The structure, organization and regulation of chromatin (the complex of DNA and structural components) is critical to ensuring that cells activate relevant genes correctly and maintain the integrity of their genome. Malfunctions in these processes can result in genetic diseases and cancer formation. Researchers in the division seek to understand the multiple complex molecular systems that govern chromatin structure as well as DNA transcription, RNA processing and translation and other controls of gene expression.
Dr. Robert Bradley is a computational biologist and biophysicist who works at the intersection of several different disciplines, including cancer biology, cancer-immune interactions, and RNA processing. His broad goal is to discover novel molecular mechanisms that govern cancer initiation, progression, or response to therapy.
Our genes act as a recipe book for our cells. They contain the instructions for making all the proteins that cells need — but there are only two copies of each gene, and our cells need hundreds if not thousands of copies of a protein to function properly. To address this, cells make many copies of a gene, which can be used by the protein-building factories as protein-making instructions. These copies are called messenger RNA, or mRNA. Dr. Steven Hahn studies the molecular machines that make mRNA. At any given time, only certain genes are copied into mRNA because only those proteins are needed for specific cellular functions. Dr. Hahn seeks to understand how the mRNA-producing machines work, and how cells turn them on and off at the right time. Alterations in this process occur in many human diseases, making it critical for researchers to better understand this fundamental process.
Dr. Steven Henikoff is a molecular biologist who studies the structure, function and evolution of our DNA molecules, or chromosomes. He also develops tools for comparing gene sequences, determining the arrangement of genes in living cells and understanding the biological functions of genes. Credited with helping build the infrastructure for analyzing the human genome, Dr. Henikoff was among the first to realize that computing and the internet could revolutionize biological research. In 1992, he and his wife, Jorja Henikoff, developed a computational method that researchers have used to compare the relatedness among all living things, making it possible to uncover the roots of human diseases through the study of simpler organisms. Dr. Henikoff and his colleagues have also developed techniques that allow scientists to map features of chromosomes that are altered when genes are switched on or off. These methods have already offered new insight into how gene activity patterns may persist for many cell generations. It also may eventually help scientists determine how an embryo develops into an adult animal or how healthy cells become cancerous.
Dr. Mark Groudine studies how cells turn genes on and off, and how changes to these processes can lead to cancer. He has shown that the packaging and 3D organization of DNA changes by type of tissue, and that this influences gene expression. Dr. Groudine’s work led to the discovery of a region of DNA that helps to control the expression of hemoglobin, the oxygen-transporting protein in red blood cells. A specific type of anemia, called thalassemia, occurs when this region of DNA is missing. Similar DNA regions have been discovered for other genes and have been implicated in other diseases, including a type of lymphoma. Dr. Groudine served as director of the Hutch’s Basic Sciences Division from 1995 to 2004, deputy director of Fred Hutch from 1997 to 2016, executive vice president from 2005 to 2016, and as acting president and director of Fred Hutch in 2010 and 2014.
Dr. Gerald “Gerry” Smith studies recombination, a process cells use to increase genetic diversity by swapping, or recombining, segments of DNA from the two copies of each chromosome we inherited from our parents. When this process goes wrong, it can lead to miscarriage, developmental disorders or cancer. Dr. Smith studies the molecules involved in this critical process, including those that help repair the DNA breaks that occur as chromosomes trade sections. Using yeast as a model system, he has identified and outlined the roles of many proteins that regulate this process, most of which have human counterparts. Dr. Smith has long studied the major mechanism by which bacteria repair breaks in their DNA that naturally occur during processes such as chromosome replication. This essential mechanism employs a complex enzyme called RecBCD that both unwinds DNA from a broken end and cuts it at special sites known as "hotspots" of recombination. His team has found inhibitors of RecBCD, which could be useful novel antibiotics because bacterial DNA is often broken when bacteria infect human cells. He hopes that a deeper understanding of these fundamental processes will help provide insights and compounds that can be used to improve human health.
Dr. Arvind “Rasi” Subramaniam studies how cells produce proteins, one of biology’s most fundamental processes. The process can go awry in certain disease states, including cancer, and Dr. Subramaniam examines how certain alterations in protein synthesis may lead to disease. He uses both experimental and computational methods to better understand how cells build proteins, including how they cope when problems arise. Dr. Subramaniam’s quest to understand this fundamental process spans life forms from bacteria to mammalian cells. From this work, his lab has uncovered a quality control mechanism in cells that detects collisions between the molecular machines that produce proteins, called ribosomes, as they move along stretches of messenger RNA.
