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Building a better mousetrap (and mouse)

Yale Medicine Magazine, 2014 - Spring


A brief history of innovation in scientific methods at Yale.

The history of innovation in scientific methodology dates to antiquity, with such advances as the astrolabe in ancient Greece and the seismometer in China during the second century C.E. At Yale, it can be traced to the influence of such early figures as Benjamin Silliman, who created the first “modern” science laboratory at Yale in the early 1800s and was one of the founders of the medical school; and Russell Chittenden, who established the first laboratory in the United States for the teaching of physiological chemistry. Both men helped guide the medical school toward a focus on experimental science, uncommon in an era when most physicians received only brief exposure to science during their apprenticeships.

From this environment grew a thirst not only for new knowledge, but also for new tools with which to discover. Over the past 200 years, Yale scientists have devised numerous methods for expanding knowledge and accelerating the accumulation of data—and seeing or measuring things that had been previously beyond comprehension. The milestones that follow are excerpted from the 2010 book Medicine at Yale: The First 200 Years, by Kerry L. Falvey, and from other sources including Yale Medicine and Medicine@Yale. Do you know of an example not on this timeline that could be added to our online edition? If so, write to us at


Arnold L. Gesell, Ph.D., M.D. ’15, establishes the forerunner of the Yale Child Study Center, and uses a new technique, longitudinal motion-picture studies, to follow child development from infancy through age 6.


The Nobel Committee recommends awarding the prize in physiology or medicine to Yale scientist Ross G. Harrison, Ph.D., M.D., but because of World War I, no prize is given. Harrison is recognized for developing the technique of tissue culture, allowing cells to be grown outside the bodies of living organisms. His student, Yale College alumnus John Enders, Ph.D., will win the Nobel decades later for his work growing the polio virus using this method—a development that was crucial to the creation of the polio vaccine (as was work done in the 1940s and 1950s by Yale professor Dorothy M. Horstmann, M.D., FW ’43).


John P. Peters, M.D., is the co-author of the text that will become the veritable bible of quantitative clinical chemistry, based on methods he devised to standardize the analysis of blood and urine. As Donald Seldin, M.D. ’43, will later write, “The salutary result was a radical transformation of qualitative impressions into precise quantitative measurements.”


John F. Fulton, D.Phil., M.D., constructs a decompression chamber in his lab during World War II to study the physiologic dangers faced by Allied airmen flying in unpressurized planes at high altitudes. His work leads to better flight suits and education of pilots on the dangers of high-altitude aviation.


During his three years as a postdoc in New Haven, Herbert W. Boyer, Ph.D., FW ’66, produces two key papers on bacterial genetics that set him on a course as a pioneer in the fields of genetic engineering and biotechnology. Boyer will later team up with Stanley Cohen, M.D., of Stanford to invent methods of genetic recombination for the large-scale replication of human proteins in E. coli (above) and establish the world’s first biotechnology company, Genentech, in 1976.


Seymour R. Lipsky, M.D., and Csaba Horváth, Ph.D., develop high-performance liquid chromatography, an essential tool for identifying or isolating substances for research and for determining the purity of biochemical molecules—a crucial step in drug development. Lipsky is at left with associate Maurice Godet.


Alvan R. Feinstein, M.D., HS ’54, lays out the foundation of the new science of clinical epidemiology in his book Clinical Judgment. Feinstein will propose new methods of study design, data interpretation, and the measurement of study outcomes that are the standard in clinical research today.


Gerhard Giebisch, M.D., joins the Yale faculty. He and colleagues will devise novel micropuncture and patch-clamp methods to study how the kidney handles potassium—work that is largely responsible for current understanding of the mechanisms underlying regulation of renal potassium excretion.


George Palade, Ph.D., comes to Yale from The Rockefeller University, where he created methods that combined electron microscopy with new biochemical strategies to elucidate the fine structure and function of cellular organelles—an unparalleled body of work that laid the foundation of modern cell biology and won Palade the Nobel Prize the following year.


Jon W. Gordon, Ph.D. ’78, M.D. ’80, and Frank H. Ruddle, Ph.D., create the first genetically engineered mouse stably integrating foreign DNA. The so-called transgenic mouse has become an essential tool of biomedical scientists, allowing researchers to add and delete genes in experimental animals in order to observe normal gene function and determine how genetic defects contribute to disease.


Richard P. Lifton, M.D., Ph.D., then a fellow at the University of Utah, and colleagues apply the technique of linkage analysis to hunt for genes in the extended families of individuals with rare diseases. This new approach yields one of the first papers showing that a mutation intrinsic to the kidney is critical for blood pressure homeostasis. Lifton will come to Yale in 1993 and identify more than 20 genes associated with blood pressure, cardiovascular disease, and bone density using this method.


Robert G. Shulman, Ph.D., and colleagues at Yale turbocharge their outdated MRI system by adding echo planar imaging, enabling one of the earliest functional MRI studies; it will be the first to show the brain responding to individual events, in this case a single visual stimulus. Shulman’s team subsequently collaborates with Greg McCarthy, Ph.D., to perform the first fMRI measurements of a person performing a cognitive task.


Vincent A. Pieribone, Ph.D., and colleagues identify two corals (Lobophyllia hemprichii and Favites spp.) that produce fluorescent proteins, which, like jellyfish green fluorescent protein, are used as markers of gene expression. In 2013, they will develop a new molecular probe called ArcLight, which allows one to measure electrical activity of genetically targeted sets of neurons in a living organism, a prerequisite for understanding the complex language of the brain.


Tian Xu, Ph.D. ’90, and colleagues engineer the piggyBac transposon in mice. This “jumping gene” makes the mouse a mutant factory: when the animal breeds, the transposon causes random genetic mutations in the mouse’s offspring—one gene per mouse is disabled. Compared to current methods for making experimental mice, known as knockouts, using piggyBac is 100 times quicker and cheaper. PiggyBac also carries a genetic marker to turn the mouse pink for easy identification.


Yale scientists develop a method of whole-exome sequencing that enables the detection of gene variants with a high degree of sensitivity. The approach is also highly efficient in that it examines only complete coding regions, or 1 percent of the human genome. The method is used to diagnose a kidney disorder in a 5-month-old boy in Turkey, the first-ever genetic diagnosis by whole-exome (or whole-genome) screening.


A group led by Laura Niklason, M.D., Ph.D., develops a method for creating artificial lung tissue, which succeeds in facilitating gas exchange for a brief period in a rat model. The advance is cited by Time magazine as one of the 50 Best Inventions of 2010.


Immunobiologists at Yale create a mouse with human versions of genes that are important for innate immune cell development and function: monocytes, macrophages, and natural killer cells. This “humanized mouse model” may be used to mimic the human immune system in scenarios of health and pathology, and may lead to new therapies for human disease.

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