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P53: The Gene That Cracked the Cancer Code by Sue Armstrong
‘And if you’re going to generate a mouse for the first time you don’t want a mutant that’s kind of wimpy.’ Meanwhile, at MIT in Boston, Tyler Jacks – renowned for creating one of the two first p53 knock-out mice in 1992 – was on the same track. His lab was busy generating two different mouse models that mimicked LFS – one with the same point mutation as Lozano’s mice, corresponding to human R175H, and another corresponding to R273H. The two groups published their findings in the same edition of Cell in December 2004. What distinguished their mouse models from others designed to test the activity of mutant p53 was that here the gene was being switched on naturally in response to signals from the cell’s environment. In most other models, the gene was switched on artificially by the researchers – and herein lay the big sticking point.
Available at cshperspectives.com/content/2/2/a001107.full For the information on Stanley Prusiner, I relied on the archive of the Nobel Foundation, which awarded him the Prize for Medicine in 1997. See www.nobelprize.org/nobel_prizes/medicine/laureates/1997 Other key references were two papers, published simultaneously in the same journal, Cell, Volume 119, 2004, by Tyler Jacks and Gigi Lozano and their colleagues: ‘Mutant p53 Gain of Function in Two Mouse Models of Li-Fraumeni Syndrome’ by Kenneth P Olive et al. (847–860) and ‘Gain of Function of a p53 Hot Spot Mutation in a Mouse Model of Li-Fraumeni Syndrome’ by Gene A Lang et al. (861–872). See also ‘Mutant p53: one name, many proteins’ by William A. Freed-Pastor and Carol Prives, in Genes and Development, 2012, Volume 26, 1268–86. Chapter 19: Cancer and Ageing – a Balancing Act? The epigraph from John Maddox, editor emeritus of Nature, comes from his introduction to The Eighth Day of Creation by Horace Freeland Judson, page xii.
Research, he realised, was what he wanted to do, and after graduating from Wisconsin he managed to get into MIT, the hothouse of bright minds and exciting science, where Mario Capecchi had discovered his calling some 30 years earlier. At MIT Lowe met Tyler Jacks, a young researcher who had picked up Capecchi and colleagues’ new technology with enthusiasm and was busy creating transgenic mice of all kinds to investigate cancer-related genes. Jacks had made some knock-out mice in which various tumour suppressors had been deleted and he was asking the simple and obvious question: do the animals get cancer? He had a mouse model with p53 knocked out, but he had been beaten to it in his experiments by another scientist who had been investigating the same question, so his p53 knock-out mice were sitting around with not much to do. Jacks was happy to let Lowe suggest alternative experiments with them. Lowe was already fascinated by apoptosis. He had done some work with cell cultures, watching it happen, to his great surprise, in response to oncogene activity, and he was not sure what role, if any, p53 was playing.
Albert Einstein, British Empire, Build a better mousetrap, conceptual framework, discovery of penicillin, double helix, Drosophila, epigenetics, Fellow of the Royal Society, life extension, mouse model, phenotype, selective serotonin reuptake inhibitor (SSRI), stem cell, stochastic process, Thomas Kuhn: the structure of scientific revolutions
Secondly, the studies also show us that a particular class of epigenetic modification is not in itself good or bad. It’s where the modification happens that matters. In the rat model, the decreased DNA methylation of the cortisol receptor gene is a ‘good’ thing. It leads to increased production of this receptor, and a general dampening down of the stress response. In the mouse model, the decreased DNA methylation of the arginine vasopressin gene is a ‘bad’ thing. It leads to increased expression of this hormone and a stimulation of the stress response. The decreased DNA methylation of the arginine vasopressin gene in the mouse model occurred through a different route to the one used in the rat hippocampus to activate the cortisol receptor gene. In the mouse studies, separation from the mother triggered activity of the neurons in the hypothalamus. This set off a signalling cascade that affected the MeCP2 protein.
Take a small scraping of skin cells from our patient, whom we shall call Freddy. Grow these cells in culture until we have enough to work with (this is pretty easy). Use the four Yamanaka factors to create a large number of iPS cells, treat these in the lab to turn them into beta cells and put them back into the patient. There will be no immune rejection because Freddy will just be receiving Freddy cells. Recently, researchers have shown they can do exactly this in mouse models of diabetes4. It won’t be that simple of course. There are a whole range of technological hurdles to overcome, not least the fact that one of the four Yamanaka factors, c-Myc, is known to promote cancer. But in the few years since that key publication in Cell, substantial progress has been made in improving the technology so that it is moving ever closer to the clinic. It’s possible to make human iPS cells pretty much as easily as mouse ones and you don’t always need to use c-Myc5.
