Benjamin Waterhouse introduces the smallpox vaccine to the United States and helps gain acceptance for the new procedure.
Oliver Wendell Holmes identifies the cause and prevention of puerperal fever, also known as childbed fever.
John Collins Warren, the School’s first dean, provides the first public demonstration of anesthesia in surgery.
Reginald Heber Fitz provides the first clinical description of appendicitis; he also advocates performing appendectomies.
1890s–1910Insect-borne disease transmission; scurvy; heat-killed vaccines
Theobald Smith identifies the mechanism of insect-borne disease transmission, discovers the cause of scurvy and develops the concept of heat-killed vaccines.
Paul Dudley White introduces the electrocardiograph to the United States.
1922Insulin; founding of Joslin Diabetes Center.
Elliott Joslin introduces insulin to the United States and subsequently founds Joslin Diabetes Center.
1923Heart valve surgery
Eliot Cutler performs the world’s first successful heart valve surgery at the Peter Bent Brigham Hospital, today part of Brigham and Women’s Hospital.
Marius Smith-Petersen devises a three-flanged nail to secure the bone in hip fractures.
1927Iron lung; syphilis test
- Philip Drinker invents the iron lung to help polio-paralyzed patients breathe.
- William Hinton develops a blood test for the detection of syphilis.
1929First polio patient saved
In a first, the newly developed Drinker Respirator (iron lung) saves a polio patient at Peter Bent Brigham in collaboration with Children's Hospital Medical Center, today Boston Children’s Hospital, and the Harvard School of Public Health.
1930s–1940sOveractive thyroid; rickets; osteoporosis
Fuller Albright recognizes the disease of overactive parathyroid, develops an effective treatment for vitamin D-resistant rickets and provides insights into the treatment of osteoporosis.
1933Intracellular fluid and electrolytes
James Gamble and colleagues give the first demonstration of the need to replace intracellular fluid and electrolytes in those subjected to extreme loss of food and water.
1938Corrective heart surgery for children
Robert Gross performs the first successful closure of the patent ductus arteriosus, a congenital heart defect of infants, ushering in an era of corrective heart surgery for children.
1942Burn treatment; blood bank; emergency-response plans
While treating victims of the Cocoanut Grove fire in Boston, Massachusetts General Hospital physicians demonstrate the efficacy of a new approach to burn treatment and the value of new blood bank and emergency-response plans.
A Mass General researcher perfects the use of Pap smear to detect cervical cancer.
At Boston Children’s, Louis Diamond describes Rh disease, a condition resulting from incompatibility of a baby’s blood with the mother’s, and develops a transfusion procedure that replaces the blood of newborns affected by Rh disease.
1947Artificial kidney; pediatric remission of acute luekemia
- Carl Walter, John Merrill and George Thorn perfect the Kolff-Brigham artificial kidney for clinical use.
- Working at Boston Children’s, Sidney Farber is responsible for the first successful pediatric remission of acute leukemia.
1948Stenotic mitral heart valves
The first series of successful operations is performed at Peter Bent Brigham for repair of stenotic mitral heart valves.
1949Vaccine culture technique; cortisone; White classification
- John Enders, Thomas Weller and Frederick Robbins grow poliovirus in culture, paving the way for polio vaccines. Their technique also leads to vaccines against measles, mumps, rubella and chickenpox.
- Doctors at Robert Breck Brigham Hospital, now part of Brigham and Women’s, become the first to administer cortisone, a steroid treatment, to patients with rheumatoid arthritis.
- Helping women with diabetes who wish to have children, Joslin physician Priscilla White introduces the White classification of diabetic pregnancies, a widely used method to categorize patients’ risk and tailor treatments accordingly.
Sidney Farber and colleagues at what is now Dana-Farber Cancer Institute achieve the first remissions in Wilms tumor of the kidney, a common form of childhood cancer. By prescribing the antibiotic actinomycin D in addition to surgery and radiation therapy, they boost cure rates from 40 to 85 percent.
McLean Hospital researchers discover brain proteolipids, a new class of molecules necessary for brain structure and function. This discovery provides a basis for understanding normal brain development and abnormalities underlying psychiatric illness.
Surgeon Joseph Murray performs the first successful kidney transplant on identical twins at Peter Bent Brigham.
