What is Developmental Biology?
Most broadly put, developmental biologists seek to understand the emergence of all the complexity of a human, an insect or a flower from a single fertilized ovum. Many Stanford faculty both within and outside of the Department of Developmental Biology investigate key developmental questions.
The Emergence of Form From Uniformity
One of the most fundamental questions of developmental biology is how initially symmetric or unformed structures give rise to highly complex three-dimensional functional organs and tissues. An obvious example is the formation of an embyro from an egg, but other examples include the way that a bacteria selects the site for the formation of a flagellum, or a yeast cell its bud site, or a field of epithelial cells the site for the formation of hair cells. Understanding the ways that this fundamental biologic problem is solved by Nature is the topic of projects in the laboratories of Lucy Shapiro, Anne Villeneuve, Matthew Scott, Dale Kaiser, Harley McAdams, Stuart Kim, Margaret Fuller, James Nelson and Jeff Axelrod.
Self renewal: stem cells and cloning
The origins, functions and uses of stem cells are developmental issues that have recently become the center of media attention. These cells have the remarkable property of continually renewing themselves while giving rise to different cell types that can give rise to the cells necessary to make an organ, such as the immune system or the brain. Perhaps, most astounding is the recent discovery that the egg cytoplasm has the ability to reset the nucleus of many cell types to a ground state. From this ground state, perhaps defined by genomic chromatin structure the nucleus can serve as a stem cell to all the cells of an entire organism and produce a genetically identical or "cloned" individual. More specialized stem cells are well defined for the hematologic system and methods of purification of these stem cells, developed at Stanford in the Weissman laboratory, have become the basis of treatment of treatment of leukemia. Stems cells for neurons are being defined and may be useful for treating the many degenerative neurologic diseases. Studies in this area have excited the imagination of the general public, politicians and religious leaders. Work in this area is being conducted in the laboratories of Margaret Fuller, Irving Weissman, James Spudich, Lucy Shapiro, Anne Villeneuve, Seung Kim, and several others on the campus including Helen Blau and Paul Khavari.
Communication between cells and within cells: pattern formation
Although the form of a human, insect or dog is clearly preprogrammed in DNA, development requires extensive communication between cells. Thus much of the work of developmental biology is directed at understanding these pathways of communication and how they lead to the eventual organization of cells within a tissue or an organism.
For example, Roel Nusse's laboratory has found that a group of extracellular proteins known as the wnts play extensive roles organizing cells in the brain, the immune system, as well as many other tissues. Work in Matthew Scott's lab has shown that another family of secreted proteins, Hedghog, interacts with Patched receptors to regulate the associations and formation of essential regions of the brain and spinal cord. These same signaling mechanisms play important roles in causing cancer as indicated below. Matthew Scott, Roel Nusse, Irving Weissman, Will Talbot, and Stuart Kim.
Development of Cell Types and Organ Systems
The origins of individual organ systems from stem cells involves general rules, which are being dissected in fruit flies and worms. These general rules form the conceptual framework for the understanding of the origin of the many thousands of cell types that make up the mammalian body. The ligands receptors, signaling pathways and the way that they are coordinated to form an organism are being studied in many laboratories at Stanford. Matthew Scott's, Roel Nusse's, Marlene Rabinovitch's and Gerald Crabtree's laboratory have defined fundamental signaling pathways essential for the formation of many cell types and organ systems. Seung Kim's laboratory is studying the development of the pancreas and David Kingsley's laboratory the skeletonal system. Work in Irv Weissman's laboratory is directed at understanding the formation of the hematopoetic system and the immune system while Tom Quertermous and Marlene Rabinovitch study the development of the heart, Paul Khavari's lab the development of the skin, Mark Krasnow the development of the lungs and respiratory systems, and Margaret Fuller's lab studies the development and differentiation of sperm. Seung Kim, David Kingsley, Gerald Crabtree, Irving Weissman, Matthew Scott, Roel Nusse, Margaret Fuller, Marc Tessier Lavigne, Paul Khavari, Thomas Quertermous, Mark Krasnow.
