John C. Sheehan
Encyclopedia
John Clark Sheehan was an American organic chemist whose work on synthetic penicillin
Penicillin
Penicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....

 led to tailor-made forms of the drug. After nine years of hard work at the Massachusetts Institute of Technology
Massachusetts Institute of Technology
The Massachusetts Institute of Technology is a private research university located in Cambridge, Massachusetts. MIT has five schools and one college, containing a total of 32 academic departments, with a strong emphasis on scientific and technological education and research.Founded in 1861 in...

 (M.I.T.), he became the first to discover a practical method for synthesizing penicillin V. While achieving total synthesis, Sheehan also produced an intermediate compound
Chemical compound
A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...

, 6-aminopenicillanic acid
6-APA
6-APA is the chemical compound -6-aminopenicillanic acid.-Use:6-APA is the core of penicillins. It is obtained from the fermentation brew of the Penicillium mold and used as the main starting block for the preparation of numerous semisynthetic penicillins.-Manufacture:This useful compound is made...

, which turned out to be the foundation of hundreds of kinds of synthetic penicillin. Dr. Sheehan’s research on synthetic penicillin paved the way for the development of customized forms of the lifesaving antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...

 that target specific bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

. Over the four decades he worked at M.I.T., Sheehan came to hold over 30 patents, including the invention of ampicillin
Ampicillin
Ampicillin is a beta-lactam antibiotic that has been used extensively to treat bacterial infections since 1961. Until the introduction of ampicillin by the British company Beecham, penicillin therapies had only been effective against Gram-positive organisms such as staphylococci and streptococci...

, a commonly used semi-synthetic penicillin that is taken orally rather than by injection. His research covered not only penicillin, but also peptides, other antibiotics, alkaloids, and steroids.

Biography

He was born on September 23, 1915 in Battle Creek, Michigan
Battle Creek, Michigan
Battle Creek is a city in the U.S. state of Michigan, in northwest Calhoun County, at the confluence of the Kalamazoo and Battle Creek Rivers. It is the principal city of the Battle Creek, Michigan Metropolitan Statistical Area , which encompasses all of Calhoun county...

 to Florence and Leo Sheehan. His father was then a sports editor and police reporter for a local newspaper, The Battle Creek Enquirer. Leo C. Sheehan left home at the age of fifteen and found work as a reporter in San Francisco. As a skill writer, he progressed quickly with The Battle Creek Enquirer and became the managing editor. At one point, he functioned as the ghostwriter
Ghostwriter
A ghostwriter is a professional writer who is paid to write books, articles, stories, reports, or other texts that are officially credited to another person. Celebrities, executives, and political leaders often hire ghostwriters to draft or edit autobiographies, magazine articles, or other written...

 for Frank Murphy
Frank Murphy
William Francis Murphy was a politician and jurist from Michigan. He served as First Assistant U.S. District Attorney, Eastern Michigan District , Recorder's Court Judge, Detroit . Mayor of Detroit , the last Governor-General of the Philippines , U.S...

, who was once the governor
Governor
A governor is a governing official, usually the executive of a non-sovereign level of government, ranking under the head of state...

 of Michigan
Michigan
Michigan is a U.S. state located in the Great Lakes Region of the United States of America. The name Michigan is the French form of the Ojibwa word mishigamaa, meaning "large water" or "large lake"....

 and a Supreme Court Justice. Sheehan’s mother was a genealogist who later became the Michigan registrar for the Daughters of the American Revolution
Daughters of the American Revolution
The Daughters of the American Revolution is a lineage-based membership organization for women who are descended from a person involved in United States' independence....

. His paternal grandfather, John W. Sheehan, was a successful lawyer, while his maternal grandfather, Nathaniel Y. Green, was a bank manager who had a keen interest in science and nature. Green played a role in stimulating John C. Sheehan’s interest in science by giving him a microscope
Microscope
A microscope is an instrument used to see objects that are too small for the naked eye. The science of investigating small objects using such an instrument is called microscopy...

 with an oil-immersion lens. He also introduced Sheehan to the curator of a local museum and took his grandson to meetings where Green frequently met with others passionate about astronomy
Astronomy
Astronomy is a natural science that deals with the study of celestial objects and phenomena that originate outside the atmosphere of Earth...

.

At a young age, John Sheehan had been fascinated by science
Science
Science is a systematic enterprise that builds and organizes knowledge in the form of testable explanations and predictions about the universe...

