HHMI's Holiday Lectures on Science
Summary: HHMI's Holiday Lectures on Science The Howard Hughes Medical Institute is a philanthropy that supports biomedical research and science education. As part of its mission to strengthen science education, the Institute presents the Holiday Lectures on Science, an annual series that brings the latest developments in a rapidly moving field of research into the classroom. These lectures are videotaped and technical, but even the lay person can learn from them. Audio files are available, but you do lose the visual aids. However, they are still useable. Previous subjects have included, dengue, RNA, and the idea of quorum sensing which is how bacteria decide when to attack, or fireflies coordinate their flashing sequence.
Human tissues vary in their ability to heal and regenerate. The nervous system has weak powers of regeneration, while the skin is quick to make new cells for repair. Mammalian muscle cells are intermediate in their ability to regenerate. Human muscle can regenerate in response to minor wounds and normal wear and tear, but humans will not grow a new bicep, for example, in response to amputation. The heart is the most important muscle in the body and yet has feeble regenerative capabilities. Research into the wholesale production of new replacement organs and limbs is in its infancy, but research into enhancing normal levels of regeneration is progressing rapidly. Recent discoveries concerning the location and characteristics of adult stem cells and the signals that wounded tissue produces to activate stem cells have increased our understanding of regeneration. Insulin-like growth factor 1 (IGF1) is an example of an important stem cell communication molecule. If the activity of the growth factor is experimentally enhanced, muscle regeneration improves.
A 50-minute discussion between students and the lecturers, moderated by Dr. Jonathan D. Moreno, director of the Center for Biomedical Ethics at the University of Virginia, and Dr. Debra J.H. Mathews, assistant director for science programs at Johns Hopkins University.
The heart acts as a dual pump, sending oxygen-depleted blood to the lungs to be reinvigorated and pumping oxygen-rich blood to vital organs throughout the body. A collection of specialized cells, called the pacemaker, coordinates the contraction of the heart’s four chambers by generating electrical impulses that spread all over the heart. Hormonal secretions alter heart activity in various ways, as can risk factors such as smoking and male gender.
"Telltale Genes: Charting Human Disease" by Richard P. Lifton, MD, PhD Why children resemble their parents has intrigued scientists for thousands of years. The discovery of DNA as the basis of heredity led to an explosive growth of knowledge about the human genome and allowed the identification of genes that predispose people to different diseases. The Human Genome Project aims to determine the entire 3 billion base pair sequence of DNA and ultimately identify all the genes, estimated between 60,000 and 100,000, that define humans.* *The first draft of the human genome was published in 2001. Most researchers have revised their estimates of the number of genes in the human genome downward, many to as low as 30,000.
Although heart disease typically occurs after middle age, seemingly fit and healthy young individuals can die suddenly from unrecognized heart disease. In many cases, the culprit is hypertrophic cardiomyopathy, a disorder characterized by thickening of the ventricular muscle. It is caused by mutations in genes that encode proteins of the sarcomere, the contractile apparatus of muscle cells.
High blood pressure, or hypertension, contributes to heart attacks, strokes, and kidney failure. Since many factors regulate blood pressure, it has been difficult to determine the cause of hypertension. Molecular genetic approaches have identified genes that, when mutated, cause either increased or decreased blood pressure. Interestingly, all the genes identified to date function by regulating the amount of salt and water retained by the kidney.
Over the course of a year, a typical American consumes nearly a million calories and yet weight generally fluctuates very little. That's because the body has mechanisms for keeping track of calories and carefully balancing food intake and energy output. And that's what makes dieting so difficult. As we cut calories and lose weight, our metabolism slows, making it more difficult to take off the pounds. Obesity, then, is not the result of a complete lack of discipline but is largely a function of biology. Studies of twins and adopted children show that obesity is heritable and that genes play an important role in determining body size. In the past decade, researchers have discovered some of these genes and are learning how they influence eating and body weight. Studying mice that are massively obese, Dr. Friedman and his colleagues identified the gene for leptin, a hormone produced by fat cells. Leptin-named after the Greek word for "thin"-feeds into the circuit of neurons in the brain that controls eating and energy expenditure. When we lose weight, leptin concentrations fall. This dip in leptin levels instructs the body to find more food. For this reason, most diets eventually fail. Dr. Friedman introduces the genes and circuits that control appetite. By understanding how these systems interact with the environment, researchers might someday develop treatments for obesity.
