With grants between $1 million and $1.5 million to individuals and scientific teams, these researchers receive enough funding to produce momentum in their respective fields.

Allen Distinguished Investigators are passionate thought leaders, explorers, and innovators who seek world-changing breakthroughs. Their ideas are transformative and their scientific insights are game-changing. What the Investigators share is a pioneering spirit, the ability to imagine possible futures of science, and the ability to create new ways of thinking to share with the world.

Talent is everywhere. Allen Distinguished Investigators may come from small universities or large institutions, cities, or towns across the world. We explore the landscape of bioscience to identify distinguished leaders who will make a difference.

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2022

Nutrient Sensing

Researchers in this cohort are developing new technologies to measure or visualize nutrient levels within cells. Their work addresses a key need in the field, namely the ability to capture detailed information about metabolites, chemical compounds, and other nutrients in live individual cells. These new techniques could propel understanding of the basic biology of cells as well as how metabolism or nutrition processing goes wrong in diseases like diabetes or malnutrition.

Expansion Mass Spectrometry: Literally Stretching Metabolite Sensing to New Spatial Limits

Right now, there’s no good way to measure the distribution of nutrients inside individual cells. Lydia Kisley and Laura Sanchez are leading the development of a technique to address this problem by physically expanding cells — picture a cell stretched on silly putty — and capture details of nutrient location and amount in those cells. Their new method is called Expansion Mass Spectrometry and the scientists plan to use it to study nutrients in and around ovarian cancer cells to better understand metabolism in these cancer cells and how cells’ local environments influence nutrient location and amounts.

Spatial nutrientomics based on DNAzyme and DNA aptamer sensors

Yi Lu is leading a project to engineer DNA molecules in a variety of ways to detect and visualize nutrients in single cells. Because nutrients are often very small molecules — think individual sodium ions or sugar — it’s very difficult to capture them under a microscope using standard methods, and even methods that can detect small nutrient molecules have difficulty separating out nutrients of similar sizes. Lu’s technique aims to light up individual nutrients with DNA fluorescent sensors; the team will also develop methods to send these sensors to different parts of the cell simultaneously to visualize multiple metabolic reactions in the same cell.

Visualizing lipid nutrient turnover in human tissue models

Our bodies rely on fats and their molecular cousins, collectively known as lipids. These slippery molecules construct our cell walls and store 90% of our energy, and their dysregulation is associated with diseases like diabetes and fatty liver disease. André Nadler, Meritxell Huch, and Alf Honigmann are leading a project to apply a technology they developed to visualize lipids in cells using fluorescence microscopes. They’re now using this technique to study the turnover and transport of lipids in laboratory models of the two main organs for nutrient uptake and processing, the intestine and the liver.

Subcellular Compartmentalization of Metabolism

Our cells are incredibly diverse. Visualising the metabolism of individual cells is critical to understanding how our organs and body work. However, metabolic reactions happen in milliseconds in areas 50 times thinner than a human hair. Bilal Sheikh, Niculina Musat, and Hryhoriy Stryhanyuk are developing a new technology dubbed Meta-SCOPE to visualize metabolism in single cells, shedding light on important but to-date invisible cellular processes.

Protein lifespan

Proteins are the building blocks of life — nearly all cellular structures and processes are built and carried out by proteins. Do our proteins age like our bodies age? While scientists have discovered how cells turn over old proteins to create new forms, it’s not clear how lifespan varies among different kinds of proteins, what it means to have “old” proteins, or how the cellular environment could affect protein aging. Researchers in this cohort are building new technologies and designing experiments to address important questions around protein lifespan and aging.

Controlled labeling of the nascent proteome to track protein lifespan in mammalian cells

While techniques exist to capture the entire suite of proteins in an individual cell — also known as a proteome — it’s still difficult to capture the dynamics of protein synthesis and degradation on a large scale. To understand the variation of protein lifespan in the context of the entire proteome, Abhishek Chatterjee and Eranthie Weerapana are developing new technologies to tag and measure newly created proteins at specific timepoints. They’ll use this technique to study protein lifespan in a type of immune cell known as a T cell.

