Stephen’s motor neurons had begun to die, one by one, and messages were failing to get through to his right hand. As more of those nerves died, fewer and fewer messages would get through the spine, and the rest of Stephen’s musculature would wither away.
Before he read Rothstein’s paper, Jamie Heywood dreamed of a cure, but he had no plan of attack. Mostly he was trying to become an educated consumer. He called his brother and his mother in Newtonville a few times a day with advice about vitamins and the drug riluzole. Now, as he absorbed Rothstein’s hypothesis, Jamie began to develop a maddening hope that he really might save Stephen.
Rothstein looked at the molecular action inside the cell, and there he told a story that is like Kafka’s parable writ small.
The life of the cell is almost as complicated as the life of a city, and the cell’s architecture resembles a medieval city’s. The cell has outer walls, and somewhere deep inside the walls are the walls of its dark and massive nucleus. Walls within walls, like the Castle in old Prague, the city and inspiration of Kafka.
The nucleus is packed with DNA. This DNA is powerless to do anything by itself, just as the brain is powerless without the body, or an emperor is powerless without the help of a thousand servants, minions, and messengers. Messengers are continually streaming in through the gates of the nucleus. These messengers bring word from the very edges of the cell and from outside its walls. Other messengers are continually streaming back out through the palace gates bearing replies that must travel to the city walls and beyond.
These messages are as vital to the life of the cell as the messages of the brain are to the body. Outside the walls of each nerve cell, for instance, there is always a standing pool of chemicals, including glutamate. This pool lies in the spaces between nerve cells like water and mist in a moat. If glutamate levels in the pool begin to rise outside the nerve cell walls, the cell goes into crisis mode, much as if the River Elbe were rising in Dresden. All along the moat a corps of engineers, really just a crew of glorified bailers, fights the rising tide before it floods the city.
These bailers are molecular machines. Sometimes they wear out. Sometimes in the rising tide they begin to be overwhelmed. Then chains of messengers rush from the outer wall through the old city squares and into the palace: We need bailers! And the emperor replies, Conscript bailers! If this imperial message should fail to reach the city wall, the bailers would be overwhelmed. The flood would rise. The city of the cell would die.
In Rothstein’s paper, he makes his way into the very heart of the cell. There he spells out precisely what the emperor whispers into the ear of the imperial messengers, and what the messengers take away.
In the first days of January 1999, about two weeks after Stephen’s call, Jamie asked Joe Gally to help him prepare a list of questions for Rothstein. Then he steeled himself and phoned Rothstein’s office number at Johns Hopkins. Jamie was thrilled and surprised when Rothstein actually took the call. Sitting in his monk’s cell at the institute, Jamie went through his list of questions one by one, scribbled pages of notes, desperately trying to keep up, and trying not lose his list in the growing pile of paper. Then he spent an hour and a half going over the notes with Joe Gally.
To understand Rothstein’s argument about ALS, Jamie had to know a little more about the way all this messaging works inside the cell. The DNA inside the nucleus is so imperially helpless that by itself it cannot even read its own messages. A fantastic army of servants inside the nucleus helps the DNA to read each one. This act requires, in practice, the unfolding and unpacking of one small portion of the DNA’s long, carefully wound scroll to expose just the one spot on the DNA that can read and respond to that particular message: in this case the message that says, Need a bailer out here.
DNA cannot read the message by itself and neither can it reply. By itself it is as helpless as a brain. Its army of servants has to work together to cobble together a reply. These writers, like the bailers out at the wall, are highly specialized molecular machines. As a matter of fact, DNA by itself is so helpless that the metaphor of the emperor at the center of things may someday have to go. The workings of a cell require so many hands, each of which is indispensable to life, that the cell is really more like a democracy than a kingdom. It is only because of our deep-seated romance with monarchs, our taste for the glamour and trappings of royalty, that we like to think of DNA as the imperial molecule. Biologists with leftist leanings make this point all the time, passionately, and they are correct. Every working part of the cell is vital, from the giant coils of DNA at the center to the tiny bailers at the moat.
In human DNA, the imperial message “conscript more bailers” requires a long message in the genetic code. Some of the letters in the message are gctcaccccg gcgtccgctt tctccctcgc ccacatctgc cggatagtgc tgaagaggag. A few more are aaggatatga gtctcagcaa attcttgaat aaactcccca gcgtatccta tggta. Now, contrary to the view that molecular biologists developed in the early days of their science, this is not the only information that dictates the message that goes out. DNA’s metaphorical servants and attendants have some freedom, some wiggle room, in transcribing those letters and assembling the message that will go back out through the gates. They have to work with the message in the DNA, but they can splice it together in many different ways. The message they splice together is made of a slightly different molecule called RNA. The spliced message that must now make its way out through the wall of the nucleus is called messenger RNA.
Now we are deep in the heart of the palace of life, at the moment when the dying emperor whispers to the messenger. What Rothstein had discovered was that in many of his patients with ALS, the alternatively spliced messages were failing. The cell had to make more bailers or it would die, and then the whole body and all its cells would die; but the messages were bad.
