David M. Countryman loves to teach. In Charleston, South Carolina, his appointments as assistant chief of surgery at the Ralph H. Johnson Veterans Administration Medical Center and assistant professor of surgery at the Medical University of South Carolina afford him the deep satisfaction of imparting his expertise to surgery interns, surgery residents, and medical students.

Countryman’s gateway to medical school was a B.S. in Applied Biology (with highest honors) from Georgia Tech in 1975. With an Air Force scholarship, he went to Medical College of Georgia for his medical degree. Before enrolling in Georgia Tech, he attended North Springs High School, in Atlanta, Georgia.

What attracted you to study in Georgia Tech? What is the most important thing you learned at Georgia Tech?

It’s reputation for academic excellence. I thought if I could go there and do well, I’d have a good chance to get into medical school. I was fortunate enough to get into medical school on my first attempt.

The most important thing I learned was how to study. I learned to go to classes and to study the material on a daily basis rather than just cruising until just before the test, which is what I had done in high school.

What is a vivid memory of your time at Georgia Tech?

The fraternity house—I was an officer in Sigma Alpha Epsilon—was big part of my life. I was also in the Ramblin’ Reck Club. My participation in these groups helped me learn how to interact socially with people from different countries and backgrounds.

How did you get to your current position?

After finishing medical school in 1979, I did my internship, residency in surgery, and fellowship in thoracic surgery at Keesler Air Force Base Medical Center, in Biloxi, Mississippi. I was fully trained by 1985.

To fulfill my obligation to the Air Force for the scholarship, I worked at Scott Air Force Base Medical Center, as chief of general and thoracic surgery. I also had faculty appointments in St. Louis University School of Medicine and in the Uniformed Services University of the Health Sciences School of Medicine.  

When my obligation was over in 1989, I went into private practice in general, thoracic, and vascular surgery in Rock Hill, South Carolina. In 2004, I joined the Gulf Coast Veterans Health Care System, in Biloxi, Mississippi, as assistant chief of surgery and director of the surgery residency program. In 2010, I came to Charleston and assumed a similar position. This allows me to be close to three of my four children, who live in Charleston.

What roles did your Georgia Tech education and experience play in your journey to your current position?

When a prospective employer sees that you have an undergraduate degree from Georgia Tech, it means a lot. It places you ahead of prospective employees from other schools. 

Organic chemistry was big a wakeup call. On the first day of class, the professor told us that 2/3 of us were going to flunk out of the course before the year was over. That told me that this course was serious business, and I better work really hard to get past this hurdle.

At the time, almost all the schools in Tech had a course like that, the “weed out” course. In the long-term, it was better, because if you couldn’t do organic chemistry, you’re not going to be a doctor. It benefits the student to find out early if they are in the wrong field.

I struggled initially in organic chemistry, but did steadily better over the course of the year. However, after Tech, the chemistry in medical school was not nearly as difficult for me as it was for a lot of people.

The entire Tech experience prepared me to take all the different steps in my career. The skills that I learned at Georgia Tech in order to get along with different types of people help a lot in marriage, too. I’ve been married to the same woman for 38 years.

Dr. John Strange, in the School of Biology, was inspirational and personable. He made science fun. He taught physiology, which is a pretty dry course, but he made it come alive. He had a great sense of humor, which was rare among Tech professors at the time.

When I was in my junior and senior years, he hired me to help in research about catfish farming. He taught us how to do research and how to write scholarly papers. I was fortunate to get a paper published as an undergraduate.

What do you like most about your current job?

I teach general surgery to surgical residents, surgical interns, and medical students. It’s the teaching that gets me out of bed in the morning.

What has been the greatest challenge in your professional life so far?

The business aspects of private practice, because I had no training in that at all. Setting up an office, how to hire people—I had to learn these on the fly.

Now, we take the time to teach the business aspects of medicine. I do a significant amount of teaching in this area, because I’m one of the few faculty members who has had private business experience.

What has been the most gratifying experience of your professional career so far?

I’ve been voted Surgical Educator of the Year by students for two years in a row. This recognition makes want to keep doing what I’m doing. I’m 63, and I’d like to keep operating and teaching as long as I can; I love it!

If you could have taken an alternative career path, what would you be doing instead?

