How the rat became science's first domesticated model organism

Every other major mammalian model organism came to the laboratory sideways. Mice arrived as pets that geneticists happened to have on hand. Pigs and dogs came out of agriculture and companionship, pressed into medical use because their bodies happened to resemble ours. The brown rat, Rattus norvegicus, is different. Long before anyone thought to sequence its genome or run it through a maze, the rat had already been pulled out of the sewer, tamed, bred for colour and temperament, and installed in a laboratory building in Philadelphia purpose-built to standardise it. It has a fair claim to being the first mammal domesticated specifically, deliberately, for science, rather than for food, transport or companionship first.

That claim rests on an odd, occasionally charming history: a chemist's pet rat that befriended his ratting terrier, a Paris menagerie that started breeding albino rats to feed reptiles, a psychology graduate student who built a maze out of chicken wire, and a genome-sequencing consortium that made the rat the third mammal, after humans and mice, to have its DNA fully read.

An unlikely pet, then an unlikely laboratory animal

Wild Rattus norvegicus is not naturally white. The albino and hooded (patched) colour variants that filled 19th-century laboratories came from selective breeding, much of it originally driven by ratting, the once-popular blood sport in which terriers were set against rats in a pit and spectators bet on how fast the dogs could kill them. Rat-catchers who supplied these events sometimes kept unusual-coloured animals back, and a trade in "fancy rats", bred for coat colour and calm temperament rather than for the pit, grew up alongside it in Britain from the 1840s onwards.

The oldest documented scientific observation of a tame rat predates even that trade. In autumn 1822, a British chemist and pharmacist named Samuel Moss, working in Cheltenham, took in a white rat that he later named Scugg. Scugg was initially aggressive but became tame within about two weeks of regular handling and hand-feeding, and went on to form an unlikely friendship with Moss's trained rat-catching terrier, Flora: the two animals ate together, slept together, and even acted protectively toward one another when strangers approached. Moss published the account in 1836 in The Magazine of Natural History, making it the earliest known behavioural study of a rat, decades before anyone was running one through a maze for a living.

By the 1850s, white and piebald rats had moved from curiosities into working laboratory stock. The Jardin des Plantes in Paris established a colony of white rats in 1853, originally just to feed the menagerie's reptiles, and this incidental colony went on to supply Pierre Flourens's physiology laboratory in Paris. Several of the earliest rat experiments on record came out of that laboratory in 1856: Augustus Volney Waller used albino rats to study blood circulation through the transparent tissue of the eye, and Jean-Marie Philipeaux investigated the effects of removing the adrenal glands. Around the same time, in London, George Harley ran his own adrenalectomy studies, and William Savory at St Bartholomew's Hospital used albino and mixed-colour rats between 1860 and 1861 to study how low-protein and low-fat diets affected nitrogen excretion, an early precursor of modern nutrition science. In Germany, Hugo Crampe produced what is thought to be the first deliberately inbred rat line at the Agricultural School of Proskau, running seventeen consecutive generations of close inbreeding between 1877 and 1885, decades before inbred strains became routine practice.

None of this was yet organised into anything resembling a standard research animal. Rats were used because they were cheap, available, and physiologically informative, not because any institution had set out to build a reproducible research tool from them. That step happened in Philadelphia, in the first decade of the 20th century.

Philadelphia and the Wistar Institute

The Wistar Institute of Anatomy and Biology was founded in 1892 by Isaac Jones Wistar, a Philadelphia lawyer and former Civil War general, as an independent home for the anatomical collection of his great-uncle Caspar Wistar. Its purpose, in Isaac Wistar's own charter, was to sponsor and publish original scientific research, and its dedicated building opened in 1894, making it the United States' first independent biomedical research institute.

The rat's part in that story begins with Henry Herbert Donaldson, a neurologist who had started experimental work with albino rats at the University of Chicago in the early 1890s, studying the growth of the nervous system. Donaldson became director of research at the Wistar Institute in 1906 and brought his rat colony with him. Working alongside Milton J. Greenman, the Institute's business manager, and Helen Dean King, who joined the Institute in 1909, Donaldson set out to do something no one had done for a mammal before: turn the albino rat into a standardised, genetically consistent research animal through systematic inbreeding, comparable to what plant breeders were already doing with crops. King's inbreeding programme produced the line that became known as the Wistar rat, and by around 1907 the Institute had begun supplying its rats to outside laboratories, a practice that expanded through the following decade.

The effect on the field was substantial and lasting. More than half of all laboratory rat strains bred today are thought to trace back to that original Wistar colony, and the Institute's approach, breeding for uniformity rather than for any particular trait, became the template for how laboratory animal strains would be built and shared for the rest of the century. A neuroanatomist trying to standardise development studies had, more or less by necessity, created the first purpose-bred mammalian model organism.

Mazes, boxes and the birth of behavioural psychology

The Wistar colony's most immediate impact was on the young field of comparative psychology, and it happened almost as a byproduct. Willard Stanton Small, a graduate student at Clark University, built what is generally regarded as the first laboratory maze for animal research around 1900, a wire-netting enclosure modelled loosely on the Hampton Court hedge maze at the suggestion of his advisor Edmund Sanford. Small published his results as "An experimental study of the mental processes of the rat" across 1900 and 1901 in the American Journal of Psychology, treating maze-running as a window onto how associations and learning form in a mammalian brain.