Dr. Toshio “Toshi” Tsukiyama studies how cells regulate chromatin, the packaging proteins responsible for compressing several feet of DNA inside each cell’s tiny nucleus. This genetic material needs to be carefully unpacked and repacked when cells need to divide or turn on genes at just the right time — two processes that can go wrong in cancer cells. Dr. Tsukiyama has discovered that a specific family of proteins helps the most basic units of chromatin — cartwheel-shaped molecular complexes around which DNA spools — slide along DNA to help control when genes are turned on and off. He also studies how the 3D structure of DNA, the large loops and folds it undergoes, can be harnessed to regulate cellular processes. Widespread gene shutdown and DNA compaction are hallmarks of an important, energy-conserving cellular state known as quiescence. Though quiescence is a normal state for cells in many of our tissues, it can also be used by cancer cells to resist chemotherapy. A deeper understanding of this state could lead to better treatments for cancer and other diseases. Dr. Tsukiyama studies how cells create the 3D DNA structure that helps them enter quiescence and keep genes turned off.
The Avgousti Lab is focused on the mechanisms by which viruses hijack chromatin. Due to the major advancement in sequencing technologies and the expansion of the field of epigenetics, exploiting viruses to investigate chromatin biology has enormous potential. Their goal is to advance basic understanding of viral manipulation of chromatin and uncover new aspects of chromatin biology.
Dr. Nicholas Lehrbach’s research focuses on discovering the cellular pathways that normally function to remove unwanted proteins, and how they become mis-regulated in disease. High levels of abnormal or damaged proteins is a cellular feature of aging, cancer, adult-onset neurodegenerative diseases, and many rare genetic disorders. Dr. Lehrbach and his team use C. elegans to discover these pathways, understand how they work and investigate their roles in health and disease. Specifically, the team focuses on the regulation of the proteasome, an elaborate molecular machine that carries out the majority of targeted protein degradation in eukaryotic cells. By revealing how the proteasome is regulated, our work may lead to new ways to treat these diseases.
The molecular structure of proteins determines their functionality within cells and organisms. Researchers in the division are working to discover the structure of existing molecules and to synthesize new ones that might prevent or treat disease. Investigators also examine the symbiotic relationships among cell communities and how these affect human health.
Dr. Roger Brent, a molecular biologist by training, uses computational tools and simple organisms like yeast and worms to understand the basis for differences in how cells respond to information from the outside environment. Cells use this information to make decisions, such as whether or not to divide or undergo programmed cell death. Variations in how they respond likely underlies the origin of some human diseases. By building tools to carefully study and manipulate individual decision circuits in cells that are seemingly wired the same way, Dr. Brent's team can tease apart why this variability exists and understand its consequences. In addition, Dr. Brent hopes to foster a better understanding of the impact of biological research progress on our lives. To this end, he created and led the Center for Biological Futures. The goal of this interdisciplinary think tank, conducted in collaboration with social scientists and humanities scholars, was to improve understanding of the global impact of biological research progress, including how advances in biology are shaping 21st century human affairs, and to inform the choices researchers make. His team is now also pursuing pilot efforts in deep neural networks and augmented reality to accelerate the pace of their work and of biological discovery worldwide.
Dr. Melody Campbell studies how cells communicate and interact with their surroundings. She is an expert in using cryogenic electron microscopy, or cryo-EM, a microscopy technique that allows scientists to study the structure of proteins in a more physiologic environment. She hopes to understand how a protein’s structure influences its function. She uses cryo-EM to study integrins, proteins that help cells communicate and move. Integrins are more flexible than many other proteins and adopt several different conformations that are linked to their activation state. Campbell focuses on a family of integrin proteins that stud the surface of white blood cells and play a role in various autoimmune and inflammatory conditions. She aims to create a detailed picture of integrin form and function as a step toward targeted therapeutics.
Dr. Barry Stoddard is an expert in protein structure and engineering. He uses cutting-edge laboratory and computational techniques to reveal proteins’ 3D forms at the atomic level, which is key to his ultimate goal: modifying natural proteins to treat or cure human diseases. In particular, his group has made major contributions to the understanding of gene-targeting proteins, from determining their structure to creating variants for use in gene therapy. Dr. Stoddard’s work could lead to engineered proteins that are capable of correcting mutations that underlie genetic diseases like cystic fibrosis, and he’s working on proteins that could cure HIV and other chronic infections.
