We use genetic approaches to identify the molecular basis of human disease pathology. More specifically, we develop strategies to combat three major disease areas: cancer, trinucleotide repeat disorders like Huntington’s disease, and cardiovascular disease.
We combine comprehensive bioinformatics analyses with functional analyses of pathways and genes to study aging in humans and mice. We apply these approaches to identify the major pathways and genes involved in the aging of certain brain regions. We are also studying muscular dystrophy and muscle loss with aging. Ultimately, our findings may guide studies in other organs and lead to a systemic understanding of mammalian aging.
Dr. Jacks’ research has focused on developing new methods for the construction and characterization of genetically engineered mouse models or GEMMs of human cancer, and recently has moved into the burgeoning area of tumor immunology to understand the interactions between the immune system and cancer. His group has produced GEMMs with constitutive and conditional mutations in several tumor suppressor genes, oncogenes, and genes involved in oxidative stress, DNA repair and epigenetic control of gene expression. These GEMMS have been used to examine the mechanism of tumor initiation and progression, to uncover the molecular, genetic and biochemical relationship to the human diseases, as tools to study response and resistance to chemotherapy, and to explore methods in molecular imaging and early detection of cancer.
We study the molecules that allow fungi to penetrate tissues and grow in a hostile environment. Using genetics, biochemistry and genomics, we answer questions such as: What makes Candida albicans such a successful pathogen? How do fungal pathogens evolve antibiotic resistance? How do they manage to change their genetic composition so rapidly?
The Fink lab is no longer accepting students.
A research team led by MIT’s Whitehead Institute for Biomedical Research has harnessed metabolomic technologies to unravel the molecular activities of a key protein that enables plants to withstand a common herbicide.
Their findings reveal how the protein — a kind of catalyst or enzyme first isolated in bacteria and introduced into plants such as corn and soybeans in the 1990s — can sometimes act imprecisely, and how it can be successfully re-engineered to be more precise. The new study, which appears online in the journal Nature Plants, raises the standards for bioengineering in the 21st century.
“Our work underscores a critical aspect of bioengineering that we are now becoming technically able to address,” says senior author Jing-Ke Weng, a member of the Whitehead Institute and an assistant professor of biology at MIT. “We know that enzymes can behave indiscriminately. Now, we have the scientific capabilities to detect their molecular side effects, and we can leverage those insights to design smarter enzymes with enhanced specificity.”
Plants provide an extraordinary model for scientists to study how metabolism changes over time. Because they cannot escape from predators or search for new food sources when supplies run low, plants must often grapple with an array of environmental insults using what is readily available — their own internal biochemistry.
“Although they appear to be stationary, plants have rapidly evolving metabolic systems,” Weng explains. “Now, we can gain an unprecedented view of these changes because of cutting-edge techniques like metabolomics, allowing us to analyze metabolites and other biochemicals on a broad scale.”
Key players in this evolutionary process, and a major focus of research in Weng’s laboratory, are enzymes. Traditionally, these naturally occurring catalysts have been viewed as mini-machines, taking the proper starting material (or substrate) and flawlessly converting it to the correct product. But Weng and other scientists now recognize that they make mistakes, often by latching on to an unintended substrate.
“This concept, known as enzyme promiscuity, has a variety of implications, both in enzyme evolution and more broadly, in human disease,” Weng says.
It also has implications for bioengineering, as Bastien Christ, a postdoctoral fellow in Weng’s laboratory, and his colleagues recently discovered.
Christ, then a graduate student in Stefan Hörtensteiner’s lab at the University of Zurich in Switzerland, was studying a particular strain of the flowering plant Arabidopsis thaliana as part of a separate project when he made a puzzling observation. He found that two biochemical compounds were present at unusually high levels in the plant’s leaves.
Strangely, these compounds (called acetyl-aminoadipate and acetyl-tryptophan) weren’t present in any of the normal, so-called wild type plants. As he and his colleagues searched for an explanation, they narrowed in on the source: an enzyme, called BAR, that was engineered into the plants as a kind of chemical beacon, enabling scientists to more readily study them.
