Gene and Epigene - The Next Cancer Therapy?

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Hyped by biotech, Wall Street and the media, gene therapy became another cancer buzz word in the 1990’s. This new space-age modality was supposed to garner breakthroughs in the treatment of various debilitating and deadly disease especially cancer. Today, there is no FDA approved gene therapy for cancer or any other disease. What happened? Here we take a look at the failed promise of gene therapy and focus on a related modality of greater potential – epigene therapy.

What is Gene Therapy?

Genes, which are carried on chromosomes, are the basic units of heredity that encode instructions on how to make proteins. It is these proteins that perform most of life’s functions and comprise the majority of cellular structures. It is widely believed that when genes are altered so that their encoded proteins are unable to carry out their normal functions, genetic disorders can result leading to disease.

Gene therapy is a technique that is designed to correct defective genes responsible for a disease like cancer. Typically, in most gene therapy studies, a “normal” gene is inserted into the defective genome to replace an “abnormal,” disease-causing gene. A carrier molecule called a vector must be used to deliver the “normal” gene into the patient’s target cells. The most common vector is a virus that has been genetically altered to carry normal human DNA.

Five Steps for Gene Therapy to Work and Five Reasons for Problems

After a virus (i.e. viral vector) has been genetically engineered to carry the normal human gene there are five basic steps for this therapy to potentially work : 1) Target cells such as the patient’s liver or lung cells must be infected with the viral vector; 2) The viral vector must unload its payload of genetic material containing the “normal” human gene into the target cells; 3) The gene must make its way into the cells and nuclei; 4) The infected cells must become normal and produce functional (i.e. normal) protein product; 5) the functional protein should stop or slow the disease process.

Current gene therapy has not proven very successful in clinical trials for a number of reasons. First, it can be difficult to ensure that steps one through five above work consistently and reliably. In addition, there are other inherent problems:

  • First, to be a permanent cure for a disease, the genes introduced by gene therapy must be long-lived and stable. Often, they are not.
  • Second, the immune system is designed to attack invaders like viruses regardless of whether they carry helpful genes.
  • Third, viral vectors can create toxicity and immune and inflammatory responses. (You may recall the avoidable death of 18-year-old Jesse Gelsinger who participated in a gene therapy trial for ornithine transcarboxylase deficiency (OTCD). He died from multiple organ failures four days after starting the treatment. His death is believed to have been triggered by a severe immune response to the adenovirus carrier virus.)
  • Fourth, once inside the patient, the viral vector could potentially revert to its previous “wild type” form and cause disease.
  • And lastly, many diseases, especially cancers, have a number of gene mutations. Multigene disorders are especially difficult to treat effectively using gene therapy because all these challenges would be multiplied by the number of genes targeted.

Mutation May Not Equal Cancer

But there may be a more universal reason why gene therapy will not cure a disease like cancer. Many of these so-called mutations found in cancer cells can also be found in healthy cells and it is becoming less clear whether DNA mutations are actually the sole cause of disease. Research over the past few years suggests that it is not.

The cause of diseases like cancer may actually be due in whole or in part to epigenetic modifications which are potentially reversible changes in gene function that occur without a change in DNA sequence (genotype). According to researchers at Johns Hopkins, “It is increasingly apparent that cancer development not only depends on genetic alterations but on an abnormal cellular memory, or epigenetic changes, which convey heritable gene expression patterns critical for neoplastic initiation and progression.”(1) Researchers from McGill University concur, “Cancer growth and metastasis require the coordinate change in gene expression of different sets of genes. While genetic alterations can account for some of these changes, many of the changes in gene expression observed in cancer are caused by epigenetic modifications.”(2)

In other words, epigenetic changes which are outside the genetic code and are due to how the gene is expressed, not the hard-wiring of the genetic sequence or code itself, are being identified with carcinogenesis.

The Epigenome Can Be Influenced by Environment

Why is this important? It is important because evidence suggests that the epigenome can be influenced by the environment which means that epigenetic modifications that lead to carcinogenesis may be reversible by changing the environment. What do we mean by environment? The environment is the totality of surrounding conditions – the milieu of the cell. What affects the milieu of the cell? Toxins, viruses, carcinogens, diet – essentially everything that our cells are exposed to. This brings us directly to what some alternative practitioners have been saying for years – that detoxification followed by the creation of a healthy milieu with appropriate diet and supplements benefits cancer patients.

Such a concept may sound like heresy to the orthodoxy within the oncology community that determines research priorities. The viability of detoxification (removing toxins, viruses, carcinogens and other biological contaminants from the body) followed by improving what a patient consumes (i.e. organic, whole, vegetarian foods, vitamin supplements, etc.) as a cancer therapy has been summarily rejected by the cancer establishment for decades. (In fact, most cancer patients are offered artificially colored, sugared, and preserved foods during their hospital stays.) Despite the growing empiric and anecdotal data that demonstrate that these factors do play a role in distinguishing long-term cancer survivors, the orthodoxy has rejected such a treatment approach as worthless. Part of their reasoning has included that there are no biological mechanisms to support such a modality. Now, epigenetics are providing a plausible biological mechanism.

Detoxification and Diet May Have Biological Plausabiliy

Is detoxification and diet a viable cancer modality by itself or in combination with other approaches? There are many long-term survivors who swear it is and offer their existence as proof. What is clear is that our body and the environment are one especially if, as epigenetics proves, the environment can effect how our genes work within our cells. Since this is now becoming accepted science perhaps it is time researchers took the next step and asked what role epigenetics may play in reversing cancer and what lifestyle decisions and exposures may impact such a role. Perhaps it is time that some resources focused on the mechanistic, reductionist and overwhelmingly failed gene therapies can be redirected.

Endnotes:

1. Ting AH, et al., The cancer epigenome–components and functional correlates. Genes Dev. 2006 Dec 1;20(23):3215-31

2. Szyf M., Targeting DNA methylation in cancer. Bull Cancer. 2006 Sep 1;93(9):961-72

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This page contains a single entry by Cancer Monthly published on December 10, 2007 9:20 AM.

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