Genetic mitochondrial disease is present in about 1 out of every 5,000 babies, who face insurmountable odds from the moment they are born. That’s because at present, there is no cure for these conditions. But a new assisted reproductive technology that prevents the transmission of mitochondrial disease from mother to child holds great promise.
Mitochondrial replacement (MR) therapy combines the nuclear DNA from the mother with healthy mitochondria from a donor egg to create a healthy new egg that can be fertilized with the father’s sperm, thereby yielding a “three-person baby.” Last year, the world’s first three-person baby resulting from this method was delivered by U.S. doctors in Mexico, where there are no laws prohibiting the procedure.
The healthy newborn got about 0.1 percent of his DNA from the donor, and the vast majority of his genetic code – specifying eye color, hair, etc. – from his mom and dad.
Mitochondrial DNA comprises just a small percentage of our total DNA, containing just 37 of the 20,000 to 25,000 protein-coding genes in our body. And while nuclear DNA comes from both parents, “our mitochondrial DNA comes directly from our mothers, so my mitochondrial genome will be exactly like my mother’s, yours will be like your mother’s, and so on,” says Lavanya Rishishwar, former grad student in the lab of Petit Institute researcher King Jordan and team lead for Applied Bioinformatics Laboratory (ABiL, a public-private partnership between Georgia Tech and IHRC Inc.).
While the method hasn’t been green lighted in the U.S. yet, the United Kingdom gave the go-ahead for MR therapy in December. This announcement came in the wake of concerns about the safety of MR therapy that were raised by evolutionary biologists, who argue that nuclear and mitochondrial genomes evolved concurrently, and therefore mitochondria from one person or population may not be compatible with nuclear material from another.
In support of the evolutionary biologists’ nuclear-mitochondrial mismatch hypothesis, a number of previous studies on model organisms have provided evidence for incompatibility between nuclear and mitochondrial genomes from divergent populations of the same species. But a recent study by Jordan and Rishishwar published in BMC Genomics lays those fears to rest.
“The alarm was raised based on work that was done on model systems,” says Jordan, associate professor in the School of Biological Sciences and director of the Bioinformatics Graduate Program. “They didn’t work with humans, they worked with fruit flies, with mice, and those experiments resulted in a host of different problems for the resulting offspring. The key is, those were artificial experiments. Meanwhile, there’s been an ongoing natural experiment that has been conducted over millennia in human populations.”
So Jordan and Rishishwar tested the nuclear-mitochondrial mismatch hypothesis for humans by observing the source: humanity. They used data from the 1,000 Genomes Project and the Human Genome Diversity Project, studying the incidents of nuclear- mitochondrial DNA mismatch seen in more than 3,500 people from about 60 populations on five continents.
“We’ve been working for some years on human population genomics and remain interested in admixed American populations,” Jordan says. “The trajectory of modern human evolution for the past 50,000 to 100,000 years starts with the journey out of Africa, followed by a long period when populations were geographically isolated for the most part. During that time, human populations genetically diverged since they were physically isolated.”
But over the past 500 years or so, since Columbus came to the new world from Europe, “that process of isolation and divergence got flipped upside down,” Jordan notes. “Over a very short evolutionary time, you had populations from the Americas, Europe, and shortly thereafter, Africa because of the transatlantic slave trade, that were all brought together.”
Hence, in the Americas we’ve seen the creation of genome sequences that are evolutionarily novel in the history of humanity, in that they contain combinations of variants that had never existed together before. Jordan and his team have been studying this for a while, and understood that healthy individuals can bear combinations of variants that had different ancestral sources within the same genomic background.
“We knew that at a very intuitive level because of our own research,” says Jordan, who stumbled on a paper in Nature expressing the grave concerns of evolutionary biologists and thought, “instead of relying on artificial experiment systems, why don’t we just try to read the results of this long, ongoing experiment of human evolution and see what it tells us.”
They found that even people with very similar nuclear DNA (nDNA) genomes can have highly divergent mitochondrial DNA (mtDNA) and vice versa. Ultimately, their results showed that mitochondrial and nuclear genomes from divergent human populations can co-exist in healthy individuals, indicating that mismatched nDNA-mtDNA combinations are basically harmless and not likely to jeopardize the safety of MR therapy.
“We tend to think that the story of our evolution is the story of migration, physical isolation, and genetic diversification,” Jordan says. “But all throughout that process, there was admixture along the way. It’s not like there was a linear, onward march. It confirms and underscores the fact that humans are a relatively evolutionarily young species, and from the genetic perspective, there is complete compatibility between human populations.”
