Conquering Cancer (Fixing Our Genes)

Conquering Cancer 

by : Aria Ratmandanu 

A UNIFIED THEORY OF CANCER

         There are two major kinds of genes involved with cancer: oncogenes and tumor suppressors. To understand how they work, think of a speeding car which has both an accelerator (oncogene) and a brake (tumor suppressor). One speeds up the car, the other stops it. The car can go out of control in two ways: either the accelerator can be stuck (an activated oncogene) or the brake can be defective (an inactivated tumor suppressor). In other words, a cell can go berserk either if it divides uncontrollably or if it loses its ability to stop dividing.

        Scientists have found over 50 types of oncogenes for cancer of the breast, colon, bladder, and lungs. These oncogenes include the gene which codes for the protein p-21 (which derives its name from the fact that it weighs 21,000 atomic units, or as much as 21,000 hydrogen atoms), as well as p-60.

       The second class of genes that can cause cancer, the tumor suppressors, include mutated versions of the genes DCC and especially p-53, which scientists are now realizing are found in the majority of common cancers. Unlike the oncogenes, these defects occur in genes which normally shut off the reproductive process; with mutations in these genes, the cells reproduce out of control, almost forever.

     Doctors expect to have by 2020 almost a complete encyclopedia of perhaps hundreds of oncogenes and tumor suppressor genes, giving us an understanding of the molecular basis for cancer and opening up scores of new ways of attacking it.

The Scourge of Cancer

           The one disease that has frustrated the most intensive crash program in history is at last yielding its secrets to molecular medicine. Cancer, one of the most dreaded of all diseases, is the second leading cause of death in the United States (after heart disease), killing half a million Americans every year. It is also one of the most pervasive. Altogether, there are 200 forms of cancer (affecting virtually every type of cell in the human body). Unlike ordinary cells, cancer cells have lost their ability to stop dividing. They are immortal—they proliferate without limit until they choke off normal bodily functions and kill the victim. (This does not mean that each cancer cell is immortal. Cancer cells can die, just like ordinary cells. The difference is that cancer cells proliferate indefinitely, so the cell line is immortal.)

           Scientists are now on the threshold of a complete understanding of how cancer develops at the molecular level. In the main, the mystery of cancer has been solved. Cancer has now been revealed to be a genetic disease, and the precise sequence of four to six mutations necessary to create a cancer cell for many common cancers is now known. “Not only have the main genes involved been identified; scientists also know the basic molecular steps through which a normal cell suddenly becomes cancerous.

         The pieces of the puzzle have finally fallen into place,” claims Robert A. Weinberg of MIT. Cancer research centers are now bursting with activity as they close in on the fine details of how cancers form and grow. As Dennis Salmon, a cancer specialist at UCLA, says: “This is the most exciting time imaginable!

           Molecular medicine has already given us the answer to one of the central mysteries of cancer—i.e., why it has such a bewildering variety of causes, from lifestyle, environment, viruses, toxins, diet, radiation, tobacco smoke, animal fat, sex hormones like estrogen, etc. About 30 percent of all cancers, in fact, can be traced to tobacco smoking alone. If we include the contribution from diet, we can establish a link to roughly 60 percent of all cancers. And by comparing ethnic groups that mature in different regions (e.g., Africans and Japanese growing up in the United States), epidemiologists have determined that a vast majority, perhaps as many as 70 to 90 percent, of all cancers can be correlated to the environment and lifestyle.

Three Stages in Medicine

         Like computers, medicine is being thrust into its third stage by the bio-molecular revolution, Anderson claims. During the first stage of medicine, shamans and mystics painfully scoured the plant kingdom for thousands of years looking for herbs that might scare dreaded spirits away, at times stumbling upon valuable remedies that are used even today. Some of our common drugs have their origin during this primitive but important stage. But for every herb that was, by trial and error, found to be effective against certain ailments, there were thousands more which did not work, some of which even injured the patients.

         For example, a country doctor who became one of the founders of the famed Mayo Clinic in Rochester, Minnesota, recorded with rare candor that most of his potions were worthless, but there were two things in his black bag which were guaranteed to work every time: morphine and his saw, which were used in amputations.

       In the second stage of medicine, which began after World War II, the mass distribution of vaccines and antibiotics temporarily vanquished whole classes of diseases. Abigail Salyers and Dixie Whitt, authors of Bacterial Pathogenesis, write: “One of the main reasons for the elevation “ of physicians to their current status as respected professionals was that antibiotics actually enabled them to cure diseases for which in the past they had only been able to provide ameliorative (and largely ineffective) therapy.

         Fortunately, we are now entering the third stage of medicine, “molecular medicine,” perhaps the most exciting and profound of all. For the first time in history, each level of pathogenesis, protein for protein, molecule for molecule, even atom for atom, is now being revealed. Like a general eagerly reading the map of the enemy’s defenses, scientists today can read a germ’s complete genome and identify the molecular weak spots in its armor.

       As Sherwin B. Nuland of the Yale University School of Medicine says: “In a 20-year period, the ancient art of healing passed from the relatively simple and restricted optimism of the antibiotic era to the seemingly endless vistas of the molecular age.

