Editing Tumor suppressor gene (section)

==History==
The discovery of [[oncogenes]] and their ability to deregulate cellular processes related to [[cell proliferation]] and development appeared first in the literature as opposed to the idea of tumor suppressor genes.<ref name=":6">{{cite journal | doi=10.1016/S0092-8674(03)01075-4 | title=Principles of Tumor Suppression | year=2004 | last1=Sherr | first1=Charles J. | journal=Cell | volume=116 | issue=2 | pages=235–246 | pmid=14744434 | s2cid=18712326 | doi-access=free }}</ref> However, the idea of genetic mutation leading to increased [[Tumor progression|tumor growth]] gave way to another possible genetic idea of [[genes]] playing a role in decreasing cellular growth and development of cells. This idea was not solidified until experiments by [[Henry Harris (scientist)|Henry Harris]] were conducted with [[Somatic fusion|somatic cell hybridization]] in 1969.<ref name=":5">Cooper, G. M. (2000). Tumor Suppressor Genes. The Cell: A Molecular Approach. 2nd Edition. https://www.ncbi.nlm.nih.gov/books/NBK9894/</ref>

Within Harris's experiments, [[tumor cells]] were fused with normal [[somatic cells]] to make hybrid cells. Each cell had [[chromosomes]] from both parents and upon growth, a majority of these hybrid cells did not have the capability of developing tumors within animals.<ref name=":5" /> The suppression of [[tumorigenicity]] in these hybrid cells prompted researchers to hypothesize that [[genes]] within the normal [[somatic cell]] had inhibitory actions to stop tumor growth.<ref name=":5" /> This initial hypothesis eventually lead to the discovery of the first classic tumor suppressor gene by [[Alfred G. Knudson|Alfred Knudson]], known as the Rb gene, which codes for the [[Retinoblastoma protein|retinoblastoma tumor suppressor protein]].<ref name=":6" />

[[Alfred G. Knudson|Alfred Knudson]], a pediatrician and cancer geneticist, proposed that in order to develop [[retinoblastoma]], two [[mutation|allelic mutations]] are required to lose functional copies of both the Rb genes to lead to [[tumorigenicity]].<ref name=":5" /> Knudson observed that retinoblastoma often developed early in life for younger patients in both eyes, while in some rarer cases retinoblastoma would develop later in life and only be unilateral.<ref name=":6" /> This unique development pattern allowed Knudson and several other scientific groups in 1971 to correctly hypothesize that the early development of retinoblastoma was caused by [[Heredity|inheritance]] of one loss of function mutation to an RB [[germline|germ-line gene]] followed by a later [[De novo mutations|de novo mutation]] on its functional Rb gene [[allele]]. The more sporadic occurrence of unilateral development of retinoblastoma was hypothesized to develop much later in life due to two [[de novo mutations]] that were needed to fully lose tumor suppressor properties.<ref name=":6" /> This finding formed the basis of the two-hit hypothesis. In order to verify that the [[Mutation|loss of function]] of tumor suppressor genes causes increased [[tumorigenicity]], interstitial deletion experiments on  [[chromosome 13]]q14 were conducted to observe the effect of deleting the [[Locus (genetics)|loci]] for the Rb gene. This deletion caused increased tumor growth in retinoblastoma, suggesting that [[Mutation|loss or inactivation]] of a tumor suppressor gene can increase [[tumorigenicity]].<ref name=":5" />