The Emperor of All Maladies

A Biography of Cancer 

         The Emperor of All Maladies, is an enthralling biography of cancer throughout generations, dating back to Imhotep, an Egyptian physician in 2625 BC to present day.  Mukherjee chronicles physicians and researchers grappling with a disease that is still not fully understood and may never be. An oncologist and researcher, Mukherjee recounts the discoveries and setbacks of a disease that seems to be outrunning any quest for expulsion. The perniciousness of cancer can be summed up through a quote from Lewis Carroll’s Through the Looking-Glass. The Red Queen tells Alice that the world keeps shifting so quickly under her feet that she has to keep running just to keep in the same position. This is our predicament with cancer; “we are forced to keep running merely to keep still.” 

            This post includes my annotations and notes from the book varying by topics of personal interest, feel free to skip to sections you may find more interesting. I reproduced a broad timeline of cancer through the centuries. Mukherjee does a wonderful job of including research from a plethora of sources, however the book did not flow chronologically. I have placed them, as best I can, in order.

            I dedicated another section purely to science. I was fascinated by my interest in the mini-biology review the book provides. In the context of cancer, lysosomes, mitochondria, and chromosomes jump off the page in comparison to dusty textbooks in a hormone-rich 9^th grade biology class.

            For me, the most compelling portion of the book was the evolution of our thought about how to attack cancer. For centuries, physicians treated the disease as one large entity, regardless of stage, region, or severity. Everything was based on surface level diagnoses. Take breast cancer, for example.  It was believed that the best way to eradicate breast cancer was to remove the entire breast, pectoral muscles, and even cut down to the ribs. After a procedure, deformities were so grotesque; some decided to keep their dignity and their cancer, foregoing the procedure. It took over a hundred years to realize that staging of breast cancer was very important. The ultimate survival from breast cancer, has little to do with how extensively a surgeon operated on a breast; it depended on how extensively the cancer had spread before surgery. Cancer is heterogeneous, there is no one-glove-fits-all approach. Stages are vital—late stage breast cancer could not be treated like early stage breast cancer.

            Physicians and researchers had to re-think their approach to cancer and start at the simplest biological level: the cell. In order to understand cancer, we needed to know what constituted a normal cell and a cancerous cell and build from there. Once this approach changed, an explosion of research provided drugs and treatment strategies that changed the landscape of oncology, especially in the field of genetics.

Building a foundation of knowledge on the ground level should occur in all facets of life. It is easy for my work as an occupational therapist to solely focus on my client’s symptoms or diagnosis. As a Christian, I can get lost in the outward appearances of my faith: daily prayer, scripture reading, or evangelism. However, the foundation of my faith is the gospel: serving a God of love, that sent His only son Jesus Christ to die for my sins, allowing me to love others with that same unfailing love. The outward appearance of my faith means nothing if I am not grounded in the foundation built on love.

The best encapsulation of the book is through a simple story of the genesis of cancer:

            "The genesis of cancer. A normal cell, say a lung cell that resides in the left lung of a 40 year old fire safety equipment installer. One morning in 1968, a minute sliver of asbestos from his equipment wafts through the air and lodges in the vicinity of that cell. His body reacts to the sliver with an inflammation. The cells around the sliver begin to divide furiously like a minuscule wound trying to heal, and a small clump of cells derived from the original arises at the site.

            In one cell in that clump an accidental mutation occurs in the ras gene. The mutation creates an activated version of ras. The cell containing the mutant gene is driven to grow more swiftly than its neighbors and creates a clump within the original clump of cells. It is not yet a cancer cell, but a cell in which the uncontrollable cell division has partly been unleashed—cancer’s primordial ancestor.

            A decade passes. The small collection of ras—mutant cells continues to proliferate, unnoticed, in the far periphery of the lung. The man smokes cigarettes, and a carcinogenic chemical in tar reaches the periphery of the lung and collides with the clump of ras-mutated cells. A cell in this clump acquires a mutation in its genes, activating a second oncogene.

            Another decade passes. Yet another cell in that secondary mass of cells is caught in the path of an errant X-Ray and acquires yet another mutation, this time inactivating a tumor suppressor gene. This mutation has little effect since the cell possesses a second copy of that gene. But in the next year, another mutation inactivates the second copy of the tumor suppressor gene, creating a cell that possesses two activated oncogenes and an inactive tumor suppressor gene.