But BAR is more than just a tool for scientists. It is also one of the most commonly deployed traits in genetically modified crops such as soybeans, corn, and cotton, enabling them to withstand a widely-used herbicide (known as phosphinothricin or glufosinate).
For decades, scientists have known that BAR, originally isolated from bacteria, can render the herbicide inactive by tacking on a short string of chemicals, made of two carbons and one oxygen (also called an acetyl group). As the researchers describe in their Nature Plants paper, BAR has a promiscuous side, and can work on other substrates, too, such as the amino acids tryptophan and aminoadipate (a lysine derivative).
That explains why they can detect the unintended products (acetyl-tryptophan and acetyl-aminoadipate) in crops genetically engineered to carry BAR, such as soybeans and canola.
Their research included detailed studies of the BAR protein, including crystal structures of the protein bound to its substrates. This provided them with a blueprint for how to strategically modify BAR to make it less promiscuous, and favor only the herbicide as a substrate and not the amino acids. Christ and his colleagues created several versions that lack the non-specific activity of the original BAR protein.
“These are natural catalysts, so when we borrow them from an organism and put them into another, they may not necessarily be perfect for our purposes,” Christ says. “Gathering this kind of fundamental knowledge about how enzymes work and how their structure influences function can teach us how to select the best tools for bioengineering.”
There are other important lessons, too. When the BAR trait was first evaluated by the U.S. Food and Drug Administration (FDA) in 1995 for use in canola, and in subsequent years for other crops, metabolomics was largely non-existent as a technology for biomedical research. Therefore, it could not be applied toward the characterization of genetically engineered plants and foods, as part of their regulatory review. Nevertheless, acetyl-aminoadipate and acetyl-tryptophan, which are normally present in humans, have been reviewed by the FDA and are safe for human and animal consumption.
Weng and his colleagues believe their study makes a strong case for considering metabolomics analyses as part of the review process for future genetically engineered crops.
“This is a cautionary tale,” Weng says.
The work was supported by the Swiss National Science Foundation, the EU-funded Plant Fellows program, the Pew Scholar Program in the Biomedical Sciences, and the Searle Scholars Program.
Researchers at the Whitehead Institute have illuminated an important role for different subtypes of muscle cells in orchestrating the process of tissue regeneration.
In a paper appearing online today in Nature, they reveal that a subtype of muscle fibers in flatworms is required for triggering the activity of genes that initiate the regeneration program. Notably, in the absence of these muscles, regeneration fails to proceed. Another type of muscle, they report, is required for giving regenerated tissue the proper pattern — for example, forming one head instead of two.
“One of the central mysteries in organ and tissue regeneration is: How do animals initiate all of the cellular and molecular steps that lead to regeneration?” says senior author Peter Reddien, a member of Whitehead Institute, professor of biology at MIT, and investigator with the Howard Hughes Medical Institute. “We’ve helped answer this question by revealing a surprising molecular program that operates within a subgroup of muscle cells that helps establish the molecular information required for proper tissue regeneration after injury.”
For more than a decade, Reddien and the researchers in his laboratory have studied the biological mechanisms that underlie regeneration in a tiny flatworm called planarians. These worms possess some impressive regenerative capabilities: When sliced in two, each piece of the worm can regrow the body parts needed to form two complete organisms. In previous studies, Reddien’s team identified a set of always-on genes, known as position control genes (PCGs), that provide cells with region-specific instructions, like a set of GPS coordinates, that tell cells where they are in the body, and thus what body part to regenerate. Interestingly, PGCs are active in planarian muscle cells, suggesting muscle may play a major role in the regeneration process.
“This discovery raised a lot of questions about how muscle participates in this process,” Reddien says.
In planarians, there are a handful of muscle cell types. For example, if you imagine the worms as simple cylindrical tubes, there are longitudinal muscle fibers, which run head-to-tail along the tubes’ long axis. There are also circular fibers, which are perpendicular to the longitudinal fibers and hug the tubes’ outer circumference.
