NOBEL PRIZES FOR DISCOVERIES IN PAEDIATRICS

A mysterious something: The discovery of insulin and the 1923 NobelPrize for Frederick G. Banting (1891�1941) and John J.R. Macleod(1876�1935)

TONSE N. K. RAJU

National Institute of Child Health and Human Development, National Institutes

of Health, Bethesda, Maryland, USA

In 1922, a 12-year-old Canadian boy, Leonard

Thomson, became the first diabetic patient to be

successfully treated with ‘a mysterious something’ �the pancreatic extract that still awaited christening

[1]. By 1923, thanks to the creative collaboration

between the University of Toronto and the Eli Lilly

Company, unlimited quantities of the extract became

available bearing the name ‘insulin’. The same year,

two of the four principal discoverers of insulin won the

Nobel Prize in Physiology or Medicine, the shortest

duration between a discovery and the coveted prize

[2].

The term ‘diabetes’ has a Greek root meaning

‘siphon’ and a Latin root meaning ‘honey’, references

to polyurea and glycosuria, two of its cardinal

symptoms. In ancient India, it was called ‘madhu

meha’ (sweet melody). Other names dramatizing the

sad suffering of its victims were ‘pissing evil’ and

‘melting down of flesh and blood’.

Until the discovery of insulin, there had been no

treatment for diabetes. Bloodletting and blistering

were common. Opium was used because ‘dope dulled

the despair’ and made the suffering tolerable. Some

experts prescribed an abundance of sugar to compen-

sate for its loss in the urine, while others felt that

fasting followed by intense exercise helped sugar to

burn. ‘‘You shall earn your bread by the sweat of your

brow’’, remarked a French doctor.

In 1869, Paul Langerhans, a German medical

student, discovered some peculiar pancreatic cells

that looked like small islands floating amid the acinar

cells. These cells were later named the Islets of

Langerhans. The role of these cells in diabetes

however, was not known.

In 1901, Oskar Minkowski of the University of

Strasbourg was testing the role of the pancreas in fat

digestion. One of his depancreatized dogs, in spite of

being housebroken, began to urinate constantly.

Minkowski discovered that the urine was loaded

with sugar, a finding similar to that seen in diabetic

patients. He and others proposed that the pancreas

had a set of external secretions helping digestion, and

an internal secretion helping sugar control. Also in

1901, Eugene Opie of Johns Hopkins University in

the United States showed that the islet cells of

Langerhans were the source of the internal secretion.

These developments in the first two decades of the

20th century propelled dozens of investigators in

search of the elusive pancreatic secretion that could

help diabetic patients. However, such attempts began

to fail miserably, in part because the process of

extraction would destroy the islet cells and their

chemical content. Some experts felt that the exocrine

secretions of the pancreas digested the islet cell

secretion. There seemed to be no way out of this

mysterious impasse.

Into such a confused world of diabetes research

entered Frederick Banting (1891�1941), a fledging

surgeon with a part-time lecturer’s position at the

University of Western Ontario in London, Ontario.

His knowledge about contemporary research in dia-

betes was superficial. On Sunday, 31 October 1920,

as he was preparing for a lecture on the pancreas to

medical students the next day, Banting read a paper in

ISSN 0803-5253 print/ISSN 1651-2227 online # 2006 Taylor & Francis

DOI: 10.1080/08035250600930328

Correspondence: T. Raju Centre for Developmental Biology and Perinatal Medicine, NICHD/NIH, 6100 Executive Blvd, Room 4B03, Bethesda, MD, 20892,

USA. E-mail: rajut@mail.nih.gov

Acta Pædiatrica, 2006; 95: 1155�1156

the November issue of Surgery, Gynecology, and

Obstetrics that described an autopsy report on a

patient who had pancreatic stones, completely ob-

structing the gland, destroying the acinar cells, but

preserving the islet cells. Banting was struck by a

brilliant idea: why not occlude the pancreatic ducts

and allow the acinar cells to atrophy? After this, one

might be able to obtain an extract from the islet cells

and test it on diabetic dogs.

