Muotri has said he hopes to use the creations to research brain function and formulate disease models without buying lab animals or expensive specimens from brain banks. So, too, are the ethical quandaries. But it will feel something. To Sestan and others, there is a mandate to keep pushing, not least because of what it might mean to the world at large: more diseases combated, more treatments developed, more lives saved and, above all, a fuller glimpse of a dauntingly complex organ.
The room has one arrow-slit window, which is almost always shuttered, and a wraparound desk buried under a minor Everest of unread journals. But having that quiet, that peace, it centers me. Focuses me. Until this year, Sestan was best known as the senior author of the first full genetic survey of the developing human brain; the paper, published in Nature, earned him a raft of awards, including the prestigious Constance Lieber Prize for Innovation in Developmental Neuroscience, which is given out every two years to a pioneering neuroscientist. That, to me, is what constitutes a great thinker.
Stubbornly, Sestan does not hold himself like a great thinker.
He likes fart jokes. He depressed his thumb; sure enough, the Subaru gave an obliging beep. When he was 11, his mother bought him a subscription to a medical encyclopedia series. He was entranced. School had been hard for him: He suffered from what he suspects now were dyslexia and attention-deficit disorder. Paging through the books, he came across an encyclopedia article by an anatomist named Ivica Kostovic, who would later serve as his mentor in medical school.
It took him a while to get there. By his own admission, he partied maybe more than he should have; he discovered Iron Maiden, grew his hair long and founded his own band, called Twilight Zone. Before his senior year of high school, as he was planning to eventually leave for college in Zagreb, he learned that his girlfriend, soon to be a sophomore, was pregnant.
They dated long-distance for two years; when she graduated, she and their son briefly joined Sestan in the capital, where Sestan set about establishing himself as a neuroscientist. He was a co-author of two papers that were among the first to locate, in the developing human brain, the enzyme that makes nitric oxide, which functions as a transmitter between neurons.
Then came the war years. But Zagreb was largely spared, and Sestan was able to stay in the capital to continue his studies. In the winter of , Sestan, still several months from earning his medical degree, convened a meeting to discuss his enzyme research. His mentor, Kostovic, who had become the deputy prime minister of the republic, was in attendance. But Yale, which offered several fellowships to promising foreign neuroscientists, did. Nenad should go. Nenad was not like that.
He always wanted the new thing. The next thing. By the summer of , Sestan had been made an assistant professor and given a lab of his own in Sterling Hall, along with a half dozen researchers and postgraduates. He was The demonstration in the Yale morgue inspired Sestan, and with the help of his team, he set about obtaining all the relevant literature on perfusion, including a study involving dog brains that had been perfused with whole blood. But it was something.
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And it kept me going. As modern medical technologies go, perfusion is a relatively old one: The first perfusion pump, invented in the s by the Nobel Prize-winning scientist and Nazi sympathizer Alexis Carrel and his close friend, the aviator Charles Lindbergh, was used to maintain blood circulation in cat thyroids during a series of transplant operations.
Sestan was determined to think like a scientist, not a philosopher. The existential questions interested him far less than the practical ones. Still, as Sestan acknowledged to me, the project was an outlier for him. The technical hurdles were immense: To perfuse a post-mortem brain, you would have to somehow run fluid through a maze of tiny capillaries that start to clot minutes after death. Everything, from the composition of the blood substitute to the speed of the fluid flow, would have to be calibrated perfectly.
In , Sestan struck up an email correspondence with John L. Robertson, a veterinarian and research professor in the department of biomedical engineering at Virginia Tech.
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Eventually, Robertson and BMI hoped, the machine would replace cold storage as a way to preserve organs designated for transplants. Sestan was intrigued, and when he traveled to the Washington area that February to present a paper on his gene-expression research, he arranged a side trip to Blacksburg to meet with Robertson in person.
On Interstate 81, near Roanoke, he was pulled over by a state trooper. They scare me. Back in New Haven, Sestan showed pictures of the machine to his colleagues. Some questioned his sanity. Others, busy with their own projects, were wary of getting involved. Zvonimir is Zvonimir Vrselja, a fellow Croat who was 28 at the time.
Angular and bright-eyed, Vrselja specialized in radiology; he has published on the vasculature of the brain and cerebral pulsatility — the way that blood moves through the cortex. Daniele was skeptical. In joining what was then still a top-secret project, he would have to rearrange his plans for his dual M.