In the cell, messenger RNA makes its way out into the crowded throngs outside the palace walls. There it finds its way to a piece of heavy machinery called a ribosome, where it is translated. The ribosome travels along the messenger RNA, reading the message and constructing a large ribbon of a molecule. This is a protein.
Now as the protein emerges from the ribosome, it carries a sort of imperial signal, and it runs through the cell toward the wall, as in the race of an imperial messenger. If the protein emerges from the ribosome without that imperial signal, it can go adrift and never reach the cell membrane. There are many diseases that occur at that stage, and they are not all neurological. The best known is cystic fibrosis, in which a simple protein emerges without the imperial signal and fails to get exported through the cell membrane. For lack of that one protein, the body’s lungs slowly become coated with slime, until the body drowns.
Technically, when the message in the DNA is turned into messenger RNA, the act is called transcription. When the messenger RNA is used to build a protein, the act is called translation. But essentially we are talking about a chain of messengers in which something can go wrong at each point.
Even the folding up of the ribbon of protein into its proper shape is a kind of translation, in a sense. And if the proteins get misfolded, they can cause a long list of diseases. And that is what goes wrong in ALS, Rothstein argued. The misspliced RNA led to mismade proteins and they never made it out of the cell—or they failed at the wall.
Glutamate is always lying in pools outside each nerve cell because it is the most common chemical compound that nerve cells throw at each other in order to pass messages back and forth. (Other messengers are serotonin and dopamine.) Glutamate is an ancient substance in the body. It is one of the body’s amino acids, the basic building blocks of proteins. If the nerve cell cannot get rid of the glutamate as fast as it piles up, then the glutamate overstimulates the cell. The cell does not literally drown in glutamate; it gets overexcited. It works itself to death. This is called excitotoxicity.
The bailer has to transport glutamate out of the moat to points inside a nearby cell where it can be safely dismantled and recycled and used to make more pro
teins. The bailer in question, the crucial bailer that Rothstein was focusing on, is a protein called excitatory amino acid transporter two, or EAAT2, pronounced Eat-Two.
At the Neurosciences Institute, Jamie pieced all this together as fast as he could. Stephen’s nerves were dying, so they were not sending signals to his muscles. For Stephen the first sign of trouble had been the thenar eminence. The muscle in there had not been getting signals from Stephen’s brain because the nerves in his spine that carried the message to that muscle were dying. And so the muscle had withered away, and a gifted young craftsman had lost the use of his right hand just as he figured out what his hand was made to do.
If Rothstein was right, the problem had started with the splicing of the imperial message, which caused the failure of those tiny bailers at the cell’s outer wall.
It was so complicated, and yet it was also simple. If Jamie could get the correct message into the nuclei of Stephen’s dying nerves, then the message might get out through the palace walls and race through the city of the cell to its outermost wall, and then far, far beyond, until it found its way at last into those waiting hands.
Eleven
Hope and Science
Jeffrey Rothstein and Robert Brown are physician-researchers: scientists who do medical research and treat patients at the same time. There are many life scientists who never see patients. Molecular medicine more than any other rests on the studies of a vast number of biologists who are essentially doing the work of anatomists, but within the cell, tracing the structures and functions of the almost endless varieties of molecules that perform the dance of life.
Rothstein’s paper about EAAT2, for instance, led into two kinds of unknown territory. One was alternative splicing. No one really understood how the cell manages to do the work of reading DNA and transcribing its message into RNA inside the nucleus.
The other rough, dark territory was protein transport. The EAAT2 gene made a protein that did not get transported properly when the DNA message was mistranslated. When the protein did get transported properly, it worked to transport another molecule, glutamate. Protein transport inside cells is still poorly understood. It takes endlessly patient and hopeful work to understand.
One of the pioneers in that field is Günter Blobel. In English, depending on how one pronounces the name, it can rhyme either with “noble” or with “Nobel.” That year, Blobel would become Rockefeller’s twentieth Nobel Prize–winner. His story is as much a quest as Jamie’s, but the older man came out of pure science and operated on that very different timescale, the urgencies of a clock whose hands take lifetimes to go around once.
It began in early February 1945, which happens to have been the same moment that scientists at Rockefeller were making the first electron micrographs of the architecture of the cell. Blobel was a child of German refugees. They came from a village in Silesia, they were fleeing the Russian front, and they were passing through Dresden, the city that called itself “Florence on the Elbe.” Günter Blobel was eight years old and it was the first city that he had ever seen. He had always loved architecture, beautiful spaces, beautiful buildings. Even at six or seven, he would ask his parents if he could go into a church. They would give him a polite, baffled shrug. You go ahead, we’ll wait for you out here.
In Dresden he saw palaces, castles, churches, and the city’s famous cathedral, the Frauenkirche, Church of Our Lady, which floated over the baroque city, a great stone dome in the shape of a bell. The war was almost over. Firebombing had already destroyed most of Berlin, Hamburg, Cologne, on and on. But in Dresden the only treasure the Germans had lost they had burned themselves. On November 9, 1938, which the Nazis called Kristallnacht, the Night of Broken Glass, they had torched the city’s synagogue, which had been designed by the same architect who built their opera house.
