Advances in Medicine

Andrew Lam, MD Author of The Masters of Medicine: Our Greatest Triumphs in the Race to Cure Humanity's Deadliest Diseases (Dallas, TX: BenBella Books, Inc., 2023) Bacterial and Viral Infection pp.75-168 Virus and Viral Infection Smallpox A book in China published in 1549: human effort to enhance the body's immune system through exposure to a pathogen, a technique believed to have been practiced since the 10th century. Pustule samples collected from smallpox survivors were dried and crushed into powder and later blown into the nostrils. Another method was to rub the material into a superficial incision on the hand or the arm. The practice (called variolation) was reported to the Royal Society in Londonthrough an employee of the East India Company, who had been working in China. In the late 18th century - Edward Jenner - cowpox and smallpox: Jenner's 7-year apprenticeship with a country doctor named Daniel Ludlow led him to embark on his own career in the 1770s. He first collected samples, then later published, cases of patients who had had cowpox and did not contract smallpox even though they exposed to smallpox patients. In 1796 he inoculated live virus from the sores of a smallpox patient to James Phipps, a boy who had previously gotten some fluid from a cowpox pustule instilled into the two incisions in the boy's arm. Phipps did not die of smallpox, and the experiement showed that cowpox could be used to protect humans from smallpox -a practice later called vaccination (the Latin word "vacca" means cow). Jenner became famous throughout Europe and North America. But at that time nobody knew or understood virus and the human immune system, and how vaccination worked. Adolf Mayer, a German chemist, and the findings of viruses in the late 19th century: The Wonder Drug Penicillin 1921-1929 p.103 the mold; 1938-1941 pp.104-116 from Oxford in London to New York City in the USA; and the Nobel Prize 1945 pp.116-120. Alexander Fleming, Howard Florey, Ernst Chain, and Norman Heatley pp.97-125 Rockefeller Foundation's Medical Sciences Division in NY City, and the Northern Regional Research Laboratory in Peoria, IL. Heart Disease pp.6-45 Heart disease was not a pressing concern to medical practitioners for centuries past, because infectious diseases were far more deadly. By 1930 average American longevity had increased to 60 years, and heart disease became the leading cause of death. Today heart disease is responsible for about 25% of all deaths in the USA, approximately 659,000/year, greater than mortality due to all types of cancer combined. 1912 a Chicago internist named James Herrick postulated that a thrombus/clot blocked a coronary artery and prevented oxygen-rich blood from reaching cardiac muscle, resulting in tissue death. => the first time doctors began to understand the importance of the three coronary coronary arteries. 1929 a young German medical intern named Werner Forssmann theorized that a catheter could be threaded up into the heartthrough a vein in the arm. This might be an effective way of injecting drugs directly into the right atrium. He experimented on himself to the awe of all present. The X-ray taken of his chest showed the catheter he threaded from his left arm into the right side of his heart with no chest pain and no fatal arrythmia => the first time medicines might be delivered directly into the heart, imaging dyes could display blood flow thru the heart, and cardiac abnormalities could be visualized in life. Forssmann was later shared the Nobel Prize in medicine in 1956. During WWII he was a medical officer serving on the Eastern Front for the Nazi Party, captured by the Americansnear the war end, and sent to an American POW camp. After released, he worked as a lumberjack, and later resumed his medical work as a urologist in West Germany. During the 1950s and up to the early 1960s:the key event that triggers a heart attack is not simply stenosisof a coronary artery, nor a clot elsewhere in the body that becomes lodged in one of the coronaries. It starts with an atherosclerotic plaque [after years of hypertension, smoking, or high cholesterol...plaques form when the endothelium which lines the inside of the artery is damaged]. Plaques slowly shrink an artery's aperture, but it is plaque rupture that triggers heart attacks, manifesting as hemorrhage, ulceration, or fissuring of a plaque. It only takes a few minutes for potent clot-forming factors and chemicals from the contents of the plaque to aggregate and form a thrombus/clot that completely occludes an