BIOLOGY 624Fall 2009 DEVELOPMENTAL GENETICS
DR. VICTORIA BAUTCH
(click here for Powerpoint)
Lecture #1: INTRO TO DEVELOPMENTAL BIOLOGY
Thurs. Aug. 27, 2009
Reading: Gilbert Ch1, 1-24; Ch2, 25-26; Ch, 77-80.
A. A short history of developmental biology
1. Who was the first recorded developmental biologist?
Aristotle, (Slide 2) who cracked open chicken eggs (in 350 BC) on each successive day of 3 week incubation and noted formation of major organs.
2. There then was a gap for about two thousand years. Next was William Harvey in 1651, who concluded that all animals came from eggs. Put an end to “spontaneous generation”. He also first noticed that “islands” of blood cells form prior to heart formation (Slide 3).
3. Things moved a little faster – the microscope was invented, and in 1672 Marcello Malpighi published first microscopic account of chick development – described neural tube, muscle forming somites, and first circulation of arteries and veins (Slide 4).
BIG DEBATE – were organs formed in miniature in the embryo and unrolled as development proceeded (preformation) (Slide 5), or were they formed de novo in each generation (epigenesis)? First theory more conservative and had political and scientific support, but over time (by the 1820’s) the second theory was shown to be correct. But those looking for support for first theory said they saw miniature organisms in the early embryos. Cautionary lesson on objective observation.
4. In the 1820’s – improved techniques and reforms in universities created a revolution in descriptive embryology.
Three German scientists, friends, each made great contributions using precise observation:
--Christian Pander studied chick embryo less than 2 years, but he discovered germ layers (ectoderm, mesoderm, endoderm), 3 distinct regions of the embryo that give rise to specific tissues (Slide 6)
He also demonstrated that tissue interactions are critical to organ development – the process of induction was described
--Heinrich Rathke: looked at embryos of lots of different vertebrates and made the observation that they were very similar to each other, especially at the early stages of development (Slide 7)
--Karl Ernst von Baer: looked at chick embryo and discovered the notochord, which separates embryo into left and right halves and induces neural tissue. (Slide 8,9)
He also extended observations of Rathke and developed a set of 4 principles that describe relationship of many vertebrate embryos.
5. Late 1800’s – Conklin pioneered the concept of fate mapping, which is the process whereby cells or groups of cells are marked and followed through several developmental changes to determine properties of descendants: what they become and where they go.
--A fate map superimposes the later fates on an earlier stage, without giving information about movements.
--Conklin made the first fate map by watching a tunicate (invertebrate) embryo develop under the microscope, and following the behavior of the descendants of specific cells.
--He was lucky that this embryo had cells with different pigments for different fates, but most embryos need experimental manipulation to follow descendants of cells – they are often labeled by injection of a vital dye, or nowadays genetically marked with expression of a reporter gene. (Slide 10, 11)
6. Late 1800’s – there was a move away from description and into mechanisms(Slide 12)– from what to how. This work was led by Wilhelm Roux and Hans Driesch, who manipulated embryos to determine if development was mosaic or regulative. These scientists pioneered basic experimental manipulations:
a. defect experiment – destroy part of embryo and see how development is affected
b. isolation experiment – remove part of the embryo and observe development of the partial embryo and the isolated part
c. recombination experiment – replace one part of the embryo with a piece from another part and observe the effects on development
d. transplantation experiment – replace one portion of the embryo with a piece from a different embryo and observe the effects on development
7. Early 1900’s – genetics was rediscovered (Mendel had published in the 1870’s), although embryologists had ideas about genetic inheritance prior to this from studying embryos. By the 1920’s THE BIG SPLIT was happening – a division between development and genetics. Thomas Hunt Morgan, a famous fly geneticist, decided genetics would study the transmission of genetic traits, not their effects. On their side, the embryologists got mad and said they would not worry about genetics unless it could explain a number of developmental principles, among them the CENTRAL IDEA that cells with the same genetic material give rise to many different cell types. (Slide 13)
8. The reconciliation began with two scientists, Salome Gluecksohn-Waelsch and Hal Waddington, in the late 1930s and early 1940s.
--Salome showed that a mouse mutation called Brachyury caused embryonic lethality by disrupting the notochord of the embryo. She could only find this mutation because the heterozygous mice lived but had short tails.
--Waddington found several fly genes that affected wings, and associated these effects with wing development. (Slide 14)
But generally it was difficult to study development in the species that were genetically amenable like the fly, and the species good for development could not be easily genetically manipulated, like the frog or sea urchin.
