Early Human Embryos Make "Mistakes" as a Matter of Survival, Could be Key to Understanding Stem Cell Development
Bedford, MA, April 07, 2010 --(PR.com)-- Early human embryos may be naturally prone to making mistakes in chromosome allocation to new cells, according to a report by Bedford Stem Cell Research Foundation scientists. Their new findings indicate rapid increases in total genetic information may be more important to embryo survival than accurate allocation of genetic information to each new cell.
These first time data come from 8-Cell stage human embryos that have been examined for expression of all human genes in a project designed to understand how human eggs remodel genetic information to produce new cells with the potential to become all the cells in the body, in other words, how embryos give rise to Embryonic Stem Cells.
The recent research focused on how early embryo cells multiply. Scientists at the Bedford Stem Cell Research Foundation (www.bedfordresearch.org) compiled data from three prior reports by other laboratories that examined in unprecedented detail the 3,803 genes (out of about 25,000, organized into 23 chromosomes) that are involved in the multiplication of adult human cells. To multiply, cells must grow in size, duplicate their chromosomes from 23 to 46, then divide the chromosomes equally into two new daughter cells. This is the process by which the body makes billions of cells every day, including blood cells, intestinal cells, hair, and sperm.
When the subset of 3,803 cell division genes in the adult human cells were compared with those expressed in the human embryo (at the 8-cell development stage, a stage every human embryo progresses through about day three of development), Bedford Stem Cell Research Foundation scientists discovered that key genes involved in slowing the process of cell division to ensure the integrity of new chromosomes were silent in the 8-Cell embryo. Moreover, genes known to push cell division faster were detected at much higher levels in the embryo cells. These data suggest early human embryo cells rapidly multiply in the absence of checkpoints to insure the accuracy of allocation of genetic information to new daughter cells.
“In light of these findings, we need to re-think the early human embryo,” said Dr. Ann Kiessling, lead author on the paper. “Each and every cell may not be identical, as has generally been believed. Like all mammals, human reproduction is designed to conserve maternal resources. Checks and balances are in place to ensure that the mother does not nurture a fertilized egg that is not robust enough to develop into a baby. The human egg appears mid-way from one menstrual cycle to the next. It must be fertilized within a day or two, and it must signal the mother it is developing. The signal from the egg must be robust and must increase every day for several weeks; failure to increase the signal results in a menstrual cycle and expulsion of the failed egg.
“Therefore, it may be more important to the embryo’s survival to increase the number of copies of the genes that generate the signal to the mother than it is to take the time to ensure accurate chromosomes in each daughter cell. Information from animal studies indicates when the embryo reaches the 16- to 32-cell stage, most of the cells become committed to placenta, only a few will give rise to the baby. Therefore, only a few cells need to be chromosomally perfect to give rise to all the tissues in the body.
“But if no cells are chromosomally perfect, embryo development will fail. The embryo cells may have an as yet undiscovered mechanism for ensuring some cells will be chromosomally perfect, perhaps related to the circadian oscillators previously reported (circadian genes oscillate according to night/day cycles), or they may possess undiscovered repair mechanisms.”
This new information indicates that not all cells in early human embryos are identical and provides a possible explanation for several known facets of human egg biology. Genetic analysis of individual cells from early embryos reveal frequent abnormalities in chromosome number. Successful derivation of pluripotent stem cells from individual cells of early embryos is extremely rare, perhaps due to this naturally occurring phenomenon of chromosomal abnormalities.
“These surprising findings need confirmation by additional studies. But they lay the groundwork for specific experiments to improve the potential of human eggs. Studies of natural pregnancy rates suggest only one in four fertilized human eggs have the capacity to develop to offspring, even fewer in older women. The development of artificially activated eggs into parthenogenetic stem cell lines is also limited to a small percentage.
“A full understanding of early human embryo cells is essential not only to help correct defects in early development, but in order to understand the rest of human biology, especially what goes wrong, including cancer, and how to harness the power of stem cells to multiply and regenerate tissues,” said Kiessling.
