Remnants of extinct monkeys are hiding inside you, along with those of lizards, jellyfish and other animals. Your DNA is built upon gene fragments from primal ancestors.
Now researchers at the Georgia Institute of Technology have made it more likely that ancestral genes, along with ancestral proteins, can be confidently identified and reconstructed. They have benchmarked a vital tool that would seem nearly impossible to benchmark. The newly won confidence in the tool could also help scientists compute ancient gene sequences and use them to synthesize better proteins to battle diseases.
For some 20 years, scientists have used algorithms to compute their way hundreds of millions of years back into the evolutionary past. Starting with present-day gene sequences, they perform what’s called ancestral sequence reconstruction (ASR) to determine past mutations and figure out the genes’ primal forerunners.
“With the help of ASR, we can now actually build those ancient genes in the laboratory and express their encoded ancient proteins,” said Eric Gaucher, an associate professor at Georgia Tech’s School of Biological Sciences. In a separate project, his lab is computing ancient proteins that were very effective in blood clotting 80 million years ago, in hopes of using them to fight hemophilia today.
That protein comes from a common ancestor humans share with rats.
Time travel substitute
But ASR algorithms have faced logical criticism. Species based on those primal genes are long extinct, and scientists can’t travel back in time to observe mutations that have happened since. So, how can anyone find any physical benchmark to verify and gauge ASR?
A team of researchers led by Gaucher did it by building an evolutionary framework out of myriad mutations. Then they benchmarked ASR algorithms against it – no time machine required. Their results have shored up confidence that the widely used algorithms are working as they should.
“Most of them did a very good job – 98% accurate,” Gaucher said of contemporary algorithms’ ability to compute ancient gene sequences. Their determination of proteins encoded by those sequences was virtually perfect.
Gaucher, research coordinator Ryan Randall and undergraduate student Caelan Radford published their results on Thursday, September 15, 2016, in the journal Nature Communications. Their research has been funded by the NASA Exobiology program, E.I. du Pont de Nemours and Company (DuPont) and the National Science Foundation.
Holographic tree branches
Ancestral sequence reconstruction is like making a family tree for genes.
The many twigs and branches at the treetop would be sequences from species alive today. Shimmying down the tree, called a phylogeny in genetics, you would find their common ancestors, millions of years old, in the lower branches.
There’s a caveat; none of the lower branches exist any longer. They vanished in the extinction of the species bearing those genetic sequences.
ASR computes them back into place using algorithms based on scientific models of evolution. It’s like replacing missing branches with holographic duplicates.
Algorithm horse race
The accuracy of those evolutionary models has been a historic sticking point. And doubts about the algorithms based on them linger in some circles that hold on to an old, tried-and-true algorithm.
So, Gaucher and researcher coordinator Randall pitted the contemporary model-based, or “maximum likelihood,” algorithms in a race against the generic, or “parsimony,” algorithm.
“Parsimony follows the simplest notion of evolution, which is that very little mutation occurs,” Randall said. The models behind contemporary “maximum likelihood” algorithms, by contrast, are laced with filigree, data-packed details.
For the race, Randall made a track of sorts by putting a gene sequence that made a single protein through multiple mutations to construct a real-life phylogeny. She used methods that closely mimicked natural evolution, but that were much, much faster.
Rainbow phylogeny racetrack
In cells, enzymes called polymerases aid in DNA duplication. They work very efficiently, but their rare mistakes are the most common source of mutations, and Randall took her lead from this.
“We used a polymerase that is error-prone to speed up mutations, and speed up evolution,” she said.
The genes used at the starting point of the lab evolution made a protein that fluoresced red when placed in bacteria. As significant mutations arose, the proteins began changing color. Bacteria containing green fluorescing proteins popped up among the red ones.
Randall divided bacteria with major mutations into new groups, creating branches in the phylogeny, as she went. Many mutations produced new colors – yellow, orange, blue, pink – and Randall ended up with a gene family tree in rainbow colors.
Show me the phenotype
The colors reflected not only new gene sequences but also new phenotypes – the actual proteins they produced, the organism’s working molecules.
“What counts is phenotype,” Gaucher said. “When you analyze DNA strictly by itself, it ignores the context, in which that DNA is connected to phenotype,” he said.
DNA can mutate and still encode the same amino acids, protein’s component parts. Then the mutation has no real effect. But when mutations cause DNA to encode different amino acids, they’re more significant.
A worthy test of ancestral sequence reconstruction algorithms must therefore include phenotype. And Randall took this into account when she selected mutated proteins.