However, Banting neither had a laboratory of his

own, nor any research experience to speak of. He took

the suggestions from his friends and met Professor

John J.R. Macleod (1876�1935) at the physiology

department in the University of Toronto in November

1920. Macleod was an expert in glucose metabolism.

He was sceptical about Banting’s ideas. However, he

agreed to help. He arranged for laboratory space

during the following summer, since laboratories

would be then less crowded. He gave some dogs for

the study and helped Banting to refine key steps in the

experimental design. Macleod also assigned a final

year masters’ degree student, Dr. Charles Best, to

provide technical assistance.

In April 1921, Banting closed his practice, sold his

house, and went to Toronto to pursue research at

Macleod’s laboratory as planned. From May to

September of that year, Banting and Best virtually

lived in the laboratory, working on dogs, learning

from their mistakes, and refining their experiments.

There were many setbacks. Removing the pancreas

was tedious. Several dogs died of infections. In some

dogs, the pancreas did not atrophy, despite complete

ligation of the ducts.

However, the first glimmer of hope came on 30 July

1921. When they injected the crude extract from the

islet cells from another dog to their diabetic dog 401,

its blood sugar concentration plummeted. Although

this dog died of coma the next day, Banting and Best

had shown for the first time that an extract from the

islet cells reduced blood sugar [1].

Much work had to be carried out over the sub-

sequent weeks and months. The pair confirmed their

findings repeatedly, and discussed them with Macleod

upon his return from a summer vacation in Scotland.

Macleod began to take more interest in the studies.

He recruited James Collip, an expert in biochemistry

and chemical extraction, to assist in purifying the

pancreatic compound. By the end of 1921, the four

scientists had succeeded in extracting enough of the

new compound for clinical use.

In January 1922, when his father carried Leonard

Thompson into the diabetic ward at Toronto General

Hospital, the boy was so emaciated and ‘reduced to

skin and bone’ that a clinic secretary remarked ‘‘I’ve

never seen a living creature as thin as he was’’. On 23

January, Leonard received an intramuscular injection

of 5 cc of the new pancreatic extract Collip had

prepared, that looked like ‘‘thick brown muck’’ [1].

Despite a rocky course and less than expected

dramatic response, Leonard miraculously recovered

with subsequent doses of the pancreatic extract,

becoming the world’s first successfully treated dia-

betic patient.

Initially, Banting and Best had called the pancreatic

chemical ‘iletin’, but the name ‘insulin’ eventually

stuck. It was perhaps proposed by Macleod, because it

had a Latin root for island and was easier to use. It did

not take long for the group and others to show that

insulin contained consistently predictable properties

in the control of diabetic hyperglycemia. Thus it was

natural that the 1923 Nobel Prize in Physiology and

Medicine was bestowed upon Frederick Banting and

John Macleod.

By the time the prizes were announced, the mutual

relationships among the four scientists had become

strained. Banting was angry that Charles Best had

been left out of the Nobel Prize. He considered

declining the prize altogether, but conceding to the

advice of colleagues and friends, accepted the prize

and proposed that he would share half of his prize

money with Best. Macleod, too, followed suit by

announcing to share his half of the money with James

Collip. Controversies abounded about their individual

roles in the discovery of insulin. Posterity has proved,

however, that without the successful collaboration of

all four, insulin could not have been discovered at that

time [1�3].

Most of the diabetic patients treated with insulin

initially were children admitted to the Hospital for

Sick Children in Toronto. One, Ms. Elizabeth Evans

Huges, the 17-year-old prized patient of Banting,

found insulin to be ‘‘unspeakably wonderful’’. She

lived for 74 years [1].

References

[1] Bliss M. The Discovery of Insulin. Chicago. The University of

Chicago Press. 1982.

[2] Raju TN. Twentieth century’s Nobel Prizes in physiology or

medicine with a note on pediatric laureates. J Pediatr 2000;/136:/

127�31.

[3] Magill, Editor. The Nobel Prize Winners (3rd edn.). Physiology

or Medicine Vol. 1, Salem Prince Inc, Pasadena (CA) (1991).

1156 T.N.K. Raju