Drexel University and Georgia Institute of Technology researchers have discovered how the Rad52 protein is a crucial player in RNA-dependent DNA repair. The results of their study, published June 8 in the journal Molecular Cell, uncover a surprising function of the homologous recombination protein Rad52. They also may help to identify new therapeutic targets for cancer treatment.
Radiation and chemotherapy can cause a DNA double-strand break, one of the most harmful types of DNA damage. The process of homologous recombination — which involves the exchange of genetic information between two DNA molecules — plays an important role in DNA repair, but certain gene mutations can destabilize a genome. For example, mutations in the tumor suppressor BRCA2, which is involved in DNA repair by homologous recombination, can cause the deadliest form of breast and ovarian cancer.
Alexander Mazin, a professor at Drexel University’s College of Medicine, and Francesca Storici, an associate professor at Georgia Tech’s School of Biological Sciences, have dedicated their research to studying mechanisms and proteins that promote DNA repair.
In 2014, Storici and Mazin made a major breakthrough when they discovered that RNA can serve as a template for the repair of a DNA double-strand break in budding yeast, and Rad52, a member of the homologous recombination pathway, is an important player in that process.
“We provided evidence that RNA can be used as a donor template to repair DNA and that the protein Rad52 is involved in the process,” said Mazin. “But we did not know exactly how the protein is involved.”
In their current study, the research team uncovered the unusual, important role of Rad52: It promotes “inverse strand exchange” between double-stranded DNA and RNA, meaning that the protein has a novel ability to bring together homologous DNA and RNA molecules. In this RNA-DNA hybrid, RNA can then be used as a template for accurate DNA repair.
It appeared that this ability of Rad52 is unique in eukaryotes, as otherwise similar proteins do not possess it.
“Strikingly, such inverse strand exchange activity of Rad52 with RNA does not require extensive processing of the broken DNA ends, suggesting that RNA-templated repair could be a relatively fast mechanism to seal breaks in DNA,” Storici said.
As a next step, the researchers hope to explore the role of Rad52 in human cells.
“DNA breaks play a role in many degenerative diseases of humans, including cancer,” Storici added. “We need to understand how cells keep their genomes stable. These findings help bring us closer to a detailed understanding of the complex DNA repair mechanisms.”
The research was supported by the National Institutes of Health, the National Science Foundation and the Howard Hughes Medical Institute.
These results offer a new perspective on the multifaceted relationship between RNA, DNA and genome stability. They also may help to identify new therapeutic targets for cancer treatment. It is known that active Rad52 is required for proliferation of BRCA-deficient breast cancer cells. Targeting this protein with small molecule inhibitors is a promising anticancer strategy. However, the critical activity of Rad52 required for cancer proliferation is currently unknown.
This new Rad52 activity in DNA repair, discovered by Mazin, Storici and their team, may represent this critical protein activity that can be targeted with inhibitors to develop more specific — and less toxic — anti-cancer drugs. Understanding of the mechanisms of RNA-directed DNA repair may also lead to development of new RNA-based mechanisms of genome engineering.
This research was supported by the National Institute of General Medical Sciences (NIGMS) of the NIH (grant GM115927), the National Science Foundation (grant 1615335), and the Howard Hughes Medical Institute Faculty Scholar Program (grant 55108574). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the sponsoring agencies.
Written by Drexel University.
CITATION: Olga M. Mazina, Havva Keskin, Kritika Hanamshet, Francesca Storici,
Alexander V. Mazin, “Rad52 Inverse Strand Exchange Drives RNA Templated
DNA Double-Strand Break Repair,” (Molecular Cell, 2017). http://dx.doi.org/10.1016/j.molcel.2017.05.019
Research News
Georgia Institute of Technology
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Media Relations Contacts: Georgia Tech – John Toon (404-894-6986) (jtoon@gatech.edu) or Ben Brumfield (404-385-1933) (ben.brumfield@comm.gatech.edu) or Drexel University -- Lauren Ingeno, (215-895-2614) (lmi28@drexel.edu).
About the Speaker
Valerie J. Paul is the Director of the Smithsonian Marine Station at Fort Pierce and the Head Scientist of the Chemical Ecology Program. She researches marine chemical ecology, marine plant and herbivore interactions, coral reef ecology, and the ecological roles of marine natural products. In her coral reef ecology research, she studies the impact of cyanobacterial bloom on coral reefs and larvae of reef building corals. She has been a fellow of the American Association for the Advancement of Science since 1996, and was the chairperson of the Marine Natural Products Gordon Research Conference in 2000.