I’d be a high school athletic coach. I played junior varsity baseball for two seasons at Tech. In Rock Hill, I was a high school baseball and football coach. The joy comes when you see that light come on and a kid starts to bunt the ball. It’s the same joy from teaching surgery students. But baseball is more fun.

What advice would you give to incoming first-year students at Georgia Tech? 

Focus on time management and finding balance among the different areas of their lives. Most of them have been stars in high school, where they haven’t had to work hard. They need to learn how to study but also to make time for relationships and extracurricular activities so that they graduate as well-rounded persons.

What’s something about yourself that’s not obvious to your colleagues?

Officiating is how I bought my wife her engagement ring, which she still has. My brother and I provided umpiring for most of the youth baseball in North Atlanta for two years. We had a lot of fun, and we made a lot of money.

If you could have dinner with any person from history, whom would you invite?

Jesus Christ. To be in his presence, to be able to soak up some of his wisdom, would be the most wonderful experience that I could possibly imagine.

Prayer has been a big part of my medical practice. I pray with my patients. It gives them a lot of peace. I always ask first if they want to do that. In 40 years, just one patient refused.

The war on cancer is 45 years old. And while there have been some significant advances since passage of the National Cancer Act in 1971, the conflict has spread out along many fronts.

With the realization now that there are more than 200 types and subtypes of cancer, the battle plan has evolved from a one-size-fits-all strategy to a data-driven, more personalized approach, which means the army of researchers and clinicians devoted to fighting cancer also has evolved.

“We’re seeing the emergence of the new cancer biology,” says John McDonald, director of the Integrated Cancer Research Center (ICRC) at the Georgia Institute of Technology. “It’s actually being driven now by technologies and expertise that lie outside the traditional framework of cancer biology. That’s why I think you’re probably going to see major breakthroughs in cancer research coming out of places like Georgia Tech and M.I.T., as opposed to traditional medical schools.”

Advances in genomics and high throughput sequencing have generated massive amounts of data, “and it’s opened up the field to people that were not trained as cancer biologists, but have the necessary skillsets for the analysis of all this new, big data,” says McDonald, a faculty researcher with the Petit Institute for Bioengineering and Bioscience and professor in the School of Biological Sciences, who has definitely seen his share of breakthroughs in his own recent research focused on ovarian cancer.

The cancer biology that McDonald knew when he was a college student has moved from an era of specialization into an era of multidisciplinary research, in which researchers from a wide range of areas now work together on common projects.

“Twenty five years ago, these people probably wouldn’t have spoken to each other because they didn’t have any common interests,” says McDonald. “I was like a kid in a candy store when we first came to Georgia Tech, and it still feels like that – the idea of being in a place where all of this expertise and creativity exist. Cancer research is not a one-person endeavor. It’s all about collaboration.”

And McDonald has plenty of collaborators within and beyond the ICRC, which occupies a busy space where molecular biology, computational science, engineering and nanotechnology converge. Together, these scientists and engineers are developing next generation cancer diagnostics and therapeutics.

Family Affair

Fatih Sarioglu trained as an electrical engineer in his native Turkey and later at Stanford University, developing particular expertise in microsystems and nanosystems, developing sensitive, small-scale devices to look at atoms. After earning his Ph.D., he says, “I wondered how I could use these skills to benefit humanity.”

Sarioglu, assistant professor in the School of Electrical and Computer Engineering and a Petit Institute faculty researcher, he spent three years as a post-doc at Massachusetts General Hospital and Harvard Medical School, learning about cancer. He found his opportunity, “to give biologists and biomedical scientists and clinicians capabilities they don’t have.”

There was a personal reason for Sarioglu’s interest in cancer, as well. The disease took the life of two grandparents. But he was particularly motivated when his mother-in-law was diagnosed, back in Turkey, with late-stage brain cancer.

“It was devastating. I knew life expectancy was about four or five months,” says Sarioglu. “But their diagnosis was based purely on the pathology, a biopsy slice.”

He asked a colleague at Mass General, David Lewis, one of the world’s top pathologists, for another opinion. Lewis’ conclusions were vastly different. The cancer was benign, operable, and Sagioglu’s mother-in-law is alive and well.

