Baylor gene study/P53

Question:

I don’t remember the details, but there is at least one drug in testing for rheumatoid arthritis that is a p53 inhibitor.  (sorry, don’t remember which one… something not out yet though, that I remember) Maybe Scios?  Think that was the company… not looking it up, but I am a TINY stockholder in this company, so I don’t want to hide this fact from anyone.  (I decided to buy on the first day the market opened after Sep 11, think it was the 14th, just for my little bit of patriotism.) Best regards, Check out our website too–do you love oak furniture? http://www.barnfurniture.com  

Response:

> By Justin Gillis > Washington Post Staff Writer > Thursday, January 3, 2002; Page A01 > snip

so i googled our p ng for P53 and got 24 or so hits.. mostly Ed anderson of pinch.com Surely or sore-ly a man ahead of his P. Ok,  taste of p53 from 1996..

" Has anyone heard of a treatment where they burn psoriasis lesions to " control them? There is a recent patent for the use of an infrared laser in psoriasis treatment but I doubt it is used to actually burn the skin. Ultraviolet phototherapy causes a sun"burn" but your post implies third degree.  Just about anything that damages the skin can trigger a psoriasis lesion and my guess is that cauterizing the skin would cause more problems than it solves. I’ve been doing a bit of reading about a cell protein called p53 that is stimulated by UV radiation. P53 causes cells to slow their reproduction rate by binding to trascription sites with the apparent purpose of allowing cells more time to repair potential DNA damage.  Sufficent p53 protein can cause the cell to cease replicating, causing cell death or aptosis. This is the way that the skin prevents mutations from sunlight. I believe this is also the mechanism that allows UV phototherapy to work as a psoriasis treatment. It appears that many things that cause cell stress also increase p53 production.  Besides ionizing radiation and other mutagens, two stong triggers (in lab culture tests) are hypoxia and hyperthermia. Hypoxia (lack of oxygen) might account for the success of occlusion. It is usually used in combination with other therapy but it makes sense that increased p53 production from various causes is additive. A MEDLINE search for hyperthemia and psoriasis turns up a couple of reports of complete psoriasis remission using thermal treatments.  One treatment used biofeedback techniques to elevate skin temperature and claimed remission of recalcitrant psoriasis after 6 months of therapy. Another report says psoriasis lesions were resolved in six of seven patients using simple hot water baths.  They also noted an unexpected side effect of increased tanning when hyperthermia treated skin was exposed to sunlight.  Hypoxia might also play a role in the success of water baths. There are no MEDLINE reports of infrared psoriasis treatments but given the success of hyperthermia treatments, a pulsed heat source might be able to create a hyperthermia stress in the skin without raising the body temperature more than necessary.  A laser might work well for this but it doesn’t sound very cost effective. Stop the presses… I’ve just found a MEDLINE report of an experimental laser ablation treatment in the UK. It might be the "burn" therapy you’re looking for: Title:        Laser treatment of psoriasis. Author:       Katugampola GA; Rees AM; Lanigan SW Address:      Department of Dermatology, Bridgend General Hospital,               Mid Glamorgan, U.K. Source:       Br J Dermatol, 133: 6, 1995 Dec, 909-13 MEDLINE ID:   96150401 Abstract:        In psoriasis, the earliest observable electron microscopic changes are in the dermal papillary vasculature. The flashlamp-pumped pulsed tunable dye laser can achieve selective photothermolysis of the dermal vasculature. This laser was used to treat eight patients with chronic plaque psoriasis, as it was hypothesized that the ablation of dermal papillary vasculature would arrest the early events leading to the evolution of psoriasis, and produce resolution of the plaques. At the final assessment, performed 10 weeks after three fortnightly laser treatments, five of the eight patients recorded an improvement of > or = 50%, and one showed complete resolution of the treated plaques of psoriasis. Although not practicable in the treatment of widespread psoriasis, we conclude that selective photothermolysis of the dermal vasculature by pulsed tunable dye laser offers an alternative new therapy for chronic plaque psoriasis, and also demonstrates the pivotal role of the vasculature in the pathogenesis of psoriasis. (ed note: Dye lasers operate in the red end of the visible spectrum.) This sounds like a rather extreme treatment, more like plastic surgery. I guess they really do "burn" the skin (off). — Ed Anderson One of the true hero’s of P consciousness. Maybe one day we can get his great words again.. randall… forget p53, i want to fly a p51.. and forget about P.