In the spring of , Sestan made the first of several payments on a BMI machine, which Robertson and the company estimated would take half a year to fabricate. In the meantime, Daniele and Vrselja could test out a version of the system housed at Virginia Tech. It was decided that Sestan, with his academic commitments, would remain in New Haven. All three scientists were adamant that they had never once considered carrying out any tests on human specimens. Which is exactly how it should be.
But dead animals are a different matter. And to kill that number of animals, it just seemed absurd. Almost immediately after arriving in Virginia, Vrselja and Daniele ran into a very big problem. But there is not a lot of good literature on pig vasculature. We had to figure that out from scratch.
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Every morning for several weeks, the scientists woke up around to be at the slaughterhouse as the first pigs were led to the killing floor. Finally, placing the skull on ice, they would drive it back with them to the lab in Blacksburg. It was difficult not to get discouraged.
And initially they were working without neurosurgical tools. With every two steps forward, they seemed to be taking another one back. By running food coloring through the arteries of the brain, Vrselja and Daniele could see how blood traveled through the organ, but the arteries split and joined at such irregular intervals that it took days to figure out how each one influenced the circulation of blood.
By the 20th brain, they had a sense of which arteries connected to which; by the 40th, they had worked out what vessels needed to be closed off — and what sections of the skull needed to remain attached. Still, both the original and the current iteration, which Yale is seeking a patent for using the name BrainEx, work in fundamentally the same way.
First, the brain is mostly freed from the skull; all the dangling arteries, save the carotids, are cauterized or sutured. Next, the organ is flushed of residual blood.
A small thermal unit a miniature air-conditioner and heater sits under the football, controlling the temperature of the organ; the pressure and speed of the perfusate, meanwhile, are governed by a type of pump. As the British mathematician John Womersley managed to quantify more than half a century ago, blood does not circulate through our arteries at a uniform rhythm — it circulates in pulses, in concert with the shudder of our hearts.
It was a mess. By that summer, Vrselja and Daniele had fine-tuned the pulse generator and attached a number of custom sensors, which ran on software designed by Vrselja; the technology allowed them to experiment more easily, and widely, with different settings. As the weeks went on, Vrselja and Daniele discovered something encouraging: The interior brain tissue had a moist gray hue, as a living organ would — a sign that some cellular function had been restored.
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But to know for sure, they would have to perform the requisite lab work. Over the course of that spring, they fixed brains from separate specimen sets and delivered them to Sestan. Active brain cells can have a variety of shapes, depending on the type and function.
But dead or dying or inactive brain cells tend to look alike, as if a bomb has been set off somewhere in the nucleus and the entire structure has imploded from within. In the face of almost everything that was known about the brain — in the face of centuries of scientific research — the cells from the experimental group were metabolically active.
Sestan, hunched over the microscope, could hardly believe what he was seeing. Soon, the scientists had ratcheted up the length of the perfusions, from one hour to two or three, and Sestan found himself staring down a fresh and unusual dilemma. And yet by all accounts, the longer Vrselja and Daniele perfused the pig brains, and the better they got at the process, the more brain cells were restored.
BIS results are categorized on a scale from zero to Zero is the absence of electrical activity — a chunk of wood would score a zero on the bispectral index — while 90 to is consistent with full cerebral function in a living human. A person between 40 and 60, target numbers for general anesthesia, will be unresponsive to most stimuli. That summer, Sestan was preparing a grant application when Vrselja and Daniele summoned him to the perfusion room.
The BIS readout had just hit 10 — at the low end of what is called burst suppression, a stuttering pattern often observed in human patients in a deep coma. The first was to a contact at the National Institutes of Health. Latham is tall and ruddy, with neatly parted gray hair and a big, gaptoothed smile. The Paozhi processing stage distills herbs to their essence by crushing, roasting, burning, or frying to eliminate impurities.
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The grinder is sometimes used on soft herbs, like mint, the mortar and pestle on hard ones. The herbs are steadily boiled, often for hours, causing a chemical change believed to blend their healing properties. The medicine is consumed in a broth or tea of reed roots or applied as a patch at acupuncture points.
Generic remedies can be sold as pills or in packets, but some say teas from raw herbs are more effective.
Cheng has focused his research solidly in the realm of science, developing antiviral drugs for chronic diseases, such as hepatitis B. But he has also wondered whether there were other cures, based on herbs like wormwood, awaiting rediscovery. He opens a jar and hands me a pinch of a powder—a mixture of four herbs he calls PHY During the s Cheng noted that many cancer patients stopped chemotherapy because of its side effects, including diarrhea and severe nausea.
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