            Now a fatal march is on; an unraveling begins. The cells, now with four mutations, begin to outgrow their brethren. As the cells grow, they acquire additional mutations and they activate pathways, resulting in cells even further adapted for growth and survival. One mutation in the tumor allows it to incite blood vessels to grow’ another mutation within this blood-nourished tumor allows the tumor to survive even in areas of the body with low oxygen.

            Mutant cells beget cells beget cells. A gene that increases the mobility of the cells is activated in a cell. This cell, having acquired motility, can migrate through the lung tissue and enter the bloodstream. A descendant of this mobile cancer cell acquires the capacity to survive in the bone. This cell, having migrated through the blood, reaches the outer edge of the pelvis, where it begins yet another cycle of survival, selection, and colonization. It represents the metastasis of a tumor that originated in the lung.

            The man is occasionally short of breath. He feels a tingle of pain in the periphery of the lung. Occasionally, he senses something moving under his rib cage when he walks. Another year passes, and the sensations accelerate. The man visits a physician and a CT scan is performed, revealing a ring-like mass wrapped around a bronchus in the lung. A biopsy reveals lung cancer. A surgeon examines the man and the CT scan of the chest and deems the cancer inoperable. Three weeks after the visit, the man returns to the medical clinical complaining of pain in his ribs and his hips. A bone scan reveals metastasis to the pelvis and the ribs.

            Intravenous chemotherapy is initiated. The cells in the lung tumor respond. But during the treatment, one cell in the tumor acquires yet another mutation that makes it resistant to the drug used to treat the cancer. Seven months after his initial diagnosis, the tumor relapses all over the body—in the lungs, the bones, the liver. On the morning of October 17, 2004, deeply narcotized on opiates in a hospital bed in Boston, the man dies of metastatic lung cancer, a sliver of asbestos still lodged in the periphery of his lung. He is 76 years old."

Major Events

2625 BC

Imhotep—Egyptian Physician first documented account of Cancer. In his writings, he described a female patient with a lump on her breast.

1775

Percival Pott found the first carcinogen: soot in chimney sweeps. A carcinogen is hazardous external stimuli that can spread disease.

1846-1867

Anesthesia—the dissociation of pain from surgery was discovered using ether.

1855

During the Crimean war, legend runs that a Turkish soldier rolled a cigarette for the first time using tobacco and newspaper. Smoking prevention is a major theme in cancer prevention.

1867

Antisepsis—developed by Louis Pasteur (French Chemist) who added carbolic acid to paste to wounds after surgery.

1860s

Gregor Mendel identified characteristics in his purebred plants that were inherited from one generation to the next-the color of the pea flower, the texture of the pea seed, the height of the pea plant. His research was the impetus for genetics.

1909

The term gene was coined after Mendel’s work with pea plants and realizing that there was a unit of inheritance based down from parent to child.

Late 1800s

The first antibiotic—Trypan Red was made.

Early 1900’s

In Germany, chemists began to synthesize not just dyes and solvents, but an entire universe of new molecules: phenols, alcohols, bromides, alkaloids, alizarins, and amides, chemicals never encountered in nature.

WWI

One particular toxic gas created during the time of Ehrlich was a colorless, blistering liquid produced by reacting the solvent thiodiglycol with HCl. It became known as mustard gas.

1918

Spanish Flu Influenza: Over 600,000 die.

1928

Hermann Joseph Muller discovers that x-rays could vastly increase the rate of mutation in fruit flies. Radiation was known to cause cancer (Marie Curie’s leukemia).

1938

March of Dimes campaign was created for polio. A massive and highly coordinated national fund-raising effort that asked every citizen to send FDR a dime to support polio education and research.

The 1940s

George Beadle discovered that genes carried instructions to build proteins—complex, multidimensional macromolecules that were the workhorses of the cell

1944

      Lawmakers in New York unveiled a novel program to provide subscriber-based health insurance to groups of employees in New York (HIP) the ancestor to the modern HMO.

      Oswald Avery discovered that genes were carried by one chemical, deoxyribonucleic acid (DNA). Physically, genes were carried within the cell in the form of chromosomes. Chemically, genes were composed of DNA.

1945

American Cancer Society was formed

The late 1950s

Francis Crick discovered that the genesis of proteins from genes requires an intermediary step—a molecule called ribonucleic acid (RNA).

1955

Sabin and Salk prepared the first polio vaccines. Commercially used in 1961.