One of the most debilitating aspects of Rett syndrome is the profound mental retardation that is an almost universal symptom. Nobody knew if it would be possible to reverse a neurodevelopmental problem such as mental retardation once it had become established, but the general feeling about this wasn’t optimistic. Adrian Bird remains a major figure in our story. In 2007 he published an astonishing paper in Science, in which he and his colleagues showed that Rett syndrome could be reversed, in a mouse model of the disease. Adrian Bird and his colleagues created a cloned strain of mice in which the Mecp2 gene was inactivated. They used the types of technologies pioneered by Rudolf Jaenisch. These mice developed severe neurological symptoms, and as adults they exhibited hardly any normal mouse activities. If you put a normal mouse in the middle of a big white box, it will almost immediately begin to explore its surroundings.
Junk DNA: A Journey Through the Dark Matter of the Genome by Nessa Carey
This leads to increased production of the beta-amyloid that is essential for the formation of the plaques.31 It’s been reported that the levels of this long non-coding RNA are increased in the brains of patients with Alzheimer’s disease, but it’s difficult to interpret these data. This could just be a consequence of increased expression in that region generally. Remember the earlier analogy – the more you chop up logs, the more sawdust you create. But researchers managed to find a way of specifically decreasing the expression of just the long non-coding RNA in a mouse model which frequently develops Alzheimer’s pathology. The knockdown of the long non-coding RNA resulted in decreased BACE1 protein and fewer beta-amyloid plaques. This supports the idea that the long non-coding RNA may play a causative role in this devastating disease.32 It’s not just the central nervous system that can be influenced by long non-coding RNAs. Neuropathic pain is a condition in which the sufferer feels pain, even when there is no physical stimulus.
It may be a combination of both these factors, plus others that we have not yet identified. But where we have this uncertainty – parent and child with the same genetic change but different symptoms – it’s vital to develop additional lines of evidence to support any hypothesis about the impact of the variant base. The researchers who identified the C to T change in the enhancer did exactly this, by testing the effect of this change in a mouse model. They showed that when the C was present, this stretch of junk DNA acted as an enhancer of morphogen expression. But when the C was replaced by a T the region no longer acted as an enhancer, and levels of the morphogen never reached the critical levels in the brain. Morphogens and the pancreas The morphogen that is implicated in the development of extra digits or in the various forms of holoprosencephaly isn’t the only example of a human condition caused by a change in a regulatory region of DNA.
Researchers used these mice and applied genetic techniques to dial down the expression of one of the key messenger RNAs that would normally be controlled by the Fragile X protein. When they did this, the scientists detected marked improvements in the animals. Spatial memory was better and the mice behaved appropriately around other mice. They were also less susceptible to seizures than the standard Fragile X mouse models. These symptomatic improvements were consistent with underlying changes that the scientists detected in the brains of the animals.14 Neurons in normal brains have little mushroom-shaped spines that are characteristic of strong, mature connections. The neurons of humans and mice with Fragile X syndrome have fewer of these, and a larger number of long, spindly, immature connections. After the genetic treatment, there were more mushrooms and fewer noodles.
Speculative Everything: Design, Fiction, and Social Dreaming by Anthony Dunne, Fiona Raby
3D printing, augmented reality, autonomous vehicles, Berlin Wall, Buckminster Fuller, Cass Sunstein, computer age, corporate governance, David Attenborough, en.wikipedia.org, Fall of the Berlin Wall, game design, global village, Google X / Alphabet X, haute couture, life extension, Mark Zuckerberg, mouse model, New Urbanism, Peter Eisenman, RAND corporation, Richard Thaler, Ronald Reagan, self-driving car, Silicon Valley, social software, technoutopianism, Wall-E
Although technically possible, the project had to remain speculative for ethical reasons. The first step was to acquire some genetic material containing Elvis's DNA, achieved when Barhad managed to purchase one of Elvis's hairs on eBay.' The next step would be to have the DNA sequenced to identify behavioral traits such as sociability, athletic performance, and susceptibility to addiction and obesity. Barhad then identified a company that creates mouse models for scientific experiments and would in theory be able to produce a transgenic Elvis mouse using the genetic material he provided. Next, Barhad built a tower of custom designed environments based on ones used in laboratories to test traits in genetically modified mice. Each compartment simulated key biographical moments in Elvis's life. By going through the process of designing an Elvis mouse based on current technologies, Barhad highlighted the absurdity of thinking of clones as anything more than a material reproduction of another living thing.
It is an important space, a place where the future can be debated and discussed before it happens so that, at least in theory, the most desirable futures can be aimed for and the least desirable avoided. Although it is not possible for designers to build actual products using biotechnology yet, we should not let that stop us from getting involved; we can still create functional fictions that help us explore the kind of biotechnological world we wish to live in. Koby Barhad, All That 1 Am: From a Speck of Hair to Elvis Presley's Mouse Model, 2012. © Koby Barhad. The universe of possible worlds is constantly expanding and diversifying thanks to the incessant world-constructing activity of human minds and hands. Literary fiction is probably the most active experimental laboratory of the world-constructing enterprise.' Although design usually references sculpture and painting for material, formal and graphic inspiration, and more recently the social sciences for protocols on working with and studying people-if we are interested in shifting design's focus from designing for how the world is now to designing for how things could be-we will need to turn to speculative culture and what Lubom r Dolezel has called an "experimental laboratory of the world-constructing enterprise."
