Embryo Project Encyclopedia

Leonard Hayflick studied the processes by which cells age during the twentieth and twenty-first centuries in the United States. In 1961 at the Wistar Institute in the US, Hayflick researched a phenomenon later called the Hayflick Limit, or the claim that normal human cells can only divide forty to sixty times before they cannot divide any further. Researchers later found that the cause of the Hayflick Limit is the shortening of telomeres, or portions of DNA at the ends of chromosomes that slowly degrade as cells replicate. Hayflick used his research on normal embryonic cells to develop a vaccine for polio, and from HayflickÕs published directions, scientists developed vaccines for rubella, rabies, adenovirus, measles, chickenpox and shingles.

Leonard Hayflick in the US during the early 1960s showed that normal populations of embryonic cells divide a finite number of times. He published his results as 'The Limited In Vitro Lifetime of Human Diploid Cell Strains' in 1964. Hayflick performed the experiment with WI-38 fetal lung cells, named after the Wistar Institute, in Philadelphia, Pennsylvania, where Hayflick worked. Frank MacFarlane Burnet, later called the limit in capacity for cellular division the Hayflick Limit in 1974. In the experiment, Hayflick refuted Alexis Carrel's hypothesis that cells could be transplanted and multiplied indefinitely from a single parent cell line.

Telomeres are structures at the ends of DNA strands that get longer in the DNA of sperm cells as males age. That phenomenon is different for most other types of cells, for which telomeres get shorter as organisms age. In 1992, scientists showed that telomere length (TL) in sperm increases with age in contrast to most cell of most other types. Telomeres are the protective caps at the end of DNA strands that preserve chromosomal integrity and contribute to DNA length and stability. In most cells, telomeres shorten with each cell division due to incomplete replication, though the enzyme telomerase functions in some cell lines that undergo repetitive divisions to replenish any lost length and to prevent degradation. Cells, and therefore organisms, with short telomeres are more susceptible to mutations and genetic diseases. While TL increases in a subset of sperm cells and longer telomeres may prevent early disintegration of DNA, it may also prevent natural mechanisms of apoptosis, or cell death, from occurring in abnormal sperm.

Apoptosis, or programmed cell death, is a mechanism in embryonic development that occurs naturally in organisms. Apoptosis is a different process from cell necrosis, which is uncontrolled cell death usually after infection or specific trauma. As cells rapidly proliferate during development, some of them undergo apoptosis, which is necessary for many stages in development, including neural development, reduction in egg cells (oocytes) at birth, as well as the shaping of fingers and vestigial organs in humans and other animals. Sydney Brenner, H. Robert Horvitz, and John E. Sulston received the Nobel Prize in Physiology or Medicine in 2002 for their work on the genetic regulation of organ development and programmed cell death. Research on cell lineages before and after embryonic development may lead to new ways to reduce or promote cell death, which can be important in preventing diseases such as Alzheimer's or cancer.

In the second half of the
twentieth century, scientists learned how to clone organisms in some
species of mammals. Scientists have applied somatic cell nuclear transfer to clone human and
mammalian embryos as a means to produce stem cells for laboratory
and medical use. Somatic cell nuclear transfer (SCNT) is a technology applied in cloning, stem cell
research and regenerative medicine. Somatic cells are cells that
have gone through the differentiation process and are not germ
cells. Somatic cells donate their nuclei, which scientists
transplant into eggs after removing their nucleuses (enucleated eggs).
Therefore, in SCNT, scientists replace the nucleus in an egg cell
with the nucleus from a somatic cell.

The Hayflick Limit is a concept that helps to explain the
mechanisms behind cellular aging. The concept states that a normal human
cell can only replicate and divide forty to sixty times before it
cannot divide anymore, and will break down by programmed cell death
or apoptosis. The concept of the Hayflick Limit revised Alexis
Carrel's earlier theory, which stated that cells can replicate
themselves infinitely. Leonard Hayflick developed the concept while
at the Wistar Institute in Philadelphia,
Pennsylvania, in 1965. In his 1974 book Intrinsic
Mutagenesis, Frank Macfarlane Burnet named the concept after
Hayflick. The concept of the Hayflick Limit helped scientists study
the effects of cellular aging on human populations from embryonic
development to death, including the discovery of the effects of
shortening repetitive sequences of DNA, called telomeres, on the
ends of chromosomes. Elizabeth Blackburn, Jack Szostak and Carol
Greider received the Nobel Prize in Physiology or Medicine in 2009
for their work on genetic structures related to the Hayflick
Limit.

Experiments conducted by Elizabeth Blackburn, Carol Greider, and Jack Szostak from 1982 to 1989 provided theories of how the ends of chromosomes, called telomeres, and the enzyme that repairs telomeres, called telomerase, worked. The experiments took place at the Sidney Farber Cancer Institute and at Harvard Medical School in Boston, Massachusetts, and at the University of California in Berkeley, California. For their research on telomeres and telomerase, Blackburn, Greider, and Szostak received the Nobel Prize in Physiology or Medicine in 2009. Telomeres and telomerase affect the lifespan of mammalian cells and ensure that cells rapidly develop within developing embryos.

In the 1990s, researchers working at the Roslin Institute in Edinburgh, Scotland, performed cloning experiments in collaboration with PPL Therapeutics in Roslin, Scotland, on human coagulation factor IX, a protein. The team of scientists used the methods identified during the Dolly experiments to produce transgenic livestock capable of producing milk containing human blood clotting factor IX, which helps to treat a type of hemophilia. By using a cell's resting state, called quiescence, or G0, and transferring modified nuclear material from one cell to an egg cell that had had its nuclear material removed, the researchers developed a method to produce genetically modified mammals, including humans. Angelika E. Schnieke, Alexander J. Kind, William A. Ritchie, Karen Mycock, Angela R. Scott, Marjorie Ritchie, Ian Wilmut, Alan Colman, and Keith H. S. Campbell published the results of their experiments as Human Factor IX Transgenic Sheep Produced by Transfer of Nuclei from Transfected Fetal Fibroblasts (hereafter called Human Factor IX). The article details the methods that produced the cloned sheep named Polly, as well as other cloned and genetically altered sheep.

In the 1990s, Ian Wilmut, Jim McWhir, and Keith Campbell performed experiments while working at the Roslin Institute in Roslin, Scotland. Wilmut, McWhir, and Campbell collaborated with Angelica Schnieke and Alex J. Kind at PPL Therapeutics in Roslin, a company researching cloning and genetic manipulation for livestock. Their experiments resulted in several sheep being born in July 1996, one of which was a sheep named Dolly born 5 July 1996. Dolly was the first sheep cloned and developed from the nuclei of fully differentiated adult cells, rather than from the nuclei of early embryonic cells. They published their results in Viable Offspring Derived from Fetal and Adult Mammalian Cells (abbreviated Viable Offspring) on 27 February 1997.

When cells-but not DNA-from two or more genetically distinct individuals combine to form a new individual, the result is called a chimera. Though chimeras occasionally occur in nature, scientists have produced chimeras in a laboratory setting since the 1960s. During the creation of a chimera, the DNA molecules do not exchange genetic material (recombine), unlike in sexual reproduction or in hybrid organisms, which result from genetic material exchanged between two different species. A chimera instead contains discrete cell populations with two unique sets of parental genes. Chimeras can occur when two independent organisms fuse at a cellular level to form one organism, or when a population of cells is transferred from one organism to another. Chimeras created in laboratories have helped scientists to identify developmental mechanisms and processes across species. Some experiments involving chimeras aim to provide further knowledge of immune reactions against disease or to create animal models to understand human disease.