The first clinical trials of oral contraceptives get underway at Boston Lying-In Hospital, now part of Brigham and Women’s.
In a key advance toward the improved understanding of brain structures, McLean researchers develop a procedure for extracting and identifying brain lipids.
1960Platelets; proton beam therapy; implantable cardiac pacemaker
- Dana-Farber researchers develop the means to collect, preserve and transfuse platelets to control bleeding.
- Mass General clinicians become the first to use proton beam therapy to treat tumors of the eye, neck and brain.
- The first implantable cardiac pacemaker is developed at Beth Israel Hospital, today part of Beth Israel Deaconess Medical Center.
1962Human limb reattachment; heart rhythm restoration
- A surgical team, led by Ronald Malt, at Mass General performs a replantation of a severed arm, thus achieving the first successful reattachment of a human limb.
- Bernard Lown becomes the first to use direct electric current to restore the rhythm of the heart.
1964Human blood storage
Mass General innovators make practical for the first time the long-term storage of human blood.
Working at Joslin, William Beetham and Lloyd M. Aiello pioneer pan-retinal coagulation, a treatment that uses lasers to halt the sight-stealing proliferation of blood vessels in people with diabetes.
Mass General clinicians pioneer telemedicine, the practice of medicine over closed-circuit television.
1969Intra-aortic balloon catheter
Mass General cardiac surgeons collaborate in the development of an intra-aortic balloon catheter.
1970Human oncogene; positron emission tomography (PET) scan
- Dana-Farber researchers clone the gene ras and demonstrate that, when mutated, this gene—the first known human oncogene—helps spur the development of many common human tumors.
- Mass General researchers pioneer the positron emission tomography (PET) scan, an imaging technique that made possible one of the first noninvasive looks at functional changes within the brain and other organs.
1973Noninvasive fetal heart monitoring
Clinicians at the Boston Hospital for Women, now part of Brigham and Women’s, develop noninvasive fetal heart monitoring, enabling a safer and more accurate way to detect fetal distress during labor.
Mass General dermatologists Thomas Fitzpatrick and John Parrish introduce the field of photochemotherapy, which uses light and special medications to treat disorders such as psoriasis.
1976Insulin resistance receptors
C. Ronald Kahn, recruited to Joslin, discovers alterations in the receptors associated with insulin resistance, found in obesity and type 2 diabetes.
1977Virus particle structure
Stephen C. Harrison in the HMS Department of Biological Chemistry and Molecular Pharmacology is the first to determine the structure of an intact virus particle, leading to the understanding of the mechanisms of viral entry and assembly.
1978Prenatal DNA sequencing
Stuart Orkin and his team at Boston Children’s develop new DNA sequencing techniques for the reliable prenatal diagnosis of several genetic defects that cause thalassemia, a deadly form of anemia.
1979Magnetic resonance imaging (MRI)
Mass General radiologists pioneer the use of MRI, or magnetic resonance imaging, to diagnose illness and injury.
Researchers at Harvard Medical School and affiliated institutions make, and continue to make to this day, numerous key discoveries in the HIV/AIDS field.
1981Artificial skin; premature puberty reversal
- Researchers at Mass General, Massachusetts Institute of Technology (MIT) and the Shriners Burns Institute create the first artificial skin made from living cells.
- Mass General researchers develop a technique for reversing the premature onset of puberty in girls.
1982Discovery of telomeres
- Jack Szostak, HMS professor of genetics and the Alexander Rich Distinguished Investigator at Massachusetts General Hospital, co-discovers telomeres, regions of repetitive DNA that protect the ends of chromosomes and that shorten each time a cell divides. Together with the discovery of telomerase, the enzyme that builds telomeres, these findings—important in the study of cancer, aging and stem cells—led to Szostak’s sharing the Nobel Prize in Physiology or Medicine in 2009.
1983Congenital birthmark treatment; Huntington's disease
- Using a pulsed dye laser, Mass General researchers become the first to treat the congenital birthmarks known as port-wine stains without scarring.
- James Gusella leads the HMS Genetics team that finds a genetic marker for Huntington’s disease, a fatal inherited condition. This same gene-finding technique later enables scientists to find genetic markers for other inherited diseases.
1984Oncomouse; skin replacement; TIMI
- Genetics scientists, led by Philip Leder, create the first genetically engineered mouse model of cancer, subsequently dubbed the “oncomouse.”