Dr. Roland Strong is a biophysicist who uses protein engineering and structural biology — capturing the 3D shapes of proteins at their atomic level — to better understand the microscopic players that make up our immune systems. He works to both advance our basic knowledge of immunity and engineer proteins that could form the basis of new therapies or vaccines for cancer, HIV and other diseases. He led the development of Daedalus, a rapid protein-production system that supports preclinical studies at the Hutch and the University of Washington. Dr. Strong’s work has shed light on the molecular barriers to developing an effective HIV vaccine and pointed to improvements on vaccine design for infectious diseases, including HIV, using a computational approach.
Normal cellular processes as well as environmental stressors can disrupt the genetic and structural integrity of a cell. Researchers in the division are investigating the processes by which cells recover from these stressors. Additionally, they seek to understand cellular division, metabolism and fate by answering fundamental questions about normal and abnormal cell function, development and how dysregulation of these processes contribute to disease, including cancer.
Dr. Biggins' work focuses on understanding how cells regulate division and chromosome movement during cell division to ensure accurate self-renewal, proliferation and development. Her lab takes an interdisciplinary approach that combines biochemical, biophysical, cell biological, genetic and structural approaches using yeast and human cells as model systems. Dr. Biggins led the team that originally isolated the kinetochore, the large molecular machine that coordinates chromosome sorting, from yeast cells. This accomplishment paved the way for critical new findings, including the role that tension plays in chromosome sorting.
Dr. Linda Breeden studies a state known as quiescence, in which cells conserve resources and energy by halting growth and many other cellular processes. Though most cells spend most their lifetimes in this state, much less is known about quiescence than growth. Dr. Breeden studies how rapidly dividing cells move into quiescence, and how quiescent cells transition back into growth and division when environmental triggers change. Dr. Breeden’s work could shed light on the ways that tumor cells find to avoid entering — or to quickly exit from — this quiet, nongrowing state.
Dr. Jon Cooper studies the networks of proteins that cells use to communicate with each other — networks that also play a critical role in the transformation of healthy cells into cancer cells. In particular, his team studies how some proteins undergo chemical changes that regulate how healthy and cancerous cells divide, become more specialized and migrate in the body. His lab has discovered several of the key steps that cells use to signal when and how to grow, providing the field with important clues about how this signaling process goes awry in cancer cells. This information could help researchers fix corrupted signaling pathways that lead to cancer and other diseases. Dr. Cooper directed the Basic Sciences Division at Fred Hutch from 2009 to 2018.
Dr. Bob Eisenman’s research is focused on the MYC network: a group of genes that are important for normal growth and development but, when mutated, are profoundly involved in a multitude of human cancers. All of these factors encode gene-regulatory proteins that control cellular programs in response to signals from the environment. Dr. Eisenman’s laboratory uses genetic and molecular analyses to understand in detail the functions of these proteins and the pathways they control with the eventual goal of modulating their functions as a means of treating cancers.
Dr. Emily Hatch studies the nuclear envelope — the membrane that encases the nucleus of the cell — and how changes to its structure can lead to genetic diseases and drive cancer development. Under some conditions, the nuclear envelope can rupture, causing proteins, DNA and even cellular subcompartments to end up in the wrong area of the cell before the envelope either repairs itself or collapses. Dr. Hatch and her team study this process, which has been linked to cancer development and progression. A deeper understanding of this phenomenon may lead to a better understanding of how cancer develops.
Dr. Susan Parkhurst studies the cytoskeleton, the cell’s internal framework. The cytoskeleton is a dynamic structure, constantly forming and breaking down to meet the cell’s changing needs, including changes in shape and movement. Problems with building and deconstructing the cytoskeleton arise in many human diseases. Wound healing, in which cells move to fill a gap, and the organization of the nucleus, the cell’s DNA storeroom, rely on the cytoskeleton. Dr. Parkhurst studies its roles in these normal conditions and what goes wrong in cancer cells. She aims to identify new cancer treatment targets or discover ways to make existing therapies more effective.