1960s

The mammogram is used for the first time in x-rays in America. The tool was only powerful when they realized that the screening depended on age. For women above 55, the incidence of breast cancer is high enough that even a relatively poor screening tool can detect an early tumor and provide a survival benefit.

Mid 1960s

The bone marrow represented the frontier of toxicity, an unbreachable barrier that limited the capacity to deliver obliterative chemotherapy, “the red ceiling” as some oncologists called it. However, E. Donnall Thomas harvested bone marrow and found that it helped obliterate leukemia.

1967

The first hospice care was provided in London to care specifically for the terminally ill and dying, evocatively naming it St. Christopher’s—not after the patron saint of death, but after the patron saint of travelers. In the United States the first hospice was launched in 1974 at Yale-New Haven hospital.

1971

The last cigarette commercial was broadcast on television.

1973

Janet Rowley identified a unique chromosomal aberration that existed in leukemia cells. Dubbed the Philadelphia chromosome, the result was a translocation in which the head of the chromosome 22 and the tail of chromosome 9 has been fused to create a novel gene. This gene was named abl. They found like src, it functioned like a kinase—a protein that tagged other proteins with a phosphate group and thus unleashed a cascade of signals in a cell. In CML cells, the translocation created a new chimera, ­Bcr-abl, a hyperactive, over exuberant kinase that activated a pathway that forced cells to divide incessantly.

1981

The journal Lancet published an article about eight cases of an unusual cancer called Kaposi’s sarcoma, a slow-growing, violet-colored, indolent tumor that crept along the skin of elderly Italian men that, while occasionally serious, was often considered a somewhat glorified form of mole or carbuncle. One case was diagnosed with a rare pneumonia called PCP (pneumocystis carinii). Originally coined, GRID (gay-related immune deficiency), AIDS was first discovered.

1982

Berry Marshall discovers bacteria growing after a long incubation period. They called their growth Helicobacter Pylori—helicobacter for its appearance and pylorus for “gatekeeper” for its location near the outlet valve of the stomach. They could not find any experiment to use, so Marshall swallowed the bacteria and became violently ill, with nausea, vomiting, night sweats, and chills. They created an antibiotic using bismuth and his infection was eradicated.

1983

Simultaneously, Luc Montaginier and Robert Gallow discovered that AIDS was an RNA virus that could convert its genes into DNA and lodge into the human genome—a retrovirus. AIDS activism, particular ACT UP, changed the landscape for medicinal activism petitioning for higher use of experimental drugs, even those that had not undergone rigorous clinical trials. This experimentalism would permeate throughout the cancer scene.

1984

Biologists working on stem cells, had invented a new technology that allowed them to introduce exogenous genes into early mouse embryos, then creating a living mouse of those modified embryos.

1993

Charlotte’s Law mandated coverage for bone marrow transplantation for eligible patients in the state of Massachusetts, after HMO refused to pay for bone marrow transplants. However, 5-10% of woman ran the risk of developing cancer based on the treatment itself. $2-$4 billion was spend between 1991-1999 for transplantation.

Science

Statistics

Power

Is a measure of the ability of a test or trial to reject a hypothesis. This depends most critically on how intensively he has tested the hypothesis and thus, on the number of samples that have independently been tested. Therefore, for any trial to be adequately “powered,” it needs to recruit an adequate number of patients.

Survival rates

Were originally biased when looking at screening tests. A simple way to avoid bias is to not measure survival rates, but overall mortality. A nation with a larger fraction of older citizens will seem more cancer-ridden than a nation with younger citizens, even if actual cancer mortality has not changed.

Age Adjustment

Imagine two very different populations. One population is markedly skewed toward young men and women. The second population is skewed toward older men and women. If one measures the “raw” cancer deaths, the older-skewed population obviously has more cancer deaths.

Biology

Hormones

      Hormone manipulations could choke the growth of hormone-dependent cancer: breast and prostate cancer. Hormones typically work by binding to a receptor in a target cell.

      Estrogen is the principal hormone secreted by the ovaries. In 1968 Jensen found the estrogen receptor. Some breast cancer was responsive to the estrogen receptor (ER positive) and some was not (ER negative).

      Growth hormones are made by pituitary cells.

Blood Antigens and Antibodies

      Proteins in the blood called blood antigens, varied between individuals and were inherited in families, thus implying a genetic source for this variation.

      Antibodies are immunological proteins that bind their targets with exquisite affinity and specificity.

