Hayflick Limit

 

 

Human chromosomes (grey) capped by telomeres (white)

 

 

 

The Hayflick limit (or Hayflick Phenomenon) is the number of times a normal cell population will divide before it stops, presumably because the telomeres reach a critical length. The Hayflick limit was discovered by Leonard Hayflick in 1961, at the Wistar Institute, Philadelphia, when Hayflick demonstrated that a population of normal human fetal 1) ___ in a cell culture divide between 40 and 60 times. It then enters a senescence phase (refuting the contention by Alexis Carrel that normal cells are immortal). Each mitosis shortens the telomeres on the DNA of the cell. Telomere shortening in 2) ___ eventually makes cell division impossible, and it correlateswith aging. This mechanism appears to prevent genomic instability and the development of cancer.

 

Prior to Hayflick’s discovery, it was believed that vertebrate cells had an unlimited potential to replicate. Alexis Carrel, a Nobel prize-winning surgeon, had stated “that all cells explanted in culture are immortal, and that the lack of continuous cell replication was due to ignorance on how best to cultivate the cells”. He supported this hypothesis by claiming to have cultivated fibroblasts from chick hearts, and to have kept the 3) ___ growing for 34 years. This indicated that cells of vertebrates could continue to divide indefinitely in a culture. However, other scientists were unable to reproduce Carrel’s result. In fact, Carrel’s result was due to an error in his experimental procedure: chick embryonic 4) ___ cells were added to the culture daily. This allowed for the cultivation of new fresh cells in the culture, and not simply the infinite reproduction of the original cells present in the culture. Dr. Hayflick first became suspicious of Carrel’s theory while working in a lab at the Wistar Institute. Hayflick was preparing normal human cells to be exposed to extracts of cancer cells when he noticed the normal cells had stopped proliferating. At first he thought that he had made a technical error in preparing the experiment, but later he began to think that the cell division processes had a counting mechanism. Working with Paul Morehead, he designed an experiment that showed the truth about normal cell 5) ___.

 

The experiment proceeded as follows. Hayflick and Morehead mixed equal numbers of normal human male fibroblasts that had divided many times (cells at the 40th population doubling) with female fibroblasts that had divided only a few times (cells at the 10th population doubling). Unmixed cell populations were kept as 6) ___. When the male “control” culture stopped dividing, the mixed culture was examined and only female cells were found. This showed that the old cells “remembered” they were old, even when surrounded by young cells, and that technical errors or contaminating viruses were unlikely explanations as to why only the male cell component had died.The cells had stopped dividing and become senescent based purely upon how many times the cell had 7) ___. These results disproved the immortality theory of Carrel and established the Hayflick Limit as accredited biological theory which, unlike the experiment of Carrel, has been reproduced by other scientists. Hayflick describes three phases in the 8) ___ of a cell. At the start of his experiment he named the primary culture “phase one.” Phase two is defined as the period when cells are proliferating — Hayflick called it the time of “luxuriant growth”. After months of doubling the cells eventually reach phase three, a phenomenon of senescence — cell growth diminishes and then stops altogether.

 

This limit has been found to correlate with the length of the telomere region at the end of a strand of 9) ___. During the process of DNA replication, small segments of DNA at each end of the DNA strand (telomeres) are unable to be copied and are lost after each time DNA is duplicated.The telomere region of DNA does not code for any protein; it is simply a repeated code on the end region of DNA that is lost. After many divisions, the telomeres become depleted and the cell begins apoptosis, or cell 10) ___. This is a mechanism that prevents replication error that would cause mutations in DNA. Once the telomeres are depleted due to the cell dividing many times, the cell will no longer divide and the Hayflick limit has been reached.

 

This process errs in cancer cells. 11) ___ cells turn on an enzyme called telomerase which is able to restore telomere length. Thus the telomere of cancer cells is never shortened, giving these cells infinite replicative potential.A proposed treatment for cancer is a telomerase inhibitor that would prevent the restoration of the telomere, allowing the cell to 12) ___ like other body cells.On the other hand, telomerase activators might repair or perhaps extend the telomeres, thus extending the Hayflick limit of healthy cells. This might strengthen the telomeres of immune system cells enough to prevent cancerous cells from developing from cells with very short telomeres. Carnosine can increase the Hayflick limit in human fibroblasts, and also appears to reduce the rate of telomere shortening.

 

ANSWERS: 1) cells; 2) humans; 3) culture; 4) stem; 5) division; 6) controls; 7) divided; 8) life; 9) DNA; 10) death; 11) Cancer; 12) die

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