artery, and cell death can begin within 60 seconds. The most fortunate heart attack victims benefit from the prompt arrival of emergency medical personnel who are able to defibrillate a patient out of an arrhythmia, and speed the patien to the emergency room. 1963 a radiologist at the Univ. of Oregon named Charles Dotter and Dr. Melvin Judkins developed a series of stiffer catheters with incrementally increasing diameters to relieve the obstruction by dilating the blood vessel until blood could flow freely again. Coronary Angioplasty Late 1960s an East German physician named Andreas Gruntzig attended a lecture about Charles Dotter's techniques, and developed them into intravascular balloons. With the help of an emeritus chemistry professor who had worked on polyvinyl chloride (PVC), Gruntzig could develop a catheter with a balloon glued to the end and a hole thru which imaging dye could be emitted. The catheter would travel to the aorta over a stiffer guide wire that could be pre-maneuvered to the desired location (the cathete was too flimsy and flexible to be threaded on its own). He first tried his technique called balloon angioplasty in dogs' coronary arteries successfully, then for the first time on a human in 1974, and in 1977 the first coronary bypass surgery by balloon on a human. By the early 1980s, leading doctores adopted Gruntzig's technique to treat coronary artery disease=> now from the emergency room the patient suffering a heart attack is rushed to the cardiac catheterization lab, where an interventional cardiologist can perform balloon angioplasty (using a balloon to deploy a miniture wire stent). Gruntzig's coronary angioplasty has saved millions of lives to date. Cardiac Surgery - Open Heart Surgery During the first half of the 20th century little to no further headway in cardiac surgery was made. After WWII Dr. Dwight Harken, a Harvard-trained US Army surgeon, used his finger-plugging method to stem the bleeding for wounded soldiers with severe chest wounds. Later he learned to pre-place sutures around the metal fragment (in the chest wound) in a purse-string configuration so that he could more rapidly close the hole after pulling out the fragment. After the war this method proved the foundation for the next leap forward, the first attempt to venture inside the heart itself to treat mitral stenosis. Dr. Charles Bailey, another WWII veteran from Philadelphia, was the first to attempt to use Harken's method of purse-string technique to pre-place a ring of sutures in the left atriumjust above the mitral valve in November 1945 on a patient dying from mitral stenosis. Although in several cases the patients died, both surgeons were pioneers of cardiac surgery. But until someone devised a way to provide oxygenated blood to the body without using the heart, the 4-to-12 minute constraints would consign the nascent filed of cardiac surgery to only the most simplistic maneuvers. In 1951 a Canadian surgeon, Dr. William Mustard, used monkey lungs to try his new approach to extracorporeal oxygenaione of blood. After that he tried on 12 children with life-threatening cardiac abnormalities, some of them survived after the operations for some time, one with almost 2 weeks, thus proving that it was possible to oxygenate a patient's blood outside the body. Dr. Walt Lillehei from the University of Minnesota tried the method of cross-circulation first on dogs, then on children with congenital heart defects. The idea stemmed from his knowledge of fetal circulation. In 1954 the procedure worked but still its triumph was premature. Dr. John Gibbon, a surgeon and a researcher from Boston, built a prototype machine to keep cats alive on complete heart-lung bypass for up to 25 minutes in 1939. Thomas Watson, a CEO of IBM, learned about Gibbon's vision and supported him with funding and engineers to improve his prototype machine. On May 6 1953 at Jefferson Medical College in Philadelphia, Dr. Gibbon successfully performed the first case using what would become the modern heart-lung machine. Within 8 years the first coronary artery bypass graft operation (CABG) had been performed. In the late 1960s CABG techn iques were improved by Dr. Rene Favaloro, an Argentina surgeon working at the Cleveland Clinic, by using a leg vein as a graft to convey blood from the aorta to the diseased coronary artery past the point of obstruction. Today bypass surgery is the mainstay of the cardiac surgery. Heart Transplant December 3, 1967 Dr. Christiaan Barnard performed the first heart transplant in history at Groote Schuur