“It showed me that we still have to improve how we diagnose cancer,” says Sarioglu, whose lab develops microfluidic chips that can isolate tumor cells out of billions of other cells. At Mass General, he worked on a device that captures clumps of tumor cells before metastasis, preventing the spread of cancer.

He’s continued that work since arriving at Georgia Tech in 2014, developing microchip technology that analyzes cells accurately and at very high speeds. Essentially, it is a better way to find the needle in the haystack, a minimally invasive way to diagnose cancer, liquid biopsy.

“The possibilities are endless, really,” says Sarioglu, who counts McDonald and Fred Vannberg (an expert in DNA sequencing who specializes in the molecular analysis of cancer) among his research collaborators. “The technology is applicable to all types of cancer.”

Doing Better

The primary tumor is rarely the killer in cancer. Nine times out of 10, cancer kills because it spreads to other parts of the body. So when a patient gets a cancer diagnosis, one of his first questions is, “has it metastasized?”

“You can obviously appreciate the anxiety. The physician and patient wonder the same exact thing. That’s the first question,” says Stanislav Emelianov, professor in the Georgia Tech/Emory Wallace H. Coulter Department of Biomedical Engineering (BME), a Georgia Research Alliance Eminent Scholar and the Joseph M. Pettit Chair in School of Electrical and Computer Engineering.

“Then there are more questions. What is the prognosis, the treatment, how do I deal with this – a lot of questions that can be better answered if we know the answer to the first question,” says Emelianov, whose team designs ultrasound imaging devices and algorithms, and has embarked on a project supported by a grant from the Breast Cancer Research Foundation to use light and sound and a non-radioactive molecularly targeted contrast agent, to answer that anxious first question.

The traditional approach has been to inject radioactive material and tracking that, then biopsy, which involves incision of the skin to expose the lymph node and taking pieces out to look for cancer.

“It is accurate, but it is also invasive, complicated and uses radioactive material,” Emelianov says. “We can do better.”

Emelianov speculates that in the future, we may be able to “weaponize” these contrast agents to actually kill cancer cells. Meanwhile, his team also is using its advanced imaging technology in collaboration with colleagues at Emory University’s Winship Cancer Center, to diagnose thyroid cancer and differentiate between malignant and benign tumors.

Tech’s Cancer Army

There are more than 40 faculty researchers at Georgia Tech who are members of the ICRC. They come from 12 different departments or schools. And there are an additional 16 researchers from academic and medical institutions that are affiliate members. It’s a diverse intellectual force that is giving Georgia Tech its own identity in cancer research.

“We can be a major player in cancer,” says McDonald. “How many medical schools have this breadth of expertise?”

He’s talking about young researchers like Susan Thomas, awarded Georgia Tech’s first grant from Susan G. Komen (breast cancer research foundation), supporting her work in immunotherapy for breast cancer; and Manu Platt, whose lab developed a new technique to give patients and oncologists more personalized information for choosing breast cancer treatment options.

And he’s referring to computer scientists like Constantine Dovrolis, who has spent the last few years investigating a phenomenon called “the hourglass effect” that is present in both technological and natural systems. He’s adapting what he learned studying embryogenesis with Georgia Tech biologist (and Petit Institute researcher) Soojin Yi to his collaboration with McDonald in cancer research.

He’s also thinking of BME-based researchers James Dahlman and William Lam.

Dahlman, an assistant professor who came to Georgia Tech earlier this year, works on cancer in two ways. Focusing extensively on primary lung tumors as well as lung metastasis, his team works on delivering genetic drugs to tumors.

“We have changed their gene expression, and either slowed tumor growth or caused established tumors to recede,” says Dahlman, an expert in gene editing. “In some cases, we have delivered multiple therapeutic RNAs to tumors, so that tumor cells are hit with a genetic ‘one-two’ punch that affects multiple cancer causing genes.”

His lab also creates tools to understand how cancer genes cause tumor resistance, studying how combinations of genes influence tumor growth, “because cancer is such a complicated disease and the genetics of cancer are notoriously difficult to understand,” Dahlman says. “It’s driven by many genes working together at once.”

For Lam, the war on cancer is waged in a lab and on the front lines, in a clinical setting. In addition to being a biomedical engineer, he’s also a pediatric hematologist-oncologist who treats patients at Children’s Healthcare of Atlanta.