Hyperplasia

Cancer is cellular hyperplasia-the disturbed pathological growth of cells. In cancer, the cell acquires autonomous proliferation; it is driven by an internal signal.

Chromosomes

Chromosomes (colored bodies)-humans have 46 (23 matched pairs) one inherited from each parent Male (X, Y), Female (X, X). Boveri discovered that chromosomes must carry information vital for the proper development and growth of cells. The inheritance of sex is linked to chromosomes.

Proteins

Proteins carry out the bulk of cellular functions. They form enzymes, catalysts that speed up biochemical reactions vital to the life of the cell.

Stem Cells

Umbilical cord contains one of the richest known sources of blood-forming stem cells—cells that can be stored away in cryobanks and used for a bone marrow transplant to treat leukemia in the future, an intensely precious resource often flushed down a sink in hospitals after childbirth. Many of our adult organs possess a tiny population of stem cells that are capable of immortal regeneration. Stem cells are the body’s reservoir of renewal. Whereas cancer stem calls act as the persistent reservoir of cancer—generating and regenerating cancer infinitely.

Antifolates

Interrupt the metabolism of folic acid and stave all cells of a crucial nutrient requires for cell division. Nitrogen mustard and cisplatin chemically react with DNA, and DNA damaged cells cannot duplicate their genes and thus cannot divide.

Insulin

      Insulin is a protein that regulates blood sugar and be used to controlled diabetes is made by pancreas cells

Genes

      Genes located in chromosomes are duplicated when a cell divides and are transmitted into progeny (offspring) cells. Next, a gene, in the form of DNA, is converted into its RNA copy. Finally, the RNA message is translated into a protein. The protein, the ultimate product of genetic information, carries out the function encoded by the gene.

·      The conversion of DNA to RNA is called transcription.

·      Oncogene is a gene that is capable of causing cancer.

·      Translocation-flip-flop transposition of two pieces of chromosomes (Down’s Syndrome). Chromosomal translocations can create new genes call chimeras.

·      Kinase—an enzyme that attached phosphate groups to other proteins. The attachment of the protein acted like an “on” switch—activating the protein’s function.

·      Src was found to induce a cell to change its state from nondividing to dividing, ultimately inducing accelerated mitosis, the hallmark of cancer. Research found that cellular src protein possess the same kinase activity to activate proteins, but it was far less hyperactive; in contrast to viral src, it was tightly regulated—turned on and turned off during cell division. Perhaps src, the precursor to the cancer-causing gene, was endogenous to the cell. Perhaps viral src has evolved out of the cellular src.

·      Proto-oncogene (discovered by Varmus) was that a precursor of a cancer causing gene was a normal cellular gene. This discovery showed that cancer genes came from within the human genome.

·      Knudson’s gene, Rb (comes from Retinoblastoma), performs the opposite function of src. It suppresses cell proliferation, and it is the inactivation of such a gene that unleashes cell division. It has been coined an anti-oncogene. The retinoblastoma gene encodes a protein, also named Rb, with a deep molecular “pocket.” Its chief function is to bind to several other proteins and keep them tightly sealed in that pocket, preventing them from activating cell division. When the cell decides to divide, it tags Rb with a phosphate group, a molecular signal that inactivates the gene and thus forces the protein to release its partners. Rb thus acts as a gatekeeper for cell division, opening a series of key molecular floodgates each time cell division is activated and closing them sharply when the cell division is completed. Mutations in Rb inactivate this function. The cancer cell perceives its gates as perpetually open and is unable to stop dividing.

·      Oncogenes were its jammed accelerators and inactivated tumor suppressors its missing brakes. Although viruses do not universally cause cancer, certain viruses cause particular cancer, such as HPV causing cervical cancer. When the mechanism driving this cancer was deciphered, HPV turned out to inactivate Rb’s and p53’s signal—underscoring the importance of endogenous genes in even virally induced cancers.

·      BRCA-1 and BRCA-2—a gene that strongly predisposes humans to breast and ovarian cancer. It is one of the most common cancer-linked genes found in humans

·      Proto-oncogenes and tumor suppressor genes (Ras, Mek, Erk) have pathways. In normal cells, this pathway is tightly regulated. In cancer cells, activated ras chronically and permanently activates Mek, which permanently activates Erk, resulting in uncontrolled cell division—pathological mitosis.

