Researchers at the University of Massachusetts Medical School (UMMS) report today on a new technique that improves the ability of scientists to target individual genes for inactivation—a technique with broad potential implications for both basic science research and human disease.
Two scientific teams at UMMS, one led by Scot A. Wolfe, PhD, an assistant professor in the Program in Gene Function & Expression and the Department of Biochemistry & Molecular Pharmacology, and the other by Nathan D. Lawson, PhD, an associate professor in the Program in Gene Function and Expression and the Program in Molecular Medicine, working with a small fish—the zebrafish—commonly used as a model organism in biomedical research, developed a method to create and deliver a tailor-made “restriction enzyme” that inactivates a specific gene in a zebrafish embryo.
The paper, “Targeted gene inactivation in zebrafish using engineered zinc-finger nucleases” appears as an Advance Online Publication of the journal
Nature Biotechnology (25 May, 2008;
http://dx.doi.org/10.1038/nbt1398 ), and was supported by grants from the National Heart, Lung and Blood Institute and the National Institute of General Medical Sciences.
“The best way to figure out what a gene does in an organism is to replace it with a non-functional version, breed the individual, and then look at the offspring to see what’s wrong with them,” said Laurie Tompkins, Ph.D., who oversees genetic mechanisms grants at the National Institute of General Medical Sciences, “The problem is that it’s hard to swap in non-functional genes that are inherited by the offspring. These investigators have devised a way to do this, which will enable many scientists to answer questions that were previously out of reach.”
“We believe that this work will fundamentally change how researchers make knockouts—research organisms in which one or more genes have been genetically engineered to be turned off—in many model organisms,” said Dr. Wolfe. “In this paper, we demonstrate the feasibility of this approach for gene inactivation using the zebrafish, but we believe that this technology should be applicable to other vertebrate and non-vertebrate systems with exciting implications for the development of new models for the study of human disease.”
The collaboration between the Lawson and Wolfe laboratories merges the strengths of two different research programs to achieve important advances at the interface of their interests: the Wolfe laboratory’s focus on understanding and engineering protein-DNA recognition in zinc finger proteins and the Lawson laboratory’s interest in developing new technologies that facilitate biological studies in zebrafish to better understand development and disease.
“The zebrafish has really become quite established as a model organism in the past several years,” said Dr. Lawson. “I began using the zebrafish model to study angiogenesis because of its external development and transparent embryos – we can actually watch blood vessels as they grow in the zebrafish embryo. This allows us to gain novel insights into this process that are not easy to make in mouse models. However, we had not previously been able to directly knock out a gene of interest, an approach available in the mouse. The work we have done with the Wolfe lab will open up completely new avenues for our own research and will further strengthen the use of the zebrafish model. More significantly, this technique will now allow us to make zebrafish models that may provide insight into the progression of human vascular disease.”
Source: University of Massachusetts Medical School
Related stories:
Primordial fish had rudimentary fingers
Tetrapods, the first four-legged land animals, are regarded as the first organisms that had fingers and toes. Now researchers at Uppsala University can show that this is wrong. Using medical x-rays, they found rudiments of fingers in the fins in fossil Panderichthys, the “transitional animal,” which indicates that rudimentary fingers developed considerably earlier than was previously thought.
New insight into most common forebrain malformation
St. Jude Children's Research Hospital scientists have identified one of the molecular mechanisms underlying the genetic brain malformation called holoprosencephaly (HPE). The findings not only yield insights into the most common developmental malformation of the anterior brain and face in newborns, but also help in understanding the intricate process by which the brain forms in the developing fetus.
Scientists identify single microRNA that controls blood vessel development
Scientists from the Gladstone Institute of Cardiovascular Disease (GICD) and UCSF have identified a key regulatory factor that controls development of the human vascular system, the extensive network of arteries, veins, and capillaries that allow blood to reach all tissues and organs. The research, published in the latest issue of
Developmental Cell, may offer clues to potential therapeutic targets for a wide variety of diseases, such as heart disease or cancer, that are impacted by or affect the vascular system.
Metabolic insight to illuminate causes of iron imbalance
New insight into key players in iron metabolism has yielded a novel tool for distinguishing among root causes of iron overload or deficiency in humans, the researchers report in the August issue of
Cell Metabolism, a publication of Cell Press. While the body needs iron to produce hemoglobin, a substance in red blood cells that enables them to carry oxygen, too much iron can build up and eventually damage organs.
Consortium develops new method enabling routine targeted gene modification
A multi-institutional team led by Massachusetts General Hospital (MGH) investigators has developed a powerful new tool for genomic research and medicine – a robust method for generating synthetic enzymes that can target particular DNA sequences for inactivation or repair. In the July 25 issue of
Molecular Cell, the researchers describe an efficient, publicly available method to engineer customized zinc-finger nucleases (ZFNs), which can be used to induce specific genomic modifications in many types of cells.
Research provides insight into development of congenital circulatory defects
University of Pittsburgh-led researchers could provide new insight into how two common congenital circulatory problems—aortic arch deformity and arteriovenous malformations (AVMs)—develop in humans, as reported in the June 15 edition of
Developmental Biology.
Common herbicide disrupts human hormone activity in cell studies
A common weedkiller in the U.S., already suspected of causing sexual abnormalities in frogs and fish, has now been found to alter hormonal signaling in human cells, scientists from the University of California San Francisco (UCSF) report.
Bloodless Worm Sheds Light on Human Blood, Iron Deficiency
Using a lowly bloodless worm, University of Maryland researchers have discovered an important clue to how iron carried in human blood is absorbed and transported into the body. The finding could lead to developing new ways to reduce iron deficiency, the world's number one nutritional disorder.