One of the most basic questions in biology throughout history is regarding our origins: how did we came to be? Paleonto-biologists look of answers in our past, evolutionary biologists look at other species (our biological cousins, so to speak). But developmental biologists look for it from how we were created: the first few moments of our conception.
By studying this, we may discover more than our origins, maybe even our purpose in nature. |
"Developmental Biology, in capitals, is the wave of the future. The creeping reductionism of biochemistry and molecular biology has taken over the cell and heredity, and looks covetously toward the heights of development and evolution. Recent literature is last year. Ancient literature is a decade ago. The rest is history, doubtfully alive."
Charles R. Scriver, Biographical Memoirs of Fellows of the Royal Society (1999)
The multidisciplinary approach to the study of development first arose before the turn of the 20th century as an integration of embryology (initially the descriptive study of embryonic development) with cytology (the study of cellular structure and function) and later with genetics (the study of inheritance). The leading cytologists of that time (primarily E.B. Wilson at Columbia University in New York City) recognized that development of the embryo is a manifestation of changes in individual cells and that an understanding of the fundamental principles of development would come from studying cellular structure and function.
Wilson recognized that the characteristics of an organism gradually emerge by utilization of the inherited information that is located on the chromosomes. Therefore, it was important to comprehend the nature of that information and how it is utilized during development. However, in the absence of concrete evidence, there was a great deal of rampant speculation as to how the chromosomes participate in development. The German embryologist Wilhelm Roux was the source of much of this speculation.
Wilson recognized that the characteristics of an organism gradually emerge by utilization of the inherited information that is located on the chromosomes. Therefore, it was important to comprehend the nature of that information and how it is utilized during development. However, in the absence of concrete evidence, there was a great deal of rampant speculation as to how the chromosomes participate in development. The German embryologist Wilhelm Roux was the source of much of this speculation.
Roux believed that the fertilized egg receives substances that represent different characteristics of the organism, which - as cell division occurs - become linearly aligned on the chromosomes and are subsequently distributed unequally to daughter cells. This "qualitative division" fixes the fate of the cells and their descendants because some of the determinants are lost to a cell at each division. Roux in 1888 appeared to have confirmed his theories by an experiment he conducted on frog eggs.
Another German embryologist, Hans Driesch in 1892, approached the problem differently with sea urchin embryos. Instead of destroying one of the cells of the two-celled embryo, he separated the cells from one-another and found that isolated cells at the four-cell stage also develop normally. Thus, Driesch concluded that each cell retains all the developmental potential of the zygote. The conflict between these two opposing views of development has been settled in favor of Driesch's interpretation by numerous cell separation experiments.
The experiment conducted by Roux illustrates the importance of proper experimental design. Roux had introduced an artifact into his experiment by allowing the damaged half of the embryo to remain attached to the uninjured half, interfering with its development. Roux had done something that nobody had done before: He manipulated embryos and observed the effects of these manipulations on them. For this reason, many embryologists consider him to be the "Father of Experimental Embryology."
Mystery of the Century
Embryologists became disillusioned with genetics and preoccupied themselves with describing development and experimenting on the interactions and rearrangements of the cells and tissues that form embryos. A remarkable series of experiments conducted by the German embryologist Hans Spemann and his student Hilde Mangold in 1924 fired the imagination of embryologists and spawned a new era of embryological investigation that was truly the heyday of embryology. Spemann and Mangold demonstrated that the transplantation of a small amount of tissue from the dorsal side of an early embryo of Triturus (tailed amphibian) could induce host tissue to form a secondary embryonic axis, including neural tissue. Spemann concluded that the behavior of an implanted region (the dorsal lip of the blastopore) reflects its normal function in inducing the primary axis and designated it as the embryonic organizer. A vast amount of experimental data was collected, but the essential nature of the organizer and the process of embryonic induction remained a mystery until recent years. Current progress in understanding embryonic induction has come from research on a class of protein molecules called growth factors, which were discovered by Rita Levi Montalcini and Viktor Hamburger in the 1950s. A large number of growth factors have now been discovered that play important roles in a variety of developmental processes, including embryonic induction. |
These discoveries have fostered intense investigation into how cell-cell interactions are involved in organizing the embryonic body plan, and embryonic induction has re-emerged as one of the most active topics of investigation in developmental biology.
