Alfred George Knudson, Jr. (August 9, 1922 – July 10, 2016) was an American

physician A physician, medical practitioner (British English), medical doctor, or simply doctor is a health professional who practices medicine, which is concerned with promoting, maintaining or restoring health through the Medical education, study, Med ...

and

geneticist A geneticist is a biologist or physician who studies genetics, the science of genes, heredity, and variation of organisms. A geneticist can be employed as a scientist or a lecturer. Geneticists may perform general research on genetic process ...

specializing in

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

genetics Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinians, Augustinian ...

. Among his many contributions to the field was the formulation of the

Knudson hypothesis The two-hit hypothesis, also known as the Knudson hypothesis, is the hypothesis that most tumor suppressor genes require both alleles to be inactivated, either through mutations or through epigenetic silencing, to cause a phenotypic change. It ...

in 1971, which explains the effects of

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

carcinogenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cell (biology), cells are malignant transformation, transformed into cancer cells. The process is characterized by changes at the cellular, G ...

(the development of cancer).

Early life and education

Knudson was born in

Los Angeles, California Los Angeles, often referred to by its initials L.A., is the List of municipalities in California, most populous city in the U.S. state of California, and the commercial, Financial District, Los Angeles, financial, and Culture of Los Angeles, ...

in 1922. He received his B.S. from

California Institute of Technology The California Institute of Technology (branded as Caltech) is a private research university in Pasadena, California, United States. The university is responsible for many modern scientific advancements and is among a small group of institutes ...

in 1944, his M.D. from

Columbia University Columbia University in the City of New York, commonly referred to as Columbia University, is a Private university, private Ivy League research university in New York City. Established in 1754 as King's College on the grounds of Trinity Churc ...

in 1947 and his Ph.D. from

in 1956. He held a

Guggenheim fellowship Guggenheim Fellowships are Grant (money), grants that have been awarded annually since by the John Simon Guggenheim Memorial Foundation, endowed by the late Simon Guggenheim, Simon and Olga Hirsh Guggenheim. These awards are bestowed upon indiv ...

from 1953 to 1954.

Career and research

After an initial faculty appointment at the City of Hope Medical Center in California, Knudson became the Associate Dean for Basic Sciences at the State University of New York at the Stony Brook School of Medicine. From 1970 to 1976, Knudson served as the Dean of Graduate School of Biomedical Sciences,

University of Texas Health Science Center at Houston The University of Texas Health Science Center at Houston (UTHealth Houston) is a public academic health science center in Houston, Texas, United States. It was created in 1972 by The University of Texas System Board of Regents. It is located ...

in the

Texas Medical Center The Texas Medical Center (TMC) is a List of neighborhoods in Houston, neighborhood in south-central Houston, Texas, United States. It is immediately south of the Houston Museum District, Museum District and west of Texas State Highway 288. Over 6 ...

. He was affiliated with Fox Chase Cancer Center in

Philadelphia Philadelphia ( ), colloquially referred to as Philly, is the List of municipalities in Pennsylvania, most populous city in the U.S. state of Pennsylvania and the List of United States cities by population, sixth-most populous city in the Unit ...

from 1976 until his death in 2016. Knudson is best known for his "

two-hit hypothesis The two-hit hypothesis, also known as the Knudson hypothesis, is the hypothesis that most tumor suppressor genes require both alleles to be inactivated, either through mutations or through epigenetic silencing, to cause a phenotypic change. It ...

," explaining the incidence of hereditary cancers, such as

retinoblastoma Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye. It is the most common primary malignant intraocular cancer in children, and 80% of retinoblastoma cas ...