P-53: The Key to Most Cancers

       One reason why scientists feel confident in predicting that whole classes of cancers may be curable  by 2020 is that most cancers are caused by mutations in just a handful of genes, the most significant being p-53. Although hundreds of genes involving cancer may exist, the key to curing most cancers may be to focus on the common ones implicated in the vast majority of cancers and neutralize them via gene therapy or “smart molecules.

       Every year, we find that mutated versions of p-53 are implicated in more and more cancers, from cancer of the lung, colon, breast, esophagus, liver, brain, and skin to leukemia. It has been found in 52 common forms of cancer, and the percentage of cancers that have faulty p-53 is staggering: 90 percent of all cervical cancers, 80 percent of all colon cancers, 40 to 60 percent of all ovarian cancers, 35 to 60 percent of all bladder cancers, and 50 percent of all brain cancers. “This quite clearly is the most commonly mutated gene we’ve yet found in human cancers,” notes Bert Vogelstein of the Johns Hopkins School of Medicine. It is so important that scientists have dubbed p-53, when it functions normally, the “guardian of the genome.” P-53 is so essential for cancer formation that in 1994 Science magazine named it “Molecule of the Year. Understanding p-53 has also solved some long-standing mysteries which have dogged the field for decades.

     P-53 normally prevents reproduction in a damaged or mutated cell and promotes cell suicide (called apoptosis). When p-53 is mutated or neutralized, deranged cells can continue to proliferate within “the body, thereby creating tumors.

     As we now understand, the reason for its appearance in a wide variety of cancers lies in its molecular structure; it is extremely long and delicate (consisting of 2,362 base pairs). Mutations in p-53, which is located on the short arm of chromosome 17, can occur at over 100 sites along the gene. Hence, p-53 is riddled with potential sites for mutations. (By contrast, other commonly found genes involving cancer usually have harmful mutations occurring at only a half dozen sites.)

        The gene is actually an aggregate, consisting of four or more identical copies of a smaller subunit. All four subunits must act correctly in order for p-53 to properly control cell multiplication. The fact that p-53 is such an unwieldy molecule makes it particularly vulnerable to mutations. For example, colon cancer results from the mutation of perhaps four to six genes. A typical cancer of the colon may proceed in the following fashion: the loss of function of the APC gene, the activation of the K-ras gene, and the loss of the DCC and p-53 genes.”

          This, in turn, solves one of the central riddles of cancer, why it often takes twenty to forty years for a cancer to develop after the first exposure to radiation, asbestos, and other carcinogenic materials. The reason it takes so long is that a series of multiple mutations must occur before the growth mechanism of a cell is finally disrupted. This successive disabling of the cell’s reproductive mechanism usually takes time, often decades, to occur.

          All this has tremendous practical implications. Blood tests are becoming available to find out if people have a mutated version of p-53. Although it takes three to five more mutations to trigger a cancer, a mutation in p-53 may be the most important of them all. By 2020, tests for defective p-53 and hundreds of other genes implicated in cancer will be commonplace.Second, gene therapy will target defective p-53 genes to see if they can be replaced by a normal version of the gene.

          Third, p-53 will give us an understanding of why certain classes of chemicals and agents in the environment cause cancer. P-53 has several “hot spots” where chemical toxins can bring about mutations. For “example, aflatoxin, a potent cancer-causing chemical found in moldy food, which can lead to liver cancer, is known to cause a mutation in p-53 by changing G to T. By analyzing the ways in which certain chemicals cause mutations in p-53, one may be able to understand why environmental factors and toxins can cause cancer.

        Such discoveries could significantly affect the fortunes of “multibillion dollar industries. The tobacco industry, for example, has been able to defeat lawsuits brought by the families of smokers who died of lung cancer by claiming that no one can definitely prove that tobacco smoke causes cancer. Since the link between tobacco smoke and lung cancer is indirectly established through epidemiology and statistics rather than biochemistry, the tobacco industry has always claimed in court there is no “smoking gun” which implicates tobacco smoke.

        All this changed in 1996, when scientists proved that the chemical benzoapyrene diol epoxide (BPDE), which is commonly found in tobacco smoke, causes a characteristic set of mutations in p-53 at three specific sites. These three mutations are the “fingerprint” of BPDE and are easily detected in p-53 mutated by tobacco smoke. These are precisely the mutations implicated in lung cancer. Since over 400,000 Americans die of lung cancer each year (80 to 90 percent linked to smoking, according to the American Cancer Society), this could have enormous political and economic repercussions. In the future, lawsuits may be decided on the basis of whether cancers can be traced to specific molecular “fingerprints” along key genes such as p-53, p-16, ras, and “ so on.

       By 2020, scientists will have found the genetic fingerprints of hundreds of different kinds of chemical pollutants in our environment. By matching a person’s cancer with the genetic fingerprint left by a carcinogen, scientists in many cases will be able to tell precisely what gave this person cancer. This could have a profound effect on how pollutants are regulated and who pays for the damage. It may also help solve the mystery of why breast cancer is on the rise in the West, which has stumped epidemiologists around the country.