The Molecular Biology Revolution
The molecular biology revolution in the middle of the 20th century provided the means to study the role of genes in development that Wilson and his contemporaries lacked. The key technological advance for the study of gene control of development was the ability to isolate and clone genes. The roles that individual genes play in development could then be assessed directly. The patterns of expression of individual genes could be followed by tracing the products of their expression in the embryo.
Analyses of expression of specific genes during development have revealed regions of those genes that regulate their expression and have identified proteins in the nuclei of embryonic cells that interact with those regions of genes to mediate their regulation. Furthermore, regulatory cascades have been demonstrated in which early-acting genes encode nuclear proteins that regulate genes that are expressed later.
Much of the current research in developmental biology involves attempts to understand the cellular and intercellular events that signal the nucleus to express genes or initiate a sequence of gene expression.
Among the most powerful techniques in the armament of contemporary biologists is the ability to introduce cloned genes into embryos and assess their effects on development. Another major advance has been the development of techniques to eliminate or "knock out" specific genes and determine the effects on development. These two techniques allow investigators to test directly the roles of specific genes during development.
Molecular biology obtained a very powerful tool to facilitate the study of nucleic acids when the polymerase chain reaction (PCR) was developed. This technique allows investigators to amplify specific sequences of DNA many-fold from a minute amount of starting material, using oligonucleotide primers that flank the region of interest in DNA. Not only did PCR facilitate gene cloning, but it provided developmental biologists with a new tool to study RNA from embryos. Because of their small size, embryos are notoriously poor sources of RNA. This is not critical if one is able to collect very large numbers of synchronously-developing embryos. However, that is not always possible. With a modification of the PCR technique, called RT-PCR, RNA is isolated, a cDNA copy of the RNA is made using the enzyme reverse transcriptase and the cDNA is then amplified many-fold using PCR. Thus, a virtually unlimited amount of DNA representative of RNA at a particular stage of development or from a particular region of the embryo can be produced.
The Molecular Biology Revolution
The molecular biology revolution in the middle of the 20th century provided the means to study the role of genes in development that Wilson and his contemporaries lacked. The key technological advance for the study of gene control of development was the ability to isolate and clone genes. The roles that individual genes play in development could then be assessed directly. The patterns of expression of individual genes could be followed by tracing the products of their expression in the embryo.
Analyses of expression of specific genes during development have revealed regions of those genes that regulate their expression and have identified proteins in the nuclei of embryonic cells that interact with those regions of genes to mediate their regulation. Furthermore, regulatory cascades have been demonstrated in which early-acting genes encode nuclear proteins that regulate genes that are expressed later.
Much of the current research in developmental biology involves attempts to understand the cellular and intercellular events that signal the nucleus to express genes or initiate a sequence of gene expression.
Among the most powerful techniques in the armament of contemporary biologists is the ability to introduce cloned genes into embryos and assess their effects on development. Another major advance has been the development of techniques to eliminate or "knock out" specific genes and determine the effects on development. These two techniques allow investigators to test directly the roles of specific genes during development.
Molecular biology obtained a very powerful tool to facilitate the study of nucleic acids when the polymerase chain reaction (PCR) was developed. This technique allows investigators to amplify specific sequences of DNA many-fold from a minute amount of starting material, using oligonucleotide primers that flank the region of interest in DNA. Not only did PCR facilitate gene cloning, but it provided developmental biologists with a new tool to study RNA from embryos. Because of their small size, embryos are notoriously poor sources of RNA. This is not critical if one is able to collect very large numbers of synchronously-developing embryos. However, that is not always possible. With a modification of the PCR technique, called RT-PCR, RNA is isolated, a cDNA copy of the RNA is made using the enzyme reverse transcriptase and the cDNA is then amplified many-fold using PCR. Thus, a virtually unlimited amount of DNA representative of RNA at a particular stage of development or from a particular region of the embryo can be produced.