Event Details
A long time ago, in a city far, far away, a mathematician solved a puzzle, the solution of which made our modern, connected world possible. Georgia Tech's School of Music and School of Mathematics have teamed up with local Atlanta artists to create a performance combining contemporary dance, original music, and storytelling. Called The Seven Bridges of Königsberg, the concert celebrates this history and aims to spark people’s curiosity and convey the wonder of mathematics.
The classic puzzle that inspired Leonhard Euler to found the fields of topology and graph theory (or network theory) asked the simple question: Is it possible to cross all of the seven bridges of the city of Königsberg exactly once, with no repetition or backtracking?
Euler was not content with a yes-or-no answer. Instead he began to think about the nature of connectedness in a mathematical way, as it applies to all possible cities with any number of islands and bridges; as well as to networks of transportation, commerce, and communication; to the pathways by which diseases or ideas spread; and ultimately to our contemporary interconnected life.
The Seven Bridges of Königsberg was selected by a new program called Science in Vivo, funded by the Simons Foundation, to receive one of its inaugural 10 awards as an Experimental Site “exploring what is possible when science experiences for the public are integrated into existing cultural gatherings.”
The debut performance on Sept. 13, 2018 will take place on the Georgia Tech campus along Atlantic Ave, where an installation of the Seven Bridges of Königsberg puzzle was constructed earlier this year.
To tell about the foundation of graph theory, the Georgia Tech Symphony Orchestra will perform a new composition by composer Marshall Coats, while a math team and dancers interpret the story and some concepts about graphs, as choreographed by guest artist Kristel Tedesco.
This performance will be repeated at the Bailey Center in the Kennesaw State University on Sept. 23, 2018. Other versions of the show will take place at public locations around Atlanta and the Southeast region in September and October.
In addition to the spectacle, the audience will have opportunities to explore mathematical puzzles and games and to personally engage with the mathematicians and artists.
The Seven Bridges of Königsberg is a production of Mathematics in Motion, Inc. and the Georgia Tech Schools of Music and Mathematics, with financial support from the Georgia Tech College of Design, the Georgia Tech College of Sciences, the Georgia Tech Office of the Arts as one of the Creative Curriculum Initiatives, and Science in Vivo.
Event Schedule
11:00 AM Interactive exposition by Club Math
12:15 PM Remarks by School of Mathematics Chair and College of Design Dean Steven French
12:20 PM Music and Dance Performance
1:00 PM Interactive engagement with Club Math
Directions to Seven Bridges Plaza
The Seven Bridges Plaza is along the Atlantic Drive Promenade, right next to the Howey Physics Building.
By Georgia Tech Trolley: Get off at the intersection of Ferst Drive and Atlantic Drive. Walk toward the Einstein Statue, The Seven Bridges Plaza will be on the right, past the Howie Building. You can catch the Georgia Tech Trolley at the MARTA Midtown station.
By private transportation:
If you are coming from south of Atlanta:
- Take I-85 North to 10th Street/14th Street/Ga Tech (Exit No. 150)
- Take a left onto 10th Street at the light at the end of the ramp
- Go straight through 3 traffic lights
- Take a left onto State Street (the next light)
- Go through one stop sign
- The Howey Physics Building is the first building on the left. A Visitor Parking Lot is in front of the Building.
If you are driving from the east or west:
- Take I-20 into the city.
- Exit North onto I-75/85.
- Take I-75/85 North to the ramp of 10th Street/14th Street/Ga Tech.(Exit 150)
- Take a left onto 10th Street at the light at the end of the ramp.
- Go straight through 3 traffic lights.
- Take a left onto State Street (the next light).
- Go through one stop sign.
- The Howey Physics Building is the first building on the left. A Visitor Parking Lot is in front of the building.
Event Details
The NASA Astrobiology Institute marks its 20th anniversary this year and Georgia Tech is throwing a party! This celebration will feature talks and a poster session by faculty members, NASA Postdoctoral Program Fellows, graduate students, and postdoctoral researchers in Georgia Tech's vibrant astrobiology community.
The celebration is hosted by Frank Rosenzweig, professor of biological sciences and principal investigator of the NAI program Reliving the Past.
The event is sponsored by the NASA Astrobiology Institute and the Georgia Tech College of Sciences, School of Chemistry and Biochemistry, School of Biological Sciences, and the Parker H. Petit Institute for Bioengineering and Bioscience.
The event is by by invitation only.