- Cell Biology researcher Howard Green and colleagues become the first to grow human skin in large quantities in the laboratory, allowing skin replacement in patients with extensive burns.
- Brigham and Women’s researchers launch a series of national clinical studies known as the Thrombolysis in Myocardial Infarction (TIMI) trials, which demonstrate that new clot-busting drugs can save heart muscle and improve patients’ chances of surviving a heart attack.
1986Kawasaki disease retrovirus; Alzheimer's disease
- Boston Children’s researchers identify a retrovirus as the probable cause of Kawasaki disease, an infectious illness occurring predominantly in children under five.
- Investigators at Boston Children’s isolate and locate on chromosome 21 the gene for the brain protein found in the degenerative nerve tissue of people with Alzheimer’s disease.
1987Early-onset Alzheimer's gene; Duchenne muscular dystrophy gene
- Mass General researchers contribute to the discovery of the first gene associated with inherited early-onset Alzheimer’s disease.
- Louis Kunkel and colleagues at Boston Children’s discover the gene that causes Duchenne muscular dystrophy.
1988Laser tattoo removal
Mass General researchers develop laser treatment for removal of pigmented lesions and tattoos.
1989Tumor blood vessel growth compound
Judah Folkman and his research team at Boston Children’s produce a synthetic compound that inhibits the growth of blood vessels associated with tumors.
1990sProteasome-inhibiting cancer therapy
Alfred Goldberg and HMS colleagues conduct basic investigations that lay the foundation for the first proteasome-inhibiting cancer therapy.
1992Diphtheria toxin structure; amyloid beta
- The structure of diphtheria toxin structure is discovered, which leads to the discovery of a safer, more economical vaccine.
- Brigham and Women’s researchers discover that a protein (amyloid beta) thought to be an early, causative feature of Alzheimer's disease is also present in healthy individuals and that patients with Alzheimer's produce too much of this protein or cannot break it down properly.
1993Neovascular macular degeneration; microRNAs; paralyzed vocal cord surgical method; colon cancer gene; VEGF molecule
- Massachusetts Eye and Ear clinicians pioneer the use of photodynamic therapy for neovascular macular degeneration.
- HMS Genetics researcher Gary Ruvkun codiscovers small regulatory RNAs called microRNAs, revealing a new world of RNA regulation at an unprecedented small scale.
- Innovators at Mass. Eye and Ear develop a surgical method to restore speech, swallowing and normal breathing in patients with paralyzed vocal cords.
- Dana-Farber scientists identify the gene that causes an inherited form of colon cancer, which leads to diagnostic screening to determine whether people are predisposed to contract the disease.
- Mass. Eye and Ear researchers discover VEGF, a molecule implicated in diabetic retinopathy and age-related macular degeneration, the most common forms of blindness.
In studies of wound repair, HMS researchers at Boston Children’s find a key molecule, known as PR-39, that binds growth factors and proteins necessary for the mending process.
1995Triple-organ transplant; kidney disease blood glucose levels
- Brigham and Women’s surgeons perform the nation's first triple-organ transplant, removing three organs from a single donor—two lungs and a heart—and transplanting them into three individual patients, giving each a new lease on life.
- Joslin clinical researchers identify blood glucose levels that limit kidney disease.
1996How cells sense oxygen; Alzheimer's treatments; immune system advances
- William G. Kaelin Jr., Sidney Farber Professor of Medicine at HMS and Dana-Farber Cancer Institute and senior physician in medicine at Brigham and Women's Hospital, shows that cells lacking the VHL (von Hippel-Laudau) gene and its associated protein are incapable of sensing oxygen and later shows that these cells are unable to degrade HIF-1-alpha, a master regulator of the cellular response to low oxygen levels. These discoveries lead to Kaelin’s sharing the Nobel Prize in Physiology or Medicine in 2019.
- McLean scientists discover the first evidence of a chemical abnormality in nerve-cell function in the brains of people with Alzheimer’s, a finding that ultimately leads to the first treatments for the disease approved by the U.S. Food and Drug Administration.
- Building on insights into the functioning of the human immune system, Dana-Farber researchers, led by Lee Nadler, devise a way to neutralize immune system cells responsible for graft-versus-host-disease, a potentially dangerous side effect of organ and tissue transplants.