·      For these cancer cells to grow they require a blood supply. A tumor thus “acquires” its own blood supply by insidiously inciting a network of blood vessels around itself and then growing, in grapelike clusters around those vessels—tumor angiogenesis.

·      Cancer cells that become habitually dependent on the activity of a gene for their growth can amplify that gene by making multiple copies of the gene in the chromosome. This is called oncogene amplification.

DNAàRNAàProtein (The Central Dogma of molecular biology)

Epidemiology

The Classical Triad of Epidemiology

Association, isolation, retransmission

Prevention

For lung cancer, the driver of decline was primarily prevention. For colon and cervical cancer, the declines were almost certainly due to the successes of secondary prevention—cancer screening. For breast cancer there have been three important interventions: mammograms (screening), surgery, and adjuvant chemotherapy (chemotherapy after surgery to remove remnant cancer cells).

Smoking

Carcinogensis through smoking: The changes began in the bronchial airways. As smoke traveled through the lung, the outermost layers, exposed to the highest concentrations of tar, began to thicken and swell. Within these thickened layers, the next stage of malignant evolution occurred: atypical cells with ruffled or dark nuclei in irregular patches. In a yet smaller fraction of patients, these atypical cells began to show the characteristic cytological changes of cancer, with bloated abnormal nuclei often caught dividing furiously. In the final stage, these clusters broke through the thin line of the basement membranes and transformed into carcinoma. Cancer, formed slowly overtime. Carcinogens had a common, distinctive functional property: they altered genes.

Viruses

      Infects lung cells and produces more influenza virus, but did does not leave a permanent fingerprint in our genes; when the virus goes away, our DNA is left untouched, however Rous Sarcoma Virus behaved differently and physically attached itself to the cell’s DNA, restructuring the DNA. It was discovered that Rous Sarcoma Virus carried a special property that could convert RNA back into DNA, reverse transcription. A virus that has this capability has been called a retrovirus.

      In viruses, genes are sometimes carried in their intermediary RNA from. Certain viruses have dispensed with the original DNA copy of genes and keep their genome in the RNA form, which is directly translated into viral proteins once the virus infects the cell.

      The genes of retroviruses exist as RNA outside cells. When these RNA viruses infect cells, they make a DNA copy of their genes and attach this copy to the cell’s genes. This DNA copy, called a provirus, makes RNA copies, and the virus is regenerated, phoenix like, to form new viruses. The virus is this constantly shuttling state, rising from the cellular genome and falling in again, RNA to DNA to RNA to DNA, ad infinitum.

Drugs

      A drug, in bare conceptual terms, is any substance that can produce an effect on the physiology of an animal. Drugs can be complex, multifaceted chemicals—molecules derived from nature (soil-inhabiting fungi) such as penicillin. Fleming’s discovery of penicillin on moldy bread and the monumental impact of the accidental finding—could not easily have been predicted, nor could the sudden demise of iron-lung technology that evolving techniques in virology allowed the growth of poliovirus and the preparation of a vaccine.

The Human Genome Project

      Led by Francis Collins, the project has the full sequence of the normal human genome, completed in 2003. The hope is to sequence the genome of all cancers to identify key mutations.

Gene Mutation

      In individual specimens of breast and colon cancer, between 50-80 genes are mutated; in pancreatic cancer, about 50-60, however Vogelstein found that between 11-15 pathways are typically dysregulated in a cancer cell and these mutations can be further studied.

      As cancer cells divide, they accumulate mutations due to accidents in copying of DNA, but these mutations have no impact on the biology of cancer. These are passive mutations. There are also driver mutations. These altered genes directly goad the growth and the biological behavior of cancer cells. Once the crucial driver mutations in any given cancer have been identified, we will need to launch a hunt for targeted therapies against these genes.

      Low fiber, red meat rich diets increase the risks of colon cancer and obesity is linked to breast cancer, but much more about these links remains unknown, especially in molecular terms.

      DDT and aminotriazole (pesticides) have been shown to cause cancer in animals in high doses, but thousands of chemicals proposed, as carcinogens remain untested.

Word Roots

Typhoid

A stormy disease with erratic, vaporous fevers, arose from the Greek tuphon, the father of winds-a word that gives rise to the modern typhoon

Influenza

Emerges from the Latin influential because medieval doctors imagined that the cyclical epidemics of flu were influences by stars and planets revolving toward and away from earth.