“I selected for variants to purposely make it hard on the algorithms to infer the phenotypes,” she said. The race ensued, and the algorithms got limited information to infer the evolutionary tree’s many dozens of past mutations.
ASR a sure bet
Though the tried-and-true parsimony algorithm performed well, maximum likelihood performed better. “Even though it got the same number of residues (DNA sequences) wrong as parsimony, the incorrectly inferred sequences were still more likely to encode the right phenotypes,” said undergraduate student Caelan Radford, who analyzed the experiment’s statistics.
The margin of error was so tiny that it would not interfere in the determination of past species.
The experiment’s outcome was not too surprising, because prior simulations had predicted it. But the researchers wanted the scientific community to have physical proof that feels trustier than proof from a computer. “It’s a computer algorithm. It will do what you will tell it to do,” Gaucher said.
Short history of ASR
Doubts about ancestral sequence reconstruction -- and maximum likelihood algorithms in particular -- go far back. The idea of performing ASR first came up in 1963, but it didn’t get started until the 1990s, and back then, researchers battled fervently over wide-ranging methods.
“People would come up with the craziest notion as to why one model was best,” Gaucher said. “They’d say, ‘Well, if I simulate this weird mode of evolution along these branches here, my algorithm will work better than your algorithm.’”
The parsimony algorithm was a way of reigning in the chaos that grew out of a lack of data in evolutionary models at the time. “When the model is wrong, ‘maximum likelihood’ fails miserably,” Gaucher said.
But, now, a host of data and analysis give scientists a great picture of how evolution works (and it’s not a parsimony principle): For ages, nothing moves, then change bursts forth, then things stabilize again.
“You get this quick evolution, so lots of stuff works and lots of stuff fails, and the stuff that works then goes on and kind of maintains its status and doesn’t change,” Gaucher said. By confirming the high accuracy of the algorithms, the Georgia Tech team has also corroborated the validity of current evolutionary science they’re based on.
Kelsey Roof and Divya Natarajan of Georgia Tech coauthored the paper. Research was funded the NASA Exobiology program (grant number NNX12AI10G), DuPont (Young Professor Award) and the National Science Foundation (grant number 1145698). 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.
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The lab of Greg Gibson at the Georgia Institute of Technology has been awarded a grant of $2.3 million to study the subtle genetic underpinnings of autoimmune-related diseases by taking a computational approach.
The National Institutes of Health made the award as part of an $11.1 million total investment in research funds slated for five institutions, including Georgia Tech. The researchers’ work could increase understanding of the causes of diabetes, Crohn’s disease, rheumatoid arthritis, forms of heart disease, and more afflictions where inflammation is at issue, and where there may be a connection to autoimmunity.
"We know that hundreds of genes impact autoimmunity, but the challenge is to narrow down the actual DNA sequence changes that have an impact. This grant combines our statistical genetics expertise with evolutionary genetics and genome editing by collaborators,” said Greg Gibson, a professor at Georgia Tech’s School of Biological Sciences.
In its research, Georgia Tech will work together with Rice University in Houston and Temple University in Philadelphia. Gibson's researchers will handle statistical analysis and interpretation; Rice's scientists will carry out gene editing, and evolutionary geneticists at Temple will contribute insights on which gene sites should or should not be variable in the human genome.
Attacking friends: Autoimmunity
Our cells work together with masses of microbes that are an integral part of the human body, but the immune systems of people with related diseases can attack the microbes and healthy human cells, and lead to inflammation. “Lymphocytes, for example, could be attacking the body,” Gibson said.
“We’re looking at genes that regulate the immune system,” he said. “They’ve all got subtle effects. What counts is that they all work together. We’re looking for sections of genetic code that work a little oddly.”
Researchers will put data through algorithms to better identify genetic variants in sections of the human genome that do not encode proteins, but have regulatory functions, the NIH said in a news release. These are sections of DNA that, for example, turn encoding genes on and off.
Subtleties multiplied: Susceptibility
They have been lesser studied but are known to be critical and could provide new information on yet undiscovered pathways composed of multiple faint characteristics that add up to disease.
"Taken alone, some small characteristic may appear indistinct, and at the same time, it’s really hard to read how a big group of them work in total,” Gibson said. “But their cumulative effect is dramatic, and unfortunate.”
Recent genomic research methods have compared the complete genomes of patients with diseases to those without them, leading to thousands of statistical hints. Now new data and interpretive approaches are needed to effectively sift through these to see the foundations of diseases, or make predictions of who is most at risk, and what people can do to reduce the risk.
