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December 22, 2005
2005 HHMI International Research Scholars: Baltics, Central and Eastern Europe, and Russia
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Peter Chumakov
Englehardt Institute of Molecular Biology
Moscow, Russia
Prevent a key antioxidant enzyme from doing its job, and cancer may
develop. Peter Chumakov wants to know why. As the head of the Cell
Proliferation Laboratory at the Englehardt Institute of Molecular
Biology in Moscow, Russia, Chumakov has spent the last 10 years
uncovering mechanisms of disease prevention, specifically those
involving the p53 tumor suppressor gene—known as the
“guardian of the genome.” His landmark 2004 paper in
Science magazine established that p53-regulated molecules
called sestrins function as antioxidant enzymes, protecting the genome
against DNA-damaging oxygen reactions. Sestrins help re-establish DNA's
defenses against oxidation by removing harmful peroxide formed during
cell signaling. As an HHMI international research scholar, Chumakov
will build on that work by investigating the role sestrins play in
normal cell signaling as well as in disease development—looking
specifically at how the inhibition of sestrins may contribute to the
development of cancer.
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Edward Darzynkiewicz
Warsaw University
Warsaw, Poland
Most cap designers work on headgear, but biochemist Edward
Darzynkiewicz has spent his career studying another kind of cap, the
cap structures on messenger RNA molecules (mRNA). These molecules are
critical for the ribosome—a large molecular complex where
proteins are synthesized—to recognize the RNA so it can begin
translating the information it encodes into protein. Messenger RNAs of
important human parasites, such as nematodes, have unique cap
structures, and Darzynkiewicz thinks that proteins that interact with
these caps may be useful drug targets. Understanding the underlying
mechanism of the interactions of cap structures and the proteins that
bind them could also lead to new drug targets for cancer. Having
previously synthesized a library of over 200 cap analogs, his team has
also developed fluorescence methodologyto easily study cap-binding
interactions. That should aid in the design of new cap analogs able to
inhibit cap-binding proteins and thwart disease agents.
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Olga Dontsova
Moscow State University
Moscow, Russia
Protein synthesis in the ribosome is a very efficient and highly
coordinated process that occurs through certain stages involving number
of specific ligands or binding chemicals. During different translation
stages the functional centers of the ribosome should communicate. Olga
Dontsova is using biochemical and genetic approaches to unravel the
molecular basis for such communication, as well as the dynamics of the
translational apparatus as amino acids are added to the forming
protein, a process known as translation elongation. These data should
reveal new potential binding sites for antibiotics to block translation
in bacteria. Dontsova will also explore how transfer-messenger RNA,
which rescues ribosomes stalled because they lack a stop
codon—the nucleotide that signals protein synthesis to
end—can be rearranged to enable it to pass through the ribosome.
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Miklós Erdélyi
Institute of Genetics, Hungarian Academy of Sciences
Budapest, Hungary
A developing embryo must rely on external factors, primarily from
the mother, to direct its initial development. Hungarian molecular
geneticist Miklós Erdélyi intends to use cDNA
microarrays, a technology that enables scientists to identify levels of
gene expression in a biologic sample, to identify novel RNA copies of
genes that are found only in reproductive cells. He wants to identify
the ones that contribute to maternal control of embryo development and
to investigate their roles in differentiation of the embryo's
reproductive cells. In addition to determining how many of these
specialized RNAs exist in Drosophila, he also hopes to link
specific RNAs with observable traits related to reproductive cell
development. Erdélyi hopes to identify those that have been
evolutionarily conserved from Drosophila to mice.
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Alexei Finkelstein
Institute of Protein Research
Moscow, Russia
Solving the multi-dimensional problem of protein folding is more
than an academic Rubik's cube. It may provide insights into diseases
such as Alzheimer's and type 2, or adult-onset, diabetes. Having helped
determine how a protein finds its own unique fold among millions of
alternatives, Alexei Finkelstein, an HHMI international research
scholar for over a decade, is taking on a new challenge: how to predict
the unique fold from the amino acid sequence of a protein chain. To do
so, he'll seek to develop a new force field—the calculations used
to determine the strength of molecular interactions—to improve
protein structure prediction as well as drug design. Improved accuracy
in these calculations should help determine folding of larger proteins,
as well as folding in a complicated environment. Using a new approach
based on the solubility of molecular crystals, Finkelstein believes he
can help drug designers better hit their mark.