When it comes to weight control, appetite isn't everything. Our relative leanness-or lack thereof-also depends on how our bodies balance the storage and burning of dietary fat. And what we eat can make a big difference. Fat, it turns out, carries instructions about how it should be used. Saturated fats, the type found in meat and dairy products, are hard for cells to break down, so they tend to get tucked away. Unsaturated fats, found in olive oil and other plant oils, are readily consumed for energy. What's more, they direct the body to burn more fat. Having too much fat lying around is bad because it can trigger insulin resistance—the first step on the path to diabetes. Fat encourages muscle to reject glucose as an energy source. To keep this sugar from building up in the blood, the pancreas produces extra insulin. Over time, however, the pancreas becomes overworked and can no longer compensate. So blood sugar rises and diabetes develops. Exercise improves the situation, because the stretching of muscle fibers provokes cells to take up glucose, removing it from the blood. Unfortunately, more weight usually goes hand in hand with less exercise-even in mice. Rodents treated to a "Western" diet, rich in fat, grow pudgy and sluggish, sitting more often than they scurry. In humans, a high-fat diet coupled with poor exercise leads to syndrome X, a metabolic disorder characterized by insulin resistance, high blood pressure, and heart disease. Dr. Evans describes how fat communicates with muscle and how diet and exercise influence that relationship, promoting good health or precipitating disease.
Like most things in the body, metabolism is governed by a complex interaction among genes. In particular, a family of proteins called PPARs (for peroxisome proliferator-activator receptors) controls how the body uses sugar and fat. One member of this family, PPAR-gamma, acts as a master switch that drives the formation of fat cells and regulates the storage of fat. The receptor snatches fat from the blood and squirrels it away inside fat cells. By whisking fat from the blood, PPAR-gamma encourages muscle to burn sugar and allows the body to remain sensitive to insulin. Drugs that activate PPAR-gamma are currently used to treat diabetes. Although they don't help people lose weight, the drugs do restore patients' sensitivity to insulin. A sister protein, called PPAR-delta, regulates how muscles burn fat. When kept on a high-fat diet, mice that lack PPAR-delta become obese. Mice that are engineered to produce an overactive version of the receptor in their muscle tissue remain sleek and lean. PPAR-delta revs up cellular fat-burning pathways and beefs up the animals' slow-twitch muscle mass. This type of muscle, highly developed in marathon runners and migrating birds, prefers to use fat as an energy source. The engineered animals put this muscle to good use. When placed on a rodent-sized treadmill, these "marathon mice" will run twice as far as their normal relatives. Dr. Evans reviews how PPARs regulate body weight-and how drugs that stimulate PPARs might help people slim down and improve their health without altering their appetite.
By four years old, the boy weighed 90 pounds and consumed more than 1,100 calories in a single sitting-approximately half the recommended daily intake for an adult. Genetic testing revealed that the child possessed a rare mutation that disabled his leptin gene. Without the hormone, he kept gaining weight because his body told his brain that he was starving. When doctors treated the boy with leptin, his calorie intake was slashed by 84 percent and he eventually got down to a normal weight for his age. In studies of obese mice, Dr. Friedman has found that leptin actually restructures the brain, rewiring the neural circuit that controls feeding. The hormone reinforces the nerve cells that encourage the body to slenderize and prunes the neurons that compel eating. Leptin isn't the whole story. For most of us, a combination of genes regulates our weight. These powerful systems are part of our genetic heritage. Some researchers think that such "thrifty genes" provided our ancestors with a survival strategy for coping with famine. Individuals who stored calories in times of plenty could avoid starvation when food grew scarce. Thus, obesity could be a product of these genes that evolved to keep us alive. Dr. Friedman describes his continuing hunt for the genes that make us fat, research that has carried him to a small island in the Pacific where obesity is rampant. By analyzing DNA collected from all the adults on the island, Dr. Friedman hopes to learn more about why some people are overweight while others are lean.