His Ph.D. was actually focused on the biophysics of childhood leukemia, and his research in this area has focused on a small percentage of patients who develop leukostasis (stroke-like symptoms and lung failure).

“We always thought it was due to the biophysical properties of leukemia cells, which become big and sticky and jam up the plumbing of our blood vessels in our brain and lungs, which happen to have the smallest blood vessels,” says Lam, who is collaborating with Todd Sulchek, associate professor in mechanical engineering and a Petit Institute researcher.

“We’re combining some of Todd’s microfluidic technologies and our microfluidic technologies, to develop more high throughput ways to address this issue,” says Lam.

He’s also collaborating with the lab of BME professor Krish Roy on developing a ‘lymphoma on the chip’ model, to study how new cell therapies can directly affect the killing of cancer cells, as a way to determine whether those therapies have what it takes to work in the patient.

It’s all part of the multidisciplinary, “basement to bench to bedside” approach that Lam’s lab, with its connections to Georgia Tech, Emory University and Children’s Healthcare, has become known for.

“Within our lab, we’re certainly interested in technology development,” Lam says. “But then, we’re also interested in the assessment of the technology and, ultimately, directly translating that to the patient. Our lab lives in that entire space.”

LINKS

Integrated Cancer Research Center

McDonald Lab

Georgia Tech Cancer Army

CONTACT:

Jerry Grillo
Communications Officer II
Parker H. Petit Institute for
Bioengineering and Bioscience

Lake Lanier in Georgia is the primary water reservoir serving suburban and metropolitan Atlanta. When the lake’s water level drops below a certain point, calls go out for water conservation and news reports show images of the red mud shoreline. In some affected counties, water restrictions are imposed. The combination of usage restrictions and changes in precipitation eventually averts the crisis. But, when the crisis ends, water usage rebounds – until the next shortage.

Inspired by this example, researchers at the Georgia Institute of Technology have developed a theory to unite the study of behavior and its effect on the environment. In doing so, they combined theories of strategic behavior with those of resource depletion and restoration, leading to what they term an “oscillating tragedy of the commons.” The research was reported in November 8 in the journal Proceedings of the National Academy of Sciences. 

The study of how behavior affects resource depletion has a long history. The originating example is that of small farmers who share a common pasture. Each farmer has to decide whether to graze some or all of his flock, while also considering what actions other farmers might take. To avoid losing out to a competitor, each farmer decides to attempt to maximize the benefit by grazing as many sheep as possible. Consequently, the sheep overgraze and damage the pasture. Paradoxically, the benefit to each farmer over the long run is less than if they had cooperated and each grazed fewer sheep.  

That individuals acting out of their own self-interest can be worse off than had they coordinated is termed a “tragedy of the commons” – a concept introduced nearly 50 years ago by the ecologist Garrett Hardin. (The use of the term “tragedy” denotes its inevitability). However, the originating example does not include a mechanism by which incentives for cooperation change as the resource is depleted.

“Our actions can substantively change the environment and, in turn, the changing environment influences the incentives for future action,” said Joshua Weitz, who led the study and is a professor in Georgia Tech’s School of Biological Sciences and director of the Interdisciplinary Graduate Program in Quantitative Biosciences. “The theory in our paper proposes a unified approach for the co-evolution of actions and environment.” 

Other authors on the study include postdoctoral fellow Ceyhun Eksin and graduate teaching assistant Keith Paarporn, both members of the Weitz group in the School of Electrical and Computer Engineering, as well as Professors Sam Brown and Will Ratcliff, both faculty in the School of Biological Sciences.

There are many other prominent examples of tragedies of the commons. One example is that of antibiotic resistance in microbes. The widespread use of antibiotics among humans and in agriculture selects for antibiotic resistance strains. Over time, the spread of resistance renders antibiotics ineffective for use in patients with otherwise curable infections. Hence, individuals trying to maximize their own benefit can unintentionally degrade the collective value of the antibiotics.