Food Allergy: Adverse Reactions to Foods and Food Additives by Dean D. Metcalfe
active measures, Albert Einstein, bioinformatics, epigenetics, hygiene hypothesis, impulse control, life extension, meta analysis, meta-analysis, mouse model, pattern recognition, phenotype, placebo effect, randomized controlled trial, selection bias, statistical model, stem cell
Lastly, prior sensitization to an antigen through extraintestinal routes affects the development of a hypersensitivity response. Sensitization to peanut protein was demonstrated by application of skin preparations containing peanut oil to inflamed skin in children . Similar results were obtained by Hsieh’s group in epicutaneous sensitized mice to the egg protein OVA . The dose of antigen administered is also critical to the form of oral tolerance generated. In mouse models, low doses of antigen appear to activate regulatory/suppressor T-cells [39,40]. There are an increasing number of such cells identified, of both CD4 and CD8 lineages. Th3 cells were the initial regulatory/suppressor cells described in oral tolerance [40–42]. These cells appear to be activated in the PP and secrete transforming growth factor-β (TGFβ). This cytokine plays a dual role in mucosal immunity; it is a potent suppressor of T- and B-cell responses while promoting the production of IgA (it is the IgA switch factor) [34,43–45].
This cytokine plays a dual role in mucosal immunity; it is a potent suppressor of T- and B-cell responses while promoting the production of IgA (it is the IgA switch factor) [34,43–45]. TGF-β is the most potent immunosuppressive cytokine defined and its activities are broad and non-specific. A recent investigation of the adaptive immune response to cholera toxin B subunit and macrophage-activating lipopeptide-2 in mouse models lacking the TGF-βR in B-cells (TGFβRII-B) demonstrated undetectable levels of antigen-specific IgA-secreting cells, serum IgA, and secretory IgA (SIgA) . These results demonstrate the critical role of TGF-βR in antigen-driven stimulation of SIgA responses in vivo. The production of TGF-β by Th3 cells elicited by low-dose antigen administration helps explain an associated phenomenon of oral tolerance, bystander suppression.
As mentioned earlier, oral tolerance is antigen specific, but if a second antigen is co-administered systemically with the tolerogen, suppression of T- and B-cell responses to that antigen will occur as well. The participation of other regulatory T-cells in oral tolerance is less well defined. Tr1 cells produce interleukin (IL)-10 and appear to be involved in the suppression of graft-versus-host disease (GVHD) and colitis in mouse models, but their activation during oral antigen administration has not been as clearcut [47–49]. Frossard et al. demonstrated increased antigen induced IL-10 producing cells in PP from tolerant mice after β-lactoglobulin feeding but not in anaphylactic mice, suggesting that reduced IL-10 production in PPs may support food allergies . There is some evidence for the activation of CD4⫹CD25⫹ regulatory T-cells during oral tolerance induction protocols but the nature of their role in the process is still under investigation [51–54].
The Future of the Brain: Essays by the World's Leading Neuroscientists by Gary Marcus, Jeremy Freeman
23andMe, Albert Einstein, bioinformatics, bitcoin, brain emulation, cloud computing, complexity theory, computer age, computer vision, conceptual framework, correlation does not imply causation, crowdsourcing, dark matter, data acquisition, Drosophila, epigenetics, Google Glasses, iterative process, linked data, mouse model, optical character recognition, pattern recognition, personalized medicine, phenotype, race to the bottom, Richard Feynman, Richard Feynman, Ronald Reagan, semantic web, speech recognition, stem cell, Steven Pinker, supply-chain management, Turing machine, web application
Thus we envision a connection matrix in which associated with each neuronal bar code are a few additional bits of information specifying the neuron’s position in the circuit and its identity. A cheap and rapid method for deciphering the wiring diagram of a neural circuit or of an entire organism would have a profound impact on neuroscience research. Many neuropsychiatric diseases such as autism and schizophrenia are thought to result from disrupted neuronal connectivity, but identifying the disruptions even in mouse models is a major challenge given current technology. More fundamentally, knowledge of the neuronal wiring diagram would provide a foundation for understanding neuronal function and development in the same way that knowing the complete genomic sequence provides the starting point for much of modern biological research in the postgenomic era. BOINCing may not solve the brain, but it promises to bring us one step closer.
Indeed, there has been much interest in the demonstration of protein-coding differences between FOXP2 in humans and chimpanzees (as well as more recent work on human-Neanderthal sequence differences elsewhere in this gene). Again, functional experiments are playing a central part in helping scientists to assess the biological relevance of the sequence changes, using the same systems (cell lines, mouse models, and such) as those used for investigating the mutations that cause disorder. Even so, if we want to comprehensively join the dots between genes and human cognition, we cannot only depend on growing cells in the laboratory or making genetically modified animals. In recent years a new weapon has been added to the armory, one that could be powerful for making links to the human brain but that has to be wielded with care.
