped next to him in the window seat. More than a few fellow travelers looked curiously at the arrangement; some inquired directly.
“I tried not to be coy,” said Annese. “I told them the cooler contained a very important scientific specimen. I didn’t say a brain. I didn’t want to risk upsetting any passengers.”
Sophisticated and articulate, educated and trained in Italy, England and the United States, the 43-year-old Annese came to the University of California San Diego in 2005 to develop and direct the Brain Observatory, with an ambitious plan to create a new and unrivaled collection of human brains for scientific study.
These brains, normal and with various pathologies, will be preserved on thousands of slides that, in turn, are converted into extraordinarily high-resolution digital images freely available online. Researchers around the world will be able to use the material to conduct investigations ranging from parsing basic cognitive functions or the physical effects of diseases like Alzheimer’s to more abstract inquiries such as how memories are created and changed and the organic nature of consciousness.
The project has already begun with a handful of brains. Annese envisions the collection as a kind of library, each brain containing a life story. “We strive to treat the brains we study not as anonymous tissue, but as representations of a person and of a mind. We want to write books about people’s lives, neurological biographies that survive in glass and pixels.”
In this most novel of libraries, Molaison’s brain is the rarest of volumes. He is the most famous amnesic of all time, perhaps the most-studied neurological patient in history.
When he was 10 years old, Molaison began suffering epileptic seizures and blackouts, which increased in severity and frequency until, in his 20s, he was no longer able to work or live alone. In 1953 at the age of 27, Molaison agreed to undergo a radical experimental operation intended to relieve his suffering. Dr. William Beecher Scoville, a noted neurosurgeon at Hartford Hospital in Connecticut who had refined many of the techniques used in lobotomies, suctioned out finger-sized portions of the temporal lobes on both sides of his brain. The removed tissue contained most of Molaison’s hippocampus, a brain region whose function was poorly understood at the time, if at all.
The seizures largely stopped, but so too did Molaison’s ability to form new memories, though he could recall parts of his life before the surgery, a condition called severe anterograde amnesia. Scoville and a Canadian psychologist named Brenda Milner quickly realized that Molaison represented a tragic but rare opportunity to explore how human memory works.
With Molaison serving as willing and genial subject, identified only as H.M. to protect his privacy, they began a series of studies. In a landmark 1957 paper, Scoville and Milner described H.M.’s bifurcated memory for the first time. The paper, which has been cited by other researchers almost 2,000 times, led to the startling realization that memory is not a generalized brain function, but rather is controlled by key regions like the hippocampus, which regulates the flow of information destined to become long-term memory.
In many ways, H.M. appeared to be an ordinary fellow. He liked crossword puzzles and watching TV. He was polite, funny and self-effacing. “He was a very endearing person,” said Annese, who met H.M. once in 2006 during early planning for the Brain Observatory and library. “I was happy to get to know the man.”
Surprisingly, even with no ability to form long-term memories, H.M. could learn new things, in particular new muscle memory skills like drawing or playing golf. He didn’t remember taking lessons or practicing, but the acquired abilities stuck.
That discovery generated another new and fundamental insight into human cognitive function. There are different types of memories: Long-term declarative memories, which H.M. could no longer form; short-term memories which H.M. still possessed to a degree; and motor memories, such as recalling how to ride a bike, which H.M. never lost.
Each kind of memory, scientists deduced, must essentially be created and reside in different parts of the brain. Sometimes H.M. learned and remembered things that happened post-surgery, such as the assassination of John F. Kennedy in 1963. This suggested portions of H.M.’s memory system survived his 1953 surgery or that other regions had taken up some of those duties. No one really knew.
To really understand what was going on inside H.M.’s head, researchers needed to venture more deeply inside the brain itself.
The Brain Observatory is divided between an elaborately equipped wet lab for handling flesh-and-blood brains, and separate areas housing high-powered microscopes and computers for digitizing them.
Converting biology to bytes takes time. It is complex, painstaking and fraught with unprecedented technical challenges. A brain like H.M.’s represents a singular chance to advance scientific knowledge, but there is almost no room for mistakes.
“It’s a huge responsibility that many labs might not want,” said Annese.
Within four hours of his death, Molaison’s body was moved to Massachusetts General Hospital (MGH), where researchers, led by Suzanne Corkin, a professor of behavioral neuroscience at the Massachusetts Institute of Technology who had worked with H.M. for 46 years, conducted an overnight series of magnetic resonance imaging scans, a last chance to record his brain’s structure and condition “in situ.”
The next morning, after Annese had flown overnight to get there, he and MGH neuropathologist Matthew Frosch delicately removed H.M.’s brain from his skull.
“I was sweating bullets,” Annese later told the journal Science.
Like all fresh brains, H.M.’s had the consistency of Jell-O. It could be easily damaged, harm that might render it less useful — perhaps even useless — for further study. But the removal went smoothly and the brain was immediately deposited in formalin, suspended by a string so that it wouldn’t become deformed by resting on the bottom of the container. It would remain in formalin for two months until firm enough to travel safely to San Diego.
After returning in February with the brain, Annese conducted a second, more exhaustive series of MRI scans over two days, producing a more comprehensive anatomical map and a final record of the brain intact.
Next, the brain was immersed for weeks in increasing levels of sucrose solution. As the sucrose (sugar) infused the brain, it replaced water in cells, reducing the risk that ice crystals might later form, which could cause tissue to tear and reduce the brain’s research value.
High-security freezers house the project’s brains. (Annese has 10 so far.) The freezers are constantly and continuously monitored, with emergency backup power and an automatic alert system.