PRO-Watch: an approach to monitor protein lifespan in aging worms

Janine Kirstein and Tim Clausen are building a “protein lifespan” kit to carefully track the complete life cycle of a single protein. They’ll use a specially designed fluorescent tag to monitor the creation, maturation, aging, and degradation of a single muscle protein, myosin, in the microscopic worm C. elegans. They are also tracking mutated versions of myosin known to cause neuromuscular disease in humans, to understand how protein aging, misfolding and other aspects of protein lifespan might play a role in these diseases.

Precision live single-cell nano-surgery for revealing proteome dynamics

Current techniques to access and understand large numbers of proteins from individual cells involve mechanically or chemically breaking cells open. These disruptive methods kill cells and can significantly muddle the very biological processes researchers aim to study. Gary Mo is developing “nano-scalpels” to precisely extract proteins from cells. This relies on a newly discovered method to reverse pore formation on the cellular plasma membrane. Mo and his team will make these pores open and close on demand, allowing them to take tiny biopsies from inside cells. By keeping cells functioning throughout such operations, they aim to follow and reveal the key features of proteomic balance within living cells.

Ageing proteins: biology or chemistry? Systematic characterization of young and old proteins in vivo

Some proteins, like those in the lenses of our eyes, are as old as we are, while some proteins are created and degraded much more rapidly. How do cells know how old their proteins are, and how do they decide when to replace them? To understand these vast differences in protein aging and lifespan, Mikhail Savitski and Alexander Aulehla are leading a project to ask whether certain modifications on proteins mark their age or target them for turnover.

2021

Neural Circuit Design

Researchers in the Neural Circuit Design cohort are studying evolutionary principles in the brain circuits that control movement, focusing on animals and systems that are not traditionally studied in the laboratory. Their studies will flesh out a more complete picture of the diversity of nervous systems and motor neural circuits in the animal kingdom, as well as pinpointing common and conserved principles of motion and motor control.

Building a model of a complex brain unconstrained by shared evolutionary history

Robyn Crook, Ph.D., is leading a project at San Francisco State University to study the neural control of movement in cephalopods, animals that have the most complicated nervous systems of the invertebrate world. She and her team will map the neural connections, or connectome, in the octopus arm and, for the first time, capture real-time neural activity in the octopus brain as the animal moves in natural ways.

Identifying the circuit mechanisms of jumping in Scaptodrosophila larvae

Lucia Prieto-Godino, Ph.D., and Samuel Rodriques, Ph.D., are leading a project at The Francis Crick Institute to understand how a new kind of behavior arises in evolution. They will study brain cell types and circuits in larvae of a species of fruit fly that has evolved to jump 10 times their body length in the air, and then compare those to a related fruit fly species that cannot jump.

Reconstructing the development and functional architecture of the motor neural circuits of the last common animal ancestor

Where did modern nervous systems come from? Joseph Ryan, Ph.D., Mark Martindale, Ph.D., and James Strother, Ph.D., are leading a project at the Whitney Laboratory for Marine Bioscience to better understand the nervous systems of ctenophores, marine animals also known as comb jellies that represent one of the oldest branches of the animal kingdom. By mapping these evolutionarily ancient animals’ neural circuits and studying their neural development, the researchers will provide insight into the earliest animal nervous systems and shed light on general principles of modern brains.

Micropeptides and immunity

Our genomes contain vast amounts of DNA that remain poorly understood. A recent arrival on the scene of genomic “dark matter”: micropeptides, tiny proteins coded by tiny genes that had long escaped notice due to their size but that appear to be present in large numbers in our genome and that of every other living thing. These small molecules likely play roles in many different biological processes; scientists are recently uncovering their influence in several different diseases and in the function of the immune system. Scientists in the Micropeptides cohort are shedding new light on how micropeptides influence immunology, in health and in disease.