To assess the roles of these different muscle cell types in regeneration, first author Lucila Scimone and her colleagues needed a method to selectively remove them. When myoD, a gene found specifically in the longitudinal fibers, is inhibited, those fibers fail to form. Similarly, the nkx1-1 gene marks the circular fibers, and when its function is reduced, they do not develop. Using these genes as molecular scalpels, Scimone and her co-authors could test the effects of ablating these distinct muscle groups on regeneration.
Surprisingly, when the longitudinal fibers were removed, the results were dramatic. The worms live quite normally, but when they are injured (the head removed, for example) they cannot regenerate the missing parts.
“This is an amazing result; it tells us that these longitudinal fibers are essential for orchestrating the regeneration program from the very beginning,” says Scimone, a scientist in Reddien’s lab.
As the researchers dug deeper into the finding, they learned that the functions of two critical genes are disrupted when longitudinal fibers are missing. These genes, called notum and follistatin, are known for their fundamental roles in regeneration, controlling head-versus-tail decisions and sustained cell proliferation, respectively, following tissue injury.
In addition to this essential role for longitudinal fibers, the research team also uncovered a key role for circular fibers. When these muscles are missing, planarians are able to regenerate missing body parts, but what regrows is abnormally patterned. For example, two heads may be regenerated within a single outgrowth, instead of one.
These results underscore an important and previously unappreciated role for muscle, widely known for its contractile properties, in instructing the tissue regeneration program. The Whitehead researchers will continue to probe the role of different muscle cell types in planarian regeneration and also explore whether other animals with regenerative capabilities possess a similar muscle-localized program for conferring positional information.
“It’s hard to understand what limits humans’ abilities to regenerate and repair wounds without first knowing what mechanisms are enabling some animals, like planarians, to do it so amazingly well,” Reddien says.
This work was supported by the National Institutes of Health, Howard Hughes Medical Institute, and the Eleanor Schwartz Charitable Foundation.
Following the successful completion of the Human Genome Project, the challenge now is to decipher the information encoded within the human genetic code — including genes, regulatory controls and cellular circuitry. Such understanding is fundamental to the study of physiology in both health and disease. At the Broad Institute, my lab collaborates with other to discover and understand the genes responsible for rare genetic diseases, common diseases, and cancer; the genetic variation and evolution of the human genome; the basis of gene regulation via enhancers, long non-coding RNAs, and three-dimensional folding of the genome; the developmental trajectories of cellular differentiation; and the history of the human population.
Our lab is fascinated by the molecular machinery that directs core cellular processes, and in particular how these processes are modulated and rewired across different physiological contexts. Our work has focused on the proteins that direct chromosome segregation and cell division, including the macromolecular kinetochore structure that mediates chromosome-microtubule interactions. Although cell division is an essential cellular process, this machinery is remarkably flexible in its composition and properties, which can vary dramatically between species and are even modulated within the same organism — over the cell cycle, during development, and across diverse physiological situations. To define the basis by which the kinetochore and other core cellular structures are rewired to adapt to diverse situations and functional requirements, we are currently investigating diverse transcriptional, translational, and post-translational mechanisms that act to generate proteomic variability both within individual cells and across tissues, cell state, development, and disease.
We focus on plant epigenetics — that is, the heritable information that influences cellular function but is not encoded in the DNA sequence itself. We use genetic, genomic and molecular biology approaches to study the fidelity of epigenetic inheritance and the dynamics of epigenomic reprogramming during reproduction, primarily in the model plant Arabidopsis thaliana. More specifically, we investigate the interplay among repetitive sequences, DNA methylation and chromatin structure in these dynamic processes.
Using Drosophila, we study how neurons form synaptic connections, as well as how synapses transmit information and change during learning and memory. We also investigate how alterations in neuronal signaling underlie several neurological diseases, including epilepsy, autism, and Huntington’s Disease. We hope to bridge the gap between the molecular components of the synapse and the physiological responses they mediate.