Inferior: How Science Got Women Wrong-And the New Research That's Rewriting the Story by Angela Saini
Albert Einstein, demographic transition, Drosophila, feminist movement, gender pay gap, meta analysis, meta-analysis, mouse model, out of africa, place-making, scientific mainstream, Steven Pinker, the scientific method, women in the workforce
It mirrors something we see in human adults—women tend to have a higher percentage of fat mass in their bodies than men. “A second example is that if we give the mouse a heart attack, the animals with two X chromosomes do worse than the animals with one X chromosome,” he adds. “And the third example in the mouse model is with multiple sclerosis, where we induced a multiple sclerosis–like disease in the mouse, and the animals that are XX do worse than the animals that are XY.” Multiple sclerosis in humans, being an autoimmune disease, affects more women than men. Their take-home message is that many of the sex differences we see in health are rooted deep down in genetics. “The study of mouse models has provided convincing evidence that cells with two X chromosomes are intrinsically different from those with one X chromosome. Sex differences caused by the number of X chromosomes can have a profound effect on disease,” Arnold and his colleagues wrote in their paper about the experiment, published in 2016 in the journal Philosophical Transactions of the Royal Society of London B.
Antifragile: Things That Gain From Disorder by Nassim Nicholas Taleb
Air France Flight 447, Andrei Shleifer, banking crisis, Benoit Mandelbrot, Berlin Wall, Black Swan, Chuck Templeton: OpenTable, commoditize, creative destruction, credit crunch, Daniel Kahneman / Amos Tversky, David Ricardo: comparative advantage, discrete time, double entry bookkeeping, Emanuel Derman, epigenetics, financial independence, Flash crash, Gary Taubes, George Santayana, Gini coefficient, Henri Poincaré, high net worth, hygiene hypothesis, Ignaz Semmelweis: hand washing, informal economy, invention of the wheel, invisible hand, Isaac Newton, James Hargreaves, Jane Jacobs, joint-stock company, joint-stock limited liability company, Joseph Schumpeter, Kenneth Arrow, knowledge economy, Lao Tzu, Long Term Capital Management, loss aversion, Louis Pasteur, mandelbrot fractal, Marc Andreessen, meta analysis, meta-analysis, microbiome, money market fund, moral hazard, mouse model, Myron Scholes, Norbert Wiener, pattern recognition, Paul Samuelson, placebo effect, Ponzi scheme, principal–agent problem, purchasing power parity, quantitative trading / quantitative ﬁnance, Ralph Nader, random walk, Ray Kurzweil, rent control, Republic of Letters, Ronald Reagan, Rory Sutherland, selection bias, Silicon Valley, six sigma, spinning jenny, statistical model, Steve Jobs, Steven Pinker, Stewart Brand, stochastic process, stochastic volatility, The Great Moderation, the new new thing, The Wealth of Nations by Adam Smith, Thomas Bayes, Thomas Malthus, too big to fail, transaction costs, urban planning, Vilfredo Pareto, Yogi Berra, Zipf's Law
Oberyszyn, 2010, “Short-term Stress Enhances Cellular Immunity and Increases Early Resistance to Squamous Cell carcinoma.” Brain, Behavior and Immunity 24(1): 127–137. Dhabhar, F. S., A. N. Saul, T. H. Holmes, C. Daugherty, E. Neri, J. M. Tillie, D. Kusewitt, T. M. Oberyszyn, 2012, “High-Anxious Individuals Show Increased Chronic Stress Burden, Decreased Protective Immunity, and Increased Cancer Progression in a Mouse Model of Squamous Cell Carcinoma.” PLOS ONE 7(4): e33069. Diamond, Jared, 1988, “Why Cats Have Nine Lives.” Nature, Vol. 332, April 14. Dixit, A. K. and R. S. Pindyck, 1994, Investment Under Uncertainty. Princeton, N.J.: Princeton University Press. Djebbar, Ahmed, 2001, Une histoire de la science arabe. Éditions du Seuil. Dook, J. E., C. James, N. K. Henderson, and R. I. Price, 1997, “Exercise and Bone Mineral Density in Mature Female Athletes.”
New York: Pantheon. Haigh, J., 2000, “The Kelly Criterion and Bet Comparisons in Spread Betting.” Journal of the Royal Statistical Society: Series D (The Statistician) 49(4): 531–539. Hajek, A., 2003, Interpretations of Probability. Citeseer. Halagappa, V.K.M., Z. Guo, et al., 2007, “Intermittent Fasting and Caloric Restriction Ameliorate Age-Related Behavioral Deficits in the Triple-Transgenic Mouse Model of Alzheimer’s Disease.” Neurobiology of Disease 26(1): Hald, Anders, 1998, A History of Mathematical Statistics from 1750 to 1930. New York: Wiley. Hald, Anders, 2003, A History of Probability and Statistics and Their Applications Before 1750. Hoboken, N.J.: Wiley. Haleblian, J., C. E. Devers, et al., 2009, “Taking Stock of What We Know About Mergers and Acquisitions: A Review and Research Agenda.”