Drosophila: The Molecular Rosetta Stone
The molecular biology era has brought with it unprecedented opportunities for understanding how development occurs. Its most powerful applications and much of the explosive progress in contemporary developmental biology come when molecular biology is coupled with genetic analysis. Let's explore an example of this synergism by considering the development of the eye of the fruit fly, Drosophila melanogaster. The eye of Drosophila is a so-called compound eye, consisting of multiple facets with photoreceptors that detect light and transmit light images to the brain. Although its structure is very different from that of the human eye and from the simple photoreceptors in primitive worms, the eyes of Drosophila serve essentially the same function as they do in these other organisms. Why does an eye form in flies, worms and people? What genes are involved, and how is their expression controlled? Did photoreceptors evolve many times, or did the capacity to form them appear once and undergo changes over evolutionary time to result in the eyes of modern-day animals? |
The Cellular Basis of Development
A fully-developed human consists of approximately 1 x 10 ^14 cells. Coordinating the activities and locations of that many cells is a monumental task of logistics. Each cell has its own location and particular role to play in the body. Without coordination, chaos would result. Production of embryonic form and structure (morphogenesis) depends upon the concerted activities of many cells. Cells must often move relatively large distances within the embryo, and once they have arrived at their final destinations, they must establish stable multicellular structures with specific morphologies and functions. These activities require that cells have the ability to control their shape and to interact effectively with their environment. An understanding of how individual cells acquire their location, form and function during development is also a monumental task. Cell biology has provided the tools to study cellular behavior during development, and developmental biologists have seized upon the opportunities that these technologies provide for understanding how development proceeds.
Effective interactions of cells with both their non-cellular environment and other cells are key to coordinating cellular activities. In order to interact with their surroundings, cells must perceive signals and have the ability to respond appropriately. These signals are often large molecules such as peptides or large proteins that cannot enter their target cell. Hence, cells must have receptors on their surface that enable them to detect these molecules in their environment and transduce those external signals into signals that can be transmitted into cell interior. Signals are often passed within the cell from one molecule to another numerous times before they reach their final destination, which could be either the nucleus or a cytoplasmic organelle. This is referred to as a signal transduction cascade. The most commonly-used cascades involve a sequence of phosphorylations. Phosphorylation can be like a binary switch that alters molecular function. As each consecutive member of the cascade is phosphorylated, it - in turn - phosphorylates the next member. A profound change in cells can be produced when a signal arrives in the nucleus and either activates or represses the expression of a specific gene. Such is the consequence of signaling by growth factors during embryonic induction.
Mutations of the genes encoding proteins of this system can occur later in life and deregulate cellular function, particularly growth control, leading to cancer. It is ironic that the system that is so important in coordinating cell growth during embryonic development can also be so destructive in later life if it malfunctions.
A fully-developed human consists of approximately 1 x 10 ^14 cells. Coordinating the activities and locations of that many cells is a monumental task of logistics. Each cell has its own location and particular role to play in the body. Without coordination, chaos would result. Production of embryonic form and structure (morphogenesis) depends upon the concerted activities of many cells. Cells must often move relatively large distances within the embryo, and once they have arrived at their final destinations, they must establish stable multicellular structures with specific morphologies and functions. These activities require that cells have the ability to control their shape and to interact effectively with their environment. An understanding of how individual cells acquire their location, form and function during development is also a monumental task. Cell biology has provided the tools to study cellular behavior during development, and developmental biologists have seized upon the opportunities that these technologies provide for understanding how development proceeds.
Effective interactions of cells with both their non-cellular environment and other cells are key to coordinating cellular activities. In order to interact with their surroundings, cells must perceive signals and have the ability to respond appropriately. These signals are often large molecules such as peptides or large proteins that cannot enter their target cell. Hence, cells must have receptors on their surface that enable them to detect these molecules in their environment and transduce those external signals into signals that can be transmitted into cell interior. Signals are often passed within the cell from one molecule to another numerous times before they reach their final destination, which could be either the nucleus or a cytoplasmic organelle. This is referred to as a signal transduction cascade. The most commonly-used cascades involve a sequence of phosphorylations. Phosphorylation can be like a binary switch that alters molecular function. As each consecutive member of the cascade is phosphorylated, it - in turn - phosphorylates the next member. A profound change in cells can be produced when a signal arrives in the nucleus and either activates or represses the expression of a specific gene. Such is the consequence of signaling by growth factors during embryonic induction.
Mutations of the genes encoding proteins of this system can occur later in life and deregulate cellular function, particularly growth control, leading to cancer. It is ironic that the system that is so important in coordinating cell growth during embryonic development can also be so destructive in later life if it malfunctions.
