Chapter 12 Chapter 12 Eternal Life

The loss of control of oncogenes and the defects of tumor suppressor genes provide a complete explanation for the unlimited growth of cancer cells.Mutated forms of these two types of genes work together to cause cells to grow uncontrollably when they must be dormant.Mutant forms of the ras oncogene and three tumor suppressor genes commonly involved in colon cancer are a vivid example describing the cooperative relationship between two classes of gene variants.However, this view ignores an important fact of cell biology: There are two different ways that tissues limit cell proliferation.One is to deprive cells of growth factors, or to expose cells to growth-inhibiting signals.These conditions cause cells to go dormant and stop growing.This approach, which is essential for maintaining normal order within tissues, has been rendered ineffective by changes in various proto-oncogenes and tumor suppressor genes.

Another way to limit cell proliferation is the one-shot: coaxing cells to commit suicide in an attempt to control cell numbers.The demise of the victim is also an important means of controlling the size of the cell population. Cells in many tissues in the body are doomed to die for a variety of reasons.There is a simple experiment that can illustrate one reason for cell death.If cells are taken out from a certain tissue and cultured in Jll[, the cells will divide, but after a certain round, the cells stop growing, lose their vitality, and eventually die.These steps are called cellular senescence and crisis.Taking human cell populations as an example, cells typically grow at a rate of once a day for 50 to 60 days and then stop growing.This barrier that prevents cells from multiplying indefinitely is called "cell mortality."

Cell mortality is an important anti-cancer self-defense mechanism.Normal tissues endow their cells with a limited number of divisions, seemingly intended to create a barrier against tumor development.This barrier ensures that early tumor cell populations can only divide for a certain number of rounds, and stop growing after the tumor cells have exhausted their ration. However, the developing tumor cell population must break through the cell-mortal barrier.Without the ability of precancerous cell populations to divide indefinitely, they cannot expand to a life-threatening size.When tumor cells were placed in a petri dish, they had in fact demonstrated the ability to reproduce indefinitely, indicating that they had become "immortal."

Until recently, the phenomenon of cellular mortality was a great mystery that puzzled biologists.How do cells know when to stop growing and grow old?How does a progeny cell know when it has exhausted its quota of divisions?Cells seem to have some sort of record, or collective memory, of their past history.Every growth and division of cells in the family is recorded by some kind of counting device, counting the number of cell generations in the tissue from the progenitor cells in the early embryo. There are several other examples related to this kind of generation counting.In some families in China, the first letter of a child's name indicates their seniority in the family tree, distinguishing them from their predecessors in the family.Cells in human tissue must have similar markings, telling them their place in the developmental history of the organism from the time of conception.There is a "generational alarm clock" logging these tokens.When the alarm clock reaches the preset time and counts a certain number of generations, it will ring loudly, telling the cells to stop growing and go to death.Cancer cells, however, are good at dancing with long sleeves. They are capable of turning a deaf ear to the alarm bell and continuing their endless growth and division.

For a long time, the counting mechanism adopted by the generation alarm clock has been ignored.Recent exciting research in a number of laboratories has finally revealed the molecular basis of the generational alarm clock, proposing a remarkably clever and surprising approach to the problem of counting cell generations. The discoveries about generational computing, like many of those cited in this book, came from fields of research that seemed unrelated to cancer.They arose from the observations of two geneticists, Barbara McClintock and Hermann Müller, in the 1900s.The two concluded that Drosophila chromosomes have special endpoints to prevent chromosome fusion and collapse.Muller calls them telomeres.Telomeres act like the guards on the ends of shoelaces that prevent fraying.Each human chromosome is a linear structure, so it has two telomeres.

In 1972, almost 40 years later, James Watson, one of the discoverers of the double helix structure of DNA, added to the story.At this point, some of the details of cell division, including the process of DNA replication, are understood.Every time a cell prepares to divide, it copies its DNA to ensure that each of its daughter cells receives the same genetic information.Earlier, we said that DNA replication and editing can be accurate to less than one in a million cumulative errors.However, Watson points out a striking exception to this rule of efficient and precise genome replication: Due to the biochemical mechanism employed by DNA polymerase, the enzyme responsible for DNA replication, the ends of chromosomal DNA are not always accurately mapped. copy.As a result, each time the cell replicates DNA, the telomeres that make up the ends of the DNA are shortened by about 100 bases.

A few years later, Elizabeth Blackburn, a geneticist studying the single-celled pond protozoa Cedarium, discovered the structure of telomeres.Like the rest of the chromosome, the Rila is made of a DNA double helix.But the DNA sequence structure of telomeres is unusual. It is composed of many identical DNA sequences arranged repeatedly.In human chromosomes, telomeres are composed of the base sequence TTAGGC repeated about 1000 times. Combining these research results leads to a big mystery: if the replication mechanism of protozoa such as leather paramecia cannot ensure that the telomeres of chromosomes are replicated correctly, how can they divide infinitely year after year? In 1984, Blackburn's research group figured out the answer. Paramecium cells have a special enzyme called telomerase, whose job it is to add repetitive DNA sequences, rebuilding telomeres and making up for the usual deficiencies in the DNA replication machinery.