Mining the human gut microbial microproteome for modulators of inflammation

The human microbiome, the bacteria and other microbes that live in and on us, is inextricably interwoven with our health. Ami Bhatt, M.D., Ph.D., Michael Bassik, Ph.D., and Livnat Jerby, Ph.D., are leading a project at the Stanford University School of Medicine to look at the role of the gut microbiome’s micropeptides, tiny proteins that are themselves poorly understood, in human health and disease by studying how these micropeptides send signals to our immune cells.

Discovery of micropeptides in human immune cells and systemic lupus erythematosus

Sarah Slavoff, Ph.D., Grace Chen, Ph.D., and Joseph Craft, M.D., are leading a project at Yale University to explore the roots of the devastating autoimmune disease lupus, in which a patient’s immune system attacks their own organs. Ancient viral DNA sequences, known as human endogenous retroviruses, are permanently stitched into our genomes and, mysteriously, are linked with several human diseases including lupus. The team will investigate the hypothesis that human endogenous retroviruses produce tiny difficult-to-detect proteins known as micropeptides that could drive lupus.

The origin, evolution, and dynamics of micropeptides in the immune system

Li Zhao, Ph.D., and Mandë Holford, Ph.D., are leading a project at The Rockefeller University and CUNY Hunter College to better understand how immune genes that code for tiny proteins known as micropeptides arise in evolution. The team will characterize many poorly understood immune-related micropeptides in humans and fruit flies and focus on an evolutionarily new fruit fly micropeptide to better understand its function in the immune system and how it evolved.

Synthetic biology advances for human tissues

The field of synthetic biology has made incredible advances in recent years, and yet the complexity of mammalian biology presents an additional challenge for scientists aiming to engineer tissue or organoids in the lab. The investigators in the Mammalian Synthetic Development cohort are working to cross many of the barriers to mammalian synthetic biology, including several approaches to improve the development and engineering of organoids, lab-grown mini-organs typically derived from human stem cells. Their work spans many parts of the human body, including the liver, lungs, brain, and connective tissues.

Engineering the stromal secretome to program organ development and maturation

Pulin Li, Ph.D., is leading a project at the Whitehead Institute for Biomedical Research to improve the development of organoids, lab-grown mini-organs grown from human stem cells, by introducing a type of supportive tissue known as the stroma. Organoids that include a more complex and complete suite of tissues like the stroma may yield more information about human health and disease, as well as allow for rapid and accurate preclinical drug testing.

Actuoids: guided tissue morphogenesis using soft actuation

Adrian Ranga, Ph.D., is leading a project at KU Leuven to apply the emerging field of “soft robotics” to brain organoids, lab-grown mini-brains derived from human stem cells. Currently, brain organoids are missing several key structures and physical attributes of the real thing, which may be due in part to a lack of natural mechanical forces that shape and influence our developing brains. Ranga and his team will use newly developed materials and devices to stretch and fold brain organoids as they grow in the hopes of creating more life-like mini-brains for use in basic research and drug discovery.

Mid-terminal human synthetic liver organogenesis

A better understanding of how human livers develop could allow researchers to grow new organs in the lab, filling a clinical need for transplantation for those with late-stage liver disease. Kelly Stevens, Ph.D., is leading a project at the University of Washington to explore the complete suite of factors involved in human liver development, including chemical cues, mechanical forces, blood supply, and environmental factors.

Engineering branching networks through synthetic turing morphogen circuits

Wilson Wong, Ph.D., Chris Chen, M.D., Ph.D., and Darrell Kotton, M.D., are leading a project at Boston University to test a classic but unproven theory about how our lungs develop their complicated branching structures. The researchers will develop new tools to genetically engineer lung cells derived from human stem cells and attempt to recreate lung tissue’s complex branching in the lab. Ultimately, these tissues could be used in therapeutics for lung cancer and other lung diseases.

