## Metadata - Author: [[Jonathan Weiner]] - Full Title: His Brother's Keeper - Category: #books ## Highlights - “Pleasant it is, when over a great sea the winds trouble the waters, to gaze from shore upon another’s tribulation: not because any man’s troubles are a delectable joy, but because to perceive from what ills you are free yourself is pleasant.” ([Location 746](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=746)) - Of all the pathologies in medical textbooks, amyotrophic lateral sclerosis is one of the most painful diagnoses for a doctor to deliver and a patient to receive. It has been a death sentence ever since its discovery a century and a half ago by Jean Martin Charcot. In France it is still called Charcot’s disease. In America it goes by the name of its most famous victim, Lou Gehrig. ([Location 979](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=979)) - In ALS, nerves in the spine begin to die one by one. These are what are known as the motor nerves, because they carry signals from the brain to the muscles of the body. Without signals from those motor nerves, the muscles wither and atrophy. As more nerves die in the spine, the body becomes progressively paralyzed. The damage travels up and down through the spinal cord until it reaches the brain stem, which controls the muscles that allow a human body to breathe and swallow. Even then, patients remain wide-awake and fully conscious. They can still see and hear, feel and reason. They watch their muscles wither away until they can no longer breathe, and they suffocate to death. ([Location 982](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=982)) - For nothing in the whole world can be brought To equal the agility of thought. LUCRETIUS ([Location 1069](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=1069)) - Joe was a very useful member of the journal club. When he brought in a paper, he could not only explain why it was exciting, he had also read all the references the authors cited at the bottom of their paper; and he knew a good deal about them, and about their references, too. Each piece of new science is like a brick in a city that rests on seven cities buried underneath. ([Location 1141](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=1141)) - 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. ([Location 1226](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=1226)) - 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. ([Location 1231](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=1231)) - John Donne wrote on his sickbed, “I observe the Phisician, with the same diligence, as hee the disease; I see he feares, and I feare with him: I overtake him, I overrun him in his feare, and I go the faster, because he makes his pace slow; I feare the more, because he disguises his fear, and I see it with the more sharpnese, because hee would not have me see it.” ([Location 1470](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=1470)) - Compared with ALS, even brain cancer is a lesser condition. ([Location 1485](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=1485)) - His voice had a quality that I thought I recognized. It was a voice that sounded strong from having taken in the worst and still resolved to fight for the best. I heard what we are always trying to define: grace under pressure, action in the face of suffering, the will to hope in the teeth of despair, courage. ([Location 1601](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=1601)) - “I’m in a slight depression right now. I’m trying to align people’s interests in a way that won’t hold up time — because the only thing that matters to me is time.” Then I heard his spirits rebound — or rather, I listened as he talked his way back up, as if he could buoy himself by an act of will, or sell himself hope by selling it to me. There was theater in this: By showing us both how well he could sell hope, he was showing that he could sell others. ([Location 1605](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=1605)) - Translating research into treatment should be straightforward, like translating thought into action, but here the biomedical empire was inept, almost paralyzed. ([Location 1646](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=1646)) - I knew it had to end badly. I think he knew it, too. But I still hoped that through sheer energy, will, and intelligence, Jamie would snatch some kind of victory in spite of everything — and not be destroyed with Stephen. The longer I listened to him talk that afternoon, the more trouble I had keeping my head and remembering what Ralph had written about the slimness of Jamie’s chances. And I still had some distance from the story. If I was having trouble, I wondered how Jamie could manage — young, speeding, unsleeping, with his impossible project to sell, and a brother to save. ([Location 1801](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=1801)) - In the Galápagos, it did not take many finches to start a new line: All it took was one lost flock. A million years ago, a few birds were blown out to sea on freak winds, and landed on the bare new lava of the islands. There they were cut off from their kind. At first they were isolated only by geography. Then they were isolated by their genes. They evolved what is known in the jargon as reproductive isolation. They diverged, and diverged some more, and today there are a dozen species of Darwin’s finches. To create a new human species, genetic engineers would not have to engineer billions of babies. All they would need is to engineer reproductive isolation in a few babies. All they would need is fifty Adams and fifty Eves. No one could predict the fate of those hundred babies, of course, but by definition they would be a new species, as separate from the rest of us