Will p53 be the first widely altered human gene?

p53 (aka TP53) is one of the most intensively studied proteins encoded in the human genome, and presently there are over 64,000 scientific papers dealing with various aspects of its function. Initially thought to promote cancer and later to suppress cancer, our understating of p53 has dramatically changed over the past thirty years. p53 is now known to regulate several hundred different genes and gene products and be involved in an enormous number of different functions, including cancer suppression and the regulation of cell division, aging, cell death, responses to hypoxia, embryo implantation, DNA repair, mitochondrial function, cellular anti-oxidant defenses, and promoting aerobic metabolism and exercise tolerance. Over the last ten years transgenic animals carrying extra p53 copies have shown a high resistance to developing cancer, and drugs that activate p53 in tumor cells have shown promise as anti-cancer therapies.

Since p53 is mutated in over 50% of human cancers, a successful anti-cancer therapy targeting p53 could have wide applications to many differ type of cancer. Therefore p53 is a likely candidate for the first genetic alterations performed on humans to lower individual disease risk. Increased normally regulated wild type 53 protein expression could lower ones cancer risk, without side effects. Obviously further research must be done and the decision made if such actions are ethical.

p53 was first identified in 1979 by six separate labs that found it associated with cancer-causing viral proteins and also highly expressed in mouse tumor cells. It was named “p53” as it appeared to have a molecular weight of 53 kilodaltons, or 53,000 times the weight of one hydrogen atom. Within a short time p53 over expression was seen in many different types of human cancer and placing p53 into normal cells often changed them into tumor cells. Initially p53 was thought to promote cancer development as a “tumor promoter gene” By 1989 improved DNA sequencing revealed that “tumor p53” had a different DNA sequence (a mutated sequence) than “normal cell p53” and the short arm of chromosome 17, where the p53 gene resides is often lost in human cancers.

Since 1989 over 25,000 different p53 gene mutations have been found, with p53 mutated in over 50% of all human cancers, making p53 mutation the most common genetic change in human cancer. Last, in 1990 a rare highly cancer-prone human genetic disease “Li-Fraumeni syndrome” was identified where p53 protein expression is lost. Additionally, lab-created transgenic mice lacking p53 expression were found to develop cancer nearly 100% of the time, at young ages for mice. p53 was soon known as a tumor suppressor gene. Strangely, some mutated forms of p53 where found with new functions (“gain of function mutations”) not found in “normal” or wild type p53, that actually promoted cancer. This is almost unique to p53 and the mechanism(s) by which this happens are poorly understood.

After 1990, with the development of improved and novel molecular biology techniques, the vast cellular communications network regulated by p53 were increasingly understood. Under unstressed conditions cellular p53 levels are very low and difficult to detect. When cells are exposed to many different damaging agents (heat, radiation, hypoxia, oxidants, toxic metals, UV light, etc) p53 levels enormously increase within fifteen minutes, altering cellular gene expression and inducing adaptations required for cell survival. Interestingly, UV light-induced increases in p53 are required for increases in skin melanin and normal tanning. The same p53 increase also increases beta-endorphin (endogenous opiate-like molecules) levels, often causing “sun-seeking behaviors” So p53 is one reason why sunlight can “feel good”.

p53 also coordinates an exact and carefully graded cellular damage response. At low damage levels, DNA and cellular repair occurs and the cell survives and continues to function. At high damage levels, where cell damage can be so severe that cancer-causing mutations are likely, the cell undergoes either programmed cell death (called “apoptosis”), or permanently senesces, meaning it can never divide again. Also with high cellular damage p53 will inhibit the formation of new blood vessels (called “angiogenesis”), preventing an increased blood supply cancers need for growth. Thus p53 powerfully guards against cells becoming cancerous. Due p53’s central role in cancer suppression, it was named “Molecule of the Year” by the journal Science in 1993.

While p53 loss or mutation powerfully contributes to carcinogenesis, over expression of p53 also have profound effects. Chronic and constant expression of an activated-mutated p53 causes premature aging in mice, with osteoporosis, generalized organ atrophy, diminished stress tolerance, and interestingly a high resistance to spontaneous cancers. However, placing additional copies of wild type p53 into the genome of transgenic mice greatly reduced the spontaneous cancer formation (from 47% to 17%), but did not cause premature aging. Thus, increased wild type p53 expression in a mammal, reduces the risk for cancer, without causing premature aging if the p53 is under normal cellular regulation. It is likely that the same relatively small genetic change in humans would result in a greatly decreased cancer risk, without causing premature aging or the early appearance of age-associated diseases (diabetes, atherosclerosis, etc). Although extreme care would have to be practiced if a genetic alteration were introduced into a humans to bring about an “improvement” such a genetic change would greatly decrease the risk of getting a dread disease.

