It turns out that our genes are not fixed for our entire lives. The longer we live the more our personal set of genes (personal genome)changes. Environmental stresses (infectious disease, pesticides, flame retardants and other chemicals) change which genes are turned on and off during our lives. In fact identical twins are less and less identical the older they live.
Gene expression is the term used by scientists to indicate that some genes in a cell make gene products or express genes. While other genes in the same cell are turned off and do not express gene products.
Most of our DNA (which contains our genes) is turned off in most of our cells most of the time. It has to be other wise we would die. We cannot have a yard and a half long neuron extending from your back to the end of your big toe suddenly expressing the genes used to make a white blood cell that is less than one tenth the size of a period on this page. Every cell in our body has all the DNA to make any other cell in our body. Yet various cells in our body are VERY different.
A long skinny elastic muscle cell has the same DNA as do round globular fat cells and hard calcium covered bone cells. Very weird to realize that any cell in our body no matter what organ it comes from has all the genes needed to make every other cell in our body even to duplicate our entire body.
If most of the DNA in most cells was not turned off most of the time, we could not survive. The genes for muscle cells to function must be turned off in bone cells and blood cells etc. Imagine if our white blood cells needed to kill infectious agents (bacteria viruses) suddenly turned on their bone cell genes, they would grow a 'shell' of bone and be useless to fight off an infection. The infectious agents that our body's surfaces are bathed in would have a field day. They could eat us alive uncontested by white blood cells. Some kinds of leukemia kill because white blood cells never turn on the genes needed to fight off infections.
As we age, environmental shocks and stress interact with the process that turns off and on genes. Usually the process helps us better adapt to our circumstances. A famous case of changed gene expression was documented in the children born to women in Holland who were pregnant during the last year of the war when the Nazis starved the entire Dutch nation. It turned out that these children as they aged had many times higher rates of type 2 diabetes and other metabolic diseases than other non-starved populations. The gene expression of these children was changed in the womb.
The turned on genes in those Dutch children are not so good in times of plenty, but durning times of starvation, they provide a protective advantage. The children were pre-prograsmmed in the womb to survive in a time of limited food. Sadly the programming stayed that way, even when food supply increased after the war ended. These genes could have been protective had the food supply stayed limited but instead turned out to kill them early when food was abundant.
Today we are beginning to understand the process that turns genes on and off. Wouldn't it have been nice if we could have re-programmed the genes of the children born to starved mothers in Holland? It was not possible then but now we begin to see how it might work. HDAC is one of the first steps to get non-working, turned off genes to function again.
Cancer and autoimmune disease fit into a very large category of chronic conditions that we are NOT born with. Instead we lead perfectly healthy lives until suddenly our disease process starts. It seems logical to infer that one possible cause of this sudden expression of a disease may be due to a sudden change in our gene expression in some critical set of cells. Drugs like HDAC are one way to turn on protective genes and end the tryanny of autoimmune disease.
There are other ways to re-start protective genes which are non-functioning due to slight errors in the DNA four "letter" sequence. These errors result in the wrong gene products or no gene products being produced. Sometimes these gene products are crucial to preventing autoimmune disease. In these cases the gene is not turned off rather it is non-functioning in the protective sense. These other ways include the use of micro RNA's and drugs that allow ribosomes to read through an error. More explanation of these techniques and drugs in a future post.
The important point is that there are now many options to correct gene defects. We are no longer stuck with the our current gene expression. Genes can be fixed. Good genes can be turn on. Bad genes can be turned off. Even the mechanism for making protective gene products can be fixed.
HDAC's are one step in the direction of autoimmune cures. The following article is about turning on a gene that protects against prostate cancer. When the gene is incorrectly turned off prostrate cancer results.
***Notice their were two side effects--one positive one negative. The HDAC treated mice lived longer than mice normally do. (Increased life span whoopee!!)But in the not so good category, the testicles in the treated male mice degenerated temporarily durning treatment.
The article is from Eurekalert.org
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Ohio State University Medical Center
Experimental agent blocks prostate cancer in animal study
COLUMBUS, Ohio – An experimental drug has blocked the progression of prostate cancer in an animal model with an aggressive form of the disease, new research shows.
The agent, OSU-HDAC42, belongs to a new class of drugs called histone deacetylase (HDAC) inhibitors, compounds designed to reactivate genes that normally protect against cancer but are turned off by the cancer process.
The study, conducted by the Ohio State University Comprehensive Cancer Center researchers who also developed the drug, showed that the agent kept mice with a precancerous condition from developing advanced prostate cancer.
Instead, the animals either remained at the precancerous stage, called prostatic intraepithelial neoplasia (PIN), or they developed benign enlargements of the prostate called adenomas. The main side effect of the treatment was a reversible shrinkage of the testicles.
Of the animals not given the drug, 74 percent developed advanced prostate cancer.
The findings are reported in the May 15 issue of the journal Cancer Research. Human testing of the compound is expected to begin early next year.
“This study shows that an agent with a specific molecular target can dramatically inhibit prostate cancer development in an aggressive model of the disease,” says coauthor Dr. Steven Clinton, director of the prostate and genitourinary oncology clinic at Ohio State’s James Cancer Hospital and Solove Research Institute. “We hope to see this agent in clinical trials soon and ultimately used for prostate-cancer prevention or therapy.”
Furthermore, when the drug treatment was stopped after 24 weeks, two of the animals were followed for an additional 18 weeks. The animals developed adenomas but were alive after 42 weeks, well beyond their normal 32-week life span.
“The drug not only kept the animals cancer free, but also prolonged their life span,” says Ching-Shih Chen, who led the drug’s development and the new study at the Comprehensive Cancer Center. Chen is also professor of pharmacy and of internal medicine.
A veterinary pathologist on the study, first author Aaron Sargeant, graduate research associate in veterinary biosciences, was intrigued that adenomas occurred in the treated animals. “Adenomas are not commonly found to be part of prostate-cancer development in this system,” he says. “This drug appears to shift tumor progression from its usual aggressive course to a more benign direction.”
For this study, Chen, Sargeant, Clinton and their colleagues used a strain of transgenic mice that develops PIN at about six weeks of age, then progresses to advanced prostate cancer by 24 to 32 weeks.
The researchers added the drug to the diet of 23 of the cancer-prone mice beginning at six weeks of age, when the animals develop the precancerous condition, and continued the treatment for 18 weeks.
They then examined the animals. Of the treated mice, one showed signs of early stage cancer, but 12 still had only the precancerous condition and 10 had adenomas.
In contrast, 17 of 23 control animals developed advanced prostate cancer, two had early stage cancer, three had the precancerous condition and one an adenoma.
Experiments using a nontransgenic strain of the same mouse – they do not develop prostate cancer – showed that the degeneration of the testicles that accompanied the drug treatment was reversible when the drug treatment stops.
Chen noted that 186,320 cases of prostate cancer are expected this year, with 28,660 deaths from the disease. “Our findings are very exciting, considering that an agent capable of reducing prostate-cancer risk by only 10 percent could prevent 18,600 cases of the disease in the United States each year,” Chen says.
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Funding from the National Cancer Institute, Department of Defense, William R. Hearst Foundation and the Prostate Cancer Foundation supported this research. Aaron Sargeant is supported by a fellowship from Schering Plough Research Institute organized by the American College of Veterinary Pathologists and Society of Toxicologic Pathology Coalition for Veterinary Pathology Fellows.
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