. Humans inherit two copies of every gene, one from each parent (except for genes on the X and Y chromosomes in males). Some people inherit one mutated version and one normal version of the retinoblastoma gene, which produces the

retinoblastoma protein Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye. It is the most common primary malignant intraocular cancer in children, and 80% of retinoblastoma cas ...

involved in controlling

cell cycle The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...

progression. The inherited

is "the first hit." Over time, a mutation may arise in the normal version in one cell, thus producing "the second hit," which leaves the cell unable to control the process of cell division in an orderly manner, leading to cancer. Knudson's insight was to compare the incidence of retinoblastomas, including the number of tumors, the ages of occurrence, and whether tumors occurred in both eyes, among children in families with and without hereditary predisposition to retinoblastomas. Children in families with a hereditary predisposition have more tumors at a younger age and usually have tumors in both eyes. Children in families without the hereditary predisposition usually have only one tumor at a later age. The differences in occurrence can be explained by the rate of gene mutation during cell division (a somatic mutation), and a model that requires only one somatic mutation per tumor in hereditary cases but requires two somatic mutations, one on each copy of a particular cell cycle control gene, in one cell lineage in non-hereditary cases, i.e. the co-occurrence of two rare events. Knudson subsequently showed that the model was not only applicable to retinoblastoma but also to

Wilms' tumor Wilms' tumor or Wilms tumor, also known as nephroblastoma, is a cancer of the kidneys that typically occurs in children (rarely in adults), and occurs most commonly as a renal tumor in child patients. It is named after Max Wilms, the German sur ...

s of the kidney. These studies led to the concept of

tumor suppressor genes A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or re ...

, which Knudson called "anti-oncogenes."

Honors and awards

He received numerous prizes and honorary doctorates for his work, most prominently the 1998

Albert Lasker Award for Clinical Medical Research Albert may refer to: Companies * Albert Computers, Inc., a computer manufacturer in the 1980s * Albert Czech Republic, a supermarket chain in the Czech Republic * Albert Heijn, a supermarket chain in the Netherlands * Albert Market, a street mar ...

. He also received the 1999 American Society of Pediatric Hematology/Oncology (ASPHO) Distinguished Career Award, the 2005

American Association for Cancer Research The American Association for Cancer Research (AACR) is the world's oldest and largest professional association related to cancer research. Based in Philadelphia, the AACR focuses on all aspects of cancer research, including Basic research, basic, ...

(AACR) Award for Lifetime Achievement in Cancer Research, and the 2004

Kyoto Prize The is Japan's highest private award for lifetime achievement in the arts and sciences. It is given not only to those that are top representatives of their own respective fields, but to "those who have contributed significantly to the scientific, ...

in Life sciences. He was a member of the

National Academy of Sciences The National Academy of Sciences (NAS) is a United States nonprofit, NGO, non-governmental organization. NAS is part of the National Academies of Sciences, Engineering, and Medicine, along with the National Academy of Engineering (NAE) and the ...

, the

American Philosophical Society The American Philosophical Society (APS) is an American scholarly organization and learned society founded in 1743 in Philadelphia that promotes knowledge in the humanities and natural sciences through research, professional meetings, publicat ...

, and the

American Academy of Arts and Sciences The American Academy of Arts and Sciences (The Academy) is one of the oldest learned societies in the United States. It was founded in 1780 during the American Revolution by John Adams, John Hancock, James Bowdoin, Andrew Oliver, and other ...

Personal life

After a long illness, Knudson died on July 10, 2016, at the age of 93 at his home in Philadelphia . His wife of 40 years, Anna Meadows, was a distinguished pediatric oncologist (now retired) at the

Children's Hospital of Philadelphia The Children's Hospital of Philadelphia, also known by its acronym CHOP, is a children's hospital in Philadelphia, Pennsylvania. Its primary campus is located in the University City, Philadelphia, University City neighborhood of West Philadelph ...

at the

University of Pennsylvania The University of Pennsylvania (Penn or UPenn) is a Private university, private Ivy League research university in Philadelphia, Pennsylvania, United States. One of nine colonial colleges, it was chartered in 1755 through the efforts of f ...

References

External links

Oncology Luminaries: Dr. Alfred G. Knudson

Interview on March 5, 2013

Commentary on Alfred G. Knudson, Jr.
{{DEFAULTSORT:Knudson, Alfred G. 1922 births 2016 deaths Members of the United States National Academy of Sciences American geneticists Kyoto laureates in Basic Sciences Recipients of the Lasker–DeBakey Clinical Medical Research Award Columbia University Vagelos College of Physicians and Surgeons alumni California Institute of Technology alumni Members of the American Philosophical Society Fox Chase Cancer Center people City of Hope National Medical Center