1997p73 gene; asprin
- An HMS Cell Biology team discovers a novel gene, p73, which resembles the powerful tumor-suppressor gene p53, but unlike its counterpart, p73 is found on only one chromosome and acts in ways quite different from its famous relative.
- Investigating how aspirin reduces inflammation, Brigham and Women’s scientists discover that aspirin targets COX, an enzyme involved in the formation of prostaglandins and thromboxanes, compounds that are part of the inflammatory response.
1998Adult live-donor liver transplant
Surgeons at Beth Israel Deaconess perform the first adult live-donor liver transplant in New England.
1999Fluorescent molecular probes
Ushering in a powerful new way to detect nascent cancers, Ralph Weissleder and colleagues at Mass General develop fluorescent molecular probes that fluoresce upon contact with tumor enzymes, allowing the detection of minute clusters of tumor cells.
2000Brain abnormalities associated with abuse and neglect
- McLean researchers identify four types of brain abnormalities associated with abuse and neglect experienced in childhood.
Studying a tiny cluster of nerve cells behind the eye, HMS Neurobiology researchers discover a pathway involved in how the brain’s circadian clock sends signals that control the body’s daily rhythms.
2002Rheumatoid arthritis pathway; C-reactive protien
- Researchers at HMS and Joslin identify a pathway linked to the cartilage deterioration and bone attrition of rheumatoid arthritis.
- Paul Ridker and colleagues at Brigham and Women’s find that C-reactive protein predicts the chances of developing heart disease, leading to new guidelines for predicting cardiovascular disease.
2003Multidrug-resistant tuberculosis treatment; source of preeclampsia
- Research conducted in resource-limited nations by the HMS Department of Social Medicine, now Global Health and Social Medicine, provides the first hard evidence that people infected with multidrug-resistant tuberculosis can be treated successfully by developing community-based outpatient treatment models.
- Beth Israel Deaconess researchers pinpoint the source of preeclampsia, a life-threatening complication of pregnancy and one of the leading causes of maternal and infant mortality worldwide.
2004Blood stem cells; protein transfer
- Led by Stuart Orkin, Boston Children’s scientists identify the first regulatory molecule that puts the brakes on the proliferation of blood stem cells and also preserves the integrity of those stem cells, enabling them to produce functional blood cells over a long period of time.
- HMS Cell Biology researchers discover the architecture of the first transmembrane protein-conducting channel, paving the way for an understanding of how proteins are transferred.
2005Prenatal nutrition; herpes vaccine candidate
- Mary-Elizabeth Patti and colleagues at Joslin show that poor prenatal nutrition permanently damages the function of insulin-producing cells in the embryo’s pancreas, raising the risk that the child will later develop type 2 diabetes.
- In studies to combat the herpes simplex virus type 2, the most common form of genital herpes, David Knipe in HMS Microbiology and Immunobiology develops a replication-deficient vaccine called dl5-29, which stimulates the immune system from inside host cells, a quality other vaccines lack, and becomes a leading candidate in human vaccine trials.
2006Cholesterol mechanism; DNA sequencing techniques
- Dana-Farber researchers identify a molecular mechanism in the liver that explains how eating foods rich in saturated fats and trans-fatty acids causes elevated blood levels of "bad" cholesterol and triglycerides, increasing the risk of heart disease and certain cancers.
- HMS Genetics researcher George Church introduces revolutionary "next generation" DNA sequencing technologies.
2007Cellular switch; rheumatoid arthritis gene; brown-fat cell switch
- Investigators, led by Donald Ingber, director of the Wyss Institute for Biologically Inspired Engineering at Harvard University, demonstrate how to turn cells on and off using magnets, leading to potential ways to correct cellular functions that diseases interrupt.
- Researchers at Brigham and Women’s and the Broad Institute of MIT and Harvard discover a gene involved in rheumatoid arthritis, a painful inflammation that affects 2.1 million Americans and can destroy cartilage and bone within afflicted joints.
- Dana-Farber scientists, led by Bruce Spiegelman, identify a molecular switch in mice that turns on the development of beneficial brown-fat cells, which generate heat and counter obesity.