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By Justin Gillis Washington Post Staff Writer Thursday, January 3, 2002; Page A01 A critical protein that protects animals from cancer in their early years appears, in later life, to cause much of the deterioration associated with aging, according to a provocative new study. The study suggests that the protein, known as p53 — a central cog in the cancer-fighting machinery of many animals, including humans — eventually shuts off the body’s ability to renew its organs and tissues, producing bone and muscle deterioration and other hallmarks of aging. The results, reported by scientists at the Baylor College of Medicine in Houston, "raise the shocking possibility that aging may be a side effect of the natural safeguards that protect us from cancer," two commentators said in an editorial accompanying the study, which appears today in the journal Nature. The research was done in mice, and its applicability to people is uncertain. But mice and humans are close evolutionary relatives, and the study is likely to set off a race to clarify the relationship between cancer biology and aging in humans. Arnold Levine, president of Rockefeller University and co-discoverer of p53, called the study "extraordinary." Bert Vogelstein, a top cancer researcher at Johns Hopkins University, said the results were "fascinating" and "surprising." He added: "Like all good research, it raises a lot more questions than it answers." Among the questions is whether any attempt to create an anti-aging pill would be likely to raise cancer rates. The Nature commentary says scientists working on aging now have to consider the prospect that "drug-related approaches to interfere with this process may come at a price — the disruption of our natural mechanisms for keeping cancer at bay." The research also raises the possibility that younger people treated with chemotherapy may be subject to premature aging later in life, a question that has never been rigorously examined. The findings add weight to the developing hypothesis that the body has to walk a line between cancer protection and aging, that they are, in effect, two sides of a coin. "You have a fine balance," said Lawrence Donehower, the researcher whose laboratory conducted the study. "Too much p53 and you get this aging effect; too little and you get cancer. My guess is that evolution has selected just the right level." The new paper started with a failure in the lab, then turned into a classic tale of scientific luck and alertness. Eight years ago, in Donehower’s cancer lab at Baylor College of Medicine, researchers were trying to create mice with a weakened version of p53, a vital protein that prevents cells from growing out of control and turning into tumors. These mice might have been susceptible to tumors similar to those in human patients. But the techniques for manipulating genes were crude at the time, and instead of making mice with weakened p53, Donehower and colleagues accidentally made mice with a hyperactive version of the protein. They were exasperated. "We sort of set the mice off in a corner of our mouse colony and ignored them," Donehower said. Ordinary mice are prone to tumors, and the researchers noticed that virtually none of the mutant mice were getting them. That alone was not so surprising, because p53 is such an effective tumor suppressor. But as time went on, the tumor-free mice looked stranger and stranger. "I couldn’t quite figure out what it was until my lab technician, Ben Cooper, said the words, ‘These mice just look old,’ " Donehower recalled. "That was like a light bulb." A young graduate student, Stuart Tyner, grabbed the project as part of his doctoral thesis. "I felt like this was kind of a gold mine," he said. He subjected the mutant mice to tests that confirmed what was already becoming obvious to the naked eye: They were fading fast. At an age when normal mice are still fairly vigorous, the bones of the mutant mice became brittle and porous, and they developed hunchbacks. Their hair thinned. Their muscles and other body parts shrank. They recovered poorly from wounds and other stresses. They lost weight. Even though virtually none of them came down with cancers, they died, on average, at 96 weeks, compared with 118 weeks for normal mice. Their enhanced cancer resistance was accompanied, in other words, by a 20 percent drop in life span. "The major impact of the study is that it more tightly links tumor suppression and aging," Donehower said. "It really surprised us." By the standards of a protein, p53 was already the focus of intense research, and the new paper raises the possibility that it is a prime mechanism in two of the most important aspects of human biology. "I think the Donehower paper makes an enormous contribution," said Levine, the Rockefeller University president. "It’s not that everyone knows it’s right yet, or that there aren’t other lines of evidence that are important. But it’s conceptually extraordinary." Levine, who co-discovered p53 in 1979, compares the protein to the spell-check program in a computer. The machinery that copies genetic instructions inside cells is prone to error. The role of p53 is to help make sure the genetic instructions get copied accurately so the cells do not lurch out of control and turn into tumors. If things are going badly, p53 can stop the cell’s reproductive cycle until the damage is repaired. In the worst case, it can switch on an internal suicide program, forcing the cell to kill itself for the sake of the larger organism. The highly effective cancer "surveillance" of p53 is a major reason animals are not overwhelmed by tumors from a young age, instead living long enough to reproduce. The new work suggests, in effect, that this same protective machinery comes back to haunt the animal as it ages. Exactly how remains unclear, but the researchers speculate that it involves stem cells, the primordial cells that serve as feedstock to regenerate organs and tissues. Donehower’s data suggest that the normal level of p53 that protects against tumors eventually becomes a brake on stem cells, arresting their growth and depriving the body of its capacity for renewal. By this reasoning, having more p53 will mean fewer tumors in the early years — but, as the mice study suggests, at the price of premature aging, because stem cells will be shut down more rapidly and renewal capacity depleted earlier. Donehower’s results might seem counterintuitive at first, since cancer is largely a disease of the elderly. How could aging go hand-in-hand with a mechanism that protects against cancer? The Nature commentators suggest that this puzzle is easily resolved. Cancer results from the out-of-control growth of individual cells, and it typically occurs after they have accumulated enough genetic mutations over time to break down the normal protective machinery, including p53. Aging, by contrast, is a bodywide phenomenon, and the Donehower results suggest it arises at least in part because, as stem cells accumulate genetic mutations over time, still-functioning p53 shuts down their reproductive ability, just as it would in a nascent cancer cell. In this view, the aged body may suffer a cruel double assault, contracting cancer partly from the breakdown of p53 in individual cells at just the moment when active p53 in stem cells has depleted its reparative capacity. When in a given individual this happens may depend on natural genetic variation. A great deal of work remains to confirm Donehower’s findings, and the paper is likely to open new fields of inquiry. One immediate question is the effect in younger people of chemotherapy drugs, which attack cancer by deliberately damaging DNA, the genetic material. If these drugs activate p53 by causing genetic damage in healthy cells, could that eventually accelerate aging, even in patients who took the drugs decades ago? Finally, the work raises the question of whether it will ever be possible to manipulate aging. Even if the findings are verified, some scientists remain optimistic that there will be ways, late in life, to turn down p53 levels without causing undue harm, buying extra years of life. That’s far from certain, but knowledge can only help, Donehower said. "If we know why we age," he said, "it’s all the better in terms of developing anti-aging approaches." Hey all my favorite words… do you know which ones? Ci is one… And Baylor was the scene of the big P gene study, now at the NPF. randall… i see p people everywhere.. er, p-53 reduced people, that is.

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