In the 1970s, the Soviet geneticist Olovnikov (A, M. lovnikov) proposed the theory of telomeres related to the phenomenon of cell death, which was unknown to Western researchers.Normal cells in mammals, unlike paramecium cells, cannot rebuild telomeres, he points out.So after 30, 40 or 50 cell divisions, the telomeres wear out and can no longer protect the vital parts at the ends of the cell's chromosomes.After this, the chromosomes fuse end to end with each other, causing genetic chaos, and the cell stops growing and eventually dies.It is the disintegration of telomeres that sets off the alarm bell, telling the cell that it has used up its ration of dividing rounds.

Olovnikov's inference was finally confirmed.By the early 1990s, research results in many laboratories revealed that the telomeres of human cells gradually shorten as cells grow and divide repeatedly.Finally, due to insufficient telomeres, the cells begin to age, then go into crisis, and finally die. Not all human cells are destined to undergo the disintegration of telomeres, causing chromosome fusion.At least one family of cells in the human body escaped this catastrophe and gained immortality—the germ cells: sperm and eggs.In order for genes to be perpetuated from generation to generation, germ cells must ensure their own longevity.This kind of transmission, which is not limited by time and era, is necessary for a species that lasts for millions of years.

How did germ cells escape the crisis triggered by Rilla's disintegration?Unlike all other cells in the body, germ cells express telomerase, which makes up for the deficiency caused by DNA polymerase.Within a short time after the egg is fertilized, many, if not all, cells of the early embryo possess telomerase.Before long, however, telomerase production disappeared in the progeny of cells that make up most tissues, except in the progeny of germ cells.This disappearance imposes a limit on the proliferative potential of many progeny cells—a barrier that prevents cancer from developing. Cancer cells have revived telomerase, defying the divine handiwork of nature.All human cells, normal or not, carry the genetic information to make telomerase.But this information, possessed by most normal cell lines, is suppressed as early as embryonic development.By some unknown means, the cancer cells unearth this information lurking in the DNA and use it again to make telomerase.

The telomerase gene is the apple on the tree of knowing good and evil. "Most normal human cells cannot have it. Once cancer cells get it and resurrect telomerase, cancer cells can rebuild and maintain both sides of their chromosomes indefinitely." End, to ensure that they have unlimited replication ability. Now there is only one obstacle to restrain the proliferation of cancer cells - the ability of the tumor patient's body to withstand the unlimited proliferation of tumor cells. In some tumors, telomerase arrives late during the multistep process of turning normal cells into cancerous ones -- just when the evolving precancerous cell population is about to use up its quota of divisions.The appearance of telomerase in cells depends on a gene that regulates a key component of telomerase.Current research is focusing on figuring out how the gene goes off in normal cells and emerges in tumor cells. Previously, we have seen how the activation of oncogenes and the inactivation of tumor suppressor genes can have a profound effect on the external relationship of cancer cells—the interaction of cells with their surrounding environment.The recovery of telomerase is a completely different change, purely a chore of the cell, the repair and overcoming of the cell's own internal limitations. The cloning of the telomerase gene has excited those working to develop new ways to fight cancer.Time and time again, efforts to create effective cancer drugs have been thwarted by the resemblance between normal and cancer cells.Although we have enumerated many genetic differences that can distinguish normal cells from cancer cells, these mutations represent only a tiny fraction (less than 0.01%) of the genome.Most of the genes in normal cells and cancer cells are exactly the same.Similar genetic content exhibits similar appearance, behavior and biochemical makeup. These similarities explain why all experiments with drugs designed to kill cancer cells end up dead, as well as normal cells.These drugs do not have the ability to select -- that is, to leave normal cells as little as possible while onslaught on cancer cells.Few medical anti-cancer drugs in development pass the first test of toxicity to normal tissues. However, telomerase is a rare exception to the shared norm of traits of the two types of cells, so it is likely to be the Achilles heel of cancer cells; telomerase is indispensable for the growth of cancer cells; and most Telomerase is not present in normal cells, so their continued survival is not dependent on telomerase.This suggests a clear strategy for drug development: Create a drug that specifically attacks and inhibits telomerase, leaving the thousands of other enzymes in the cell intact.The highly targeted drug stops cancer cells from spreading and has little effect on normal cells. However, Baibi has time.Some normal cells, such as white blood cells, also have telomerase under certain conditions.That is to say, the growth of these normal cells is also inseparable from telomerase, so anti-telomerase drugs may also affect some normal cells and produce adverse side effects.Still, overall, the development of such anti-telomerase drugs is attractive.It will take another 10 years for researchers to figure out whether drugs against telomerase can be made and whether they will be effective in treating tumors.