2008RIPKI inhibitors; metastatic melanoma remission
- HMS Cell Biology researchers discover necroptosis and its inhibition by small-molecule inhibitors of RIPK1, which leads to clinical studies of RIPK1 inhibitors as potential therapies for amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease.
- Dana-Farber scientists achieve a medical first by using a targeted drug to drive a patient's metastatic melanoma into remission.
2009LIN28 protien; RNA interference; cancer cells' starvation; brown fat
- Boston Children’s stem-cell researchers, led by George Q. Daley, find that LIN28, a protein abundant in embryonic stem cells, is aberrantly expressed in about 15 percent of all cancers, revealing a possible new target for drug development.
- An HMS Genetics team, led by Stephen Elledge, uses a technique called RNA interference (RNAi) to dial down the production of thousands of proteins and determine which are required for cancer cells to survive, exposing a hidden set of drug targets for possible new cancer therapies.
- Joan Brugge and HMS Cell Biology colleagues discover that cancer cells perish not only via cell suicide, or apoptosis, they can also die of starvation by losing their ability to harvest energy, findings that point toward new tumor-killing strategies.
- Joslin scientists, headed by Aaron Cypess, demonstrate that adults retain energy-burning brown fat, a discovery that paves the way for new treatments for obesity and type 2 diabetes.
An HMS Neurobiology team, led by Michael Greenberg, finds that environmental stimuli activate certain sections of DNA, enhancing the process by which messenger RNAs are created, and that these “enhancer regions” play a role in driving gene expression, the first evidence of widespread enhancer transcription.
2011Kidney failure markers; cancer cell vulnerability; global health care budget models
- Andrzej Krolewski and colleagues at Joslin identify two novel markers that, when elevated in the bloodstream, accurately predict the risk of kidney failure in patients with type 1 and type 2 diabetes.
- Challenging a half century-old theory that chemotherapy works by targeting fast-dividing cells, Dana-Farber researchers report that cancer cells on the verge of self-destructing are especially vulnerable to chemotherapy.
- Michael Chernew and J. Michael McWilliams, HMS Health Care Policy faculty, demonstrate that global budget models can lower health care spending while improving quality in commercially insured populations and Medicare.
2012Tumor suppressor gene p53; ancient migration; infectious disease diagnostics
- HMS Systems Biology researchers, led by Galit Lahav, use a combination of mathematical models and experiments to show that the tumor suppressor gene p53 uses pulsed signals to trigger DNA repair and cell recovery, and that the rhythm of these pulses carries crucial information.
- Analyzing more than 300,000 DNA sequence variations from Native American and Siberian populations, HMS Genetics researcher David Reich and colleagues reveal that North and South America were populated in three ancient waves of migration.
- Scientists, led by Deborah Hung in the HMS Department of Microbiology and Immunobiology and at Mass General and Brigham and Women’s, show that a detailed RNA signature of specific pathogens can identify a broad spectrum of infectious agents, forming the basis of a diagnostic platform to earlier determine the best treatment option for infectious diseases.
2013Cardiac hypertrophy reversal; cathepsin k pathways
- In studies of aging factors, Amy Wagers and Richard T. Lee, HMS researchers in Stem Cell and Regenerative Biology, discover that a substance called GDF-11 reverses cardiac hypertrophy, or thickening of the heart muscle, an important contributor to heart failure.
- Roland Baron, of Harvard School of Dental Medicine and Mass General, reveals pathways by which the gene cathepsin K promotes bone resorption and formation, pointing to potential new therapies for osteoporosis.
2014Hematopoietic stem cells; pancreatic stem cells
- Scientists in the HMS Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, led by Derrick Rossi, reprogram mature blood cells into blood-forming hematopoietic stem cells, thereby extending the possibility of transplantation to patients for whom a histocompatible donor cannot be identified.
- Stem Cell and Reproductive Biology researchers, led by Douglas Melton, successfully generate mature human insulin-producing pancreatic beta cells from stem cells in vitro, which, when transplanted into mice, secrete insulin appropriately in response to glucose levels.
2015Bioartificial replacement limb; PD-1 pathway; The Lancet Commission on Global Surgery; pseudogene; damaged protein disposal; multiple sclerosis; somatic mutations; deafness gene therapies
- A team at Mass General takes the first steps in creating a bioartificial replacement forelimb suitable for transplantation in humans.