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Tamás F. Freund
Institute of Experimental Medicine,
Hungarian Academy of Sciences
Budapest, Hungary
Cannabinoids—mind-altering chemical compounds that can be
introduced into the body by smoking cannabis—also can be
manufactured inside the brain. Those compounds are called
endocannabinoids, and their molecular mechanism of action may shed
light on the development of anxiety and memory loss. Recent research
revealed that neurons release a unique signaling molecule, thought to
be an endocannabinoid, which scientists were surprised to find works by
suppressing the release of neurotransmitters. Malfunctioning of this
signaling system may result in learning and memory loss, as well as
anxiety disorders. Tamás Freund will explore the role of
endocannabinoids in neuronal signaling, extending10 previous years of
research to identify the mechanisms of action of cannabinoids in the
cerebral cortex and basal ganglia, a group of nuclei in the brain
associated with motor and learning functions. Although only a handful
of endocannabinoids have been found so far, Freund hopes to identify
the entire cascade of molecular events involved in this unusual
communication between neurons. A better understanding of the molecular
machinery at work could lead to new and more effective treatments for
anxiety and drug dependence. This is Freund's third HHMI international
research scholar award.
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Maria Borisovna Garber
Institute for Protein Research
Moscow, Russia
In biology, knowledge of a molecule's three-dimensional structure is
crucial to understanding its cellular function mechanism. X-ray
crystallography has been an important tool for investigating
biomacromolecular structures since the determination of the structures
of myoglobin and hemoglobin half a century ago. Maria Garber and her
team will use this tool to determine the protein structures used during
the process of translation of messenger RNA (mRNA) molecules to
synthesize proteins and regulate gene expression. Continuing into her
second decade as a HHMI international research scholar, she wants to
shed light—literally and figuratively—on the interactions
that enable specific proteins and RNA molecules to find one another
within the cell. Her targets include the proteins involved in the
initial step of translation, as well as proteins that regulate gene
expression in bacteria. Once the structures of those proteins are
known, she plans to introduce mutations to the RNA-binding sites of the
proteins to determine the interactions responsible for RNA-protein
recognition.
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Mikhail Gelfand
Institute for Information Transmission Problems,
Russian Academy of Sciences
Moscow, Russia
Mikhail Gelfand is one of a growing number of biologists who work at
a computer rather than a lab bench. While his counterparts work in
vivo, the bioinformatics specialist probes biological systems “in
silico.” Gelfand compares genomes of different organisms to
develop methods for identifying genetic regulatory signals, as well as
to predict the functions of genes. With his previous HHMI international
research scholar grant, he identified dozens of enzymes and
transcription factors this way, including a new class of cellular
regulatory elements called riboswitches. Now Gelfand will turn his
attention to the evolution of regulatory systems in bacterial genomes.
While seeking to establish a link between metabolic pathways and
regulatory networks, he plans to develop algorithms for large-scale
analyses of gene regulation. Gelfand will also test his hypothesis that
evolution favors the creation of many unique proteins from single genes
by a process called alternative splicing, generating greater potential
diversity even from related genomes.
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Pavel Georgiev
Institute of Gene Biology
Moscow, Russia
Even though it only lives roughly 37 days, the fruit fly has much to
teach humans about aging. Drosophila melanogaster has the
ability to maintain the length of its telomeres, structures at the ends
of a chromosome that prevent it from unraveling and losing important
DNA each time the cell divides. In humans, these structures dwindle
over time—a process many think is linked to aging. Pavel
Georgiev, a molecular biologist, intends to look for new genes
important for Drosophila's telomere functioning. To determine
what factors contribute to telomere elongation, Georgiev will test his
hypothesis that the structure of the telomere DNA in combination with
associated proteins plays a significant role. A HHMI international
research scholar for the past 10 years, Georgiev will work to unravel
the regulatory underpinnings of gene expression in Drosophila by
searching for the specific proteins involved.