, especially explosives and rocketry
Rocket
A rocket is a missile, spacecraft, aircraft or other vehicle which obtains thrust from a rocket engine. In all rockets, the exhaust is formed entirely from propellants carried within the rocket before use. Rocket engines work by action and reaction...

. He started with a simple chemistry
Chemistry
Chemistry is the science of matter, especially its chemical reactions, but also its composition, structure and properties. Chemistry is concerned with atoms and their interactions with other atoms, and particularly with the properties of chemical bonds....

 set and then progressed to a basement laboratory
Laboratory
A laboratory is a facility that provides controlled conditions in which scientific research, experiments, and measurement may be performed. The title of laboratory is also used for certain other facilities where the processes or equipment used are similar to those in scientific laboratories...

 where he built models and performed experiments. A model airplane that he built with a delta wing
Delta wing
The delta wing is a wing planform in the form of a triangle. It is named for its similarity in shape to the Greek uppercase letter delta .-Delta-shaped stabilizers:...

 won a competition in his self-design class. Apart from science, Sheehan was also very competitive in other activities. He was an excellent marble shooter in elementary school, representing his school in the state championships. In addition, he was the winner of a city-wide yo-yo
Yo-yo
The yo-yo in its simplest form is an object consisting of an axle connected to two disks, and a length of twine looped around the axle, similar to a slender spool...

 competition, the winner of a Boy Scout election, an active member of his high school football
American football
American football is a sport played between two teams of eleven with the objective of scoring points by advancing the ball into the opposing team's end zone. Known in the United States simply as football, it may also be referred to informally as gridiron football. The ball can be advanced by...

 team, as well as Battle Creek College’s best tennis
Tennis
Tennis is a sport usually played between two players or between two teams of two players each . Each player uses a racket that is strung to strike a hollow rubber ball covered with felt over a net into the opponent's court. Tennis is an Olympic sport and is played at all levels of society at all...

 player. Sheehan’s father had a long struggle with cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

 and died at age fifty.

Sheehan had two brothers, Joseph Sheehan and David Sheehan. Joseph is a professor
Professor
A professor is a scholarly teacher; the precise meaning of the term varies by country. Literally, professor derives from Latin as a "person who professes" being usually an expert in arts or sciences; a teacher of high rank...

 of psychology
Psychology
Psychology is the study of the mind and behavior. Its immediate goal is to understand individuals and groups by both establishing general principles and researching specific cases. For many, the ultimate goal of psychology is to benefit society...

 at the University of California
University of California
The University of California is a public university system in the U.S. state of California. Under the California Master Plan for Higher Education, the University of California is a part of the state's three-tier public higher education system, which also includes the California State University...

 and ran training programs for relieving speech defects with his wife, Vivian. David Sheehan, the youngest of the three, worked in the manufacturing industry in Battle Creek. John Sheehan married Marion Jennings shortly after receiving his Ph.D and had three children: John C. Sheehan Jr., David E. Sheehan, and Elizabeth (Betsy) S. Watkins. He had six grandchildren.

Education

John Sheehan attended Catholic
Catholic
The word catholic comes from the Greek phrase , meaning "on the whole," "according to the whole" or "in general", and is a combination of the Greek words meaning "about" and meaning "whole"...

 grade schools, even though John and his brother Joseph were not particularly religious later in life. He studied chemistry
Chemistry
Chemistry is the science of matter, especially its chemical reactions, but also its composition, structure and properties. Chemistry is concerned with atoms and their interactions with other atoms, and particularly with the properties of chemical bonds....

 and political science
Political science
Political Science is a social science discipline concerned with the study of the state, government and politics. Aristotle defined it as the study of the state. It deals extensively with the theory and practice of politics, and the analysis of political systems and political behavior...

 at Battle Creek College. In 1937, Sheehan graduated as the valedictorian
Valedictorian
Valedictorian is an academic title conferred upon the student who delivers the closing or farewell statement at a graduation ceremony. Usually, the valedictorian is the highest ranked student among those graduating from an educational institution...

 of his class and won a scholarship
Scholarship
A scholarship is an award of financial aid for a student to further education. Scholarships are awarded on various criteria usually reflecting the values and purposes of the donor or founder of the award.-Types:...

 for graduate studies in any subject of his choice. He decided to study organic chemistry
Organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...

 at the University of Michigan
University of Michigan
The University of Michigan is a public research university located in Ann Arbor, Michigan in the United States. It is the state's oldest university and the flagship campus of the University of Michigan...

