Christopher D. Lima, Ph.D.
Memorial Sloan-Kettering Cancer Center
Christopher Lima doesn’t pick easy problems. A structural biologist, he is
investigating how cells attach small proteins—like ubiquitin and the
related molecule SUMO—to other proteins to modify their function or fate.
Alongside those studies, he is exploring the molecular mechanisms that
underlie RNA processing and degradation—modifications to an RNA copy of a
gene that influence its stability and ability to be used as a template for
protein production. These fundamental cellular processes present challenges,
because the cellular machines that carry them out are complex, often made
up of many proteins or parts. Further, they involve reactions in which many
of the structures Lima is trying to study exist only temporarily, changing
quickly as the reactions proceed.
Lima is known for using ingenious methods and sheer persistence to determine
the structures of the proteins and complexes involved in RNA processing and
protein modification and following up with genetic and biochemical
experiments that clarify how they function in cells. His work is revealing
how an RNA-degrading complex called the exosome recognizes damaged or
unneeded RNAs; how the small protein SUMO, which helps direct proteins to
certain parts of the cell and influences their interactions with other
molecules, gets attached to its targets; and how these processes are
regulated.
Harmit S. Malik, Ph.D.
HHMI Early Career Scientist
Fred Hutchinson Cancer Research Center
Tales of battles, ancient and modern, are written in our genes—and Harmit
Malik is their Homer. A geneticist, virologist, and evolutionary biologist,
Malik chronicles an endless genetic arms race not just between organisms and
pathogens but also within an individual species’ genome.
Malik sees the human genome as a tapestry documenting past evolutionary
conflicts. Delving deeper into genes that help fend off viral invaders,
Malik and his colleagues have shown that adaptations in those genes offer a
record of virus evolution. That insight created a whole new field, indirect
paleovirology, in which scientists try to identify ancient viruses by virtue
of the imprints they left on the evolution of host genes. The structure of
our genome reflects a “negotiated truce,” he says, and the best way to
understand that truce is to reconstruct the events that produced it. This
approach has profound implications for medicine as well as science, because
it uncovers new antiviral strategies, new mechanisms of immunity, and new
clues about autoimmune diseases like lupus.
Malik’s lab is also investigating evolutionary competition between
components that are involved in the essential process that ensures that
chromosomes divide and segregate equally during cell division. He has
pioneered the idea that chromosomal competition for evolutionary dominance
can drive the unexpectedly rapid evolution of these essential components.
These findings have direct implications for how chromosomal imbalances can
occur in cancer and for how two recently diverged species can become
reproductively isolated from each other.
Tirin Moore, Ph.D.
HHMI Early Career Scientist
Stanford University
Tirin Moore wants to understand how the brain’s sensory and motor networks
work together to produce higher cognitive functions. His studies of the
neural circuits and processes that control visual attention are advancing
scientists’ understanding of how the human brain extracts information from
the environment to guide behavior.
Moore identified the neural circuitry that enables us to focus our visual
attention on something of interest while ignoring irrelevant information in
the visual field. His research showed that neurons in the brain’s
prefrontal cortex that were previously known to control eye movement also
help focus attention, even in the absence of movements. When an animal plans
a gaze shift to a visual target, the prefrontal neurons fire more strongly.
This action modulates signals within the visual cortex, where visual
information is processed, which in turn enhances sensory signals related to
the target, and thus attention.
Moore believes that defects in this function are the root cause of attention
deficit hyperactivity disorder (ADHD) and that his research could lead to
improved treatments for this and other conditions that impair attention. For
example, people with ADHD have abnormal dopamine transmission in the
prefrontal cortex. He showed that altering dopamine levels within the
prefrontal cortex in the brains of macaque monkeys increased the fidelity of
sensory signals within the visual cortex, just as voluntarily directed
attention does.
Moore’s comprehensive studies of visual attention continue, and as he
develops new tools to address fundamental problems in systems-level
neurobiology, he intends to expand his research to other perceptual and
cognitive functions.
Vamsi K. Mootha, M.D.
Massachusetts General Hospital
Vamsi Mootha has a passion for mitochondria. These ancient cellular
organelles, which house the cell's power generators, can cause a host of
diseases when they malfunction. Mootha first learned of these conditions as
a medical student, and began both doing basic research on the organelle and
seeing his first patients with mitochondrial disease. These experiences led
him to dedicate his research training and professional lab to the biology of
this organelle.
Mootha aims to bridge the divide between molecular studies and the
physiology of complex systems. Mitochondria contain small amounts of their
own DNA, and Mootha was struck by how much research on mitochondrial
diseases focused its search there—even though most mitochondrial proteins
are actually encoded by DNA in the cell's nucleus. Using his background in
math and computational biology, he set out to create a more complete picture
of mitochondrial biology and its contribution to disease.
He has since resolutely pushed the field forward. On the physiology side,
his lab characterized the molecular identity of the mitochondria's calcium
uniporter, a key channel of communication between the organelle and its cell
. And on the disease side, he used cutting-edge and innovative approaches to
define the 1,100 proteins in mammalian mitochondria, developed
computational tools to predict protein function, and linked mitochondrial
gene mutations to human disease.