9. One exception to statement above was a class of fly mutations called homeotic mutations, studied by Ed Lewis in the 1970s. These mutations resulted in the replacement of one body part by another – ie. a leg would grow out of head in place of an antenna. These genes clearly affected a whole developmental program – “make a leg” vs. “make an antenna”. (Slide 15)
10. Final convergence occurred in the last 20 years, with the advent of:
-- model organisms that are amenable to both genetic analysis and embryological manipulations (ie C. elegans, zebrafish)
-- better genetic tools for all models, especially those historically difficult to study like the mouse (ie knockout mutations)
--much better experimental tools to study development in all models, especially those whose development was difficult to study like the fly (ie better microscopes, real time imaging, expression localization to individual cells, genetic manipulation of small groups of cells in embryos)
The convergence was best signified by the work of Christiane Nusslein-Volhard and Eric Wieschaus, who set up a huge genetic screen for early developmental mutations in the fly in the 1980’s. They and Ed Lewis won the Nobel Prize in 1995 for their work with these mutations showing that morphogen gradients are set up in the egg that specify the major embryonic axes. (Slide 16)
B. A basic outline of development (Slide 17):
1. Gametogenesis – formation of the germ cells, or gametes that will produce the embryo. In organisms we study consists of a male sperm and female oocyte or egg. This involves reduction division, or meiosis.
2. Fertilization – the union of the sperm and egg = zygote
3. Cleavage – a series of very rapid mitotic divisions the divides the large zygote volume into many smaller cells.
4. Gastrulation – a series of dramatic movements whereby the cells largely change neighbors, which sets up a series of important inductions (a special type of communication between embryonic cell groups). These movements also result in the formation of the three germ layers – ectoderm, mesoderm, and endoderm.
5. Organogenesis – the continued interactions of layers and tissues to form organs such as the heart, brain, liver. The embryo continues to grow as well.
6. SOMETIMES – there is an intermediate stage (larval stage or tadpole) upon hatching (often for feeding and growth) then a metamorphosis to form the adult (often primary role of adult is reproduction).
C. Why study development?
1. Because it is fascinating! - the study of how things become
2. Many ramifications for human health and disease –
-- diseases and conditions resulting from human developmental mutations (Slide 18)
--cancer is essentially a group of cells who no longer obey the “rules” of developmental biology
--the exciting field of stem cells brings development right into the living rooms and eventually into the bodies of many humans!
3. The use of multiple approaches and models makes it a truly integrated scientific discipline – nowadays genetic, molecular, cellular and organismal (old embryological) types of experiments are both done and done in combination in different models.
D.Course outline and policies (use Webpage for info)—
--goals, models, certification
--format, exams, grades, papers
BIOLOGY 624Fall 2009 DEVELOPMENTAL GENETICS
DR. VICTORIA BAUTCH
(click here for Powerpoint)
Lecture #1: INTRO TO DEVELOPMENTAL BIOLOGY
Thurs. Aug. 27, 2009
Reading: Gilbert Ch1, 1-24; Ch2, 25-26; Ch, 77-80.
A. A short history of developmental biology
1. Who was the first recorded developmental biologist?
Aristotle, (Slide 2) who cracked open chicken eggs (in 350 BC) on each successive day of 3 week incubation and noted formation of major organs.
2. There then was a gap for about two thousand years. Next was William Harvey in 1651, who concluded that all animals came from eggs. Put an end to “spontaneous generation”. He also first noticed that “islands” of blood cells form prior to heart formation (Slide 3).
3. Things moved a little faster – the microscope was invented, and in 1672 Marcello Malpighi published first microscopic account of chick development – described neural tube, muscle forming somites, and first circulation of arteries and veins (Slide 4).
BIG DEBATE – were organs formed in miniature in the embryo and unrolled as development proceeded (preformation) (Slide 5), or were they formed de novo in each generation (epigenesis)? First theory more conservative and had political and scientific support, but over time (by the 1820’s) the second theory was shown to be correct. But those looking for support for first theory said they saw miniature organisms in the early embryos. Cautionary lesson on objective observation.
4. In the 1820’s – improved techniques and reforms in universities created a revolution in descriptive embryology.
Three German scientists, friends, each made great contributions using precise observation:
--Christian Pander studied chick embryo less than 2 years, but he discovered germ layers (ectoderm, mesoderm, endoderm), 3 distinct regions of the embryo that give rise to specific tissues (Slide 6)
He also demonstrated that tissue interactions are critical to organ development – the process of induction was described
--Heinrich Rathke: looked at embryos of lots of different vertebrates and made the observation that they were very similar to each other, especially at the early stages of development (Slide 7)
--Karl Ernst von Baer: looked at chick embryo and discovered the notochord, which separates embryo into left and right halves and induces neural tissue. (Slide 8,9)
He also extended observations of Rathke and developed a set of 4 principles that describe relationship of many vertebrate embryos.
5. Late 1800’s – Conklin pioneered the concept of fate mapping, which is the process whereby cells or groups of cells are marked and followed through several developmental changes to determine properties of descendants: what they become and where they go.