, receiving his Master’s in 1938 and his PhD in 1941. His doctorate advisor, Werner E. Bachmann, was involved in the synthesis of steroid
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...

 hormones. As a post-doctoral fellow, Sheehan collaborated with Bachmann on the commercially feasible production of RDX
RDX
RDX, an initialism for Research Department Explosive, is an explosive nitroamine widely used in military and industrial applications. It was developed as an explosive which was more powerful than TNT, and it saw wide use in WWII. RDX is also known as cyclonite, hexogen , and T4...

 also known as cyclonite, which turned out to give the Allies
Allies of World War II
The Allies of World War II were the countries that opposed the Axis powers during the Second World War . Former Axis states contributing to the Allied victory are not considered Allied states...

 a huge advantage at sea during World War II
World War II
World War II, or the Second World War , was a global conflict lasting from 1939 to 1945, involving most of the world's nations—including all of the great powers—eventually forming two opposing military alliances: the Allies and the Axis...

.

Early career

After the efficient completion of RDX synthesis, John Sheehan had the experience of applying organic chemistry to real-life problems. Having struggled against pneumonia
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...

 and mastoiditis
Mastoiditis
Mastoiditis is an infection of mastoid process, the portion of the temporal bone of the skull that is behind the ear which contains open, air-containing spaces. It is usually caused by untreated acute otitis media and used to be a leading cause of child mortality. With the development of...

 in his earlier years, Sheehan was eager to start working on antibiotics. He wrote, “If my doctors had had a course of treatment as effective as that made possible by penicillin, I would probably not have lost that year.” In 1941, he accepted a position at Merck & Co.
Merck & Co.
Merck & Co., Inc. , also known as Merck Sharp & Dohme or MSD outside the United States and Canada, is one of the largest pharmaceutical companies in the world. The Merck headquarters is located in Whitehouse Station, New Jersey, an unincorporated area in Readington Township...

 in Rahway, New Jersey
Rahway, New Jersey
Rahway is a city in southern Union County, New Jersey, United States. It is part of the New York metropolitan area, being 15 miles southwest of Manhattan and five miles west of Staten Island...

. He worked there until 1946 as a senior research chemist under the supervision of Dr. Max Tishler
Max Tishler
Max Tishler was a scientist at Merck & Co. who led the research teams that synthesized ascorbic acid, riboflavin, cortisone, miamin, pyridoxin, pantothenic acid, nicotinamide, methionine, threonine, and tryptophan...

. Sheehan had good results for his work on many projects, including those on calcium pantothenate, streptomycin
Streptomycin
Streptomycin is an antibiotic drug, the first of a class of drugs called aminoglycosides to be discovered, and was the first antibiotic remedy for tuberculosis. It is derived from the actinobacterium Streptomyces griseus. Streptomycin is a bactericidal antibiotic. Streptomycin cannot be given...

, and vitamin B6
Vitamin B6
Vitamin B6 is a water-soluble vitamin and is part of the vitamin B complex group. Several forms of the vitamin are known, but pyridoxal phosphate is the active form and is a cofactor in many reactions of amino acid metabolism, including transamination, deamination, and decarboxylation...

. However, he wanted to pursue the synthesis of penicillin, which was hard in an industrial setting driven by results given that many scientists of his time believed that it was impossible. John Sheehan’s work attracted the attention of Arthur C. Cope
Arthur C. Cope
Arthur C. Cope was a highly successful and influential organic chemist and member of the National Academy of Sciences. He is credited with the development of several important chemical reactions which bear his name including the Cope elimination and the Cope rearrangement.Cope was born on June...

, who was the head of the Department of Chemistry at the M.I.T. at the time. He decided to join the M.I.T. faculty as an assistant professor at a salary that was half of what he made at Merck. Within his first few years at M.I.T., John Sheehan was already recognized for his ingenuity in synthetic organic chemistry, especially for his new methods of synthesis of peptides, three new syntheses of β-lactams, first synthesis of the penicillin ring system, and his work on several other natural products.

Synthesis of penicillin

For three decades after the discovery of natural penicillin by Sir Alexander Fleming
Alexander Fleming
Sir Alexander Fleming was a Scottish biologist and pharmacologist. He wrote many articles on bacteriology, immunology, and chemotherapy...