A 45-minute question-and-answer session with the lecturers and students attending the Holiday Lectures on Science. The session is moderated by Sally Squires, columnist for the Washington Post.
The Darwinian revolution was the first revolution in biology. This lecture traces the discovery of evolution through Charles Darwin’s long voyage, many discoveries, and prodigious writings. It is a dramatic story of how a medical school dropout and future clergyman transformed our picture of nature and our place in it. Darwin developed two great ideas in The Origin of Species that have shaped 150 years of evolutionary biology: the descent of species from common ancestors and their modification through natural selection. Darwin also introduced the concept of the “fittest,” but how are the fittest made? The second revolution in biology was triggered by discoveries in genetics. Genetic variation, selection, and time combine to fuel the evolutionary process. The action of selection is now visible in DNA, both in preventing injurious changes and in favoring advantageous changes in traits.
The products of natural, and human, selection are all around us. Humans have transformed wild plants into useful crops by selective breeding. Human selection has also produced pets and other domesticated animals with sizes and shapes very different from their wild ancestors. Controlled genetic crosses can be used to identify and locate the genes responsible for artificial selection in domesticated species. Genetic crosses in maize and dogs, for example, suggest that few genetic changes are needed to dramatically transform the shape and structure of plants and animals. Natural selection in wild populations can also generate amazing diversity in a surprisingly short amount of time. Ocean stickleback fish, for example, colonized numerous freshwater streams and lakes produced by retreating glaciers after the last Ice Age. Differential survival and reproduction under natural selection have generated dramatic changes in morphology, physiology, and behavior as the fish adapted to different food sources, predators, and water conditions. Genetic studies of recently evolved freshwater fish confirm that many evolutionary traits are controlled by relatively few genes. It appears that natural populations, like domesticated populations, can evolve rapidly under the influence of a few simple genetic changes.
Recent studies have identified important genes that direct embryonic development. Specific developmental regulators control the formation of heads and tails, backs and bellies, forelimbs and hindlimbs, and the left and right sides of the body. Many key developmental genes are conserved among animals that look very different. A diversity of body forms can emerge from changing where and when these shared developmental regulators are expressed. For example, fins and limbs have been extensively modified in many different animals. Major changes in the fins of stickleback fish occur by altering the expression pattern of a major developmental control gene involved in hindlimb development. Intriguingly, fish evolving independently in widely separated waters have alterations in the same basic genetic and developmental elements. Fossils suggest that similar developmental mechanisms were used in animals that evolved millions of years ago. The great extent of shared developmental machinery reveals a deep common ancestry for living forms and makes it possible to discover general rules of evolution from highly detailed studies of select organisms.
The story of animal evolution is marked by key innovations such as limbs for walking on land, wings for flight, and color patterns for advertising or concealment. How do new traits arise? How has the great diversity of butterflies, fish, mammals, and other animals evolved? The invention of insect wings and the evolution of their color patterns are beautiful models of the origin of novelty and the evolution of diversity. This lecture explores how new patterns evolve when “old” genes learn new tricks. Old genes learning new tricks also applies to our own species and the evolution of traits that distinguish us from earlier hominids and other apes: our big brains, bipedal locomotion, and speech and language. The complete picture of human evolution involves new information emerging from the fossil record, genetics, comparative physiology, and development. Despite immense advances in evidence and understanding, there remains a societal struggle with the acceptance of our biological history and the evolutionary process, the roots of which are discussed in this lecture.