The NIH hopes statistical methods will allow prediction of possible effects some variants have on susceptibility to disease and on drug response. The funding comes from the NIH’s National Human Genome Research Institute (NHGRI)'s Non-Coding Variants Program, and the National Cancer Institute (NCI).
A new study in the journal Nature analyzes genomic diversity in 125 human populations at an unprecedented level of detail, tackling questions related to our species’ demographic history and dispersal out-of-Africa. The study is based on 379 high-resolution whole-genome sequences from across the world, generated by an international collaboration led by Mait Metspalu from the Estonian Biocentre, Estonia, and Toomas Kivisild from the University of Cambridge, U.K.
“This endeavor was uniquely made possible by the anonymous sample donors and the collaboration effort of nearly 100 researchers from 74 different research groups from all over the World,” Metspalu said.
The lab of Joseph Lachance in the School of Biological Sciences at Georgia Institute of Technology is one of these research groups. “By studying a global panel of individuals, we are able to identify genetic variants that are shared among different subsets of humanity and decipher our evolutionary past,” Lachance said.
The high geographic coverage of the samples permitted the researchers to study many aspects of genetic and phenotypic differences between individuals and populations using a common spatial framework. Researchers found that the sharpest genetic gradient in Eurasia separates East and West Eurasians. This barrier runs roughly along the Ural Mountains in the north, opens in the Steppe belt connecting Central Asia to South Siberia, and becomes strong again on the Tibetan plateau, elongating south toward the Indian Ocean while separating South and Southeast Asia.
In addition to increasing our understanding of the challenges that humans faced when settling down in ever-changing environments, the deluge of freely available data will serve as future starting point to further studies on the genetic history of modern and ancient human populations.
The Petit Institute for Bioengineering and Bioscience has grown again with the addition of five new faculty researchers, four of them based in the Wallace H. Coulter Department of Biomedical Engineering (BME), a joint department of the Georgia Institute of Technology and Emory University.
Joining the multidisciplinary research institute are Jaydev Desai, Scott Hollister, Frank Rosenzsweig, Kalid Salaita, and Annabelle Singer.
Desai joined the Coulter Department this past summer as a professor and BME Distinguished Faculty Fellow. Former director of the Robotics, Automation, and Medical Systems (RAMS) Laboratory at the University of Maryland, Desai’s research interests are focused primarily on image-guided surgical robotics, rehabilitation robotics, cancer diagnosis at the micro scale, and grasping.
Holister comes to the Coulter Department from the University of Michigan, where he directed the Scaffold Tissue Engineering Group, which develops degradable scaffold material systems, which can be used to deliver stem cells, genes and proteins to regenerate tissue defects, leading to clinical applications that include include spine fusion and disc repair, craniomaxillofcial reconstruction, orthopaedic trauma and joint reconstruction, and cardiovascular reconstruction.
Rosenzweig, a professor in the School of Biological Sciences, spent the past 15 years at the University of Montana in Missoula. The underlying goal of his research is to enlarge our understanding of the ecological and evolutionary forces that promote and preserve genetic variation, studying how genetic variation is integrated at the level of cellular physiology to produce differences in fitness.
Salaita, an assistant professor in BME based at Emory since 2009 who was previously a postdoctoral fellow at the University of California-Berkeley, is principal investigator of a wide-ranging research group that develops chemical tools to better understand how chemical and physical signals are transmitted in living systems.
Singer is an assistant professor of BME, where her lab group works on uncovering how complex patterns of activity across populations of neurons are decoded to guide behavior in health and disease, using a combination of novel tools, including robotic patch clamp recordings, large-scale extracellular recordings, cutting edge data analysis methods, new behavioral paradigms, and novel brain stimulation tools.
Now with more than 180 faculty researchers, the Petit Institute is an internationally recognized hub of multidisciplinary research, where engineers and scientists are working on solving some of the world’s most challenging health issues. With 18 research centers and more than $24 million invested in state-of-the-art core facilities, the Petit Institute is translating scientific discoveries into game-changing solutions to solve real-world problems.
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Mary Beth Brown came to Georgia Tech to do research in Applied Physiology. She attended the School of Applied Physiology and received a Ph.D. in 2009. The school is now the School of Biological Sciences after a reorganization in July 2016.
Before Georgia Tech, Brown attended St. Petersburg High School, in St. Petersburg, Florida. She received a B.A. in Exercise Science from Lenoir-Rhyne University, in North Carolina, and an M.S. in Physical Therapy from the University of Miami, in Florida. She practiced as a physical therapist for almost 10 years prior to returning to school to pursue her Ph.D.