as Neanderthals, Homo habilis, and Cro-Magnon. ([Location 2016](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=2016)) - I felt a creator’s pride in my idea. I was experiencing firsthand the glamour that even a very ugly thought can acquire when that thought is your own. For a few days, I understood what the atomic scientist meant at Los Alamos when he spoke of the “technically sweet.” I sat up late into the night scribbling until the nearest Homo sapiens sapiens rolled over and murmured, “My husband, Doctor Frankenstein.” ([Location 2058](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=2058)) - The creation of a new human species is one of the many strange possibilities that are now in our hands. It could be done. In the end, the only ineradicable problem in the project may be the one that Shelley and Stevenson both foresaw from the beginning, the flaw that gives their novels power: the pathos of the creatures themselves. No matter how well you made your fifty Adams and Eves, they could never mate with anyone but each other — breeding in a bottle, like fruit flies, with no escape. They would have every right to be furious. They might gnash their teeth at their creators. They might cry out as Adam does in Paradise Lost, in the lines that Mary Shelley chose as the epigraph to Frankenstein: Did I request thee, Maker, from my clay To mould me Man, did I solicit thee From darkness to promote me? ([Location 2087](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=2087)) - There was one in particular about which Matt was very excited, a radically new approach to incurable brain diseases. He was developing a brain vaccine. It was extremely exciting — revolutionary, he said. He was preparing a paper about it. The vaccine was an idea that he had developed in New Zealand. In a way, it fit with the zeitgeist. There was so much interest everywhere now in the power of the brain and mind to control diseases. Most of that sort of therapy was soft science. But he had gotten interested two years before in teaching the immune system a few new tricks. He and his colleagues were looking for a way to train it to generate an immune response to a brain protein. The immune system can be very specific: That is, it can recognize a highly restricted range of targets, and attack only those targets. That is appealing, Matt explained, because in diseases of the brain it is difficult to find drugs that are so specific. Psychiatric drugs, for instance, are notorious for their side effects. So Matt and his collaborators had decided to teach the immune system to try to treat what the immune system normally ignores. ([Location 2192](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=2192)) - This idea is radical, and most of the early reviewers of Matt’s paper thought it was impossible. For one thing, the brain is immuno-privileged: It is normally ignored by the immune system. And normally the body generates antibodies against foreign invaders, not against its own molecular machinery. But Matt’s brain vaccines would have to generate antibodies against molecules that the brain itself had made, such as neuroreceptors or bad EAAT2 pumps. ([Location 2199](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=2199)) - In Philadelphia, Jamie, Matt, and Paola planned to design and build a DNA package containing the EAAT2 gene. Gene therapists call this “the construct.” ([Location 2230](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=2230)) - Activists want action. Scientists want knowledge — for its own sake, and for the infinite and unpredictable ways that knowledge can help lead to action. Not long ago a famous biologist told the actor and activist Christopher Reeve, “You can never do enough basic science.” The Christopher Reeve Paralysis Foundation no longer supports that biologist. ([Location 2286](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=2286)) - Like gene therapists all over the world, Matt and his team were struggling with tough engineering questions. A gene has to work as part of a system, like a gear in an engine or a sentence in a paragraph. To make it work, a gene therapist has to engineer what is called a promoter sequence, which sets in motion the reading of the gene. Otherwise the gene will get into the nucleus and sit there unread. The gene therapist also has to provide a stop codon, like a period, to get the cell to stop reading the gene when it comes to the end of the message. And a gene therapist also tries to include a switch that can be turned on and off from outside. That way, if the gene they have injected is hurting the patient, they can turn it off before it does too much harm. In experimental gene therapy on flies, temperature has been used as a switch. The new gene turns on only when it is very warm. At room temperature the gene turns off again. In human beings, certain antibiotics can serve as the switch. Taken together, all this DNA — a long strand containing the promoter sequence, the gene itself, the stop codon, and the switch — is called the DNA cocktail. It is the elixir of the gene therapist. To get it into a patient’s cells, the gene therapist engineers a virus that will carry the elixir instead of its usual load of DNA. A single virus is like a syringe. It has evolved to be very efficient at injecting its DNA into a host cell so that the DNA will snake through the cell and find its way into the nucleus and insert itself into its host’s DNA. With the standard tools of genetic engineering, it is now a simple job to take a sample of viral DNA and cut away much of it, and put back the harmless bits that give the DNA the ability to snake into the heart of the cell. It is also simple to splice in a new ribbon of DNA — the elixir, the DNA cocktail. But the head of a virus, even a hollowed-out virus, is a very small