Another example stems from individual decisions about whether or not to vaccinate against childhood infectious diseases like measles, mumps and rubella. Crucially, a retracted study falsely linking autism to vaccination has inspired some parents not to vaccinate their children. Yet, when population levels of immunity drop, then these potentially lethal infectious diseases that had been prevented in the past will reappear in sporadic outbreaks or, dangerously, as large-scale epidemics. 

“Individual agents acting in their own self-interest – trying to do what’s right for them alone – can end up in a worse state than if they coordinated,” Weitz said. “For example, the decision not to vaccinate increases the frequency of individuals having a dangerous, infectious disease. As people see the disease return, the incentives for vaccination change.”  

The research proposes a new model of evolutionary games with a feedback loop in which changes to the resource – whether it be water supplies, pastureland, antibiotics, or vaccine use – change the incentives for people to take action in their own interests. The environment and the incentives co-evolve and are tied to one another, allowing the outcome to be predicted.

“Incentives to use a lot of water when water is in short supply are different than when water levels are replete,” Weitz said. “When things are bad and the commons is depleted, there may be greater incentives to cooperate than when the commons are in good condition.”

Unlike in the originating example of the tragedy of the commons, Weitz and colleagues report that tragedies can recur again and again. Formally, the researchers unite game theory with evolutionary models in which both the tendency to cooperate and the state of the environment coevolve.

The theoretical research also pointed the way to a testable principle to avert the tragedy of the commons in specific application domains. For example, in their analyses, Weitz and colleagues found that averting the tragedy of the commons was only possible when cooperation was incentivized even when the environment was depleted and others continued to act to degrade the resources.

“Another lesson is that idealism matters,” said Weitz, continuing, “A small group of cooperating individuals can, over time, change the social and environmental context for all and for the better.”

This work was supported by a grant W911NF-14-1-0402 from the Army Research Office. 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 sponsor.

CITATION: Joshua S. Weitz, Ceyhun Eksin, Keith Paarporn, Sam P. Brown and William C. Ratcliff, "An oscillating tragedy of the commons in replicator dynamics with game-environment feedback," (Proceedings of the National Academy of Sciences, 2016). http://www.pnas.org/content/early/2016/11/02/1604096113.abstract

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In the fight against cancer, doctors dish out combination-blows of surgery, chemotherapy and other drugs to beat back a merciless foe. Now, scientists have taken early steps toward adding a stinging punch to clinicians’ repertoire.

With a novel targeted therapy researchers at the Georgia Institute of Technology have purged ovarian tumors in limited, in vivo tests in mice. “The dramatic effect we see is the massive reduction or complete eradication of the tumor, when the ‘nanohydrogel’ treatment is given in combination with existing chemotherapy,” said chief researcher John McDonald.

That nanohydrogel, a type of nanoparticle, is a minute gel pellet that honed in on malignant cells with a payload of an RNA strand. The RNA entered the cell, where it knocked down a protein gone awry that is involved in many forms of cancer.

In trials on mice, it put the brakes on ovarian cancer growth and broke down resistance to chemotherapy. That allowed a common chemotherapy drug, cisplatin, to drastically reduce or eliminate large carcinomas, with very similar speed and manner. The successful results treating four mice with the combination of siRNA and cisplatin showed little variance.

Chink in the armor

The therapeutic short interfering RNA (siRNA) developed by McDonald and Georgia Tech researchers Minati Satpathy and Roman Mezencev, thwarted cancer-causing overproduction of cell structures called epidermal growth factor receptors (EGFRs), which extend out of the wall of certain cell types. EGFR overproduction is associated with aggressive cancers.

The researchers from Georgia Tech’s School of Biological Sciences published their results on Monday, November 7, 2016, in the journal Scientific Reports. Research was funded by the National Institutes of Health’s IMAT Program, the Ovarian Cancer Institute, the Deborah Nash Endowment Fund, the Curci Foundation and the Markel Foundation.

The new treatment has not been tested on humans, and research would be required by science and by law to demonstrate consistent results – efficacy – among other things, before preliminary human trials could become possible.

The current in vivo success strengthens the idea that knocking out EGFR at the RNA level may be a worthy goal to explore in the fight against carcinomas in general. The same patented nanohydrogel packed with other types of therapeutic RNA is currently being tested for the treatment of other types cancers.