Speakers, Morning Session starting at 8:30 AM
Thom Orlando, professor of chemistry and biochemistry
"An Overview of REVEALS and CSTAR Programs"
Amanda Stockton, assistant professor of chemistry and biochemistry
"High Impact Chemistry: The Icy Moons Penetrator Organic Analyzer"
Loren Williams, professor of chemistry and biochemistry
"Visualizing the Origins of Life in Biopolymers"
Nick Hud, professor of chemistry and biochemistry and principal investigator of the Center for Chemical Evolution (CCE)
"Some Highlights of CCE Discoveries on the Possible Origins and Early Evolution of Biopolymers"
Martha Grover, professor of chemical and biomolecular engineering
"Prebiotic Replication of an RNA Duplex Containing an Active Ribozyme"
Chris Reinhard, assistant professor of Earth and atmospheric sciences
"Climate and Atmospheric Biosignatures on Reducing Worlds"
Jeff Bowman for Britney Schmidt, assistant professor of Earth and atmospheric sciences
"Oceans Across Space and Time: A Multi-Institutional Effort to Understand and Identify Life in Extraterrestrial Oceans"
Jennifer Glass, assistant professor of Earth and atmospheric sciences
"Laughing Gas as a Precursor to Aerobic LIfe"
Will Ratcliff, assistant professor of biological sciences
"Solving Physical Challenges during the Origin of Multicellularity by Evolving Simple Development
James Wray, associate professor of Earth and atmospheric sciences
"Orbital Spectral Signatures of Changing Habitable Environments on Mars"
Lunch and Poster Session, 12:30-1:45 PM
Speakers, Afternoon Session, starting at 2 PM
Pedram Samani, postdoctoral researcher, Georgia Tech
"Experimental Evolution of Anisogamy: An Inquiry into the Origins of Sexes"
Peter Conlin, NPP Fellow, Georgia Tech
"Experimental Evolution of Adaptive Phenotypic Plasticity in a Temporally Varying Environment"
Caroline Turner, NPP Fellow, University of Pittsburgh
"Environmental Similariy (Mostly) Predicts Genetic Similarity"
Nadia Szeinbaum, NPP Fellow, Georgia Tech
"A Microbial Ecology Perspective on the Success of Oxygenic Photosynthesis"
Moran Frankel-Pinter, NPP Fellow, Georgia Tech
"Dynamic Polymerization of Prebiotic Depsipeptides Allows Selection of Stable Structures"
Micah Schaible, NPP Fellow, Georgia Tech
"Ionizing Radiation Effects on the Surfaces of Airless Bodies"
Event Details
Andrew Spence, PhD
Department of Bioengineering
Temple University
Abstract
How do animals use information from peripheral sense organs when they move? Long, distinguished scientific lineages have given insight into this question, both at the level of how these organs function, and how their input is integrated with more central nervous structures. Despite standing on the shoulders of these giants, interesting open questions remain; what is the relative contribution of different classes of sensory afferent to specific locomotor tasks? how is sensory feedback used as a function of phase? and to what extent can modulating sensory feedback be useful in treating neuromuscular disease or injury, and understanding mechanisms of recovery from injury? This talk will present ongoing work that seeks to use genetic tools to target and manipulate the activity of specific classes of sensory afferent in intact rodents. Early work using optogenetics in mice will be presented, followed by recent work using DREADDs to excite or inhibit large diameter afferents in rats. DREADDs are drug-activated, engineering receptors that allow remote activation or inhibition of neurons. Results of pilot work applying selective afferent modulation by DREADDs to both enhancement of the recovery from spinal cord injury, and to understanding the mechanisms underlying that recovery, in rats, suggest that this approach holds promise. Current limitations of genetic approaches will be discussed, and a risky foray into what may lie ahead will be presented.
About the Speaker
Andrew Spence is an applied physicist by training who leads a research group in animal locomotion. As a group, we are focused on how the nervous and mechanical systems work together to produce movement, taking an integrative approach that combines experimental work with mathematical modeling, instrumentation, and some robotics. Andrew did his undergraduate work in physics at UC Berkeley, before doing a PhD in neuroscience and biomedical microdevices at Cornell University. He returned to Berkeley for a postdoc, and worked with Bob Full on the control of many-legged locomotion.
Before coming to Temple University, he was a faculty member in the Structure and Motion Laboratory at the Royal Veterinary College, London, working with Alan Wilson before becoming an independent researcher. Currently his group is focused on the role of constraints (stability, energetics) in shaping quadrupedal gait control, and in applying new neurogenetic techniques (chemogenetics in the form of DREADDs; optogenetics) to dissect the control of fast legged locomotion and to better treat spinal cord injuries.
Physiology Brownbag Seminars
The Physiology Group in the School of Biological Sciences hosts Brownbag Lunchtime Seminars twice a month on Wednesdays at noon in room 1253 of the Applied Physiology Building located at 555 14th Street NW, Atlanta, GA 30318. You are welcome to bring a lunch and join us as we ruminate with us on topics in Physiology! A full listing of seminars can be found at http://pwp.gatech.edu/bmmc/physiology-brownbag-seminars-fall-2018/.