The Emperor of All Maladies: A Biography of Cancer by Siddhartha Mukherjee
Barry Marshall: ulcers, conceptual framework, discovery of penicillin, experimental subject, iterative process, life extension, Louis Pasteur, medical residency, meta analysis, meta-analysis, mouse model, New Journalism, phenotype, randomized controlled trial, scientific mainstream, Silicon Valley, social web, statistical model, stem cell, women in the workforce, éminence grise
Since different drugs elicited different resistance mechanisms, and produced different toxicities in cancer cells, using drugs in concert dramatically lowered the chance of resistance and increased cell killing. Two drugs were therefore typically better than one, and three drugs better than two. With several drugs and several iterative rounds of chemotherapy in rapid-fire succession, Skipper cured leukemias in his mouse model. For Frei and Freireich, Skipper’s observations had an inevitable, if frightening, conclusion. If human leukemias were like Skipper’s mouse leukemias, then children would need to be treated with a regimen containing not one or two, but multiple drugs. Furthermore, a single treatment would not suffice. “Maximal, intermittent, intensive, up-front” chemotherapy would need to be administered with nearly ruthless, inexorable persistence, dose after dose after dose after dose, pushing the outermost limits of tolerability.
It was a time dedicated to academic thinking, sealed away from the daily whir of labs and clinics in the floors below. It was at these afternoon conferences that Frei began to introduce the idea of megadose combination chemotherapy with autologous marrow support to the fellows and junior faculty. In the fall of 1983, he invited Howard Skipper, the soft-spoken “mouse doctor” who had so deeply influenced Frei’s early work, to speak. Skipper was inching toward higher and higher doses of cytotoxic drugs in his mouse models and spoke enthusiastically about the possibility of curative treatment with these megadose regimens. He was soon after followed by Frank Schabel, another scientist who had demonstrated that combining agents, in doses lethal for the marrow, possessed synergistic effects on mouse tumors. Schabel’s lecture was particularly galvanizing, a “seminal event,” as Peters described it. After the talk, as Frei recalled, the room was abuzz with excitement; Schabel was surrounded by young, eager investigators mesmerized by his ideas.
Grain Brain: The Surprising Truth About Wheat, Carbs, and Sugar--Your Brain's Silent Killers by David Perlmutter, Kristin Loberg
., “Treatment of Parkinson Disease with Diet-induced Hyperketonemia: A Feasibility Study,” Neurology 64, no. 4 (February 22, 2005): 728–30. 23. M. A. Reger, et al., “Effects of Beta-hydroxybutyrate on Cognition in Memory-impaired Adults,” Neurobiology of Aging 25, no. 3 (March 2004): 311–14. 24. Mary Newport, “What If There Was a Cure for Alzheimer’s Disease and No One Knew?” www.coconutketones.com/whatifcure.pdf (July 22, 2008). 25. I. Van der Auwera, et al., “A Ketogenic Diet Reduces Amyloid Beta 40 and 42 in a Mouse Model of Alzheimer’s Disease,” Nutrition & Metabolism 2 (October 17, 2005): 28. 26. D. R. Ziegler, et al., “Ketogenic Diet Increases Glutathione Peroxidase Activity in Rat Hippocampus,” Neurochemical Research 28, no. 12 (December 2003): 1793–97. 27. K. W. Barañano and A. L. Hartman, “The Ketogenic Diet: Uses in Epilepsy and Other Neurologic Illnesses,” Current Treatment Options in Neurology 10, no. 6 (November 2008): 410–19. 28.
The Cancer Chronicles: Unlocking Medicine's Deepest Mystery by George Johnson
Atul Gawande, Cepheid variable, Columbine, dark matter, discovery of DNA, double helix, Drosophila, epigenetics, Gary Taubes, Harvard Computers: women astronomers, Isaac Newton, Magellanic Cloud, meta analysis, meta-analysis, microbiome, mouse model, Murray Gell-Mann, phenotype, profit motive, stem cell
[http://dx.doi.org/10.1038/nature01322] 35. compared to bodily organs: Mina J. Bissell and Derek Radisky, “Putting Tumours in Context,” Nature Reviews Cancer 1, no. 1 (October 2001): 46–54. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2975572] CHAPTER 6 “How Heart Cells Embrace Their Fate” 1. an embryo is so much like a tumor: The complex process of implantation is described in Haibin Wang and Sudhansu K. Dey, “Roadmap to Embryo Implantation: Clues from Mouse Models,” Nature Reviews Genetics 7, no. 3 (March 1, 2006): 185–99. [http://www.nature.com/nrg/journal/v7/n3/abs/nrg1808.html] For some of the parallels with tumorigenesis see Michael J. Murray and Bruce A. Lessey, “Embryo Implantation and Tumor Metastasis: Common Pathways of Invasion and Angiogenesis,” Seminars in Reproductive Medicine 17, no. 3 (March 15, 2008): 275–90. [http://www.ncbi.nlm.nih.gov/pubmed/10797946] 2. enzymes erode the surface: L.