Development of the nervous system
Understanding the immense complexity of the nervous system presents some of the most challenging problems in developmental biology. However over the past 5 or 10 years, studies in many laboratories have shown that many of the molecules and mechanisms used in other systems are also used in the formation of the nervous system. For example, Wnt signaling and Hedgehog signaling are used in the early formative events of the nervous system and signaling by Ca2+, calcineurin and NFAT is used to convey responses to axonal guidance molecules as developing nerves make connections with their targets. The formation of the nervous system is being studied in many laboratories at Stanford including those of Roel Nusse, Matthew Scott, Ben Barres, Gerald Crabtree, Sue McConnell, Richard Tsien, Bill Mobely, Linquin Luo, and Marc Tessier Lavigne.
Plant Development
The development of plants results in some of the most beautiful objects on earth. Recently powerful genetic models have been developed for understanding the formation of flowers, the proliferation of food crops and basic mechanisms of cell biology in plants. Plant development is being studied in the laboratories of Virgina Wolbert, Ron Davis, and Sharon Long in the Stanford Biology Department and the Carnegie Institute at Stanford.
The Evolution of Form and the Mechanisms of Speciation
Work in the laboratory of David Kingsley, Matt Scott, and Roel Nusse are addressing the age old question of how species originate and how the form of an organism evolves in response to its environment. With the realization that our genome is far more plastic than we had suspected, such studies are critical to understanding the long term outlook of our species
Work in David Kingsley's laboratory has focused on the three-spine speckleback to understand how organisms have adapted to rapid environmental changes and produced new species. This small fish lives in isolated ponds and lakes and has shown the emergence of new species since the end of the Ice Age. Their work involves analysis of genetic changes in populations of fish that happen to live in beautiful places. You can see David and his lab members collecting fish at right.
Aging and Senescence
Senescence appears to be a normal part of development, preprogramed by our genetic makeup. Here studies are directed at understanding why different organisms have different life spans and what are the genes that give rise to these differences? How do these genes define the onset of age related diseases like alzheimers and others and what is the basis of genetic human diseases such as Progeria. Studies in yeast, flys and worms have provided fundamental insights into these processes. Stuart Kim.
A 99 year old man goes into a doctor's office and complains of pain in his knee. After examining the man the doctor reminds the man that his knee is, after all 99 years old. The mans says, "well my other knee is 99 years old and it doesn't hurt".
Development and Disease
Virtually every disease can be viewed as a failure of development. For example, even diseases that occur late in life, such as heart disease, arthritis or epilepsy often have their origins in embryonic defects such as the patterning of heart valves, joint formation or the migration of neurons. Treading this borderland of embryology and pathology is actually a fundamental method of learning the rules of development as the following examples illustrate. A student in David Kingsley's laboratory recently discovered the ank gene, which when inactivated produces arthritis. Such a discovery is informative both for understanding and treating human disease as well as for the information that it gives regarding the formation of joints. The most common cancer in humans is a skin tumor known as basal cell carcinoma, which was shown in Matthew Scott's laboratory to be caused by mutations in the Patched gene that plays important roles in early development. In dissecting the intracellular signaling pathways necessary for lymphocyte development the Crabtree lab discovered the mechanism of action of the immunosuppressant, cyclosporin A. This same signaling pathway has turned out to be essential for development of the heart, vascular, nervous and skeletonal systems as well as the recombinational immune system.
Work in Seung Kim's laboratory has shown that defective intercellular signaling underlies common malformations of the developing pancreas, a vital organ that regulates metabolism and nutrient supply in humans. These same signals also maintain the differentiated state of cells in the adult pancreas, thereby preventing formation of cancers.
Developmental Biology and Medicine
Clearly the closest medical disciplines to developmental biology are Pediatrics and Obstetrics, but the interface between medicine and developmental biology extends through all medicine and surgery. For example, Roel Nusse discovered the murine wnt genes, not as a developmental regulator, but as gene mutated in certain types of cancer. Other associations with disease and treatment emerge from unexpected directions. For example, a gene first cloned in the Crabtree laboratory as a protease inhibitor, and later developed by Eli Lilly, is now the mainstay of treatment of a severe form of infection know as sepsis. Studies in the Weissman laboratory have lead to the purification of hematopoietic stem cells needed for treatment of leukemia, cancer and organ transplantation. Similar approaches to purification of neural stem cells are paving the way for the development of new methods of treatment of degenerative diseases of the nervous system.