A fate-mapped human pluripotent stem cell library for designer organoids

Nozomu Yachie, Ph.D., Nika Shakiba, Ph.D., and Josef Penninger, M.D., are leading a project at the University of British Columbia to trace the “family trees” of individual stem cells as they grow and divide into organoids, lab-grown mini-organs. Better understanding of how organoid tissues are formed will help the scientists direct cell fates to more precisely engineer different kinds of organoids. The team is also working to introduce blood vessels into organoids to sustain their growth in the lab for longer.

2020

Cell Nucleus

Allen Distinguished Investigators in the Cell Nucleus cohort study the interplay between the nucleus, the largest organelle in our cells and the information center that houses our genome, and other key structures in the cell. In recent years, new technologies have made new explorations of nucleus biology possible, enabling large collaborative projects such as the National Institutes of Health-funded 4D Nucleome program. As holistic understandings of the nucleus advance, studies that explore relationships between this organelle and other parts of the cell will further our understanding of the nucleus in health and disease.

New models for nuclear homeostasis: integrating force, flow, and pressure

How does the nucleus keep its size and shape? Megan King and Simon Mochrie are leading a collaborative team to study the physical and molecular forces that maintain the correct size of our cells’ largest organelle, the nucleus, which maintains a characteristic volume in healthy cells. This size maintenance is often thrown out of whack in diseases such as cancer, but the mechanisms underlying its maintenance remain unclear.

In vivo analysis of nuclear mechanics and mechanotransduction

Daniel Starr and GW Gant Luxton are studying a protein complex known as LINC, whose role is to physically connect the nucleus to the cell’s interior scaffolding system, otherwise known as the cytoskeleton. The LINC complex is involved in translating mechanical forces inside the cell into chemical signals, but how that translation happens and how it is regulated remains unknown. In many diseases, including cancer, heart disease, muscular dystrophy, and neurodegenerative disorders, cells lose the ability to correctly translate these cues.

Nuclear-endoplasmic reticulum communication during normal remodeling and pathological alteration of these organelles

Katharine Ullman and Maho Niwa are leading a research project to investigate the interactions between the nucleus and one of its neighboring organelles, the endoplasmic reticulum. These two cellular structures are joined at the hip — together, their outer borders form one continuous, folding membrane. Despite their close connections, these structures are often studied independently, and their influences on each other beyond gene expression changes remain poorly understood. Ullman and Niwa plan to study their interactions under several different circumstances; their findings could shed light on basic cell biology and diseases like cancer in which nucleus-endoplasmic reticulum crosstalk may go awry.

Immunometabolism

Just like us, immune cells need fuel to do their jobs. Despite the tight links between human health — including our immunity — and how our bodies process what we eat, the intersection of immunology and metabolism remains a poorly understood area of human biology. Allen Distinguished Investigators working in the emerging field of immunometabolism are exploring new avenues of basic biology, health, disease, and technology development, all focused on unanswered questions about how the immune system and metabolism work together.

Decoding the 3D immuno-metabolic circuitry

All of us are made up of trillions of cells, yet it is unclear how these cells simultaneously behave as individuals and as part of a collective that makes up who we are. Drs. Will Bailis, Chris Bennett, and Ruaidhrí Jackson are leading a project to better understand the many links between immunity and metabolism at the scale of individual cells, organs, and the entire body. These inextricable links — how our diet affects our immune system, and how our immune cells in turn change metabolism — tie into all aspects of human health and disease, including cancer, diabetes and heart disease. Using laboratory mice, the researchers will study how an animal’s food affects energy production inside immune cells by genetically engineering those cells to “ignore” changes in diet. In tandem, they will study how one particular type of immune cell, known as tissue resident macrophages, uses metabolism to govern not only its own cellular function, but the function of tissues and the entire body.

Distinct immune-metabolic niches in inflammatory bowel disease

Inflammatory bowel disease, or IBD, is a class of immune diseases that stem from chronic inflammation in the intestines. Patients with IBD have widely varied symptoms and responses to treatment which can’t be fully explained by human genetics. Drs. Aida Habtezion, Nandita Garud, and Carolina Tropini are leading a project to explore how patients’ immune responses, metabolism, gut microbiomes, and environments may contribute to that variability, using a registry of hundreds of IBD patient volunteers. A better understanding of the details of variation between patients, and the reasons behind that diversity, could lead to better, more tailored treatments for this class of often crippling illnesses.

