With HHMI funding, these Yale scientists are working to solve some of the most challenging biomedical mysteries.
When the Howard Hughes Medical Institute (HHMI) has gone looking for biomedical researchers of “intellectual daring” in recent years, one place it has frequently found them has been Yale.
Named after the famed philanthropist and aviator Howard Hughes, the medical research institute provides research support with — in its own words — “the conviction that scientists of exceptional talent and imagination will make fundamental contributions of lasting scientific value and benefit to mankind when given the resources, time and freedom to pursue challenging questions.”
Yale currently boasts 16 HHMI investigators and one HHMI professor. HHMI investigators are chosen for their cutting-edge research and receive full funding for their laboratories for five-year terms; HHMI professors are honored for their commitment to making science more engaging for undergraduates and receive HHMI funding to create programs that fundamentally reform how undergraduate science is taught at research universities.
The Yale scientists receiving HHMI funding are exploring a host of important questions — from how ticks transmit diseases to how proteins fold themselves into origami-like shapes to how RNA functions. The following is a look at those scientists.
Dr. Gerald Shulman
Professor of Inaternal Medicine and Cellular & Molecular Physiology, Yale School of Medicine
Dr. Gerald Shulman’s passion is tracking down the molecular culprits involved in insulin resistance, the precursor to Type 2 diabetes. He has published more than 260 papers on this topic, and he has been elected to the Institute of Medicine, the Association of American Physicians and the National Academy of Sciences.
His lab pioneered the use of magnetic resonance spectroscopy and other non-invasive technologies used to study the complex molecular pathway that leads to insulin resistance in humans. Shulman’s findings have led to the discovery of a novel mechanism, involving alterations in intracellular fat metabolism as the major cause of insulin resistance in liver and muscle. Those insights in turn have led to the identification of several novel therapeutic targets to treat, and perhaps even prevent, Type 2 diabetes.
Anna Marie Pyle
The William Edward Gilbert Professor of Molecular Biophysics and Biochemistry
By investigating stretches of RNA that scientists once thought to be simply junk, Anna Marie Pyle has discovered a treasure chest of biological information that may shed light on humans’ evolutionary past. Pyle is an expert on RNA splicing, specifically the role Group II introns play in triggering key RNA reactions.
Pyle explains that RNA introns were once viewed as a sort of garbage surrounding exons, which carry out the key role of translating RNA into proteins that carry out all of life’s functions. However, certain introns themselves fold into unique structures that are crucial to stitching together RNA — a process that is shared by most organisms and goes deep into evolutionary history.
The work on RNA structure has led her into the study of DExH/D proteins, which are protein nanomachines that remodel RNA molecules and play a role in RNA metabolism and viral replication.
Dr. Erol Fikrig
Chief of Infectious Diseases, the Waldemar Von Zedtwitz Professor of Medicine, and Professor of Microbial Pathogenesis and of Epidemiology and Public Health
Just a few miles from where Lyme disease was discovered in the 1970s, Dr. Erol Fikrig has become an expert on the life cycle of the bacterium that causes the tick-borne disease.
It was Fikrig’s lab that discovered the Lyme disease bacterium can actually induce a tick to produce more saliva when it bites its host; this saliva contains a protein that helps the disease bacterium avoid attack by the host’s immune system. This observation has led to a new strategy to combat vector-borne diseases. Instead of targeting the organism itself, says Fikrig, perhaps scientists can attack those things in the environment that pathogens need to survive.
In addition to Lyme disease, Fikrig’s lab studies another tick-borne disease, human granulocytic anaplasmosis, and an emerging mosquito-borne agent, West Nile virus.
Professor and Vice-Chair of Genetics
The genes of mice and flies, Tian Xu is convinced, contain many answers to the mysteries of cancer tumors and their ability to metastasize.
Xu has developed multiple novel genetic methods for studying biology and disease. Utilizing these approaches, Xu’s lab has identified novel tumor suppressors and cancer pathways that have led to experimental cancer treatments. More recently, the Xu lab is deciphering the genetic basis for metastasis by using genome-wide genetic screens.
In addition, Xu has built a collaborative research effort with scientists at both Yale and Fudan University in his native China to mutate most mouse genes and to examine the defects associated with each of the mutant strains.
Sterling Professor and Chair of Immunobiology
When Richard Flavell isn’t playing guitar in his own local Bio-Rock band, he is studying how the immune system orchestrates a response to foreign invaders and why sometimes it goes awry and attacks its own tissue, causing an autoimmune disease.