The Blobels made their way to a relative’s farm twenty-five miles to the west. On the night of February 13, 1945, a huge armada of Allied planes flew low over the village, dropping flares. Half an hour later, the sky to the east, toward Dresden, began to glow red with a false dawn. Soon the light from the fire was so bright that standing outside the blacked-out farmhouse they could have read a newspaper.
That June, the boy was in a wagon train of refugees that wound its way east and crossed the valley of stones that had been Dresden. Even the Frauenkirche was gone in the plain of smoking stones. The boy smelled a stench that was heavy and sweet and bitter, something like the smell of cherries. The wagon train reached the Soviet border and turned back. Not long afterward the boy and his family passed again through the desert of stones, now with everything they owned in a wheelbarrow, and took shelter once again on the farm to the west of what had been Dresden.
When he grew up, Blobel found his way to the laboratory at Rockefeller where they had opened up the baroque architecture of the cell. He built on the work that was begun there, and arrived at a bold young man’s idea that he called the signal hypothesis. Blobel was a scientist’s scientist, someone doing pure research that seemed very far from medicine, research for the pure joy of understanding. He had the same joy that Lucretius, the poet of science, sang in ancient Rome: “There is more to learn; for me it’s pleasant work.” “I feel a more than mortal pleasure in all this.”
He spent thirty years proving the signal hypothesis. He proved it essentially by disassembling and reassembling the cell’s working parts in test tubes. He engineered exact facsimiles, restorations, of the beautiful architecture of the signal and of the invisible halls and doors through which it has to pass from the nucleus to the outer membrane. Like Kafka’s imperial messenger, any protein that was bound for the construction and reconstruction work inside the cell had to carry a signal. Blobel found the signal. And he saw that if the messenger did not have just the right signal, like the medallion worn by Kafka’s messenger, the message could not get through the cell. Sometimes it could not even get through the pores of the nuclear membrane. “But how vainly does he wear out his strength; still he is only making his way through the chambers of the innermost palace….”
For thirty years, Blobel studied the ways a cell transports proteins. It was like getting to know an ancient living city whose restoration work is never done. In his mind, Blobel compared the masterpieces of molecular architecture that he was discovering to the wonders that he remembered from the beautiful doomed city of Dresden. The baroque architecture of the nuclear pore reminded him of the Frauenkirche, Church of Our Lady, although his students and colleagues laughed when he said so. When he won the Nobel Prize in 1999, Günter Blobel held a press conference at Rockefeller and announced that he was donating his prize money, almost a million dollars, to the restoration of the church and the synagogue of Dresden.
Twelve
Almost No Time
In the first weeks of January 1999, Jamie sat at his beautiful redwood desk with the green, architect-designed file drawers underneath it. It was still covered with neat piles of papers about the different projects he had worked on for the Neurosciences Institute. Those piles were steadily disappearing under papers about ALS and stacks of medical books and guides, including, still, The Human Brain Coloring Book. After a lifetime of dyslexia, suddenly Jamie could read with ease—and read at enormous speed. On his computer’s nineteen-inch monitor, he kept many browser windows open at the same time. He would follow a lead from one of Rothstein’s papers and check it out on PubMed. Then he would click on “Related Articles” and scan a list of twenty abstracts. With a click he opened each of them in a new window. Then he paged through and discarded some and copied the ones he wanted into his files. “I could read an abstract in just—flash,” Jamie says. “I mean, I was like, boom, boom, boom, boom. My mind was in some kind of warp or something. I would click, and then I’d go, That’s relevant, not relevant; relevant, not relevant. I was already very fast at using computers. And I remember just sort of flying through things.”
Jamie cannot explain why his dyslexia vanished. “You know, everyone l
aughs at me when I say this, because I went to MIT,” he says. “But I’d never learned anything by reading before. And all of a sudden—you know, I could have gone through medical school! I could read, I could understand, I could remember. Obviously I was surrounded by astounding teachers. But it was unreal, this period of time.”
He left the institute often now and went to conferences nearby at the Salk Institute and the University of California at San Diego, lectures on anything that might be relevant to his search: mad cow disease, Alzheimer’s, Parkinson’s. He visited the offices of local ALS specialists and clinicians, most of whom had the same plastic model on display, a curving human spine and skull. He made appointments with the lecturers he thought might be able to tell him something; he talked with neurobiologists, geneticists, molecular biologists.
Around the institute, Jamie began to act as obsessive as Joe Gally. He skipped sleep, meals, haircuts. He wandered among the institute’s futuristic buildings and stared at the pebbles in the paths. Normally he walked very fast when he was going somewhere. Now he moved deliberately, looking down—not staring at the ground as if he were trying to avert his eyes from the world, but as if he were searching for something there in the stones. He even drove slowly. After a day of tutoring sessions with Joe, and confusing sessions in lecture halls, he drove home trying to calculate how much time he had. This was hard to do, because the course of the disease is so variable. How would it take Stephen? When he wondered about this, his guesses were tinted by his family pride. He was sure that with a strong young carpenter like Stephen, the disease would go slower than with most.
His Brother's Keeper Page 9