Skip to comments.The Pioneers: Three Innovative West Campus labs
Posted on 09/12/2010 3:47:57 PM PDT by proxy_user
Redefining Viable by Margot Sanger-Katz 02
Nancy Moran is studying the organisms with the worlds smallest genomes. The bacteria she examinesmany of which she discoveredare at the very edge of viable life. We are interested in what allows them to be this smallto live without genes that are considered to be essential in other organisms, she says.
Moran, an evolutionary biologist and past MacArthur genius grant winner, recently came to the Microbial Diversity Institute from the University of Arizona. She came upon the tiny genomes by studying insect biology. Several insect species, she discovered, have evolved for millions of years with symbiotic bacteria that live inside insect cells and are passed from mother to offspring.
The insects and bacteria help each other survive: the hosts give the bacteria nourishment and a protected environment, and the bacteria repay their landlords. One species Moran studies helps pea aphids make crucial amino acids their diet lacks; another makes a toxin that kills parasitic wasps that can invade the aphids bodies.
Because the bacteria are shielded from the outside world and live in very small populations, they have evolved at a much faster rate than most similar bacteria, often by shedding inessential genes. Moran says some of the genes the bacteria have lost are surprising, since theyre generally considered beneficial. Several species, for example, are missing common genes that help repair damaged DNA.
Morans work has led to insights about the ways organisms can swap and shed genes. In one recent case, she found that a species of aphid had adopted entire genes from a fungus, allowing the aphids to synthesize a beneficial chemical. But the research has also changed scientists understanding of what is required to support life.
The bacteria genomes she studies are not just tinier than any other known organismsbut many times tinier. (Still smaller genomes exist, but only in viruses, which are not considered organisms because theyre incapable of independent metabolism and reproduction.) The smallest common bacteria genomes have well over a million base pairs; E. Coli genomes have more than 4 million. Morans team has discovered a bacteria genome with only 145,000 base pairs, the smallest known. This bacterium, Hodgekinia cicadicola, makes many fewer proteins and performs many fewer functions than any known species.
When you look at that, its amazing that theyre functional, she says. After years of examining similar organisms, Moran says, shes still excited about what these outliers can teach her.
Watching the Cell at Work by Jenny Blair 97, 04MD
Vesicles are tiny sacs inside animal and plant cells that transport important proteins. Like self-enclosed spacecraft, they move about the cell, docking onto their destinations. When that destination is the cells outer membrane, for example, they deliver their cargo by fusing their membranes with the cells and emptying their contents into the outside world. When its time to leave that spot, they pinch away, then move on to their next target.
This elegant process is one that James Rothman, chair of cell biology and a 2010 winner of the Kavli Prize, has spent more than 30 years elucidating. Rothman came to Yale from Columbia University in 2008. In the 1990s, he helped discover the general mechanism by which membranes fuse. Now he studies how the process works between neurons, which use vesicles filled with neuro-transmitter to communicate. He has had a variety of co-authors. Whats remarkable about this work, he says, is how its success has required a combination of cell biologists, biochemists, engineers, and physicists.
Rothmans team studies the behavior of vesicles in isolation from their parent cells, observing them with advanced imaging technologies that allow them to measure the timing and efficiency of the fusion. With associate research scientist Erdem Karatekin, whose background is in chemical engineering and physics, Rothman created a model of nerve transmission in which synthetic vesicles behave in a test tube much as they do in naturetraveling between membranes, fusing, and releasing their contents.
Rothman has also returned with vigor to the Golgi apparatus, a structure inside the cell that processes and moves vesicles from one place to another. He had stopped investigating the Golgi a decade ago after concluding that the important questions about it couldnt be studied with existing technologies. But recent advances in microscopy, he says, allow us, using special tricks, to see fluorescent objects in the cell with much greater precision than was ever possible. The improvements that make those views possible have come from imaging experts like Karatekin and from other engineers and physicists.
Collaborating with non-biologists, then, is fundamental to his work, and Rothman hopes that the West Campus will foster more such interactions. Certainly there have been many successes of interdisciplinary research at Yale, and I would like to count [mine] among them, he says. There is no more important means that we have at our disposal to advance the causes of science and medicine.
From Test Tube to Doctors Office by Tracy Hampton
Jonathan Ellman is a master of technical, minute pro- cesseslike tert-butanesulfinamide chemistrywhose names are foreign and abstract to those in the general public. But his technical work is highly relevant to anyone who has ever filled a prescription, and his research will likely continue to improve human health. The chemist recently left his post at the University of CaliforniaBerkeley to join the Institute for Chemical Diversity, Evolution, and Function, on the West Campus.
Much of Ellmans work has centered on finding simple methods for synthesizing important pharmaceutical compounds. One branch of his research focuses on designing new ways to create aminesammonia-derived components that are found in many drugs. This is where tert-butanesulfinamide chemistry comes in: Ellman pioneered the technology in the late 1990s to streamline amine production. Every single pharmaceutical company now uses this method toward synthesizing drugs. It allows them to put compounds into clinical trials more rapidly by converting simple, commercially available compounds into more-complex bioactive structures, he explains. Recently, Ellman and his team used the process to synthesize the potential antitumor agent tubulysin D, a natural product that inhibits cell growth more potently than several currently available anticancer agents. Working with researchers at Berkeley and the University of CaliforniaSan Francisco, Ellman has shown that the chemical can eliminate certain colon tumors in mice. He has also pioneered an efficient method to convert common carbon-hydrogen bonds into more unusual chemical connections. This process has been recently used to synthesize a plant-derived chemical that is in early stages of development but may have promise to slow down neurodegenerative diseases.
In addition to his chemical synthesis projects, Ellman explores the chemistry of processes within the body, in hopes of developing treatments for little-understood medical conditions. Currently, his laboratory is developing complex chemical tools that will help researchers study how proteasesenzymes that regulate numerous biological processesbind to other proteins. This information could help identify ways to slow down such enzymes when things go awry. Since proteases play important regulatory roles in a number of diseases, Jons work is likely to have a big impact in terms of new therapeutic agents making it to market, says Stanford Universitys Matthew Bogyo, who collaborates with Ellman to uncover potential treatments for malaria.
Nancy Moran is studying the organisms with the world's smallest genomes... Rothman's team studies the behavior of vesicles in isolation from their parent cells... Jonathan Ellman is a master of technical, minute processes -- like tert-butanesulfinamide chemistry