By studying the function of genes involved in the immune response, Flavell has provided many insights into a wide variety of immune system processes, such as the differentiation of T-cells. Flavell is leading efforts to help harness immune system response to combat a host of diseases. As part of the effort, Flavell has helped launch an ambitious program to develop a working model of a human immune system in mice.
Sterling Professor of Genetics and Pediatrics
When newly made chains of amino acids try to fold into proteins in the living cell, they often need help in order to prevent misfolding and aggregation. Understanding the functions of the cellular machines called molecular chaperones, which prevent their protein charges from such illicit interactions, is the work of Arthur Horwich.
It was Horwich who first illustrated this key function in the biology of all organisms; through studies of mitochrondria, he identified how the specialized ring-shaped chaperones, known as chaperonins, mediate protein folding. Since then, using a host of technologies, Horwich’s lab has determined the structure and mechanism of action of the bacterial chaperonin, GroEL, composed of seven-membered rings.
Protein misfolding and aggregation can have catastrophic consequences; they have been implicated in a number of neurodegenerative disorders including Alzheimer’s and Parkinson’s diseases, and the paralyzing nerve disorder amytrophic lateral sclerosis (ALS, also known as “Lou Gehrig’s disease”). Horwich’s lab is focusing on one form of ALS, seeking to understand why a misfolded enzyme, despite the presence of chaperones, goes on to cause neuronal injury.
Ruslan M. Medzhitov
The David W. Wallace Professor of Immunobiology
About 500 million years ago, the early ancestors of vertebrates developed a highly specific adaptive immune system to go along with the ancient innate immune system, the generic reaction to different types of pathogens.
Ruslan M. Medzhitov has made a career investigating the borders of the two systems. Medzhitov was an impoverished graduate student in Moscow when he read a paper by the late Yale immunobiologist Charles Janeway. He made his way to New Haven where the two men helped revolutionize the field when they described how a family of Toll-like receptors of the innate system were necessary to trigger customized B and T cells to target a specific bacterial or viral invader — the hallmark of the adaptive immune system.
Today Medzhitov is studying the role of Toll-like receptors in autoimmune disorders, inflammation and allergies, and other disorders.
The Henry Ford II Professor of Molecular, Cellular and Developmental Biology and Professor of Biophysiology and Biochemistry
Ronald Breaker loves the exotic nucleic acids — whether found in nature or made in his own laboratory. Breaker has designed “riboswitches,” or RNA that can sense certain metabolites and trigger a catalytic reaction. Breaker predicted such biosensor switches existed in nature — and then went out and found them.
The discoveries have far-reaching implications for understanding RNA molecules role in evolution. And, notes Breaker, such bio-sensing capabilities may lead to the creation of engineered organisms for industrial applications and advanced molecular computing systems.
Professor of Immunobiology and Cell Biology and Dermatology, School of Medicine
When a foreign peptide meets the immune system, it is invading Peter Cresswell’s territory. He is fascinated by the behavior of Major Histocompatibility Complex molecules, which bind to foreign antigens and trigger the response of T lymphocytes. The chain reaction is called antigen processing and is one of the many mysteries of the immune system that Cresswell’s lab is investigating.
Dr. Pietro De Camilli
The Eugene Higgins Professor of Cell Biology
For more than 30 years, Dr. Pietro De Camilli has studied the mechanics of how neurotransmitters are released into the synapse, a process that is the basis of thought itself. De Camilli is a world’s expert on the formation and function of synaptic vesicles, the organelles that store and secrete fast acting neurotransmitters.
Raised in northern Italy, De Camilli did his postdoctoral work at Yale with Paul Greengard, who in 2000 was awarded the Nobel Prize for Physiology and Medicine for his research on regulation of the nervous system. Another Nobel laureate, George Palade, first recruited him to the Yale Cell Biology faculty. De Camilli has identified and/or characterized several proteins implicated in the exo-endocytosis of synaptic vesicles and discovered a key mechanism in the control of synaptic vesicle traffic.
David G. Schatz
Professor of Immunobiology, School of Medicine
How hundreds of millions of customized B and T lymphocytes are created by the reshuffling of the immune system’s genetic deck is a question that has consumed David G. Schatz for decades. He has led groundbreaking work in investigating how the adaptive immune system of vertebrates assembles a diverse group of lymphocytes that respond specifically to a host of bacterial and viral invaders.