Hospital in Capetown, South Africa. But the story of this remarkable accomplishment begins with the pioneering work of Dr. Norman Shumway, a surgeon from Stanford University who labored for over a decade to develop the ideas and techniques that made Bernard's surgery possible. Louis Washkansky a 57-year-old diabetic, received the heart of Denise Darvall, a young woman declared brain-dead after a car killed her while she was walking in a crosswalk. Although Washkansky died from pneumonia 18 days after the surgery, his transplanted heart displayed no signs of failure or rejection. Dr. Norman continued his work to perfect the post-operative care that would allow transplant recipients to live longer and better lives. In 1981 Dr. Norman was a key member of the surgical team that performed the world's first combined heart-lung transplant. At present, about 3,800 cardiac transplants are performed annually in the USA. The system of organ donation is tightly regulated by the United Network for Organ Sharing (UNOS), which pairs donors and recipients according to numerous factors, while thousands of patients remain on the waitlist. Each year, about 805,000 Americans have a heart attack or 1 every 40 seconds. Implanted difibrillators/Implanted Cardioverter-defibrillators (ICDs) depend on wires and batteries with limited lifespans. Implanted wireless pacemakers are tiny capsules that contain batteries. Possible Future Advances: A future alternative to batteries could be the use of a small radiofrequency generator implanted on the chest wall, which can transmit energy to the pacemaker the same way a wireless station charges a smartphone. Stem cell to develop many different cell types in the body => regenerative medicine to improve cardiac functions, to seed 3D-printed, biodegradable scaffolds to create functional heart valves and blood vessels. In 2016 a decellularized cadaveric heart was postulated with stem cells, infused with nutrients, and grown in a bioreactor that simulated conditions inside the body like the stress of high ventricular pressure. When stimulated with electricity, the new cardiac muscle exhibited contractions => the futuristic goal of fabricating replacement hearts. Cancer pp. 169-213 Old Approaches: To Cut or Irradiate, Dr. William Halsted, Johns Hopkins Hospital 1894 pp.172-173; 1895 Wilhelm Rontgen and the discovery of X-rays and Pierre and Marie Curie and the discovery of radioactive substances, radium (1902) and polonium (1898). Recent Approaches: Chemotherapy after WWII, and the mustard gas and the nitrogen mustard gas treatment with "Mustargen" approved by FDA in 1949 (after the "Second Pearl Harbor" Dec 2, 1943 at the harbor of Bari, Italy). Dr.Steward Alexander and Colonel Cornelius Rhoads chief of the medical division of the Chemical Warfare Service. Mustargen: a vanguard of a class of chemotherapy drugs called alkylating agents, still used today. Anti-folate and Other New Treatment in the late 1940s Dr. Sidney Farber on childhood leukemia patients at Boston Children's Hospital; raising fund for millions of dollars required to mount a serious research effort to defeat leukemia : the Children's Cancer Research Fund 1948, in collaboration with a charity "the Variety Club of New England," inspired by the National Foundation for Infantile Paralysis. Twelve-year-old boy named Einar Gustafson/"Jimmy" (from Maine) 1948 Saturday evening radio program Truth or Consequences $231,000 "The Jimmy Fund" for Farber's research. 1952 Boston's brand-new Jimmy Fund Building with clinical space and research laboratories devoted to investigating and treating childhood cancer. 1949 a superior folic acid antagonist called methotrexate proved more effective and less toxic than aminopterin. 1950s-1960s: more chemotherapeutic agents discovered and developed. How to kill rapidly dividing cancer cells? "New successes/treatments" were poisons that killed all human cells, both normal and cancerous, with side effects: Methotrexate damaged the liver and the lungs, 6-mercaptopurine prompted nausea and vomiting, Vincristine precipitated low blood sodium, peripheral neuropathy, and constipation; actinomycin D produce debilitating fatigue and skin necrosis if any of the drug extravasated outside a vein. Dr. Emil Frei and Dr. Emil Freireich at the National Cancer Institute starting cancer treatment with multiple drugs at the same time, called "VAMP," in 1961. Horrible as it was, 60% of the children leukemia patients achieved remission of remission, higher than attained with single-drug treatment. By 1975 the 5-year survival rate for childhood leukemia has risen to 53%. National Cancer Act in 1971: the USA declaring war on cancer. Today childhood leukemia is curable about 90%. p.191. 