Gene Therapy
Many childhood and genetic diseases can only be treated by introducing the defective gene. To do this is a complicated endeavor that has caught the imagination of the general public. Mark A. Kay and Paul Khavari are developing and using new methods to introduce genes into mice and humans with the goal of correcting genetic diseases. Gerald Crabtree's lab has developed a method of controlling the activity of virtually any protein using small membrane permeable synthetic ligands that can be given orally. This methods has been used to regulate the production and local release of molecules such as growth hormone, insulin, Vegf and others that are therapeutically useful.
Development of new techniques for biologic studies
Information science is playing an ever more critical role in understanding development. An aspect of these studies that is assuming increasing importance in the future is the prediction of the outcome of modifications in developmental pathways. Eventually work in this area is likely to lead to the development of predictive criteria for the genetic disease as well as the results of therapeutic efforts. Work in the laboratories of Harley McAdams and Lucy Shapiro are directed at developing methods and approaches to predict the actions of genetic circuits and how they respond to manipulation. Their work relies on classic models in phage and bacterical genetics that serve as general and widely applicable tests of the characteristics of biologic circuits.
New computer methods of evaluating transcript expression are being developed in the labs of Pat Brown, Stuart Kim
Understanding certain questions in development will require entirely new approaches. For example, how do certain behaviorial patterns develop, such as the nurturing of offspring? One can remove the function of a gene, but how can the effect of the mutation be shown to lead directly to a failure of nurturing? Understanding these more difficult problems of development will require approaches were the function of a single gene can be rapidly and reversibly removed, allowing one to define the immediate biochemical consequences of inactivating or activating a gene. Such approaches will allow primary effects to be distinquished from secondary effects and causation to be distinguished from coincidence.
New methods in manipulating signal molecules, such as myosin are being development in the labs of James Spudich. These methods allow the understanding of mechanisms of molecular moters. The flourscence activated cell sorter (FACS), which revolutionized developmental studies, was invented at Stanford by Len Herzenberg and set the model for many productive interactions between physics and biology. New techniqued development is being conducted in the labs of James Spudich, Harley McAdams, Lucy Shapiro, Stuart Kim, Gerald Crabtree, Pat Brown.
The Integrative Nature of Studies in Developmental Biology
Collaborations with others around the university are frequent. Many projects have direct medical connections, such as the Seung Kim lab's studies of pancreas development and its relations to diabetes, the Nusse and Scott lab studies of Wnt and Hedgehog signaling with their many connections to cancer, the Fuller lab studies of sperm development and their relation to fertility issues, the Shapiro lab's work on bacterial cell cycle with its potential for discovering new antibiotics, and the Weissman and Crabtree lab studies of immunity and development. Many physicians work in Department labs, and many Department students pursue joint M.D./Ph.D. degrees. Other current collaborations involved physics and engineering. Chemistry professor W.E. Moerner is working with the Shapiro lab on monitoring the behaviors of single bacterial proteins. Biological Sciences professor Steven Block is helping with the use of optical tweezers to detect the behavior of microfilament proteins. Electrical engineering professor Olav Solgaard is working with the Scott lab to develop novel injection technology. Aeronautics and Astronautics professor Claire Tomlin is working with the McAdams lab to model eukaryotic signaling systems from an engineering standpoint. Electrical Engineering professor Gordon Kino is working with the Scott lab on a miniature confocal scanning microscope. Prof. Stuart Kim of our Department has been advising people at NASA Ames research on developmental biology experiments to be done on the Space Station, and he is also working with local software companies to invent new ways to display and analyze microarray data. Many people within the Department are using DNA microarrays, often in collaboration with people in other departments. These are just a few examples of the interdisciplinary work under way in the Department.
The great range of topics is unified because they all relate to the regulators that build and organize living cells. With so much sharing of expertise, it is relatively easy for people in the Department to undertake projects in areas quite new to them. From an educational standpoint, the frequent moves into new areas are valuable training for faculty, postdocs, students, and staff. Learning is constant in this atmosphere. The ongoing successes of students and postdoctoral fellows who have passed through the Department has been a gratifying confirmation of the value of our root principles: sharing facilities, creating frequent communication opportunities, and giving all researchers in the Department the freedom and support they need to explore guided by their own curiosity and inventiveness.
