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

physician A physician (American English), medical practitioner (Commonwealth English), medical doctor, or simply doctor, is a health professional who practices medicine, which is concerned with promoting, maintaining or restoring health through th ...

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 processe ...

specializing in

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

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 Augustinian friar wor ...

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

Knudson hypothesis The Knudson hypothesis, also known as the two-hit 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 was ...

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, mi ...

carcinogenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...

(the development of cancer).

Early life and education

Knudson was born in

Los Angeles, California Los Angeles ( ; es, Los Ángeles, link=no , ), often referred to by its initials L.A., is the largest city in the state of California and the second most populous city in the United States after New York City, as well as one of the world' ...

in 1922. He received his B.S. from

California Institute of Technology The California Institute of Technology (branded as Caltech or CIT)The university itself only spells its short form as "Caltech"; the institution considers other spellings such a"Cal Tech" and "CalTech" incorrect. The institute is also occasional ...

in 1944, his M.D. from

Columbia University Columbia University (also known as Columbia, and officially as Columbia University in the City of New York) is a private research university in New York City. Established in 1754 as King's College on the grounds of Trinity Church in Manhatt ...

in 1947 and his Ph.D. from

in 1956. He held a

Guggenheim fellowship Guggenheim Fellowships are grants that have been awarded annually since by the John Simon Guggenheim Memorial Foundation to those "who have demonstrated exceptional capacity for productive scholarship or exceptional creative ability in the ar ...

from 1953 to 1954.

Career and research

After an initial faculty appointment at the

City of Hope Medical Center City of Hope is a private, not-for-profit clinical research center, hospital and graduate school located in Duarte, California, United States. The center's main campus resides on of land adjacent to the boundaries of Duarte and Irwindale, with ...

in California, Knudson became the Associate Dean for Basic Sciences at the State University of New York at the

Stony Brook School of Medicine The Renaissance School of Medicine (RSOM) is the graduate medical school of Stony Brook University located in the hamlet of Stony Brook on Long Island, New York. Founded in 1971, RSOM is consistently ranked the top public medical school in New ...

. 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) 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 T ...

in the

Texas Medical Center The Texas Medical Center (TMC) is a medical district and neighborhood in south-central Houston, Texas, United States, immediately south of the Museum District and west of Texas State Highway 288. Over 60 medical institutions, largely concentrate ...

. He was affiliated with

Fox Chase Cancer Center Fox Chase Cancer Center is a National Cancer Institute-designated Comprehensive Cancer Center research facility and hospital located in the Fox Chase section of Philadelphia, Pennsylvania, United States. The main facilities of the center are loca ...

Philadelphia Philadelphia, often called Philly, is the largest city in the Commonwealth of Pennsylvania, the sixth-largest city in the U.S., the second-largest city in both the Northeast megalopolis and Mid-Atlantic regions after New York City. Sinc ...

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

two-hit hypothesis The Knudson hypothesis, also known as the two-hit 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 was ...

," 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 it is almost exclusively fo ...

. 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 The retinoblastoma protein (protein name abbreviated pRb; gene name abbreviated ''Rb'', ''RB'' or ''RB1'') is a proto-oncogenic tumor suppressor protein that is dysfunctional in several major cancers. One function of pRb is to prevent excessive ...

involved in controlling

cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...

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 surg ...

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 red ...

, 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 Lasker-DeBakey Clinical Medical Research Award is one of four annual awards presented by the Lasker Foundation. The Lasker-DeBakey award is given to honor outstanding work for the understanding, diagnosis, prevention, treatment, and cure of disea ...

. He also received the 1999

American Society of Pediatric Hematology/Oncology The American Society of Pediatric Hematology/Oncology (abbreviated ASPHO) is an American multidisciplinary professional organization dedicated to improving care in the medical disciplines of pediatric hematology and oncology. As of 2018, it had 2, ...

(ASPHO)

Distinguished Career Award A Distinguished Career Award is an award recognizing individuals for notable Notability is the property of being worthy of notice, having fame, or being considered to be of a high degree of interest, significance, or distinction. It also refer ...

, 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, clinical, and t ...

(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, 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 Nati ...

, the

American Philosophical Society The American Philosophical Society (APS), founded in 1743 in Philadelphia, is a scholarly organization that promotes knowledge in the sciences and humanities through research, professional meetings, publications, library resources, and communit ...

, and the

American Academy of Arts and Sciences The American Academy of Arts and Sciences (abbreviation: AAA&S) 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 ...

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 (CHOP) is a children's hospital in Philadelphia, Pennsylvania, with its primary campus located in the University City neighborhood of West Philadelphia in the campus of the University of Pennsylvania. The h ...

at the

University of Pennsylvania The University of Pennsylvania (also known as Penn or UPenn) is a private research university in Philadelphia. It is the fourth-oldest institution of higher education in the United States and is ranked among the highest-regarded universitie ...

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