The Lucky Years: How to Thrive in the Brave New World of Health by David B. Agus
3D printing, active transport: walking or cycling, Affordable Care Act / Obamacare, Albert Einstein, butterfly effect, clean water, cognitive dissonance, crowdsourcing, Danny Hillis, Drosophila, Edward Lorenz: Chaos theory, en.wikipedia.org, epigenetics, Kickstarter, medical residency, meta analysis, meta-analysis, microbiome, microcredit, mouse model, Murray Gell-Mann, New Journalism, pattern recognition, personalized medicine, phenotype, placebo effect, publish or perish, randomized controlled trial, risk tolerance, statistical model, stem cell, Steve Jobs, Thomas Malthus, wikimedia commons
Meanwhile, the brain’s janitors are at work to sweep out any toxic debris that can gum up its systems if left to build up. Sigrid Veasey is a leading sleep researcher and a professor of medicine at Perelman School of Medicine at the University of Pennsylvania. She’s been working with mice to understand just what happens when the brain doesn’t get its break to conduct certain business. Using her mouse models, she’s found that when the brain is kept alert by neurons firing constantly, these brain cells shed free radicals as a byproduct of making energy.5 Free radicals are rogue molecules that have lost an electron and thus they are highly reactive in the body, damaging healthy cells and tissues. They can potentially be toxic to the brain if they are not swept up. And it turns out that during sleep, these same neurons also produce antioxidants that take care of these free radicals.
The Last Best Cure: My Quest to Awaken the Healing Parts of My Brain and Get Back My Body, My Joy, a Nd My Life by Donna Jackson Nakazawa
Lancet. 2011 Oct 1;378(9798):1244–53. Being active reduces frequency and severity of colds: Nieman DC, Henson DA, Austin MD, et al. Upper respiratory tract infection is reduced in physically fit and active adults.Br J Sports Med. 2011 Sep;45(12):987–92. and our risk of Alzheimer’s: Stranahan AM, Martin B, Maudsley S. Anti-inflammatory effects of physical activity in relationship to improved cognitive status in humans and mouse models of Alzheimer’s disease. Curr Alzheimer Res. 2012 Jan 1;9(1):86–92. Chapter Twenty proving to be remarkably helpful in patients suffering from back pain: Büssing A, Ostermann T, Lüdtke R, et al. Effects of yoga interventions on pain and pain-associated disability: A meta-analysis. J Pain. 2012 Jan;13(1):1–9. Chapter Twenty-two We’re plunking ourselves down more than ever: Clark N. Sedentary athletes: Sitting and weighting, American College of Sports Medicine, Fit Society Newsletter, Winter 2009–2010.
Albert Einstein, AltaVista, British Empire, Cass Sunstein, cognitive dissonance, correlation does not imply causation, Daniel Kahneman / Amos Tversky, en.wikipedia.org, illegal immigration, index card, Isaac Newton, loss aversion, meta analysis, meta-analysis, mouse model, neurotypical, pattern recognition, placebo effect, Richard Thaler, Saturday Night Live, selection bias, Solar eclipse in 1919, Stephen Hawking, Steven Pinker, the scientific method, Thomas Kuhn: the structure of scientific revolutions
“Media Coverage of the Measles-Mumps-Rubella Vaccine and Autism Controversy and Its Relationship to MMR Immunization Rates in the United States.” Pediatrics 2008;121(4): e836–43. Smith, Philip, et al. “Children Who Have Received No Vaccines: Who Are They and Where Do They Live?” Pediatrics 2004;114: 187–95. Smith Rebecca G., et al. “Advancing Paternal Age Is Associated with Deficits in Social and Exploratory Behaviors in the Offspring: A Mouse Model.” PLoS ONE 2009;4(12): e8456. Spinney, Laura. “UK Autism Fracas Fuels Calls for Peer Review Reform.” Nature Medicine 2004;10: 321. Spitzer, R. L. “The Diagnostic Status of Homosexuality in the DSM-III: A Reformulation of the Issues.” The American Journals of Psychiatry 1981;138: 210–15. Stehr-Green, Paul, et al. “Autism and Thimerosal-Containing Vaccines: Lack of Consistent Evidence for an Association.”