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Lajos Haracska
Biological Research Center
Szeged, Hungary
To avoid cellular catastrophe, DNA replication demands the ultimate
in quality control. Error-prone replication without adequate DNA repair
is an open invitation to mutations and cancers. Lajos Haracska, a
molecular geneticist, is working to identify one of yeast's mutation
avoidance pathways. In yeast, the RADd5
gene—known to target proteins formodification by a small protein
called ubiquitin—plays a significant role in correcting the
replication of damaged DNA and avoiding mutation. Haracska wants to
identify the molecular events that occur in the RAD5 pathway. Having already purified key enzymes
involved inubiquitin conjugation, he plans to cause mutations in those
proteins' genes to elucidate their role in the pathway. His recent
finding—that Rad5 itself can also be targeted formodification
—may prove to be an important piece of the puzzle.
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Jana Kašpárková
Institute of Biophysics
Brno, Czech Republic
Jana Kašpárková is mining metals for their
anti-cancer activity. Metal-based anti-tumor drugs have already proven
remarkably effective against testicular and ovarian cancers. Some
metals, such as platinum and ruthenium, cause tumor cell death by
damaging DNA. Unfortunately, these drugs—of which cisplatin is
the most successful—also cause negative side effects including
ear damage, nausea, and vomiting. A biophysicist,
Kašpárková will study the unique aspects of the
altered forms of DNA resulting from exposure to metal-based compounds,
hoping to understand on a molecular level the toxicity to tumor and
normal cells. To do so, she will build on her own previous anticancer
drug design to study the gene alterations caused by metal-based drugs.
An HHMI international research scholar since 2001,
Kašpárková hopes her work will help improve
understanding of metal-based drugs' effectiveness and enable design of
anticancer drugs in this class with fewer side effects.
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Maia Kivisaar
Estonian Biocentre, Tartu University
Tartu, Estonia
Scientists often try to decipher the evolutionary script by probing
microbes in a pure laboratory culture. Molecular biologist Maia
Kivisaar is focusing instead on the adaptive molecular processes
microbes use in real-world conditions. Threats from competitors and
starvation are just a few of the stressors microbes face in their
environment. To better understand how enzymes that copy or repair DNA
with a high error rate can increase mutation rates and accelerate
genetic adaptation—Kivisaar is hunting for novel genes that
affect the microbe Pseudomonas' mutation frequency. She also
hopes to determine the connections between the activation of DNA
polymerases and the efficiency of DNA repair pathways. In her first
five years as an HHMI international research scholar, Kivisaar
documented mutagenic mechanisms specific to Pseudomonas putida
cells suffering long-term starvation. She hopes her new research will
provide important insights into antibiotic resistance and
pathogenesis.
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Alexander Konstantinov
A.N. Belozersky Institute of Physico-Chemical Biology,
Moscow State University
Moscow, Russia
To generate energy, a cell reduces molecular oxygen to water, a
process known as respiration. This reaction is catalyzed by special
enzymes called oxidases, which act as primary molecular electricity
generators. That electrical energy is used by other enzymes to generate
adenine triphosphate (ATP), a high energy phosphate molecule used to
store and release energy for work within the body. The mechanism by
which oxidases generate molecular electricity is a process known as
“proton pumping.” Alexander Konstantinov wants to
understand the molecular mechanism of proton transfer across the cell
membrane, as well as the molecular mechanism of the coupling between
electron and proton transfer in oxidases. He will compare several types
of mitochondrial and bacterial cytochrome c oxidases (COX) in the
cell's energy production site, where O2, the most
common form of oxygen, is reduced as protons are pumped across a
membrane. He can do this because the three-dimensional structure of
mitochondrial and bacterial COXs have recently been solved. An HHMI
international research scholar since 2001, Konstantinov has devised an
approach combining a laser-based introduction of electrons and a
measurement tool to determine membrane potential, to help him
discriminate between steps in the pathway. He plans to use this
approach to trace the entire trajectory of energy-producing hydrogen
ions through the protein.