Recently, another unusual aspect of p53 functions was identified. p53 promotes mitochondrial function, increasing aerobic capacity. Mice lacking p53 have fewer muscle mitochondria, lower aerobic exercise tolerance, are less active, and show increased toxic cellular oxidant production compared to p53 normal mice. Additionally, in normal animals exercise increased p53 levels, increasing the number of mitochondrial and also increasing the levels of proteins associated with lowered blood pressure. Researchers have hypothesized that the increased p53 seen with exercise partially explains why aerobic exercise lowers the risk for cancer. Higher p53 levels would mean better DNA repair and increase anti-oxidant expression; both cancer risk-lowering events. This finding was unexpected, as there are no other examples yet found of tumor suppressor genes regulating exercise responses and aerobic metabolism.

Last, recently p53 is also becoming increasingly important as a target for anti-cancer therapies. New therapies that reactivate wild type p53 within or deliver wild type p53 to cancer cells, may stop or significantly slow cancer growth. Some of these therapies involve drugs that would alter mutated “tumor p53” and make it behave as wild type p53. Other therapies would block proteins that degrade p53 in cancer cells, vastly increasing cancer cell p53 levels, possibly causing cancer cell death. One therapy already in use in China uses a virus to deliver wild type p53 to cancer cells, causing them to die. Such therapies are quite new and reveal a novel way to treat cancer.

p53 is interesting to Transhumanists for several reasons. First, it is an interesting example of how science works and solves problems. Originally thought of as a minor protein that likely contributed to cancer, p53 is now known as a major tumor suppressor and regulator of numerous cellular functions, many of which are involved in normal cellular functioning and not just cancer suppression. Secondly, in only the past few years p53 has become a new target for anti-cancer therapies. It is therefore one possible candidate for widespread genetic alteration in humans to prevent disease. Third, despite what is presently know, it’s undoubtedly true that p53 research will reveal many more functions of this protein which are presently unknown. If we “go by the record”, further p53 research should have significant additional results pertaining to human health and longevity.

Hebrew University researchers discover how a single gene can keep malignant cells from spreading to healthy tissue. http://israel21c.org/health/israelis-find-key-to-containing-cancer/

The history of gene therapy drugs approval on the market http://stemcellassays.com/2011/12/history-gene-therapy-drugs-approval-market/

P53 Gene Therapy for Pulmonary Metastasis Tumor from Hepatocellular Carcinoma http://nethd.zhongsou.com/wtimg/i_6253417/94216-P53%20Gene%20Therapy.pdf
Human Genetic Enhancements: A Transhumanist Perspective http://www.nickbostrom.com/ethics/genetic.html

3 Responses

  1. Rodney says:

    p53 is “involved in an enormous number of different functions” The article does not state that it “solely regulates many functions” Additionally there are many routes to drug discovery. As you indicate, our present means of drug investigation and discovery are often not optimal. Since this is an extremely interesting and important area of research, it would be helpful if you could write an H+ article on this subject.

  2. p53 is a classic network pharmacology gene. It is involved in multiple cell functions.

    It is not however responsible for any function. No gene is responsible for any function. They produce the parts of the proteomic systems that create function and therefore can only influence it indirectly.

    These systems are complex and to have the impact that represent the breakthroughs referred to, you need to better understand the system and sub-systems, how they operate and how to intervene in them.

    Sadly for complex systems like this, complex system science has clearly demonstrated that, apart from in exceptional rare circumstances, a linear relationship between a specific function (e.g. mitochondrial energy creation, apoptosis, cancer incidence) and a single gene like p53 does not exist.

    Therefore if you want to uncover the promise of p53 a new approach is required. One that does not confuse correlation of p53 variations with differing disease states with causation but rather uses these clues as a starting point for analysing the proteomic systems at the systems level.

    Unfortunately pathway biology analysis or genetic correlation techniques traditionally used cannot do this at the all important systems level.

    Fortunately new tools in the discipline of network pharmacology can but a lot is data dependent. There is huge promise but a change of direction plus research and development of these new tools is required to address the reality of how biological systems operate and can be altered. Otherwise all that will result is a repeat of the extensive clinical trial failures created by the existing methods and thinking of how to turn these p53 observations in clinical benefit.

  1. November 4, 2012

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