The Autoimmune Connection by Rita Baron-Faust, Jill Buyon
We have already developed medicines to disable some of these cytokines, but the task is now to uncover and interfere with the pathways that lead to their release. The anti-cytokine therapies in their many forms are on the pharmacy shelves, but just remember they do not stop the disease, they only treat the symptoms. We must also target the cells that cause destruction in autoimmunity. It was long thought that once the disease was fully established, identifying markers of only “bad” cells would not exist. On the research side, at least in spontaneous mouse models, these “bad” cells can be uniquely identiﬁed. Finally, we need a greater understanding of the antigens that provoke autoimmunity to begin. This research is moving forward, albeit more slowly. It was long thought there would only be one antigen per disease, but perhaps the more typical picture is that there are many antigens that trigger disease. The challenge will be to make the agents that target these pathways nontoxic (or at least less toxic).
The Death of Cancer: After Fifty Years on the Front Lines of Medicine, a Pioneering Oncologist Reveals Why the War on Cancer Is Winnable--And How We Can Get There by Vincent T. Devita, Jr., M. D., Elizabeth Devita-Raeburn
TOP Howard Skipper, the self-proclaimed mouse doctor of the NCI; ABOVE RIGHT Jay Freireich; ABOVE Tom Frei; RIGHT Gordon Zubrod (Credit: The Website of the National Cancer Institute, www.cancer.gov). Together, they revolutionized the treatment of childhood leukemia with combination chemotherapy. Back on the boardwalk with, from left to right, Ron Yankee, who helped me decipher the cell growth rates of leukemia in our mouse model, which would help me transform MOMP into MOPP; George Canellos, nicknamer extraordinaire; and Jack Moxley Paul Carbone, chief of the NCI’s medicine branch at the time of this photo. The clinical associates gave him a terrible time—largely because he was easier to take on than the terrifying Jay Freireich. In truth, he was a good doctor and much beloved and admired by his peers. David Platt Rall, chief of chemical pharmacology at the NCI.
Warnings by Richard A. Clarke
active measures, Albert Einstein, algorithmic trading, anti-communist, artificial general intelligence, Asilomar, Asilomar Conference on Recombinant DNA, Bernie Madoff, cognitive bias, collateralized debt obligation, complexity theory, corporate governance, cuban missile crisis, data acquisition, discovery of penicillin, double helix, Elon Musk, failed state, financial thriller, fixed income, Flash crash, forensic accounting, friendly AI, Intergovernmental Panel on Climate Change (IPCC), Internet of things, James Watt: steam engine, Jeff Bezos, John Maynard Keynes: Economic Possibilities for our Grandchildren, knowledge worker, Maui Hawaii, megacity, Mikhail Gorbachev, money market fund, mouse model, Nate Silver, new economy, Nicholas Carr, nuclear winter, pattern recognition, personalized medicine, phenotype, Ponzi scheme, Ray Kurzweil, Richard Feynman, Richard Feynman, Richard Feynman: Challenger O-ring, risk tolerance, Ronald Reagan, Search for Extraterrestrial Intelligence, self-driving car, Silicon Valley, smart grid, statistical model, Stephen Hawking, Stuxnet, technological singularity, The Future of Employment, the scientific method, The Signal and the Noise by Nate Silver, Tunguska event, uranium enrichment, Vernor Vinge, Watson beat the top human players on Jeopardy!, women in the workforce, Y2K
Christina Larson, “China’s Bold Push into Genetically Customized Animals,” Scientific American, Nov. 17, 2015, www.scientificamerican.com/article/china-s-bold-push-into-genetically-customized-animals (accessed Oct. 11, 2016). 8. Hao Yin, Wen Xue, et al., “Genome Editing with Cas9 in Adult Mice Corrects a Disease Mutation and Phenotype,” Nature Biotechnology 32, no. 6 (Mar. 30, 2014): 551–53, DOI:10.1038/nbt.2884. 9. Chengzhu Long, Leonela Amoasii, et al., “Postnatal Genome Editing Partially Restores Dystrophin Expression in a Mouse Model of Muscular Dystrophy,” Science 351, no. 6271 (Jan. 22, 2016): 400–403, DOI: 10.1126/science.aad5725. 10. Jonathan Rockoff, “Why Gene-Editing Technology Has Scientists Excited,” Wall Street Journal, June 28, 2015, www.wsj.com/articles/why-gene-editing-technology-has-scientists-excited-1434985998 (accessed Oct. 11, 2016). 11. Amy Maxmen, “Easy DNA Editing Will Remake the World. Buckle Up,” Wired, Aug. 2015, www.wired.com/2015/07/crispr-dna-editing-2 (accessed Oct. 11, 2016). 12.