, the source of the antibiotic hardly changed. Scientists made the drug by natural fermentation
Fermentation (biochemistry)
Fermentation is the process of extracting energy from the oxidation of organic compounds, such as carbohydrates, using an endogenous electron acceptor, which is usually an organic compound. In contrast, respiration is where electrons are donated to an exogenous electron acceptor, such as oxygen,...

 of Penicillium
Penicillium
Penicillium is a genus of ascomycetous fungi of major importance in the natural environment as well as food and drug production. Members of the genus produce penicillin, a molecule that is used as an antibiotic, which kills or stops the growth of certain kinds of bacteria inside the body...

 mold. However, during World War II, the United States government undertook a massive effort to determine the chemical structure of penicillin and to chemically synthesize it in large quantities. The scale of this project was compared to the development of the atomic bomb. This stemmed from the dire need for the antibiotic to treat soldiers on the battlefield. More than a thousand chemists working at thirty-nine laboratories were involved in the project. Despite the huge investment by the government, none proved to be successful in solving this elusive problem.

As John Sheehan described in his book The Enchanted Ring: The Untold Story of Penicillin, after the war, most other synthetic chemists abandoned the penicillin synthesis research, convinced that it was impossible to chemically synthesize penicillin. For the nine years that he worked on penicillin synthesis, there were practically no competitors, leaving Sheehan on a lonely search for a way to synthesize the antibiotic. Most young academic chemists chose not to undertake projects that they perceived to be painfully slow because they wanted to impress faculty tenure
Tenure
Tenure commonly refers to life tenure in a job and specifically to a senior academic's contractual right not to have his or her position terminated without just cause.-19th century:...

 committees with many experiments and publications. Even though many of his friends openly questioned his decision of getting involved with the drug, Sheehan was determined to work on the chemical synthesis of penicillin at M.I.T. Once he decided that penicillin was an important problem, and one that had a solution, Sheehan never re-evaluated his position. He explained that one of the reasons he decided to switch from his job at Merck to M.I.T. was because “At M.I.T, I was a research committee of one. I could make the decision to spend the rest of my life on the penicillin problem; it was only my career that was on the line.”

At the time, it was known that the molecular weight of penicillin was around 350 g/mol, which was within the range of molecules that had already been chemically synthesized. The problem was the making the chemically unstable beta-lactam
Beta-lactam
A β-lactam ring, is a four-membered lactam. It is named as such, because the nitrogen atom is attached to the β-carbon relative to the carbonyl...

 ring that was crucial to the antibiotic properties of the molecule. Beta-lactam antibiotics inhibit the formation of the peptidoglycan
Peptidoglycan
Peptidoglycan, also known as murein, is a polymer consisting of sugars and amino acids that forms a mesh-like layer outside the plasma membrane of bacteria , forming the cell wall. The sugar component consists of alternating residues of β- linked N-acetylglucosamine and N-acetylmuramic acid...

 layer of the cell walls of Gram-positive bacteria. Most of the scientists experienced failure after failure because the “the appropriate techniques and reactions for putting together the penicillin molecule simply had not yet been discovered.” In the words of Sheehan, using traditional methods at the time was like “placing an anvil on top of a house of cards.” After nine years of dogged work in the M.I.T. laboratories, this persistent organic chemist finally solved one of chemistry’s most baffling problems at the time. In 1957, John C. Sheehan announced that his group had completed the first synthesis of penicillin V (one of the two most useful forms of the antibiotic). During the process, he had also produced an intermediate, 6-aminopenicillanic acid
6-APA
6-APA is the chemical compound -6-aminopenicillanic acid.-Use:6-APA is the core of penicillins. It is obtained from the fermentation brew of the Penicillium mold and used as the main starting block for the preparation of numerous semisynthetic penicillins.-Manufacture:This useful compound is made...

, which was later used as a foundation for preparing a variety of penicillins. This allowed researchers to combat the resistance that certain bacteria had developed to particular forms of the drug. Sheehan later published his involvement in the synthesis of penicillins in The Enchanted Ring: The Untold Story of Penicillin, which noted a complex legal skirmish over his patents on penicillin synthesis involving M.I.T. and Beecham
Beecham
- Surname :* Thomas Beecham , British chemist, grandfather of the conductor* Thomas Beecham , British conductor* Sir Joseph Beecham, 1st Baronet , eldest son of Thomas Beecham the chemist...

, a British
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...

industrial research laboratory that was also working on penicillins.
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