Defining infection-induced metabolic reprogramming: from cells to systems

Like all cells, our immune cells need energy from the food we eat to do their jobs. Drs. Russell Jones and Yasmine Belkaid have recently found that T cells, an important type of immune cell that surveys the body and detects and eliminates infected cells, use multiple kinds of fuel when they are working their hardest. Now, they are leading a project to better understand T cells’ preferred fuel sources, uncovering which types of T-cell metabolism are needed for optimal infection-fighting and which types might lead to immune dysfunction.

Bioluminescent tools for noninvasive, real-time imaging of immunometabolism

To better understand the immune system and how it dovetails with metabolism, researchers need better toolkits to track and manipulate multiple kinds of cells and molecules at once, over time, in a living animal. Drs. Jennifer Prescher and Michelle Digman are leading the development of a new technique to shine “biological flashlights” on many different immune- and metabolism-related molecules at the same time. The technique, which they dub bioluminescent phasor, will ultimately yield a large toolkit of optical tags that can light up multiple processes or proteins in the laboratory mouse’s immune system at once. Once complete, the toolkit would be available for any research lab to use, opening new avenues for discoveries about the immune system and its relationship to our diet.

Disease Models

For many disease states, the fundamental mechanisms and biology underlying multicellular development and regeneration are still a mystery. Given limitations with current animal models, several research groups are now turning to human-induced pluripotent stem cells to better model biological processes inherent in human health and disease. These Allen Distinguished Investigators are using human stem cells in innovative studies that address important outstanding questions in human disease and basic biology and will generate new methods to benefit others in the scientific community.

Early manifestations of subcellular defects in neurodegenerative diseases

Neurodegenerative diseases like Alzheimer’s or ALS typically show their devastating effects late in life, but some research hints that the diseases could affect our cells much earlier in life, possibly even before birth. Gene Yeo is leading a team investigating this possibility using human stem cells and brain organoids, tiny clusters of lab-grown brain tissue, that bear genetic mutations linked to certain forms of ALS or muscular dystrophy to study the earliest developmental changes caused by these mutations. Understanding these early effects could point to new pathways for targeted therapies.

Spatial Single-Cell Technologies

Recent advances in single-cell technologies have revealed new insights about cells’ variability and complexity. Allen Distinguished Investigators working in this area are developing new techniques to study cells one at a time in the context of their native environments — in a tissue or whole organ — that will allow them to capture the cues and signals unique to this natural context, the cells’ so-called microenvironment.

Tracking proteome dynamics in single cells

Recent single-cell technology advances reveal detailed molecular information from individual cells, but many of these methods capture snapshots of a single point in time, missing the dynamic changes of proteins or other molecules inside individual cells. Nikolai Slavov is leading the development of a new technique, dubbed SCoPE-Dyn, that will allow researchers to follow an individual cell’s “protein travelogue”: the changes over time in hundreds of different proteins across thousands of human cells. This method expands on a previous technique Slavov and his colleagues developed, SCoPE2, that uses mass spectrometry to capture protein amounts in single cells, adding the fourth dimension of time to uncover changes in each protein. Understanding these details in individual cells could ultimately lead to improvements in the emerging area of targeted protein degradation therapeutics, therapies which harness the cells’ protein turnover mechanisms to treat diseases like cancer or Alzheimer’s disease.

Past Allen Distinguished Investigators

The Allen Distinguished Investigator program was launched in 2010 by the late philanthropist Paul G. Allen to back creative, early-stage research projects in biology and medical research that would not otherwise be supported by traditional research funding programs. A total of 130 Allen Distinguished Investigators have been appointed during the past 12 years. Each award spans three years of research funding.