Tuberculosis

Coagulated out the Latin Tuber, referring to the swollen lumps of glands that looked like small vegetables

Cancer or Karkinos

Originated around 400 BC meaning,  “the crab”.

Onkos

Sub meaning for oncology, which describes tumors. A term for “mass or load or more commonly a burden. Onkos arises from the ancient word nek. And nek, unlike the static onkos, is the active from of the word load. It means to carry, to move the burden from one place to the next, to bear something across a long distance bring it to a new place.

Cancer Genotypes

It is suggested that there is a vast catalog of cancer cell genotypes that have manifestations of six essential alterations in cell physiology that collectively dictate malignant growth

1.     Self-Sufficiency in growth signals—cancer cells acquire an autonomous drive to proliferate.

2.     Insensitivity to growth-inhibitory (antigrowth signals)—cancer cells inactivate tumor suppressor genes.

3.     Evasion of programmed cell death (apoptosis)-cancer cells suppress and inactivate genes and pathways that normally enable cells to die.

4.     Limitless replicative potential-cancer cells activate specific gene pathways that render them immortal even after generations of growth

5.     Sustained angiogenesis—cancer cells acquire their own blood supply.

6.     Tissue invasion and metastasis—acquire the capacity to migrate to other organs, invade other tissue, and colonize these organize.

Characters:

Galen

Greek surgeon, physician and philosopher. 129-210 AD. Developed the theory of humorism. 4 humors:

1.     Black Bile (cancer and depression)

2.     Red hot (inflammation)

3.     White (excess of phlegm)

4.      Jaundice (overflow of yellow bile)

Eli Lilly

An American solider, pharmacist and chemist, he founded the Eli Lilly and company (pharmaceutical company) in the mid 1800s.

William Steward Halsted

Father of the Halsted Maneuver who extirpated larger areas of tissue for surgery of cancer

Wilhelm Rontgen

First to discover x-rays using an electron tube by accidently leaking radiant energy on a barium screen.

Pierre and Marie Curie

Discovered radium (radioactive material). Radium means light. Radiation would eventually burn into Mari Curie’s bone marrow leaving her permanently anemic.  Marie Curie died of leukemia in July 1934.

Paul Ehrlich

Found that aniline derivatives stained only parts of the cell, silhouetting certain structures and leaving others untouched. Ehrlich’s chemicals had successfully targeted bacteria because bacterial enzymes were so radically dissimilar to human enzymes.

Robert Koch

Discovered yet another chemical stain, this time for mycobacteria, the organisms that Koch had discovered as the cause of TB. He helped make anti-toxins or antibodies. Koch stipulated that for an agent to be defined as the cause of a disease, it would need to fulfill at least three criteria. The causal agent had to be present in diseased animals; it had to be isolated from diseased animals; and it had to be capable of transmitting the disease when introduced into a secondary host.

Richard Hill

Started randomized control trials (an English statistician) in the 1940s.

Sidney Farber

Regarded as the father of modern chemotherapy. He carried out the clinical trials for aminopterin, a folate antagonist in childhood acute lymphoblastic leukemia. He showed for the first time that induction of clinical and hematological remission in this disease was achievable

Howard Skipper

A scientist from Alabama found the chemotherapy typically killed a fixed percentage of cells at any given instance no matter what the total number of cancer cells was. He also found that by adding drugs in combination, he could often get synergistic effects on killing. 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.

Emil Frei and Emil Freireich

Both researched at the National Cancer Institute in Bethesda, Maryland. Their collaboration was symbolic of a deep intellectual divide that ran through the front lines of oncology: the rift between over moderated caution and bold experimentation.

Lester Breslow

UCLA epidemiologist who found that all measurement itself is subjective. He found that the only intervention ever known to reduce the aggregate mortality for a disease at a population level is prevention.

Henry Kettlewell

Used moth-labeling techniques to demonstrate natural selection.

William Cochran

Devised meta-analysis in the 1960’s using a composite number through all trials in the aggregate.

George Papanicolaou

(early 1900s) found aberrant and bizarre forms on the cervix with abnormal, bloated nuclei, ruffled membranes, and shrunken cytoplasm that looked nothing like normal cells. He created a technique to take a smear of the cervix (the Pap’s smear)

Ray Erickson

discovered Src (a diminutive gene for sarcoma). It was an unusual gene, it encoded a protein whose most prominent function was to modify other proteins—in essence, playing an elaborate game of tag.