- HMS Microbiology and Immunobiology scientist Arlene Sharpe and Dana-Farber researcher Gordon Freeman show that cancer cells hijack the PD-1 pathway, turning off the immune system. These findings translate into new treatments that free the immune system to fight tumors.
- Spearheaded by faculty in the HMS Department of Global Health and Social Medicine, a report by The Lancet Commission on Global Surgery reveals that 5 billion people are unable to access safe, timely and affordable surgery, leading to 18.6 million preventable deaths each year worldwide. The report also presents a blueprint for developing properly functioning surgical systems globally.
- Researchers at Beth Israel Deaconess discover that a pseudogene, an RNA subclass that has lost the ability to produce proteins, has a role in causing cancer.
- HMS Systems Biology scientists, led by Marc Kirschner, reveal the molecular processes involved in the disposal of malfunctioning or damaged proteins. These proteins are tagged with ubiquitin, which signals a cellular machine called the proteasome to pulverize the defective protein.
- In neurologic studies, Brigham and Women’s researchers discover a gene variant that may help patients with multiple sclerosis better respond to a certain medication.
- Peter Park, in the HMS Department of Biomedical Informatics, leads a study demonstrating for the first time that a large number of somatic (noninherited) mutations are present in the brain cells of healthy people and occur more frequently in the genes that neurons use most.
- Studying genes that cause deafness, researchers at Boston Children’s take key steps toward developing gene therapies to restore hearing.
2016Sigma-1 receptor structure; Zika vaccine candidate; circadian rhythm-bipolar disorder link; microbiome
- Andrew Kruse, an HMS scientist in Biological Chemistry and Molecular Pharmacology, is the first to reveal the molecular structure of the sigma-1 receptor, a cellular protein implicated in amyotrophic lateral sclerosis (ALS), a discovery that opens the door to potential therapeutic targets.
- Virologists at Beth Israel Deaconess find two candidate vaccines that provide complete protection from the Zika virus in animal models, suggesting a vaccine for humans may be feasible.
- McLean scientists link abnormalities in circadian rhythms to specific neurochemical changes in the brains of people with bipolar disorder that coincide with increased severity of symptoms in the morning.
- In studies of the microbiome, HMS Microbiology and Immunobiology researchers find an array of individual bacterial species in the human gut that work together to influence immuno-inflammatory responses.
2017Unlocking the blood-brain barrier; deciphering the structure of a scissorlike enzyme
- HMS Department of Neurobiology researchers provide the first molecular explanation for how the blood-brain barrier remains closed—by suppressing the process for transporting molecules across cells in vesicles, or small bubbles. This finding may lead to a way to deliver drugs across the barrier and into the brain to treat disorders such as brain cancer, stroke and Alzheimer’s.
- Using x-ray crystallography, HMS researchers in the Department of Biological Chemistry and Molecular Pharmacology decipher the atomic structure of ADAM10, a scissorlike enzyme that plays a critical role in normal cell-to-cell communication, but when malfunctioning, ADAM10 has been implicated in neurodegenerative diseases such as Alzheimer’s, certain cancers and asthma.
2018The 'graying' of T cells; From one cell, a detailed roadmap
- In research that may help explain the basic malfunction that drives the loss of immune defenses with aging, HMS investigators in the Department of Cell Biology pinpoint a specific metabolic pathway deficient in the aged T cells of mice; the work also suggests possible ways to restore weakened immune function using small-molecule compounds that boost T-cell performance.
- Using the technology of single-cell sequencing, which was developed at the School, HMS and Harvard scientists traced the fates of individual cells over the first 24 hours of the life of an embryo, recapitulating decades of research on the decisions cells make in the earliest stages of life and generating a detailed roadmap of which genes are turned on or off, and when, as embryonic cells transition into new cell states and types.
2019Finding herpes' Achilles' heel; viral peptides critical to natural HIV control
- In a first, HMS Department of Microbiology scientists use CRISPR-Cas9 gene editing to disrupt both actively replicating and dormant pools of herpes simplex virus in human fibroblast cells, revealing a possible strategy for achieving permanent viral control.
- By calculating network scores for the proteins that make up HIV, HMS investigators based at the Ragon Institute of MGH, MIT and Harvard identify specific amino acids in the protein structure of HIV that appear critical to the ability of the virus to function and replicate.