In less than a decade, Mootha's work in basic biology has led to genetic
diagnostics, prenatal screens, and a more complete understanding of an
organelle that can be involved in a multitude of common diseases, including
neurodegeneration, type 2 diabetes, and cancer. He sees hundreds of
mitochondrial components still waiting to be characterized, a multitude of
genetic and cellular pathways to describe, and the potential to find cures
for some devastating disorders.
Dyche Mullins, Ph.D.
University of California, San Francisco
Dyche Mullins says the most interesting questions in his lab often boil down
to this: How does a mindless mob of macromolecules actually become a living
cell? To achieve the sort of spatial organization associated with even the
simplest cells, tiny molecules must transmit and integrate information
across long distances—hundreds to hundreds of thousands of times their own
length.
One way to establish such long-range order is to assemble the individual
molecules into larger, ordered structures: membranes, cell walls, and
cytoskeletal polymers. The actin cytoskeleton, made up of actin filaments
and other molecules, is one such complex assembly. It enables cells to
change shape, to move, to transport cargo, and to establish polarity (making
one end of the cell different from the other). Scientists in the Mullins
laboratory focus on learning how cytoskeletal polymer networks are assembled
, how they function, and what roles they play in prokaryotic and eukaryotic
cells.
Mullins has discovered some of the key molecules and mechanisms that
choreograph assembly of the actin cytoskeleton. In particular, he showed
that a protein complex, called the Arp2/3 complex, creates branching
networks of filaments that push forward the leading edge of crawling cells.
His laboratory also identified mechanisms of actin assembly carried out by
proteins such as Spire and JMY, both of which are required for normal
embryonic development. In addition to identifying regulators and
understanding how they work, the Mullins laboratory is investigating how
cytoskeletal systems contribute to health problems such as drug-resistant
infections, metastatic cancers, and developmental defects.
Evgeny Nudler, Ph.D.
New York University
Taking risks and venturing into new areas of research have been common
threads in Evgeny Nudler’s career. He has made major discoveries in topics
as diverse as the mechanics of RNA synthesis, cellular adaptations to stress
, and bacterial resistance to antibiotics.
Nudler illuminated a fundamental principle of RNA synthesis, showing that
RNA polymerase works like a ratchet, powering forward and then backtracking
as it makes RNA. He then showed that this herky-jerky motion, which he
called “backtracking,” helps cells manage RNA growth and allows for gene
regulation and proofreading.
Nudler’s lab and another group discovered independently that messenger RNA
molecules called “riboswitches” sense cellular levels of metabolites—such
as vitamins, amino acids, ions, and other small molecules—and adjust gene
activity accordingly. Nudler’s group also identified an RNA molecule in
mammalian cells that, in combination with another factor, plays an important
role in sensing heat and other protein-damaging conditions.
Another discovery by Nudler’s team revealed a previously unknown defense
mechanism that bacteria use to fend off antibiotics. Humans use nitric oxide
and hydrogen sulfide to control physiological functions ranging from blood
pressure to neurotransmission. Nudler’s team has shown that bacteria
produce and use these gases for a different purpose—to protect themselves
from antibiotics, oxidative stress, and the immune system of their host.
Nudler next wants to learn how the bacteria that dwell harmlessly inside
other organisms, including humans, influence the aging of their hosts. To
tackle this question, he and his colleagues are now designing probiotic
strains of bacteria that significantly extend the lifespan of the roundworm
Caenorhabditis elegans.
Ardem Patapoutian, Ph.D.
Scripps Research Institute
Touch provides us with crucial information about our environment, yet it
remains poorly understood at the molecular level. Touch-sensitive cells can
warn of danger from hot, cold, and toxic substances. These cells can also
tell us when we experience a gentle touch or when a hammer accidentally hits
our finger. The sensing of mechanical forces and their translation into
chemical signals influence a variety of biological processes. Hearing
depends on mechanosenstion, and the sensory modality also controls the
function of the heart, blood vessels, lungs, and kidney.
Ardem Patapoutian has advanced the understanding of thermosensation with the
discovery of ion channels in touch-sensitive cells that respond to changes
in temperature. He calls them the body's molecular thermometers. For example
, one of them preferentially responds to cool temperatures and the cooling
compound menthol. Another, which also responds to cold, is a general sensor
of noxious chemicals, including ingredients in garlic and wasabi. Its
activation causes pain and inflammation.
How cells sense mechanical forces, like pressure and stretching, is one of
the last big unsolved questions in vertebrate sensory research, Patapoutian
says. It has proven difficult to pinpoint the molecules underlying cells'
sensitivity to mechanical forces, but here Patapoutian has broken new ground
, identifying two novel ion channels, Piezo1 and Piezo2, that are
responsible for that sensitivity. These channels are present in a wide
variety of tissues, and Patapoutian plans to investigate how they function
to regulate various biological processes, as well as how they may contribute
to disease. At the same time, he will continue to search for other sensory
ion channels.