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Astrid Krmpotic
Department of Histology and Embryology, University of Rijeka
Rijeka, Croatia
Natural killer (NK) cells play an important role in the immune
system's early response to viral infection. But certain viruses such as
cytomegalovirus (CMV) and other widespread infective agents have
evolved mechanisms to elude virus control by NK cells. Such viruses can
subvert NKcells using a set of proteins known as immunoevasins, which
interfere with the elimination of virally-infected cells. Astrid
Krmpoti hypothesizes that viral immunoevasins, which down-regulate
the expression of ligands—chemicals that bind to a dominant
activating NK cell receptor called NKG2D—enable the virus to
avoid immune recognition not only during the primary infection, but
also during reactivation from latency. She has proposed a series of
studies to elucidate the role of CMV-immunoevasins in helping the virus
evade NK cells and CD8+ T-lymphocytes, another kind of cell
involved in the immune response. Krmpotic hopes that her studies
will help determine whether the inhibition of the NKG2D receptor is
linked to the quality of the adaptive immune response to CMV.
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Maris Laan
University of Tartu
Tartu, Estonia
Millions of women worldwide have trouble conceiving a child.
Geneticist Maris Laan will explore the genetics behind this
reproductive difficulty by investigating the association
between—identical chunks of DNA that are adjacent to one another
on a chromosome - known as tandem duplications —and reproductive
success. Such duplications account for more than five percent of the
human genome, and they may play a role in the conversion of one gene
variant into another, as they increase the chance that bits of DNA can
be unequally swapped between chromosomes. Re-sequencing a cluster of
genes that is critical for human reproduction, Laan found that gene
conversion stimulates their high variability. Now she will analyze and
compare gene sequences in fertile and infertile women of three
tandem-duplicated gene families associated with reproductive
success.
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Sergey Lukyanov
Shemyakin-Ovchinnikov Instute of Bio-organic Chemistry, Russian Academy of Sciences
Moscow, Russia
Designing new tools to kill cells selectively and to inactivate
proteins or nucleic acids using a beam of light are important
strategies for cancer therapy and cell studies. Photosensitizers are
light-absorbing molecules capable of translating light energy into
forms of oxygen known as reactive oxygen species, which can damage or
destroy biological molecules. Proteins that could work as
photosensitizers do not occur naturally in living systems, so Sergey
Lukyanov, a molecular biologist, plans to develop a genetically-encoded
photosensitizer from green fluorescent protein (GFP) homologues Leading
the field, the newly appointed HHMI international research scholar will
screen his collection of GFP-like proteins—one of the largest in
the world, amassed from diverse species—for those capable of
light-induced production of reactive oxygen species. Lukyanov plans to
test the anti-cancer activity of his novel cell killer in mouse tumors.
He also plans to use the genetically-encoded photosensitizer to develop
a technology known as chromophore-assisted light inactivation, allowing
precise photo-inactivation of a protein of interest in a living
system.
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Marta Miaczynska
International Institute of Molecular and Cell Biology
Warsaw, Poland
Cells could not carry out different metabolic activities at the same
time were it not for membranes separating those functions from one
another. In researching how cells compartmentalize their activities,
Marta Miaczynska, a molecular biologist, found a cellular
surprise—that some endosomes, the organelles that allow material
into the cell, may actually be involved in the cellular signaling
between the plasma membrane and the nucleus that is critical for cell
proliferation. Miaczynska previously discovered that two proteins,
called APPL proteins, are involved in this novel signaling pathway. The
new HHMI international research scholar will now attempt to determine
how the membrane trafficking machinery processes the signals. Her
long-term goal is to gain new insights into how intracellular
compartmentalization contributes to the overall signaling process.
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Ferenc Nagy
Biological Research Center, Hungarian Academy of Sciences
Szeged, Hungary
Can fireflies shed light on ways to prevent cell damage from
ultraviolet (UV) radiation? Molecular biologist Ferenc Nagy thinks they
can. As the ozone layer disappears, increasing UV radiation exposure
damages DNA in plants and animals, but scientists have not yet
identified the UV-absorbing receptor molecules in these organisms'
cells. This limits their ability to determine the resulting signaling
cascades leading to physiological damage. Nagy has exploited the
light-emitting properties of a firefly enzyme called luciferase to
develop a high-throughput, noninvasive imaging technology that he will
use to look for mutant genes in this pathway in seedlings of the
laboratory weed Arabidopsis.