       But perhaps one of the most intriguing discoveries in recent years involves something called telomeres, which are now recognized as a kind of biological “clock.” By resetting the clock, one may be able to order cancer cells to die.

Cancers in 2020

       Cancer, because it is a crazy quilt of at least 200 different kinds of diseases, one for every kind of human tissue, will not be cured in its entirety by 2020. As Richard Klausner of the National Cancer Institute says: “There will never be a single cure for cancer.

        However, by 2020 scientists should have an almost complete catalog of the mutations involved in these 200 cancers, which will trigger an explosive growth in radically new cancer therapies and detections, including a variety of startling new strategies for attacking cancer’s molecular weak spots and vulnerabilities. There are several new avenues generating intense interest, many of which should reach fruition by 2020.

         The first has to do with cancer detection. Imagine being able to detect a tiny colony of cancer cells a decade before a visible tumor forms. Extremely sensitive tests are now being devised (and will soon hit the market) which can detect infinitesimal amounts of proteins that are emitted by only a few hundred cancer cells as they grow and eventually create blood vessels. These proteins can be detected by analyzing one’s urine and blood. Similarly, doctors will be able to test directly for the presence of cancer “genes in our genetic makeup. About half of all cancers are found in our hollow organs (lung, colon, bladder), which often have a mutant ras gene. By devising simple tests in our urine and blood for the ras gene (which in the future will be performed in our own home), we will be able to detect a majority of all cancers years before they form tumors or spread.

        The second approach has to do with the development of natural cancer fighters. Science is beginning to understand at the molecular level why certain natural products and vitamins help guard against cancer. Genistein, which is found in soybeans and “cabbage, is found in high concentrations in the Japanese diet and is known to suppress the formation of blood vessels in cancer tumors. (The Japanese, in fact, have concentrations of genistein in their urine 30 times that of Westerners.) Antioxidants in foods (like vitamin C and E, and lycopene in tomatoes, catechins in berries, and carotenoids in carrots) are known to reduce the mutation rate in cells by suppressing free radicals. Other vegetables contain chemicals that create enzymes which protect against cancer (such as indoles in cabbage, limonoids in citrus fruits, isothlocyanates in mustard).

         The third approach is enhancing the immune system. Normally, the antibodies created by the immune system are not sufficiently powerful to target a cancer cell. One can, however, create “monoclonal antibodies,” or chemicals which specifically target the proteins found on the surface of the cancer cell. After an initial wave of enthusiasm for such antibodies, the scientific community experienced intense disappointment. But Lloyd Old, formerly of the Memorial Sloan-Kettering Institute for Cancer Research in New York, says, “The concept remains sound, and slow, steady progress is being made in developing antibody therapies.

           A fourth approach has to do with targeting cancer genes. Gene therapy can inject the correct gene to replace the defective ones causing the cancer. Scientists have successfully injected the correct p-53 gene into cancer cells in cell cultures, thereby stopping their reproduction, and are performing human experiments as well. Alternatively, scientists could develop inhibiters to block the defective protein created by the cancer gene. For example, the protein produced by the ras oncogene can be stopped by farnesyl transferase inhibitors.

         A fifth approach centers on cancer vaccines. Although this approach was one of the first to be tried and was later abandoned, new interest in cancer vaccines has been stimulated by the biomolecular revolution. With modern techniques, one can accurately monitor the effectiveness of certain vaccines, which was almost impossible before.

          A sixth approach doctors can take is to shut off the cancer’s blood supply. In order for a cancer to grow beyond the size of a pea, it has to stimulate the growth of blood vessels and capillaries to supply nourishment for the tumor. This process of growing blood vessels is called “angiogenesis.” The strategy to block blood vessel growth is to develop angiogenesis blockers. Already “thirty biotech firms around the world are creating such angiogenesis blockers, such as TNP-470, some of which are now in clinical trials. Yet another approach targets telomerase. If we can neutralize telomerase, we can make the cells mortal again, just like other cells.

         No one knows precisely which therapy will be most effective against cancer. But the point is that the biomolecular revolution has now cracked the mystery of cancer and has given us a wealth of extremely promising new avenues for attacking cancer which will eventually replace the primitive tools of chemotherapy, surgery, and radiation available today. Many scientists believe that by 2020 entire classes of cancers may be curable.”

2050: Germ-Line Therapy ?

        So far, the excitement about fixing our genes has focused on somatic cell gene therapy—i.e., cells in our body which are not involved with reproduction. When the individual dies, the corrected genes die with that person. More controversial is germ-line gene therapy, which involves manipulating the DNA of our sex cells. In principle, germ-line therapy can banish genetic diseases in future generations. If successful, descendants would never again have to fear a particular hereditary disease.

       Scientists expect someday to make eye-opening discoveries which will make germ-line therapy a realistic possibility for humans. Scientists can already perform simple germ-line manipulation in animals, and there is no foreseeable barrier to extending this technology to humans. It is clearly a technology that has the potential to be used in disturbing as well as beneficial ways.”