The Singularity Is Near: When Humans Transcend Biology by Ray Kurzweil
additive manufacturing, AI winter, Alan Turing: On Computable Numbers, with an Application to the Entscheidungsproblem, Albert Einstein, anthropic principle, Any sufficiently advanced technology is indistinguishable from magic, artificial general intelligence, Asilomar, augmented reality, autonomous vehicles, Benoit Mandelbrot, Bill Joy: nanobots, bioinformatics, brain emulation, Brewster Kahle, Brownian motion, business intelligence, c2.com, call centre, carbon-based life, cellular automata, Claude Shannon: information theory, complexity theory, conceptual framework, Conway's Game of Life, cosmological constant, cosmological principle, cuban missile crisis, data acquisition, Dava Sobel, David Brooks, Dean Kamen, disintermediation, double helix, Douglas Hofstadter, en.wikipedia.org, epigenetics, factory automation, friendly AI, George Gilder, Gödel, Escher, Bach, informal economy, information retrieval, invention of the telephone, invention of the telescope, invention of writing, Isaac Newton, iterative process, Jaron Lanier, Jeff Bezos, job automation, job satisfaction, John von Neumann, Kevin Kelly, Law of Accelerating Returns, life extension, lifelogging, linked data, Loebner Prize, Louis Pasteur, mandelbrot fractal, Mikhail Gorbachev, mouse model, Murray Gell-Mann, mutually assured destruction, natural language processing, Network effects, new economy, Norbert Wiener, oil shale / tar sands, optical character recognition, pattern recognition, phenotype, premature optimization, randomized controlled trial, Ray Kurzweil, remote working, reversible computing, Richard Feynman, Richard Feynman, Robert Metcalfe, Rodney Brooks, Search for Extraterrestrial Intelligence, selection bias, semantic web, Silicon Valley, Singularitarianism, speech recognition, statistical model, stem cell, Stephen Hawking, Stewart Brand, strong AI, superintelligent machines, technological singularity, Ted Kaczynski, telepresence, The Coming Technological Singularity, Thomas Bayes, transaction costs, Turing machine, Turing test, Vernor Vinge, Y2K, Yogi Berra
Such approaches, however, have the potential to induce unwanted inflammatory responses as well as to provide benefit" (H. L. Weiner and D. J. Selkoe, "Inflammation and Therapeutic Vaccination in CNS Diseases," Nature 420.6917 [December 19–26, 2002]: 879-84). These researchers showed that a vaccine in the form of nose drops could slow the brain deterioration of Alzheimer's. H. L.Weiner et al., "Nasal Administration of Amyloid-beta Peptide Decreases Cerebral Amyloid Burden in a Mouse Model of Alzheimer's Disease," Annals of Neurology 48.4 (October 2000): 567–79. 52. S. Vasan, P. Foiles, and H. Founds, "Therapeutic Potential of Breakers of Advanced Glycation End Product-Protein Crosslinks," Archives of Biochemistry and Biophysics 419.1 (November 1, 2003): 89–96; D. A. Kass, "Getting Better Without AGE: New Insights into the Diabetic Heart," Circulation Research 92.7 (April 18,2003): 704–6. 53.
Behave: The Biology of Humans at Our Best and Worst by Robert M. Sapolsky
autonomous vehicles, Bernie Madoff, biofilm, blood diamonds, British Empire, Broken windows theory, Brownian motion, car-free, clean water, cognitive dissonance, corporate personhood, corporate social responsibility, Daniel Kahneman / Amos Tversky, delayed gratification, desegregation, double helix, Drosophila, Edward Snowden, en.wikipedia.org, epigenetics, Flynn Effect, framing effect, fudge factor, George Santayana, hiring and firing, illegal immigration, impulse control, income inequality, John von Neumann, Loma Prieta earthquake, long peace, loss aversion, Mahatma Gandhi, meta analysis, meta-analysis, Mohammed Bouazizi, mouse model, mutually assured destruction, Network effects, out of africa, Peter Singer: altruism, phenotype, placebo effect, publication bias, RAND corporation, risk tolerance, Rosa Parks, selective serotonin reuptake inhibitor (SSRI), self-driving car, Silicon Valley, stem cell, Steven Pinker, strikebreaker, theory of mind, transatlantic slave trade, traveling salesman, trickle-down economics, ultimatum game, Walter Mischel, wikimedia commons, zero-sum game
Mice can learn a specific fear association vicariously by observing another mouse experiencing the fear conditioning. Moreover, this is a social process—learning is enhanced if the mice are related or have mated.4 In another study a mouse would be exposed to an aggressive intruder placed in its cage.5 As shown previously, this produces persistent adverse consequences—a month later, such mice still had elevated glucocorticoid levels and were more anxious and more vulnerable to a mouse model of depression.* Importantly, the same persistent effects would be induced in a mouse merely observing another mouse experiencing that stressful intruder paradigm. An even more striking demonstration of “your pain is my pain” in another species came in a 2006 Science paper from Jeff Mogil of McGill University.6 A mouse would observe another mouse (separated from it by Plexiglas) in pain, and, as a result, its own pain sensitivity increased.* In another part of the study, an irritant would be injected in a mouse’s paw; mice typically lick their paw at that point, with the amount of licking indicating the amount of discomfort.