50 years of chemotherapy, but basic questions remain: Where did cancer come from? How did it thrive? What made it sprread? Defined by Heterogeneity Hormones and the Androgen Deprivation Therapy: 1930s Dr. Charles Huggins, a Chicago urologist: cancer could be influenced by hormones. Back in 1896 Dr. George Beason, a Scottish surgeon: removing ovaries could reduce the sizes of the patients' breast cancer tumors => Elwood Jensen, a chemist and the development of Tamoxifen, an estrogen antagonist that would work on a specific target, on estrogen receptor-positive tumors (60-80% of breast cancers are receptor-positive) during 1960s till 1971. Theory of Angiogenesis: 1967 Dr. Judah Folkman, a 34-year-old surgeon at Boston Children's Hospital,and research on the role blood vessels play in cancer tumors. 1983 his lab isolated a molecule that made the vascular endothelial cells of blood vessels grow called "fibroblast growth factor" published in Science (1983) => shrinking tumors by diminishing their blood supply=> the development of interferon alpha and the first FDA-approved anti-angiogenesis drug Avastin that blocked a protein called vascular endothelial growth factor (VEGF). Avastin is used to treat colon cancer, malignancies of the lungs, kidney, and brain. Cancer Cause - the External Factors Theory: The prevention approach with screening tests: from 1920s with Dr. George Papanicolaou a cytologist at Cornell University Medical College, and his "Pap smear" pre-cancerous test against cervical cancer in 1928, and the National Cancer Institute's large scale trial in 1952. Viral Causes Theories: 1911 Dr. Peyton Rous, a virologist at the Rockefeller Institute in New York City, studied sarcoma in chickens and hypothesized that a virus caused cancer => the Rous sarcoma virus (RSV). Then in 1957 Dr. Denis Burkitt, an Irish surgeon, and the study of aggressive lymphoma (Burkitt's lymphoma) in children in the warm and wet weather regions of sub-Saharan Africa. With other doctors' help (virologists Michaerl A. Epstein in Britain, Yvonne Barr, pathologist Bert Achong), the Epstein-Barr virus, the cause of infectious mononucleosis, was identified. Nobel prize in medicine awarded to Dr. Peyton Rous and Dr. Charles Huggins in 1966. Bacterial Cause: 1984 2 Australian doctors, Barry Marshall and Robin Warren, discovered a bacterium (Helicobacter pylori) that causes stomach inflammation leading to stomach cancer, and won the Nobel Prize in 2005. How Viruses Cause Cancer - Molecular Underpinnings: in 1970, 2 virologists, Howard Temin (UW-Madison) and David Baltimore (MIT) independently discovered certain RNA viruses used an enzyme (reverse transcriptase; opposite of what normally happens to our cells) to convert RNA into DNA copy (the usual direction of transcription is to make an RNA message from our DNA genome, which is then transported to a ribosome to instruct the production of a specified protein). So an RNA virus with reverse trancriptase could insert its RNA genetic code -converted into a DNA copy- into a host's cell's native DNA, changing a cell's genome, with the result being endless cell division. Temin and Baltimore received the Nobel Prize in 1975, sharing it with Renato Dulbecco (CalTech Lab), with whom they had worked since the 1950s. p. 199 More discoveries on oncogenes: Harold Varmus and Michael Bishop (UCSF): new theory that oncogenes were present but not necessarily activated in all of our cells. Thus, the cause: cancer originated from activating oncogenes; the viruses carrying proto-oncogenes were not the cause. Example the cancer-causing gene src/pronounced "sarc") in the Rous sarcoma virus. In the 1980s: at least a hundred oncogenes and tumor suppressor genes were discovered => new knowledge and new drugs aiming at specific molecular targets (for breast cancer, leukemia, multiple myeloma, cancers of the head and neck, lung and pancreatic cancers...) Massive Genome Atlas (2005-2018): sequence the total genome of more than 10 thousand tumors representing over 30 of the most common and dealy cancers => possible future "personalized" medicine. But chemotherapy with all its drawbacks, continues to be the mainstay of treatment for most cancer cases today. We still need new weapons in the fight against cancer. Immunotherapy Dr. William Coley (Harvard Medical School) began to study sarcoma tumor in 1891. Although his approach of