The Brave New World of Animal Cloning
Driesch's experiments in separating sea urchin blastomeres led to the concept that nuclei of cleavage-stage blastomeres retain the entire genetic repertoire that is necessary to program the development of the complete organism. The retention of complete developmental potential by cleavage-stage nuclei is called totipotency. Since Driesch's original observation, investigators have attempted to discover whether potency is lost as development proceeds. In the 1950's Robert Briggs and Thomas King developed an elegant procedure to test nuclear potency using the frog Rana pipiens. By transplantation of nuclei from cells of embryos into enucleated frog eggs, Briggs and King demonstrated that embryonic nuclei remain totipotent during cleavage, but that potency is progressively lost as development proceeds past the cleavage stage. They also demonstrated that multiple totipotent nuclei from a single embryo could be transplanted into a number of enucleated eggs to produce multiple individuals that were genetically identical. |
Thus, the donor embryo could be cloned. Various investigators have attempted to demonstrate whether cells of later-stage embryos, tadpoles or even adults retain totipotency. Conventional wisdom was that nuclei eventually undergo changes during cell differentiation that are so drastic that they cannot be coaxed into reiterating the complete developmental program.
Investigators have now shown that cells of mammalian adults can be reprogrammed to substitute for the zygote nucleus, allowing for cloning of sheep and mice. Thus, nuclear changes during cell differentiation are not necessarily irreversible. The implications of cloning of mammals are far-reaching and have caused considerable anxiety as the possibility of cloning humans has become very real.
Investigators have now shown that cells of mammalian adults can be reprogrammed to substitute for the zygote nucleus, allowing for cloning of sheep and mice. Thus, nuclear changes during cell differentiation are not necessarily irreversible. The implications of cloning of mammals are far-reaching and have caused considerable anxiety as the possibility of cloning humans has become very real.
Manipulating Reproduction
As with cloning, recent progress in understanding and manipulating the reproductive process has posed new ethical challenges for society as well as presenting new opportunities for individuals. Manipulation of the human female menstrual cycle with steroid hormones led to the development of the contraceptive pill, which has enabled couples to prevent unplanned pregnancies. The development of in vitro reproduction technology has enabled couples who would otherwise be unable to conceive a child to do so. Embryos produced by in vitro technology can be frozen and later implanted in a uterus. Whereas this is done routinely with domesticated animals with little anguish, the fate of frozen human embryos is subject to considerable debate.
Techniques have been developed for making transgenic animals, in which embryos are produced that incorporate cloned genes. This is a powerful experimental technique for use with flies, mice and frogs. However, should it also be applied to humans? What genes, and for what purposes? Clearly, developmental biology presents us with new opportunities and new challenges - not only for scientists, but for society as a whole.
As with cloning, recent progress in understanding and manipulating the reproductive process has posed new ethical challenges for society as well as presenting new opportunities for individuals. Manipulation of the human female menstrual cycle with steroid hormones led to the development of the contraceptive pill, which has enabled couples to prevent unplanned pregnancies. The development of in vitro reproduction technology has enabled couples who would otherwise be unable to conceive a child to do so. Embryos produced by in vitro technology can be frozen and later implanted in a uterus. Whereas this is done routinely with domesticated animals with little anguish, the fate of frozen human embryos is subject to considerable debate.
Techniques have been developed for making transgenic animals, in which embryos are produced that incorporate cloned genes. This is a powerful experimental technique for use with flies, mice and frogs. However, should it also be applied to humans? What genes, and for what purposes? Clearly, developmental biology presents us with new opportunities and new challenges - not only for scientists, but for society as a whole.
Ponder this
Why do all animal fetuses of different class, orders, genus, and species (including humans) look the same?
Why do embryos develop in a specific order of functional cells?
Discuss
There is an ongoing debate on the matter of gene editing. Technologies such as CRISPR allows applied biochemists to manipulate an organism on the genetic level. Research this topic and discuss its implications on society and it's impact on socio-economics and ethics. What would justify it, what wouldn't?
Further readings
Developmental biology, a primer.
Evolutionary developmental biology, a field of biological research that compares the developmental processes of different organisms.
Society for Developmental Biology, a non-profit professional society dedicated to advancement of the field of developmental biology.
Dolly the Sheep, Dolly is now displayed at the National Museum of Scotland.