After completing her Ph.D., Brown took a postdoctoral fellowship at Indiana University School of Medicine, in Indianapolis, where she currently lives. Brown is now an assistant professor of physical therapy in the School of Health and Rehabilitation Sciences at Indiana University.
What attracted you to study in Georgia Tech?
The Applied Physiology program and the opportunity to be under the guidance of Dr. Mindy Millard-Stafford in her Exercise Physiology Lab seemed like a good fit for my interests and background. Being in downtown Atlanta was exciting.
Georgia Tech, the Applied Physiology program, and its faculty met my expectations. Most importantly, I learned how to be a good researcher. As a Ph.D. student, that’s what I came to learn.
What is a vivid memory of your time at Georgia Tech?
Getting to deliver my Ph.D. dissertation presentation after four+ years of work on my topic was one of the biggest thrills of my life, and highly gratifying.
How did you get to your current position?
I took a postdoctoral fellowship position at Indiana University School of Medicine after completing my Ph.D. at Georgia Tech. Then a research tenure-track faculty position opened up in Indiana University, in the Physical Therapy department, where I wanted to be. It worked out perfectly.
What roles did your Georgia Tech education and experience play in your journey to your current position?
I had tremendous education in research. Much of this was out of the classroom. But the foundation was laid in the classroom. Also, my Ph.D. program’s willingness to support and encourage the collaboration I wanted to do with Emory School of Medicine permitted me to pursue my research question with greater breadth and depth, and that took it from being good to great. More importantly, it helped me fill my investigator tool box with many more tools to which I may not have had exposure otherwise.
Which professor(s) or class(es) made a big impact on your career path?
I teach physiology now, so my physiology courses at Georgia Tech (Systems Physiology I, II, and III) made a big impact. I particularly was influenced by Dr. Tom Burkholder, who taught the first of these courses, as well as an outstanding muscle physiology course.
Another course that was also impactful was Foundations in Molecular and Cell Biology, BIOL 7001. It was invented and directed by Dr. Nael McCarty, with contributions from many guest lecturing principal investigators from the School of Biology (now also the School of Biological Sciences). That class was one of the most challenging of my time at Georga Tech, but probably influenced my career path more than any other class, in a positive way.
What do you like most about your current job? The least?
The most: working with students in my lab. The least: faculty meetings.
What has been the greatest challenge in your professional life so far?
Learning to accept rejection is probably the greatest challenge, and it is not just a one-time event. It happens repeatedly as a researcher. Rejected grant applications, rejected manuscripts—it is hard in the beginning, and this is where more senior colleagues are helpful to provide perspective.
I have learned that it helps to take a LOT of shots at the goal. Rejections are common, even for good products. The trick is to keep submitting, keep learning from them, and keep evolving.
What has been the most gratifying experience of your professional career so far?
The most gratifying so far was my first NIH funding award, last year. It gave me the confidence to keep at it, even when things seemed to be going every way except my way in my research.
The second most gratifying was this year when I came back and gave a research talk at Georgia Tech to my former professors and current and past students of the School of Applied Physiology. It was not just an honor; it was gratifying in that I felt like it was a true, from-the-heart ‘thank you’ to them from me for the important role they played in my career path.
If you could have taken an alternative career path, what would you be doing instead?
Nothing!
Okay, maybe a professional surfer. I can’t even surf, never tried, but those women look so cool and so fearless.
What advice would you give to incoming first-year students at Georgia Tech?
To first-year Ph.D. students at Tech, I’d say be open-minded to immense possibilities. This can happen only if you get out of your comfort zone. When constructing your research projects, do not propose to study what you already know. Make sure your proposal really stretches you.
What’s something about yourself that’s not obvious to your colleagues?
I work as hard in my recreational sports endeavors as I do with my professional endeavors, and that’s because I am competitive probably to a fault. There is no just-for-fun race. I’ve taken to long, solo, endurance events (open-water swimming, marathons, ultra-distance triathlons), probably because these activities keep me from being too hard on anyone but myself.
If you could have dinner with any person from history, whom would you invite?
Hatshepsut, the woman who ruled Egypt as pharaoh starting around 1478 BC. She was feminism before feminism was even a thing. In this election year, when we are witnessing history with our first female presidential candidate, I am in complete disbelief that it has taken this long for this day to arrive. I’d like to ask Hatshepsut if she has any ideas about why this is so.
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.”
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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.
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