Sunday, April 1, 2007

Apoptosis! Die cell die! or at least de-methylate.

Die cell die!

Getting our maladapted immune cells to die and stop causing us trouble is on the cutting edge for autoimmune virtual cures. Cancer researchers are blazing this trail. They hope to get “rogue” cancer cells to die. Getting the cancer cells to die might cure at least some kinds of cancer. So far cancer researchers have the vast majority of funding to make this concept into a reality. But it is worth knowing for the autoimmune community as well.

Apoptosis is the fancy science term for the programmed cell death. What? Some of the cells in your body are programmed to die? We do not want our cells to die, do we?

Yes, indeed! One possible cause of cancer (and autoimmune disease) is a glitch in the built in cell death program. When body cells are malfunctioning, there are internal (and external) cell sensors that are supposed to cause the cell to commit apoptosis. Re-start the cell death program and the malfunctioning cancer cells will die. Cancer cured. Re-start the program for mal-functioning immune cells. They die. The autoimmune feedback loop is broken. No more autoimmune disease.

In the womb your fingers (and toes) were webbed like a duck’s feet. All the cells in the tissue between your fingers had to die, so you could use your fingers/hands for something besides swimming. They got the apoptosis command and now you can independently wiggle your fingers and toes. All the cells in your prenatal tail complete with nascent vertebrae (bones) were also told to die. Your brain was pruned as well. The pruning did not stop until you were in your late teens. Do you notice you do not think in quite the same way you did when you were twelve? Apoptotic pruning continues our entire lives. It is responsible for many of the changes that happen to our bodies as we age.

After your immune system recovers from an infection many of the extra immune cells needed to defeat the pathogen are supposed to die as well. If they do not, they stay around causing problems. Welcome to one of the triggers for autoimmune disease.

Apoptosis is a hot topic in cancer research. It seems cancer cells are also supposed to die, but they have a mutation in the final gene that causes the cell death process. Or the gene may not be mutated at all, but rather it has been turned off (by methylation). Thus the rogue cancer cell do not die. Instead they reproduce (proliferate) until they block up a vital organ. Then you die. If researchers can induce apoptosis in cancer cells then no more cancer. Here is a link describing just one of dozens of apoptosis drugs coming to market in the next few years.

You have immune cells that have proliferated when they are not supposed to. Those same cancer drugs that can trigger apoptosis in cancer cells, can also trigger apoptosis in maladapted immune cells. (The "bad guys" immune cells are a tiny fraction of your B, T, and dendritic cells. All immune cells are "born" in your bone marrow. All autoimmune disease is bone marrow disease.) There are some other problem cells in some of your joints and tendons that are stimulated to grow by the attack of your malfunctioning immune cells. If the "bad guy" immune cells would just die, then the stimulus for excess joint growth (in RA, PsA patients) would end. The autoimmune process would halt.

Another possible cause of autoimune disease is called methylation. Methylation is a new discovery in genetics (about ten year ago). It seems some genes can be turned off by zinc fingers on a methyl group. No one understands why genes are sometimes methylated (turned off). But important genes can be shut down at the wrong time e.g. the apoptosis gene.

The methylated or shut down genes can stay shut down for a life time or longer. The methylted genes can even be passed to offspring in the methylated, shut down condition. Some family genetic traits/diseases are caused by methylation. Descendents for several generations receive theshut down gene.

The study of methylated genes is called Epigenetics. It is above (epi) or on top of the genetic laws of inheritance we all learned in high school. (Remember Mendel and his peas?)

Our immune cells may be turned on all the time because the gene for turning it ‘off” has been methylated. If the methyl group is removed, voila! We are cured. There are currently drugs in development which will un-methylate genes. Those drugs are being developed for cancer but should have autoimmune therapeutic implications as well.

Or immune cells that have finished their job may need to die and do not because the final step in the apoptosis process is blocked. They stick around like the un-dead, causing big problems--think zombie movie.

Not everyone with autoimmune disease will have it because cells do not die or immune down regulating genes are not functioning. But for some of us pro-apoptotic and demethylating autoimmune cures are possible. There are a whole host of apoptosis drugs that have been developed for cancer. We should have access to them as well, but of course we do not.

Also there are demethylating drugs being developed as well. So far these drugs seem a little more dangerous then the apoptotic drugs. There is even a potential new drug that causes ‘rogue” cells to senesce. (It puts them to sleep so they do no more harm.) Think Star Trek the Next Generation episode with Piccard/Lucutis and the Borg.

We, in the autoimmune community, should have access to all of these drugs. I mean right now, not later. Cancer patients have ten times the access to new drugs that we do. Virtualy every drug that helps B cell cancr patients (CLL, non-Hodgkins Lymphoma, etc.) would help us. Stand up and yell about. Write a letter to your local paper today. Tell your federal officials. We demand the cures now!

Here are some titles of published work on the subject. Just google the title to read the article. Sorry I do not yet know how to link to URL’s.

New Concepts in the Pathophysiology of Inflammatory Bowel Disease: The Failure of Apoptosis of Immune Cells in the intestinal Mucosa. Annals of Internal Medicine January 2006
Sorry link address was too long, it will not highlight.
“Early results find activity in drug that turns on tumor ‘death’ receptors”

Here’s the arsenic cure. Arsenic in the right amount triggers apoptosis of cells that need to die. Too much and the whole body dies. “Ziopharm presents at European Society of Hematology Meeting: Updates ZIO-101 Clinical Development Strategy.”

A newly identified immunosuppressive protein in rheumatoid arthritisThe findings of a new study expose DcR3 as one of the factors culpable for RA's hallmark hyperplasia and its crippling consequences. - size 6.7K

AVN944 inhibits IMPDH and induces apoptosis-related biomarkers in patients with hematologic ...IMPDH is highly upregulated in most hematological cancers and solid tumors -- an essential role in cancer cell synthesis of DNA and RNA. ... - size 12.0K

Google ”EntreMed Panzem 2ME2”

For methylated genes, “Drug that switches on genes improves myelodyspastic syndrome treatment.”

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