Dr. James Priess studies the molecular biology of early development using the nematode C. elegans as a model system. Many animals produce large numbers of female germ cells, called oogonia, but only a few of these are selected for fertilization. The remaining cells undergo programmed cell death, a pathway that is well-conserved between humans and nematodes. Dr. Priess works to understand the factors that contribute either to the survival or destruction of developing oogonia. His team’s recent work has shown that oogonia with twice the normal number of chromosomes can become viable embryos but are recognized and targeted for destruction in normal development.
Dr. Mark Roth is a biochemist and cell biologist who studies “metabolic flexibility,” or how organisms like hibernating bears and squirrels can enter and exit dormant states. The goal of his work is to learn how to turn animals “off,” inducing a state of reversible suspended animation, which could protect against damage caused by extreme conditions. Dr. Roth discovered that certain compounds, such as hydrogen selenide, can be used to induce reversible dormancy, in which breathing and heart rate slow to a near standstill. His work using the related molecule iodide to treat heart attack in several preclinical models has been used in a multicenter Phase 2 trial in Europe and the US conducted by a company he founded: Faraday Pharmaceuticals. A pivotal Phase 3 is currently planned. In 2007 he received a MacArthur Fellowship, or “genius award,” for his research in suspended animation and in 2010 he delivered a TED talk about this work.
Today’s scientific techniques make it possible for researchers to examine the inner workings of individual cells — and produce massive amounts of data in the process. Dr. Manu Setty takes a multi-disciplinary approach to develop computational methods that make it possible to analyze and understand today’s enormous datasets. In particular, he focuses on the complex regulatory interactions that govern cell-fate choice, or how non-specialized cells choose to become cells with specialized functions. He has identified gene networks that regulate embryonic development as well as those that regulate production of blood cells in adult bone marrow. This cellular decision-making can go wrong in diseases like cancer, in which once-specialized cells sometimes regress and regain characteristics of their earlier selves that drive excessive growth. Setty seeks to understand cell-fate choice under normal conditions as a foundation for understanding how this process goes awry in disease.
Dr. Lucas Sullivan studies cell metabolism under normal and cancerous conditions. Tumors modify their metabolic pathways to support the increased demand for new cellular components and building blocks that enable excess cell growth. Dr. Sullivan works to outline the metabolic pathways that tumors rely on to grow and progress, including identifying potential targets for future cancer therapies. He also aims to deepen our understanding of metabolism in general, working to discover new molecular products of metabolism and their roles in sustaining cell survival and growth.
Studying the evolution of viruses, bacteria and the immune system enables researchers to understand how these infectious agents evade immune response and develop resistance to existing therapies. These investigations provide a deeper understanding of human immunity while revealing novel means for protecting the body from viruses like HIV and influenza.
Dr. Jesse Bloom studies evolution using viruses and viral proteins as models. Specifically focusing on the fast-evolving influenza virus, Bloom aims to understand how mutations in viral genes shape the pathogen’s ability to infect and spread. He uses computational biology and real-world data to build evolutionary models and examine different scales of viral evolution, from evolution within a single host to evolution on a global scale. In doing so, Bloom addresses both fundamental and translational questions, including those with relevance to developing more effective seasonal flu vaccines.
Dr. Michael Emerman studies how our cells interact with HIV and related retroviruses. Over millennia, our cells and the cells of other primates that are susceptible to retrovirus infection have evolved strategies to rebuff the viruses. In turn, retroviruses like HIV have evolved their own strategies to overcome our defenses. Dr. Emerman charts the course of this evolution, examining how HIV adapted to humans from its origins as a primate retrovirus. Understanding ancient viral infections can give clues to our ability to resist — or succumb — to HIV. Insights into effective cellular antiviral defenses could also shed light on avenues for development of potential future antiretroviral therapies.
Dr. Meghan Koch studies how maternal-derived signals shape infant development, immunity and metabolism. Breast milk transfers nutrients and specialized immune proteins, such as antibodies, to infants. These antibodies help protect infants from infection. They also influence the infant gut microbiome, the microbes that colonize the intestines. The microbiome is key to health, and perturbations in the microbiome of infants can have long-term effects on infant growth and immune responses later in life, including risk of allergy and asthma. Dr. Koch studies how an infant’s developing immune system “makes peace” with these microbes, and how maternal antibodies shape this process. She also examines the long-term consequences of changes in these early maternal-infant interactions.