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László Nagy
University of Debrecen Medical and Health Science Center
Debrecen, Hungary
It is no surprise that fat is at the heart of diseases such as
atherosclerosis. But scientists are just beginning to understand the
role lipids play in regulating genes involved in a broad range of
diseases. One gene known as peroxisome proliferator activated receptor
gamma, or PPAR, has been found to regulate diverse
aspects of lipid metabolism, including fat cell development and
glycerol metabolism.Molecular biologist László Nagy has
shown a potential link between two seemingly disparate
processes—lipid metabolism and inflammation. Now he plans to map
the transcriptional processes regulating the PPAR receptor. Rather
than focus on the more commonly studied mechanisms of transcription,
Nagy will investigate the mechanisms of transcriptional repression,
which he thinks may be just as important. The HHMI international
research scholar hopes to identify potential therapeutic mechanisms and
contribute to a better understanding of the regulatory roles of lipid
metabolism.
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Jozef Nosek
Comenius University
Bratislava, Slovakia
Not all DNA is created equal. DNA found inside the power plant of a
cell, the mitochondria, is typically a circular molecule, but a number
of organisms—from yeast to ciliates to slime molds—have
linear mitochondrial DNA. Jozef Nosek, an associate professor of
biochemistry, wants to know how and why they emerged in evolution. The
telomeres—the repetitive end sequences of linear DNA—are
absent in the circular form. Nosek will compare the linear chromosomes
present in the normal mitochondria of yeast to circularized mutants to
determine the principles guiding genome evolution. He has already shown
that the coding sequences in yeast's mitochondrial DNA are very similar
to counterparts in the circular mitochondrial genome of a close yeast
relative, and tht mitochondrial telomeres employ a similar maintenance
strategy as that of the ends of chromosomes of certain tumor cells. He
hopes that identifying the molecular mechanisms leading to the
evolution of linear mitochondrial genomes will shed light on the
biological role of telomeres, which many scientists think may provide
important protection against genomic instability and cancer.
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Zdena Palková
Charles University
Prague, Czech Republic
What makes a usually cooperative yeast turn pathogenic? The key may
lie in communication between microbes and between a microbe and a host.
Cells in microbial communities are capable of differentiation and of
effective changes in metabolism. Both of these survival mechanisms help
microbes cope with nutrient shortages. One of their important survival
mechanisms is the ability to change their metabolism. Microbiologist
Zdena Palková recently found that volatile ammonia serves as an
important signal for survival in yeast populations. She plans to
investigate the molecular mechanisms that enable yeast populations to
cope with stress, including adaptation, and to identify the features
that distinguish laboratory and wild strains of yeast. Palková
will explore how a yeast colony develops and is regulated. She hopes
that the basic mechanisms she uncovers will improve our understanding
of development, aging, and survival, as well as the behavior of yeast
that has become pathogenic.
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Michal Pravenec
Institute of Physiology, Czech Academy of Sciences
Prague, Czech Republic
From the complex mix of genetic and environmental factors that
contribute to cardiovascular disease, there may be a way to pinpoint
people who are genetically most at risk. Geneticist Michal Pravenec is
working to identify the genetic determinants of cardiovascular disease.
To do so, he plans to study unique rat strains which will enable him to
compare patterns of gene expression with pathophysiological traits such
as high blood pressure, increased blood lipids, or impaired insulin
action. Pravenic hopes to determine genes linked to heart disease.
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Gabor Tamás
University of Szeged
Szeged, Hungary
To function properly, neurons in the cerebral cortex—the
brain's region of learning, memory, and complex thought—must
strike a balance between excitation and inhibition. Neurobiologist
Gabor Tamás wants to define the role of slow inhibition in
information processing in the cortex. He will build on his recent
discovery of the first type of interneuron—a neuron that
communicates only with other neurons—capable of eliciting slow
inhibition. It acts through a receptor for GABA, an amino acid in the
central nervous system associated with transmission of inhibitory nerve
impulses. This receptor for inhibitory synapses also appears in the
parts of the neuron that control the cell's excitatory
synapses—motivating Tamás to explore its physiological
significance.
