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.
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.
We examine the interaction between cancer and immune cells. Using tumor mouse models designed to mimic tumor progression in humans, we investigate the co-evolution of the anti-tumor immune response and cancer. Understanding the interplay between tumor cells and immune cells will help develop and improve effective cancer immunotherapies.
We seek to understand the immune system and its application in cancer immunotherapy and vaccine development. We study the molecular and cellular mechanisms behind immunological and disease processes, leveraging the vast array of genomic data, humanized mice and clinical samples.
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.
Harvey Lodish has been a leader in molecular cell biology as well as a biotechnology entrepreneur for over five decades. Much of his early research focused on the regulation of messenger RNA translation and the biogenesis of plasma membrane glycoproteins. Beginning in the 1980s, his research focused on cloning and characterizing many proteins, microRNAs, and long noncoding RNAs important for red cell development and function. His laboratory was the first to clone and sequence mRNAs encoding many hormone receptors, mammalian glucose transport proteins, and proteins important for adipose cell formation and function. He went on to identify and characterize several genes and proteins involved in insulin resistance and stress responses in adipose cells. Over the years, he has mentored hundreds of undergraduates, PhD and MD/PhD students, and postdoctoral fellows, and continues to teach award-winning undergraduate and graduate classes on biotechnology.
Harvey Lodish closed his lab in 2020 and is no longer accepting students.
We aim to understand the epigenetic regulation of gene expression in mammalian development and disease. Embryonic stem cells are important because they have the potential to generate any cell type in the body and, therefore, have great potential for regenerative medicine. We study the way somatic cells reprogram to an embryonic pluripotent state, and use patient specific pluripotent cells to study complex human diseases.
We are interested in the molecular, cellular and neural circuit mechanisms underlying learning and memory in rodents. We generate genetically engineered mice, and analyze them through multiple methods including molecular and cellular biology, electrophysiology, microscopic imaging, optogenetic engineering, and behavioral studies. Ultimately, we aim to detect the effects of our manipulations at multiple levels in the brain — deducing which behaviors or cognitions are causally linked to specific processes and events taking place at the molecular, cellular, and neuronal circuit levels.
To survive and grow, a cell must properly assess the resources available and couple that with its growth and metabolism — a misstep in that calculus can potentially cause cell death or dysfunction. At the crux of these decisions is the mTOR pathway, a cellular pathway connecting nutrition, metabolism, and disease.
The mTOR pathway incorporates input from multiple factors, such as oxygen levels, nutrient availability, growth factors, and insulin levels to promote or restrict cellular growth and metabolism. But when the pathway runs amok, it can be associated with numerous diseases, including cancer, diabetes, and Alzheimer’s disease. Understanding the various sensors that feed into the mTOR pathway could lead to novel therapies for these diseases and even aging, as dialing down the mTOR pathway is linked to longer lifespans in mice and other organisms.
Although the essential amino acid methionine is one of the key nutrients whose levels cells must carefully sense, researchers did not know how it fed into the mTOR pathway — or if it did at all. Now, Whitehead Institute Member David Sabatini and members of his laboratory have identified a protein, SAMTOR, as a sensor in the mTOR pathway for the methionine derivative SAM (S-adenosyl methionine). Their findings are described in the current issue of the journal Science.
Methionine is essential for protein synthesis, and a metabolite produced from it, SAM, is involved in several critical cellular functions to sustain growth, including DNA methylation, ribosome biogenesis, and phospholipid metabolism. Interestingly, methionine restriction at the organismal level has been linked to increased insulin tolerance and lifespan, similar to the antiaging effects associated with inhibition of mTOR pathway activity. But the connection between mTOR, methionine, and aging remains elusive.
“There are a lot of similarities between the phenotypes of methionine restriction and mTOR inhibition,” says Sabatini, who is also a Howard Hughes Medical Institute investigator and a professor of biology at MIT. “The existence of this protein SAMTOR provides some tantalizing data suggesting that those phenotypes may be mechanistically connected.”
Sabatini identified mTOR as a graduate student and has since elucidated numerous aspects of its namesake pathway. He and his lab recently pinpointed the molecular sensors in the mTOR pathway for two key amino acids: leucine and arginine. In the current line of research, co-first authors of the Science paper Xin Gu and Jose Orozco, both graduate students Sabatini’s lab, identified a previously uncharacterized protein that seemed to interact with components of the mTOR pathway. After further investigation, they determined that the protein binds to SAM and indirectly gauges the pool of available methionine, making this protein — SAMTOR — a specific and unique nutrient sensor that informs the mTOR pathway.
“People have been trying to figure out how methionine was sensed in cells for a really long time,” Orozco says. “I think that this is the first time in mammalian cells a mechanism has been found to describe the way methionine can regulate a major signaling pathway like mTOR.”
The current research indicates that SAMTOR plays a crucial role in methionine sensing. Methionine metabolism is vital for many cellular functions, and the Sabatini lab will further investigate the potential links between SAMTOR and the extended lifespan and increased insulin sensitivity effects that are associated with low methionine levels.
“It is very interesting to consider mechanistically how methionine restriction might be associated in multiple organisms with beneficial effects, and identification of this protein provides us a potential molecular handle to further investigate this question,” Gu says. “The nutrient-sensing pathway upstream of mTOR is a very elegant system in terms of responding to the availability of certain nutrients with specific mechanisms to regulate cell growth. The currently known sensors raise some interesting questions about why cells evolved sensing mechanisms to these specific nutrients and how cells treat these nutrients differently.”
This work was supported by the National Institutes of Health, the Department of Defense, the National Science Foundation, and the Paul Gray UROP Fund.