That approach was picked up almost immediately by John B. Watson, later the founder of behaviourism, who studied under Donaldson at the University of Chicago. Watson's 1903 doctoral dissertation, Animal Education: An Experimental Study on the Psychical Development of the White Rat, Correlated with the Growth of Its Nervous System, used maze-learning in rats to test whether behavioural competence tracked the physical development of the nervous system, an early attempt to connect brain and behaviour experimentally rather than philosophically.

The rat's role in psychology deepened considerably over the following decades. Around 1930, working in a Harvard laboratory as a graduate student, B. F. Skinner built an enclosed chamber in which a rat could press a lever to receive a food pellet, and used it to study how consequences, rather than preceding stimuli, shape behaviour. Skinner set out the resulting theory of operant conditioning in his 1938 book The Behavior of Organisms: An Experimental Analysis. The apparatus became known as the "Skinner box", a label usually credited to the psychologist Clark Hull rather than to Skinner, who simply called it an operant chamber, but the name stuck and the device remains one of the most recognisable pieces of equipment in the history of psychology.

Rats also drove one of the deepest theoretical challenges to Skinner's stimulus-response model of learning. Edward Tolman, working at the University of California, Berkeley, ran a long series of maze experiments through the 1930s and 1940s that were difficult to explain through simple reinforcement alone. Rats that had explored a maze without any reward still seemed to learn its layout, and rats given a shortcut to a goal after learning a longer route would often take it immediately, as though they held an internal representation of the maze's spatial structure rather than a chain of stimulus-response habits. Tolman set out this argument in his 1948 paper "Cognitive maps in rats and men", published in Psychological Review, proposing that rats build something closer to an internal map than a set of conditioned reflexes, a concept that has since become central to cognitive science well beyond animal learning.

By the middle of the 20th century, a single species, bred initially to standardise neuroanatomy research at a Philadelphia institute, had become the experimental foundation for three of the biggest ideas in the young science of behaviour: association-based learning, operant conditioning, and cognitive mapping.

A working animal for physiology, pharmacology and toxicology

Behavioural psychology was never the rat's only laboratory role, and in terms of sheer volume of use, it was not even the biggest one. The nutritional and physiological work that had started with Savory's protein studies in the 1860s expanded enormously in the early 20th century. Elmer McCollum established what is generally credited as the first rat colony in the United States kept specifically for nutrition research, at the University of Wisconsin in January 1908, using it to test how diets built from single feed grains affected growth. That colony-based approach to nutrition research, feeding controlled diets to genetically similar animals and tracking the physiological consequences, became the model for how vitamin research was done, and McCollum's group used it to help identify vitamins A, B, D and E over the following years.

The same practical qualities that made rats useful to McCollum, being considerably larger than mice, easy to handle, comparatively docile once tame-bred, and large enough to allow repeated blood sampling and surgical procedures that would be impractical in a mouse, kept them central to physiology and pharmacology as those fields matured. Toxicology in particular has depended on rats since the field's earliest systematic era: rats are large enough to dose accurately, cheap enough to use in the group sizes statistics requires, and by the mid-20th century came with decades of accumulated reference data on their normal physiology, making abnormal results easier to interpret. Rats and mice together account for the overwhelming majority of animals used in biomedical research and regulatory toxicology testing today, a position that traces directly back to the standardisation work done at the Wistar Institute a century ago.

Reading the genome

The rat's final major landmark came almost exactly a century after Donaldson brought his colony to Philadelphia. The Rat Genome Sequencing Project Consortium, led by the Baylor College of Medicine and involving contributors including Celera Genomics and dozens of other institutions worldwide, published a high-quality draft genome sequence of the Brown Norway rat strain in Nature in April 2004, under the title "Genome sequence of the Brown Norway rat yields insights into mammalian evolution". It was the third mammalian genome to be sequenced, after the human and mouse genomes, and the three-way comparison it enabled helped researchers work out which genomic features were shared across all placental mammals, which were specific to rodents, and which had emerged more recently in the human lineage.

Where the Wistar Institute's early work had standardised the rat as a physical, breedable research tool, the genome project did the equivalent for its genetic information: it gave every laboratory using rats a shared, searchable reference, turning a century of accumulated physiological and behavioural data into something that could finally be tied back to specific genes and directly compared against the human genome.

What the rat's history adds up to

Few model organisms have a history this deliberately constructed. The mouse's rise to genetic dominance came later and rested heavily on the accident of an unusually tractable embryonic stem cell system. The rat's rise came first, and came from something closer to institutional will: a single Philadelphia laboratory decided, on purpose, that a mammal could be bred the way a crop variety is bred, consistent, reproducible and shareable, and set out to prove it. Everything that followed, the maze studies, the operant chamber, the toxicology reference ranges, the 2004 genome, built on a research animal that existed in that standardised form only because someone had decided, over a century ago, that it should.