The work appeared on line today in the Journal of Assisted Reproduction and Genetics. Scientists at the University of Athens School of Medicine, Athens, Greece participated in the study.
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These first time data come from 8-Cell stage human embryos that have been examined for expression of all human genes in a project designed to understand how human eggs remodel genetic information to produce new cells with the potential to become all the cells in the body, in other words, how embryos give rise to Embryonic Stem Cells.
The recent research focused on how early embryo cells multiply. Scientists at the Bedford Stem Cell Research Foundation (www.bedfordresearch.org) compiled data from three prior reports by other laboratories that examined in unprecedented detail the 3,803 genes (out of about 25,000, organized into 23 chromosomes) that are involved in the multiplication of adult human cells. To multiply, cells must grow in size, duplicate their chromosomes from 23 to 46, then divide the chromosomes equally into two new daughter cells. This is the process by which the body makes billions of cells every day, including blood cells, intestinal cells, hair, and sperm.
When the subset of 3,803 cell division genes in the adult human cells were compared with those expressed in the human embryo (at the 8-cell development stage, a stage every human embryo progresses through about day three of development), Bedford Stem Cell Research Foundation scientists discovered that key genes involved in slowing the process of cell division to ensure the integrity of new chromosomes were silent in the 8-Cell embryo. Moreover, genes known to push cell division faster were detected at much higher levels in the embryo cells. These data suggest early human embryo cells rapidly multiply in the absence of checkpoints to insure the accuracy of allocation of genetic information to new daughter cells.
“In light of these findings, we need to re-think the early human embryo,” said Dr. Ann Kiessling, lead author on the paper. “Each and every cell may not be identical, as has generally been believed. Like all mammals, human reproduction is designed to conserve maternal resources. Checks and balances are in place to ensure that the mother does not nurture a fertilized egg that is not robust enough to develop into a baby. The human egg appears mid-way from one menstrual cycle to the next. It must be fertilized within a day or two, and it must signal the mother it is developing. The signal from the egg must be robust and must increase every day for several weeks; failure to increase the signal results in a menstrual cycle and expulsion of the failed egg.
“Therefore, it may be more important to the embryo’s survival to increase the number of copies of the genes that generate the signal to the mother than it is to take the time to ensure accurate chromosomes in each daughter cell. Information from animal studies indicates when the embryo reaches the 16- to 32-cell stage, most of the cells become committed to placenta, only a few will give rise to the baby. Therefore, only a few cells need to be chromosomally perfect to give rise to all the tissues in the body.
“But if no cells are chromosomally perfect, embryo development will fail. The embryo cells may have an as yet undiscovered mechanism for ensuring some cells will be chromosomally perfect, perhaps related to the circadian oscillators previously reported (circadian genes oscillate according to night/day cycles), or they may possess undiscovered repair mechanisms.”
This new information indicates that not all cells in early human embryos are identical and provides a possible explanation for several known facets of human egg biology. Genetic analysis of individual cells from early embryos reveal frequent abnormalities in chromosome number. Successful derivation of pluripotent stem cells from individual cells of early embryos is extremely rare, perhaps due to this naturally occurring phenomenon of chromosomal abnormalities.
“These surprising findings need confirmation by additional studies. But they lay the groundwork for specific experiments to improve the potential of human eggs. Studies of natural pregnancy rates suggest only one in four fertilized human eggs have the capacity to develop to offspring, even fewer in older women. The development of artificially activated eggs into parthenogenetic stem cell lines is also limited to a small percentage.
“A full understanding of early human embryo cells is essential not only to help correct defects in early development, but in order to understand the rest of human biology, especially what goes wrong, including cancer, and how to harness the power of stem cells to multiply and regenerate tissues,” said Kiessling.
The work appeared on line today in the Journal of Assisted Reproduction and Genetics. Scientists at the University of Athens School of Medicine, Athens, Greece participated in the study.
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Contact
Bedford Stem Cell Research Foundation
Allison Kiessling
617-281-7902
http://www.bedfordresearch.org
Allison Kiessling
617-281-7902
http://www.bedfordresearch.org
Contact
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