Holding degrees in philosophy and politics as well as biophysics and biochemistry, Schatz did his graduate work with Nobel laureate David Baltimore at the Massachusetts Institute of Technology. He is a world leader in understanding how the processes called somatic hypermutation and V(D)J recombination can create an incredible diversity of antigen receptor genes. Schatz has also shown what happens when the process goes wrong, linking breakdowns in assembling processes to development of lymphoma, for instance.
Joan A. Steitz
Sterling Professor of Molecular Biophysics
Joan A. Steitz earned her reputation as a true scientific pioneer by discovering the role of small nuclear ribonucleoproteins (snRNPs). These complexes have been shown to play a key role in splicing pre-messenger RNA, which is created as a first step in transcribing information contained in DNA. Discoveries arising from that work may lead to insights into lupus and other autoimmune diseases.
Steitz also was a trailblazer in opening up science careers for women during the 1960s and was encouraged in her career choice by James Watson, discoverer of the DNA double helix. Steitz is married to Thomas Steitz, Sterling Professor of Molecular Biophysics and Biochemistry at Yale, and a fellow HHMI investigator.
Dr. Richard Lifton
Sterling Professor and Chair of Genetics, and Professor of Medicine and Molecular Biophysics and Biochemistry, School of Medicine
Dr. Richard Lifton was among the first scientists to believe that he would find solutions to medical problems that might lie among variations of billions of nucleotide sequences of the human genome.
By searching the genome for disease causing mutations, often in rare inherited diseases, Lifton’s team has been able to change how doctors look at cardiovascular disease and how millions of people are treated for high blood pressure. For instance, by conducting a genetic analysis of people with rare forms of blood pressure diseases, he was able to pinpoint the key role of the kidney’s ability to handle salt in the development of hypertension.
Lifton remains one of the world’s leading advocates of genome-wide analysis of human subjects to find polymorphisms that contribute to chronic disease.
Sterling Professor of Molecular Biophysics and Biochemistry and Professor of Chemistry
The big ambition of the Thomas Steitz laboratory is to understand chemical mechanisms and structures of the protein and nucleic acids involved in biology’s central dogma — the replication of DNA and its transcription into RNA as well as the translation of RNA into proteins.
Steitz’s use of x-ray crystallography has created images of many key steps along that pathway, such as an image of the large ribosomal subunit, a key ribonuclear machine that is responsible for linking the amino acid building blocks together.
Although this research of the Steitz lab could not be more basic, it has already spurred new ideas about how to create the next generation of antibiotics that target the ribosome and block the ability of bacteria to produce the proteins needed for their survival.
Shirleen G. Roeder
The Eugene Higgins Professor of Molecular, Cellular and Developmental Biology
Shirleen G. Roeder is one of the leading experts on the genetic shuffling that takes place during meiosis — the elaborately orchestrated process that creates our sex cells.
Through exhaustive studies in yeast, Roeder’s lab has been able to identify some of the key proteins involved in the transfer of segments between two chromosomes. Her work has also pinpointed many molecular mechanisms crucial to formation of gametes, or sex cells.
The Maxine Singer Associate Professor of Molecular, Cellular and Developmental Biology
Few people know as much about the inner workings of the bacterium Caulobacter crescentus as Christine Jacobs-Wagner.
The newest member of Yale’s HHMI team, Jacobs-Wagner is a world expert on the identifying roles of key proteins in the life cycle of cells. For instance, she has discovered that intermediate filaments, once thought to exist only in animal cells, also play a role in bacteria.
Scott A. Strobel
The Henry Ford II Professor and Chair of Molecular Biophysics and Biochemistry
For most of the year, Scott A. Strobel is a world leader in studying the function and structure of RNA. However, in his role as an HHMI professor, Strobel becomes a sort of academic Indiana Jones, leading undergraduates into the rainforest in search of novel microbes and a deeper love of science.
Undergraduates lucky enough to get into the popular “Rainforest Laboratory and Expedition” course spend two weeks in the Amazon rainforest collecting plants and isolating endophytes — or rarely studied microorganisms within the plant. Then in the next six months, they design experiments to characterize the organisms and screen them for biologically novel compounds.
Some do discover novel molecules — while almost all discover the breadth and challenge and excitement of scientific research.