injecting "toxin"/bacterial inoculations to cancer patients and induced high fever to galvanize the body to purge the malignacy, was ridiculed and criticized in the late 19th century, his patients (at least up to 500 of these) experienced some degree of tumor regression. In the 20th century a subfield of oncology that Dr. W.Coley initiated emerged known as cancer immunotherapy: the immune system is harnessed to treat cancer. Cancer cells, like most cells, display unique proteins, or antigens, on their surfaces that are exposed to their outside environemnt and can be bound by other proteins, such as antibodies. Whereas can cells may mutate and develop the ability to evade chemotherapy drugs, they cannot elude the properly stimulated immune system, which, like them, can evolve and adjust to the threat of different adversaries. Dr. Steven Rosenberg (National Cancer Institute) resurrected W.Coley's ideas in mid-1970s. From 1980s and 1990s to 21 st century => Rosenberg confirmed an important principle: T cells of the immune system could help defeat cancer. In Texas Jim Allison'work on T-cells of the immune system and the T-cell receptor. Today a patient's blood sample can be sent to a lab to analyze the cancer cell's genome, and identify a unique surface protein, and determine the DNA sequence required to make the protein. A virus vector carries the DNA into T cells, which then produce chimeric antigen receptors (CAR) capable of targeting the cancer cells. These customized CAR-T cells, grown in the lab until they number in the billions, are then infused back into the patient where they seek and destroy the tumor. These CAR-T cells multiply and remain in circulation for years, potentially maintaining indefinite remission. => CAR-T Therapy, promising personalized cancer vaccine and screening test for both cancer and cancer recurrence after treatment. p. 211 The defeat of cancer will not be a matter of if but when. p. 213 Diabetes pp.46-74 Type 1 diabetes: ~5=10% of diabetic patients worldwide. Three possible causes: 1. a genetic defect that inhibits proper cell function, 2. an autoimmune disorder in which the body's own inflammatory cells attack and disable the islets of Langerhans/tiny clusters of endocrine cells (making up 1-2% in the pancreas) crucial for blood sugar regulation by producing hormones vital to metabolism, like insulin (in beta cells) and glucagon (in alpha cells), and 3. a viral infection that causes damage to the cells. Type 2 diabetes:>422 million diabetics worldwide, >37.3 million Americans (10% of the population); >1/3 or >96 million American adults are prediabetic, 70% of these prebiabetics will eventually develop diabetes. Tyoe 2 patient's tissues cannot use insulin to its full effect. Causes: 1. genetics, 2. lifestyle, the most important factor, particularly with regard to obesity (80-90% of type 2 diabetics are obese; increased fat metabolism leads to a reduction of insulin receptors on cell surfaces). Treatments: in the 1950s=> oral medications (sulfonylureas to stimulate insulin release, and to lower blood glucose; metformin to reduce the release of glucose by the liver, and decrease intestinal absorption of glucose). 21st century=>orla drugs like GLP-1 agonists and DPP-4 inhibitors to mimic or boost hormones (incretins) thatstimulate increased production of insulin; SGLT-2 inhibitors to enhance kidney's ability to excrete glucose, thus lowering blood glucose. Transplantation of islet cells can be performed but not common. Use of Insulin: 1967 S\Dorothy Crowfoot Hodgkin, a scientist, used X-ray diffraction to determine insulin's precise chemical structure. In 1978 Genentech, a biotech company, was the first to produce synthetic insulinusing recombinant DNA technology, brand named Humulin, approved by FDA in 1982. Today patients use either short-acting or long-acting formulations of insulin to meet their needs, as well as wearable insulin pumps (invented in 1970s). More recently, the CGM monitor (continuous glucose monitor/ a sensor applied to the arm pr the belly with an adhesive patch, which takes readings and transmit data to a pump, smartphone or other device for precise and effective insulin dosing). Companies like Medtronic and Tandem already manufacture insulin pumps that integrate sensor readings with automatically dosed insulin to sonme extent. Potent game-changing development: the implantation of stem cells induced to become islet cellsthat produce insulin. November 2021 the first Type-1 diabetic patient received stem-cell-derived islet cells in a new clinical trial.