Dr. Harmit Malik studies genetic conflict, the competition between genes and proteins with opposing functions that drives evolutionary change. His research could have implications for a range of diseases, from HIV to cancer. As part of this work, his team developed an approach for identifying genes that divide one species from another, which could help solve the riddle of how new species evolve. Dr. Malik also studies the evolutionary processes that drive our body’s interactions with viruses, including contemporary scourges like HIV as well as ancient viruses whose fossils litter our genome. With Hutch colleagues, he has characterized the rapidly evolving interface between proteins on human cells and viruses that make us sick. This work has highlighted surprising deviations from “textbook” models of these interactions, and it is revealing gene variants that could influence our susceptibility to infection.
Dr. Nina Salama studies Helicobacter pylori, a stomach bacterium that infects half the world’s population and is associated with ulcers and gastric cancer — the third leading cancer killer worldwide. Her team found that H. pylori’s unique corkscrew shape allows the bug to colonize the stomach by burrowing into the mucus lining where it is protected from the acidic environment. They found a set of key proteins responsible for the bacterium’s twisty form. H. pylori that lack these proteins cannot set up shop in the stomach, making these proteins possible new drug targets to prevent infection. Dr. Salama is trying to understand why only some people infected with H. pylori develop stomach cancer, and how genetic variations in the bacterium affect human disease and transmission. She also works to understand how a person’s immune response to the bug influences the course of their infection.
Dr. Jhimmy Talbot studies how interactions between neurons and immune cells in the gut can help the body balance its immune and metabolic trade-offs. The gut balances two competing needs: bringing nutrients in and keeping pathogens out. Talbot showed that in the presence of food, certain gut neurons can increase nutrient absorption by reining in the activity of a specialized subset of immune cells that act to increase the gut wall’s barrier function by decreasing its permeability. His work reveals how changes in the diet or in the intestinal microbiota may lead to metabolic dysfunction and how neuroimmune interactions could be hijacked by microbes to enable infection.
Disruptions in the proliferation, migration and signaling of cells in the brain can lead to disease and mental illness. Researchers in the division study the mechanisms behind these complex systems to better understand nervous system function and the underlying causes of neurological disorders, including brain cancers.
Dr. Jihong Bai studies how the brain works. He uses tiny worms called nematodes, specifically C. elegans, to understand the basic mechanisms underlying the brain’s ability to produce sensation, perception and behavior. His research includes three major directions: how brain cells talk to one another; how they act together to produce behaviors; and how brain circuits integrate multiple sensory inputs to make decisions.
Dr. Linda Buck studies the sense of smell. In 2004, she received the Nobel Prize in physiology or medicine, shared by Dr. Richard Axel, for discovering hundreds of receptors for odors in the nose and uncovering how information from those receptors is organized in the nose and then the brain. Dr. Buck found that these receptors are used in a combinatorial fashion to detect different odors and encode their unique identities and scents. Her lab continues to unravel networks of neurons responsible for the sense of smell as well as odor effects on stress and appetite, two areas important for human health.
Dr. Cecilia Moens studies how genes control the brain’s early development, setting up the complex structure found in adult brains. She uses zebrafish as a model system in which to understand how genes control important processes, such as how cells grow and change into new cell types, and how they move and communicate with each other in a 3D environment over time. These processes are exquisitely regulated in developing organs — but the same genes that control development can promote cancer when awakened in adult tissue. A deeper understanding of the genes that control these processes will also shed light on what goes awry in cancer. Dr. Moens also focuses on the relationship between neuron location, identity and function. She is working to understand how cranial motor neurons, which control muscles in the head and neck, move to the right location, acquire their identity as motor neurons and become part of a functional, muscle-controlling circuit.
Dr. Akhila Rajan studies how bodies sense how much energy they have available, and how this information then influences factors such as activity and hunger. Our bodies store energy as fat, to be used later when external sources of energy run low. How much energy is stored is an important piece of information that influences behavior. For example, as our bodies sense that our energy stores are dropping, hunger, and the drive to find more food, will increase. But a dysfunctional energy-sensing system may underlie obesity, in which our bodies may not properly sense that we have enough energy stored already. Dr. Rajan uses fruit flies to understand how fat signals the brain, and how chronic nutrient surplus disrupts this communication. She hopes to reveal fundamental insights into this nutrient-sensing network that could point the way toward strategies to tackle obesity.