syringe. Gene therapists usually find that they have more DNA in their cocktail than they can stuff into the virus. ([Location 2365](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=2365)) - The Y chromosome is small and atrophied, and it has lost its copy of this gene — and many other genes, too. That is why boys inherit more genetic diseases than girls. ([Location 2401](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=2401)) - Usually, the story of a new drug starts with a drug company. It could be a biotech or Big Pharma. The company makes the product. Once they have their product, they need assays to define what the product is. They need to test its purity and stability. Then the substance is usually tested in vitro for activity. And then in vivo in small animals, a few mice or rats, for toxicity. Not hundreds of animals yet. Then in more mice, and rats. Then in dogs, rabbits, pigs, monkeys. “Don’t write dogs!” she cried. With animal tests, they look at safety and efficacy. They test different formulas of a drug, and when and how it is delivered. They test that the agent is safe and the route of administration is safe. Next, there is a Phase 1 study with volunteers. Usually the test involves a dozen people or so, to see if the drug is well tolerated. In Phase 2, the drug testers find out about dose and regimen. They find out what dose works best. They find the half-life of the product. They do a number of Phase 2s, with different patients. They may do four Phase 2s. This can take years. Then they design Phase 3. Here they want to hit a home run. The Phase 3 trials are double-blind, placebo-controlled. “You design absolutely the best, tightest study you can. So that at the end of the day you can apply for product license approval from the FDA. Or new drug approval.” ([Location 3338](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=3338)) - The four of them talked late while I listened, admiring the gallant way they all held up under the weight. There was the weight of hope and there was the weight of knowledge — the weight of the way things are. The odds against Jamie’s plan were so long that hope hurt: Hope almost felt like the heavier weight. When the dinner-table talk finally broke up that night, Stephen apologized to me for the intensity of the story that they had lured me into. “I’m just passing through,” I said. “If you can handle it, I can handle it.” “We’ve adapted,” Stephen said. “You’re going to come out of this with the bends.” ([Location 3500](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=3500)) - The edge of medicine is dangerous by definition. Matt was outraged that his whole field was being blamed and damned for one death. He often thought of the time he had been planning to treat a Canavan baby with his gene therapy, and the baby’s parents decided to try a bone-marrow transplant instead. The baby died. If a nine-month-old child had died in his gene therapy trial, it would have made a scandal. But a death in an experimental bone-marrow transplant made no headlines, because bone-marrow transplants were not bolts from the future. No one ever called for a ban on bone-marrow transplants. ([Location 4266](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=4266)) - I only regret that I don’t have another thirty years of creative work. I would do another long-range inquiry like in the past. I am always interested in the long-range inquiry — not the bread-and-butter questions that give you answers and that’s the end. But I know I don’t have thirty years of creative work. You have to just face reality and hope for the best. To do science, you must never lose a child’s hope,” he said, a line that became a proverb for me. “You must not fall into the cynicism of old age, that nothing matters. Once you have lost that childish hope, then you have lost a very important element for doing science.” ([Location 4669](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=4669)) - He mistook my childish enthusiasm — he felt this was immaturity. Probably he had long since lost hope himself. Many do. Psychosclerosis, you can call it. Some have it at age twenty. Many would consider them mature. Probably they are! They have nowhere to go! Other than falling off the tree and being eaten by the worms.” ([Location 4676](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=4676)) - “You can make your own religion if you want — and you can look at religions as a struggle to deal with life through metaphor, to deal with what we cannot explain. The great old solutions are worth studying, and their similarities are worth exploring. “The cell arose three and a half billion years ago! So as we sit here we are really three-point-five billion years old! So for practical purposes we can really speak of eternal life! And the Resurrection!” ([Location 4685](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=4685)) - I had a private motto: “First and Last.” I wanted what I had seen and felt when I was small to have some connection with what I would see, learn, and know in the end. I thought the whole human race wanted something like that. The beginning, middle, and end should make one unbroken story. The stem should lead up to the rim of a cup from which we could drink and still be ourselves. ([Location 4887](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=4887)) - I asked him if he was still comfortable with my writing about him. He stopped the wheelchair again in the middle of Hyde Road and looked up at me. With our eyes locked like that, his face seemed to me to grow huge, gigantic, immense. But it was the effort that was immense — the intensity of the work. He seemed to swell until he was as large as all human effort. “I’m fine,” he said. ([Location 4928](https://readwise.io/to_kindle?action=open&asin=B000FC27YU&location=4928))