--A fate map superimposes the later fates on an earlier stage, without giving information about movements.
--Conklin made the first fate map by watching a tunicate (invertebrate) embryo develop under the microscope, and following the behavior of the descendants of specific cells.
--He was lucky that this embryo had cells with different pigments for different fates, but most embryos need experimental manipulation to follow descendants of cells – they are often labeled by injection of a vital dye, or nowadays genetically marked with expression of a reporter gene. (Slide 10, 11)
6. Late 1800’s – there was a move away from description and into mechanisms(Slide 12)– from what to how. This work was led by Wilhelm Roux and Hans Driesch, who manipulated embryos to determine if development was mosaic or regulative. These scientists pioneered basic experimental manipulations:
a. defect experiment – destroy part of embryo and see how development is affected
b. isolation experiment – remove part of the embryo and observe development of the partial embryo and the isolated part
c. recombination experiment – replace one part of the embryo with a piece from another part and observe the effects on development
d. transplantation experiment – replace one portion of the embryo with a piece from a different embryo and observe the effects on development
7. Early 1900’s – genetics was rediscovered (Mendel had published in the 1870’s), although embryologists had ideas about genetic inheritance prior to this from studying embryos. By the 1920’s THE BIG SPLIT was happening – a division between development and genetics. Thomas Hunt Morgan, a famous fly geneticist, decided genetics would study the transmission of genetic traits, not their effects. On their side, the embryologists got mad and said they would not worry about genetics unless it could explain a number of developmental principles, among them the CENTRAL IDEA that cells with the same genetic material give rise to many different cell types. (Slide 13)
8. The reconciliation began with two scientists, Salome Gluecksohn-Waelsch and Hal Waddington, in the late 1930s and early 1940s.
--Salome showed that a mouse mutation called Brachyury caused embryonic lethality by disrupting the notochord of the embryo. She could only find this mutation because the heterozygous mice lived but had short tails.
--Waddington found several fly genes that affected wings, and associated these effects with wing development. (Slide 14)
But generally it was difficult to study development in the species that were genetically amenable like the fly, and the species good for development could not be easily genetically manipulated, like the frog or sea urchin.
9. One exception to statement above was a class of fly mutations called homeotic mutations, studied by Ed Lewis in the 1970s. These mutations resulted in the replacement of one body part by another – ie. a leg would grow out of head in place of an antenna. These genes clearly affected a whole developmental program – “make a leg” vs. “make an antenna”. (Slide 15)
10. Final convergence occurred in the last 20 years, with the advent of:
-- model organisms that are amenable to both genetic analysis and embryological manipulations (ie C. elegans, zebrafish)
-- better genetic tools for all models, especially those historically difficult to study like the mouse (ie knockout mutations)
--much better experimental tools to study development in all models, especially those whose development was difficult to study like the fly (ie better microscopes, real time imaging, expression localization to individual cells, genetic manipulation of small groups of cells in embryos)
The convergence was best signified by the work of Christiane Nusslein-Volhard and Eric Wieschaus, who set up a huge genetic screen for early developmental mutations in the fly in the 1980’s. They and Ed Lewis won the Nobel Prize in 1995 for their work with these mutations showing that morphogen gradients are set up in the egg that specify the major embryonic axes. (Slide 16)
B. A basic outline of development (Slide 17):
1. Gametogenesis – formation of the germ cells, or gametes that will produce the embryo. In organisms we study consists of a male sperm and female oocyte or egg. This involves reduction division, or meiosis.
2. Fertilization – the union of the sperm and egg = zygote
3. Cleavage – a series of very rapid mitotic divisions the divides the large zygote volume into many smaller cells.
4. Gastrulation – a series of dramatic movements whereby the cells largely change neighbors, which sets up a series of important inductions (a special type of communication between embryonic cell groups). These movements also result in the formation of the three germ layers – ectoderm, mesoderm, and endoderm.
5. Organogenesis – the continued interactions of layers and tissues to form organs such as the heart, brain, liver. The embryo continues to grow as well.
6. SOMETIMES – there is an intermediate stage (larval stage or tadpole) upon hatching (often for feeding and growth) then a metamorphosis to form the adult (often primary role of adult is reproduction).
C. Why study development?
1. Because it is fascinating! - the study of how things become
2. Many ramifications for human health and disease –
-- diseases and conditions resulting from human developmental mutations (Slide 18)
--cancer is essentially a group of cells who no longer obey the “rules” of developmental biology
--the exciting field of stem cells brings development right into the living rooms and eventually into the bodies of many humans!
3. The use of multiple approaches and models makes it a truly integrated scientific discipline – nowadays genetic, molecular, cellular and organismal (old embryological) types of experiments are both done and done in combination in different models.
D.Course outline and policies (use Webpage for info)—
--goals, models, certification
--format, exams, grades, papers
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