H.M.’s brain is scheduled to be sectioned on Wednesday, with segments of the procedure broadcast live via the Brain Observatory’s Web site (thebrainobservatory.ucsd.edu). Annese has been practicing the procedure on control brains.
Just prior to cutting, H.M.’s brain will be dipped in a liquid bath of isopentane at minus 40 degrees Celsius until frozen solid. The actual slicing is reminiscent of a delicatessen. The prepared brain is locked inside a cuff containing circulating ethanol to keep it precisely frozen. Too cold and the tissue might shatter during cutting; too warm and the tissue becomes sloppy. The cuff and brain are then mounted atop a commercial microtome modified by Annese with help from machinists at the Scripps Institution of Oceanography. Every component has been meticulously measured and engineered. A razor-sharp blade of tempered steel glides over the exposed brain, cutting from the front of the brain to the back, producing opaque, whitish slices that crinkle and wad on the blade’s edge like slivers of cut ginger.
Each brain slice is approximately 70 microns thick, about the width of a hair. An average-sized brain produces 2,600 to 3,000 such slices. Once the cutting begins, it continues until the brain is completely sectioned, a 30-hour endeavor.
A camera mounted above methodically records every slice, though a human operator must constantly attend to gently dab up each crumpled slice off the blade and deposit it into a sequentially numbered container filled with buffer solution.
“There’s something mesmerizing about doing this,” said Natalie Schenker, a postdoctoral research associate as she dabbed and deposited slices of control brain. “It’s like going on a journey, each slice getting you to another place in the brain.”
The majority of slices will be left untouched, cryogenically preserved for future experiments. Some slices, perhaps every 30th to 50th, will be mounted on postcard-sized glass slides. Mounting is an exacting process. A technician uses fine arts brushes to tease a wadded slice floating in a tray of buffer solution to lie flat upon an underlying slide, a physical match to the photo taken of that same slice during the cutting procedure. One mounting can take up to an hour.
The slides are then dried and some sequentially stained, what Annese calls “the club sandwich idea.” Different stain colors reveal different components of the brain. Blue shows individual neurons; brown highlights myelin-coated connective structures and support cells.
Finally, the slides are ready to be digitized. Each is placed under a microscope at 20X magnification to distinguish individual cell types. A computerized camera next begins snapping pictures of the microscopic scene. It requires 20,000 such “capture tiles” to produce a mosaic of just one slide, enough digital information to fill 200 DVDs.
Annese and colleagues have designed an automated system to do this demanding but tedious work. The data are sent to UCSD’s California Institute for Telecommunications and Information Technology (Calit2) and the San Diego Supercomputer Center, where it will be managed and stored for future use.
A fully sliced, mounted, stained and digitized brain is, in some ways, a return to wholeness, a brain reassembled in cyberspace. “We’re taking all of the two-dimensional image data (from the slides) and reconstructing them in a 3-D system,” said Alain Pitiot, a computer scientist at the University of Nottingham in England. “We’re reforming the brain so that researchers can see things in context.”
The intended result will be a bit like Google Earth. Scientists will be able to zoom in and out of a digitized brain; focusing down to the level of individual neurons or pulling back to examine whole brain circuits or regions.
When fully up and operating, the project will be an interactive affair. All data will be online and open to viewing and discussion. Neuroscientists will be able to watch procedures, make recommendations and observations, suggest experiments or request tissue samples. Nonscientists will have similar, if more limited, access.
For obvious reasons, H.M.’s brain holds special interest. It’s the catalyst for the entire endeavor. But more importantly, researchers are eager to compare what they learned about Molaison while he was alive with what they can discover in his digitally revealed brain.
“The extraordinary value of H.M.’s brain is that we have roughly 50 years of behavioral data, including measures of different kinds of memory as well as other cognitive functions and even sensory and motor functions,” said Corkin at MIT.
“We know what he was able to do and not do. Our goal is to link his deficits to damaged brain areas and his preserved functions to spared areas.”
H.M.’s brain will also be compared with those of other amnesic patients. Larry Squire, a professor of psychiatry and neurosciences at UCSD, has donated the brains of three much-studied patients. Some of Ramachandran’s patients have also agreed to donate their brains after death.
But the Brain Observatory and library project is about more that just H.M. and the mystery of memory. It promises the chance to investigate all things that ail the brain. For example, Annese is already processing brains that are part of an HIV study. And he has established partnerships with Lifesharing and the San Diego Eye Bank, which handle organ and tissue donations in San Diego County, to secure new donors.
Annese is quick to note that he’s not solely interested in afflicted or particular brains. He hopes people who have no known neurological issues will donate their brains to the Observatory, too.
“Healthy brains for study are very rare, but they are essential if we want to understand how brains age and why some people avoid neurological disease and dysfunction. We want to know what a normal brain is.”
But more profoundly, Annese hopes the Observatory and the future research that flows through and out of it will help answer the enduring question of what exactly makes each of us human and unique.
“We know that the human brain has a basic pattern,” said Annese. “We’re all born with the same kind of instrument, let’s say a violin. But how we play this violin and what we decide to play shapes this instrument during our lives. We can learn a lot by the wear-and-tear of life on our violins, how each of us has modified it. These could prove to be anatomical fingerprints of individuality, biological clues of what makes us who we are.”
frozen brain being sliced RIGHT NOW (be warned though: sometimes they have to break for messing around with ice and stuff)
first time actually posting an entry, hi thar. regardless they've been going at this since yesterday, i only started watching today. it's a 30 hour process, it's looooong, but they're in some of the interesting bits of the brain now. i don't know much about neuroanatomy but it's still really cool to watch.
edit // if you're watching now (2:30 am eastern) they're responding to tweets with post-its on the feed and it is absolutely ADORABLE