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Leos Valašek
Institute of Microbiology, Czech Academy of Sciences
Prague, Czech Republic
Building proteins is much like performing music—multiple
instruments work together to assemble a finished piece. To synthesize
proteins, a number of initiation factors must orchestrate the
multi-step process of protein translation, based on the score provided
by messenger RNA. Leoš Valášek, a molecular
biologist at the Institute of Microbiology at the Czech Academy of
Sciences in Prague, hypothesizes that a translation initiation factor
known as eIF3 that is found associated with several initiation factors
in the multifactor complex (MFC) works together with the other
consitutuents of MFC to initiate several key steps of protein
synthesis, including the accuracy of the selection of the first
methionine amino acid to be translated. To test his hypothesis, the new
HHMI international research scholar will mutate the binding sites that
mediate eIF3 interactions with other initiation factors and also seem
to make direct contact with the ribosome—a large molecular
complex where proteins are synthesized—to assess their
physiological importance. By analyzing the well-choreographed events
that guide translation, Valášek's work should produce a
better understanding of regulation of the fundamental process of
protein synthesis.
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Ceslovas Venclovas
Institute of Biotechnology
Vilnius, Lithuania
Without knowing a protein's three-dimensional structure, it's
extremely difficult tounderstand how it functions in the cell. When it
isn't possible to determine the structure solely using experimental
methods, virtual techniques can fill the void. Lithuanian computational
biologist eslovas Venclovas will use his computer modeling
expertise to improve the characterization of protein structures and
their interactions, based on the fact that evolutionarily-related
proteins tend to have similar three-dimensional structures. Using
solved protein structures as templates, he hopes to extract information
on protein-protein interactions from structural databases and assemble
structural models of protein associations. With the help of such
models, which he intends to make publicly available on the internet,
Venclovas hopes to further understanding of the molecular mechanism of
DNA replication, recombination, and rapair pathways.
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Beáta G. Vértessy
Institute of Enzymology, Hungarian Academy of Sciences Biological Researchy Center
Budapest, Hungary
Survival of a species depends on the preservation of genomic
information, yet DNA is a highly reactive molecule subject to extensive
modification. Beáta Vértessy, a molecular biologist, is
working to determine the role that the enzyme dUTPase plays in
preserving genomic information in humans, fruit flies, and
retroviruses. She is studying the enzyme's role in preventing DNA
replication mistakes. To better understand the structural basis for
enzyme action and regulation, Vértessy will investigate the role
that dUTPase plays in maintaining the integrity of DNA, first by
determining its structure-based regulatory patterns. The next
step—determining its cellular role—will require
manipulation of the enzyme. She will assess how human tumor cells
respond to decreased dUTPase levels, using the technique of RNA
interference to assess the enzyme's role as a survival factor.
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Ervin Welker
Hungarian Academy of Sciences Biological Research Center
Szeged, Hungary
Of all the degenerative brain disorders with no known cure, those
resulting from infectious proteins called prions are among the most
confounding. The mystery touches on a fundamental question in
biology—how proteins fold into their unique, functional shapes.
Deadly Creutzfeldt-Jakob disease, which can result from inherited
genetic mutations, and a variant form caused by infection from diseased
cows, are diseases associated with proteins that have acquired an
alternative fold that makes themdangerous. To find out how the abnormal
prion protein acquires that alternative fold, Ervin Welker, a Hungarian
molecular biologist, plans to determine the structural scaffold of
segments of the disease-associated prion form and then use computer
modeling to obtain the three-dimensional structure of the complete
molecule. This structure is critical to understanding the prion's
function and ability to interact with other proteins. Furthermore, the
newly-named HHMI international research scholar hopes his search for
mutations affecting the protein's conversion to an abnormal form will
contribute to finding a cure for prion disease.
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Andrey Zaraisky
Shemyakin-Ovchinnikov Institute of Bio-organic Chemistry, Russian Academy of Sciences
Moscow, Russia
The ability to reason sets humans apart from other vertebrates. The
region of the brain where this occurs is called the forebrain—the
unique part of the vertebrate brain that is responsible for higher
cognitive functions. Having already identified a novel gene called
Anf, which helps shape the developing forebrain,
developmental biologist Andrey Zaraisky now hopes to identify the other
genes involved in the regulatory cascade of the earliest stages of
forebrain development. To do so, the HHMI international research
scholar will investigate four disparate proteins involved in previously
unknown mechanisms of forebrain development regulation.
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Howard Hughes