Helper turned killer

EGFRs are receptors found in epithelial cells, which line organs throughout the body: Lungs, mouth, throat, intestines and others. In women, it also lines reproductive organs: Ovaries, uterus and cervix.

They are long proteins that poke through the cell membrane, connecting the cell’s interior with the outside. They look like squiggly worms with tiny mouths on the outside that take up a messenger protein.

In a healthy cell, those messenger molecules cause EGFRs to trigger long chains of biochemical reactions that lead to the activation of genes involved in a variety of cellular functions. In carcinoma cells, the number of EGFRs present typically skyrockets.

“In many cancers, EGFR is overexpressed,” said McDonald, who heads Georgia Tech's Integrated Cancer Research Center. “The problem is that because of this overexpression, many cellular functions, including cell replication and resistance to certain chemotherapy drugs, are dramatically cranked up.”

The cell goes haywire, metabolizes too much sugar, divides too much, and resists chemotherapy. The cancer grows into a tumor and can spread through the body.

An overabundance of EGFRs found in a biopsy is usually a sign that cancer patient prognosis is poor. “In 70 percent of ovarian cancer patients, EGFR is overexpressed at very high levels,” McDonald said.

Cell suicide: apoptosis

EGFR overexpression also makes cancer cells resistant to chemotherapy by thwarting a natural defense mechanism.

“The platinum-based chemotherapies used to treat ovarian cancers cause DNA damage, which switches on apoptosis,” McDonald said. Apoptosis is cell suicide. When cells can’t repair DNA damage, they’re programmed to kill themselves to keep the damaged cells from spreading.

The primary chemotherapy used to treat ovarian cancer works by coaxing cancer cells to trigger the suicide program, but having too many epidermal growth factor receptors gets in the way.

“EGFR overexpression hinders apoptosis; they won’t die. By knocking down EGFR, we make the cell hypersensitive to the drug. Apoptosis is reactivated,” McDonald said.

Existing EGFR targeted drugs called tyrosine-kinase inhibitors disrupt an EGFR function, but their success in treating ovarian cancer has been limited. “Clinicians have tried EGFR inhibitors to treat ovarian cancers for some years, and they only get about 20% of patients responding to it,” McDonald said. “Apparently, the particular EGFR function inhibited by these drugs is not critical to ovarian cancer.”

Guided brass knuckles

The short interfering (si) RNA designed by the Georgia Tech researchers attacks the cancer much closer to its root.

To make the protein for EGFR, RNA has to transfer its genetic code from DNA. The researchers’ siRNA binds to the cell’s RNA and stops it from working.

“We’re knocking down EGFR at the RNA level,” he said. “Since EGFR is multi-functional, it’s not exactly clear which malfunctions contribute to ovarian cancer growth. By completely knocking out its production in ovarian cancer cells, all EGFR functions are blocked.”

The nanohydrogel that delivers the siRNA to the cancer cells is a colloid ball of a common, compact organic molecule and about 98 percent water. Another molecule is added to the surface of the nanohydrogel as a guide. It makes the pellets adhere to the cancer cells like sticky cluster bombs.

Cancerous tissue may also be aiding the nanohydrogel in targeting it. “When you get into a tumor, there are a lot of blood vessels, and many are broken,” McDonald said. “This may help the nanoparticles get passively trapped in the neighborhood of tumorous tissues.”

In the in vivo trials, the siRNA, which contained a fluorescent tag, allowed researchers to observe nanoparticles successfully honing in on the cancer cells.

Fortuitous victory

“We originally selected to target the EGFR gene because its activity is easily measured, and we wanted to use it simply as an indicator that our nanoparticle siRNA delivery system was working,” McDonald said. “The fact that the EGFR knockdown so dramatically sensitized the cells to standard chemotherapy came as a bit of a surprise.”

At first, his team observed how the tumors responded to chemotherapy alone. Then they combined it with the nanoparticle treatment.

“When we gave the chemotherapy alone, the response was moderate, but with the addition of the nanoparticles, the tumor was either significantly reduced or completely gone,” McDonald said.

But he tempered enthusiasm with caution. “Further work will be required to see if the treatment completely destroyed every trace of cancer cells in the tumors that disappeared, or if future recurrence is possible.”