Event Details
Leucine Zipper and the Zinc Fingers, the world's first genetically modified rock band, have been a staple of the Atlanta Science Festival. This summer they went into a studio and recorded their first album, Atomic Anarchy. The band celebrates the recording with a live performance. Join them on Sept. 22, 2018 at 8:00 pm at Kavarna coffee house, in Decatur.
Band leader Leucine Zipper is the clone of College of Science' Jennifer Leavey. The Zinc Fingers are clones of amphibian ecologist Joe Mendelson, chemist Michael Evans, and biologist Ben Prosser.
All ages are welcome!
Event Details
School of Biological Sciences
Georgia Institute of Technology
Event Details
Giovanni Martino, Ph. D.
Emory University School of Medicine
Abstract
Although the control of locomotion seems to be an easy and automatic process, behind this apparent simplicity there is a remarkable combination of mechanical principles, neural control, and sensory input leading to efficient muscular movements of limbs. Understanding motor control and learning even for a simple movement is a big endeavor due to the many variables that come into play. How does the nervous system harness the redundancy and the large number of degrees of freedom of the musculo-skeletal system? What is the specific role of spinal, supraspinal and proprioception systems in generating rhythmic locomotor behavior? These and other similar fundamental questions concerning the motor control mechanisms are still an open issue in neuroscience. Addressing these challenges may also have important implications in the clinical scenario. Indeed, even in the presence of small lesion of the central nervous system (CNS), patients can suffer profound locomotor impairments. Motoneurons represent the ‘final common pathway’ of the CNS and thus one may infer about what is being programmed in the CNS by evaluating the spatiotemporal motoneuron locomotor output. To get insights into the functioning of locomotor controllers, the main focus of this talk is placed on the analysis of the spatiotemporal organization of multi-muscle activity patterns in normal and pathological gait.
Speaker Bio: Dr. Giovanni Martino’s research interests are largely directed towards understanding the neural control and the biomechanics of human movement in both normal and pathological conditions. In 2012, he obtained his Master’s Degree in Bioengineering (at Roma Tre University) with a thesis titled “Muscle synergies in patients with Parkinson’s Disease”, supervised by Prof. Silvia Conforto. After graduating, he began his work experience as Research Assistant at the Centre of Space Bio-medicine at the University of Rome “Tor Vergata” led by Prof. Lacquaniti, and in collaboration with the Laboratory of Neuromotor Physiology at IRCSS Santa Lucia Foundation under the supervision of Prof. Ivanenko and Prof. Andrea d’Avella. During this period, he conducted a series of studies about locomotor coordination in patients. In 2014, he started his Ph.D. in Neuroscience during which he was involved in several projects related to the spatiotemporal architecture of multi-muscle activity in both normal and pathological adult gait, and control of locomotion in children. In particular, the PhD project focused on the exploration of how healthy subjects and patients with neurological disorders (Parkinson’s disease, Cerebellar Ataxia, Cerebral Palsy, Hereditary Spastic Paraplegia) adapt locomotor patterns to the environment, by applying recognition algorithms to the multi-muscle activation profiles. These activities have resulted in publishing 9 articles (3 of them as the first author) in various peer-reviewed journals (Journal of Neurophysiology, Plos One, Frontiers in Physiology, Cerebellum, Clinical Biomechanics, Clinical Neurophysiology). Giovanni Martino recently graduated from the University of Rome Tor Vergata’s Neuroscience Ph.D. program. Currently, he is a postdoctoral research fellow in the lab of Dr. Lena Ting at Emory University School of Medicine.
Physiology Brownbag Seminars
The Physiology Group in the School of Biological Sciences hosts Brownbag Lunchtime Seminars twice a month on Wednesdays at noon in room 1253 of the Applied Physiology Building located at 555 14th Street NW, Atlanta, GA 30318. You are welcome to bring a lunch and join us as we ruminate with us on topics in Physiology! A full listing of seminars can be found at http://pwp.gatech.edu/bmmc/physiology-brownbag-seminars-fall-2018/.
Event Details
Leucine Zipper and the Zinc Fingers, the world's first genetically modified rock band, have been a staple of the Atlanta Science Festival. This summer they went into a studio and recorded their first album, Atomic Anarchy. The band celebrates the recording with a live performance.
Band leader Leucine Zipper is the clone of College of Science' Jennifer Leavey. The Zinc Fingers are clones of amphibian ecologist Joe Mendelson, chemist Michael Evans, and biologist Ben Prosser.
This event has a cover charge.
Event Details
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