One of the most promising developments in medicine today is personalized treatment based on a cancer patient's individual genes. The idea behind this approach is that if we discover what particular mutations have taken place in a specific cancer cell, we will be able to aim drugs directly at the cell with this mutation, while avoiding damage to healthy cells. Bar Ilan University Prof. Erez Levanon, however, has now discovered that a significant proportion of the mutations enabling cells to become cancerous occur not because of DNA, but because of RNA - molecules containing information duplicated from DNA that circulate freely in cells.
This discovery is likely to refute the idea on which personalized medicine is based, but it could also break new ground in treatment of autoimmune and blood vessel diseases.
All because of viruses
Surprising as it may seem, the reason for mutations discovered by Levanon lies in viruses that embedded themselves in a long evolutionary process in our genes and immune system, which sometimes becomes confused and does not distinguish between a "legitimate" gene and a real virus.
"A large proportion of our DNA results from viruses that have embedded themselves in our genes in the course of evolution," Levanon explains. "This embedding is so successful that genes that were once viral are now passed on from generation to generation and have become part of us." Some of them, however, still look like viruses, which is both a blessing and a curse.
Before delving into the significant of Levanon's discovery, here is a short reminder of the way genetics works. Every cell in our body contains our genome, which is composed of DNA. Actually, this is the body's masterplan. The DNA in the cell core copies the information in it to a material called RNA, which is free to circulate throughout the cell. Every DNA molecule produces its RNA copies according to the quantity needed by the body, which depends on environmental factors, among others.
The RNA molecules in turn transfer the information they contain to protein molecules. Some of these molecules are the body's building blocks (for example, collagen in the skin and cartilage are protein). Some are communication molecules or molecules that operate body processes. Proteins are in essence the translation of the DNA program to the real world.
Previously, it was thought that a person's DNA did not change from the time of birth to the time of death, and that every gene is therefore eventually translated to a single protein. In recent years, however, it has been learned that the operation of genes is much more complicated. First of all, while it was previously thought that mutations occur in the body's cells only from one generation to another, we now know that cells accumulate mutations over time, and these mutations are responsible for aging processes and the development of various types of cancer.
Secondly, every gene can copy the information that it contains to several types of RNA, not just one kind. This is one of the research fields of Bar Ilan VP research Prof. Shulamit Michaeli.
Levanon detected another previously unknown process - the accumulation of mutations in RNA. These result (but not necessarily, as we will see) from disruption in copying information from a healthy gene to the RNA molecules.
The genes that resemble viruses arouse an unnecessary response from the immune system against the DNA, and more frequently against the RNA molecules. Among some people, this process is positive and leads to greater resistance to infections in general. In other cases, however, this chain of events results in an autoimmune disease, in which the immune system attacks the body.
In order to cope with this situation, the body has developed a "control mechanism." A specific enzyme in the body begins to "mark" the viral genes on the RNA and changes them slightly, so that the immune system does not identify them as viral. The changes that this enzyme makes are in effect mutations in the RNA. These molecules are no longer an exact copy of the DNA.
"Such a change makes the body's genetics completely transparent to a genetic scan," Levanon says. "In other words, if I have certain DNA, but all of my RNA molecules have been changed by the 'marking enzyme,' no DNA scan can detect completely how my body is really operating.
"Cancerous cells are cells in which a great many mutations have been created. Some of them enable cells to multiply and survive against the body's control mechanisms. It is now believed that while some of these mutations are indeed in DNA, others take place in RNA. If one of them makes the cell resistant to chemotherapy, the genetic scan won't detect this. Most cancers are not explainable through DNA mutations. It appears that these are not sufficient to cause cancer."
According to Levanon, RNA mutations can be detected in a scan of genetic material, but it is logistically unreasonable to do this. "Doing this requires the entire RNA continuum, which varies from cell to cell and is temporary. It is possible for a particular cell to have one mutation in RNA one day and another mutation the next day. DNA can change when cells divide, but then each cell is the same," he says.
Where cancer is involved, this process has great evolutionary logic, because the process is reversible. "Today, the cancer cell creates a lot of mutations in RNA, some of which are useful and other are not. Tomorrow, it can stop producing the useless mutation through control by the marking enzyme. Were the cell to create so many mutations in DNA, most of them would probably be useless, and then it would be stuck with them. This way, it can preserve only what helps it to survive."
"Globes": That is depressing.
Levanon: "DNA is still more significant in the development and survival of cancer, so personalized medicine based on genes is still logical."
What coral and cancer cells have in common
Levanon says that coral probably adopt the same approach as a cancer cell, and is easier to research. "In one night, coral secrete an enormous quantity of eggs differing greatly from each other, but the variance is in the RNA, not the DNA, as a result of the same marking enzyme. The variance is therefore in the external characteristics, even though they are genetically identical. Some of the eggs survive, in which case they go back to being identical coral. If they accumulate the mutations in DNA, some of the differences being useful and others harmful, they would have had to bear the useless difference forever. The difference in the RNA disappears after the coral survives the egg stage and goes onward."
In people, some of the RNA mutations are temporary, but some are permanent and essential. "We discovered that in order to develop healthy blood vessels, people need two types of RNA that come from a single gene. Someone who has a large quantity of the marking enzyme creates both types of RNA. Someone who lacks the RNA with the mutation will development more heart diseases than others. In other words, we see that with time, these mutations become part of the design," Levanon explains. Science is still far from achieving this, but in principle, a possible route can be detected for a drug that will help some cardiac patients.
Published by Globes [online], Israel business news - www.globes-online.com - on September 16, 2018
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