If the researchers’ continuing studies further prove to be consistent, the combination of the nanohydrogel with other therapeutic RNAs could represent a significant advancement in the treatment of a wide spectrum of cancers.

Georgia Tech’s Lijuan Wang and Dr. Benedict Benigno from Atlanta’s Northside Hospital coauthored the paper. Research was funded by the National Institutes of Health’s Program for Innovative Molecular Analysis Technologies Program (grant 1R21CA155479-01), the Ovarian Cancer Institute at Northside Hospital, the Deborah Nash Endowment Fund, the Curci Foundation, and the Markel Foundation. Any opinions, findings and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the sponsoring agencies.

Luis Miguel Rodriguez-Rojas graduated with a Ph.D. in Bioinformatics with a minor in Biomedical Engineering. He came to Georgia Tech with an M.S. in Biological Sciences from Universidad de Los Andes, in Bogota, Colombia; an M.S. in Applied Informatics from Université Montpellier 2 (currently Université de Montpellier), in Montpellier, France; and B.S. in Biology from Universidad Nacional de Colombia, in Bogota. He is off to a postdoctoral position in Georgia Tech’s School of Civil and Environmental Engineering.

What attracted you to study in Georgia Tech? How did Georgia Tech meet your expectations?

The main reason was my advisor, Dr. Kostas Konstantinidis. I read some of his work while I was an undergraduate and was fascinated by his research. While studying for my master’s degree, I had the privilege of visiting his lab for two weeks. During this period, I became convinced that I wanted to work in microbial ecology, and he offered to receive me as a Ph.D. student. Once I started the program, I quickly realized that Georgia Tech exceeded my expectations, offering a far richer campus life than I had anticipated.

What is the most important thing you learned while at Georgia Tech?

Balancing work and academic life with other activities. I became involved in social dancing, a hobby I’ve cultivated and enjoyed for over three years now, learning salsa, bachata, zouk, and tango. I discovered in Georgia Tech the importance of this balance in carrying out a productive and happy academic life.

What surprised you the most at Georgia Tech? What disappointed you the most?

I was surprised by the variety of cultural activities. Having a stereotypical image of a technology institute in mind, I was pleasantly surprised by poetry recitals, concerts, dance and theater performances, and many more activities on campus. After the success of the BVN Youth Poetry Slam semifinals at Georgia Tech in summer 2015, it was a disappointment that Tech didn’t continue to build on promoting slam poetry.

Which professor(s) or class(es) made a big impact on you? Why?

Certainly my advisor, Dr. Konstantinidis. Not only did I learn about microbial ecology from him, but also his frequent encouragement to critically discuss ideas has prepared me for scholastic discussion outside of Tech.

What is your most vivid memory of your time at Georgia Tech?

I cherish with particular warmth my memories of the Salsa Club, first as a regular member and later as a board member and an instructor.

On the basis of your experience, what advice would you give to incoming new graduate students at Georgia Tech?

Learn to say no and value your free time.

Learning to say no is hard, but as graduate students we often get bombarded with options and our first instinct is to try and cover them all. Some diversity in research topics is highly desirable, but it’s important to find a balance in which, at the end, a consistent story can be told in the dissertation.

Another area in which balance is hard to find is time management. We tend to err on the side of too much academic involvement and little or no personal life. Hobbies are important, they keep us healthy, happy, and productive, and it’s our own job to cultivate them and devote some time to them.

What feedback would you give to Georgia Tech leaders, faculty, and/or staff to improve the Georgia Tech experience for future students?

I would encourage more curricular freedom for graduate students. I was fortunate enough to be in the Ph.D. in Bioinformatics, a program with great latitude on the courses I could (or should) take. And yet, even in this program, I was never presented with the possibility of attending classes outside of the main program areas, while most advisors explicitly discourage this. For example, Georgia Tech offers very interesting courses in the humanities that are never mentioned to graduate students in the sciences or engineering.

Where are you headed after graduation? How did your Georgia Tech education prepare you for this next step?

I’ll stay in Georgia Tech for a short-term postdoctoral position in the School of Civil and Environmental Engineering. I plan on continuing in an academic career, for which Georgia Tech has prepared me with valuable practical experience in research, collaborations with faculty and students from other laboratories, and proposals of novel research ideas and projects.

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

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