Wednesday, January 26, 2022

New approach in quest for cancer vaccines nets Emory chemist a Michelson Prize

"I love doing research and trying to solve problems to help people," says Rong Ma, shown receiving her PhD in chemistry at Emory in 2021. "Nothing can compare to the joy I get from doing science."

By Carol Clark

Emory chemist Rong Ma received a $150,000 Michelson Prize for her proposal to harness the mechanical processes of cells as a new approach in the long-running quest to develop cancer vaccines. Ma, who received her PhD from Emory in 2021, is a post-doctoral fellow in the lab of Khalid Salaita, Emory professor of chemistry. 

The Michelson Prizes: Next Generation Grants are annual awards to support young investigators who are “using disruptive concepts and inventive processes to significantly advance human immunology and vaccine and immunotherapy discovery research for major global diseases,” according to the Michelson Medical Research Foundation and the Human Vaccine Project, the organizations administering the awards. 

Ma was one of three scientists selected through a rigorous global competition to receive a 2021 Michelson Prize for immunotherapy research. 

“We need disruptive thinkers and doers who dare to change the trajectory of the world for the better,” says Gary Michelson, founder and co-chair of the Michelson Medical Research Foundation. “Yet promising young researchers too often lack the opportunities, resources and freedom to explore their bold ideas. The pandemic has created additional roadblocks for many of them. With the Michelson Prizes, we aim to provide early-career investigators a vital boost for their forward-thinking approaches.” 

“Rong Ma is a spectacular, highly motivated scientist,” Salaita says. “Sometimes I will tell her that a goal she sets it too lofty or difficult to pull off, but she will look back at me and say, ‘I want to do really big, difficult things.’” 

“To find specific antigens on cancer cells for cancer vaccine development is extremely challenging, partly because of the ambiguity in predicting what antigens the body’s immune cells can recognize,” Ma says. “Many researchers are focused on using genetic sequencing techniques to find genetic mutations and predict tumor-specific antigens to achieve this goal.” 

Ma’s proposal, however, is to use the mechanical forces transmitted by immune cells to antigens as a marker to identify and evaluate whether an antigen can trigger a potent immune response. If the method works in a mouse-model system, Ma explains, the long-range vision would be to isolate the immune cells that are mechanically active when recognizing cancer-specific antigens. The identified antigens and isolated immune cells could then be used to train the body to defend against cancer cells. 

A love of complex systems 

As an undergraduate in her native China, Ma majored in environmental sciences. The interdisciplinary nature of environmental sciences taught her to think about complex problems from different perspectives and to integrate knowledge across specialties. 

During a masters’ program in environmental science and technology at City University in Hong Kong, Ma came across cancer research and decided to shift her focus to medicinal chemistry. “I love working on complex systems,” Ma says, “but I realized that I had a better chance of making a valuable contribution by focusing on a smaller-scale complex system, like the immune cells.” 

She was especially intrigued by research published in 2016 by the lab of Khalid Salaita, which specializes in the mechanical forces of cellular processes. The Emory researchers found that T cells, the security guards of the immune system, use a kind of mechanical “handshake” to test whether a cell they encounter is a friend or a foe. The lab had developed special tools to make this discovery — DNA-based tension sensors that light up, or fluoresce, in response to a minuscule mechanical force of a piconewton — about one million-millionth the weight of an apple. 

Ma came to Emory for her PhD in chemistry, so that she could work in the Salaita lab and help advance this technology. “At that point, it was a relatively new perspective to investigate the mechanical forces of cells and begin to understand these processes,” Ma says. “It opened up a whole new world of research for me.” 

Harnessing molecular forces 

The Salaita lab has continued to develop the tension sensors and further observe and characterize the mechanical forces of T cells. “We’ve advanced our understanding to the point where we can start exploring how to harness the molecular forces in cells for mechanically triggered therapeutics,” Ma says. 

T cells continuously patrol through the body in search of foreign invaders. They have molecules known as T-cell receptors (TCR) that can recognize specific antigenic peptides on the surface of a pathogenic or cancerous cell. When a T cell detects an antigen-presenting cell (APC), its TCR connects to a ligand on the APC. If the T cell determines the ligand is foreign, it becomes activated and starts a signaling chain to recruit other cells to come and help mount an immune response. 

The human body contains millions of different T cells and they specialize in recognizing specific antigenic peptides and binding with them. A current approach for research into cancer vaccines is to painstakingly try to identify which peptides are antigenic and which T cells are activated by them.

Studying the binding process in a laboratory solution, however, turns out not to be the most reliable method for pairing a cancer peptide with the T cell that it triggers. That’s because, in the body, cells are moving and sliding past each other’s surfaces. A T cell receptor needs to grab on to a cancer peptide and give a strong “handshake” in order for it to stick. 

“It turns out that testing the binding in solution is not the same as binding in more dynamic, real-world conditions,” Salaita explains. “Rong Ma has figured out a way to measure the duration of the binding ‘handshake tug’ at the interface of the cell and a glass slide presenting these antigens. We believe this method may be further developed into a much better way to determine which particular cancer peptides are going to trigger a response in which particular T cell, and even which T cell receptor is doing the tugging.” 

Testing the method 

In experiments, Ma will try to establish a proof-of-concept of this method. If it proves effective, then it may be possible to amplify those cancer-specific T cells and T cell receptors in a laboratory to help cancer immunotherapy development. The challenge of pairing the body’s millions of different T cell receptors with the billions of different antigens that may exist remains daunting. 

“Some of the preliminary data we have gathered looks promising, and the Michelson award will help us get the remaining data we need to test our method.” Ma says. “A cancer vaccine is the ultimate vision. We still have a long way to go to achieve that, but we hope that our method may provide another step forward.” 

This year’s Michelson Prize winners will receive their rewards in a virtual ceremony on March 10. “It is inspiring to see their passion for innovation and their courage to think out of the box,” says Wayne Koff, CEO and president of the Human Vaccines Project. “I look forward to their future breakthrough discoveries and how their research can contribute to the Human Vaccines Project’s mission of developing the first AI model of human immunity.”


T cells use 'handshakes' to sort friends from foes

Chemists reveal the force within you

Molecular beacons shine light on how cells 'crawl'

Wednesday, January 19, 2022

First genome-wide ancient human DNA from Sudan shines new light on Nile Valley past

"Ancient DNA is difficult to recover from areas that are extremely hot, because DNA tends to degrade in heat," says Kendra Sirak, shown in 2017 when she was an Emory PhD student of anthropology. While still a student, she began developing new techniques for extracting ancient DNA samples that are opening new vistas into the human past.

By Carol Clark

The first genome-wide, ancient human DNA data from Sudan reveals new insights into the ancestry and social organization of people who lived more than 1,000 years ago in the Nile Valley, an important genetic and cultural crossroads. 

Nature Communications published the analyses of the DNA of 66 individuals from a site in ancient Nubia known as Kulubnarti, located on the Nile River in Sudan, just south of the Egyptian border. 

“Before this work, there were only three ancient genome-wide samples available, from Egypt, for the entire Nile Valley,” says first author Kendra Sirak, who began the project as a PhD student at Emory University. “And yet the region was, and still is, an incredibly important part of the world in terms of the movement, meeting and mixing of people.” 

Sirak was the last graduate student of the late George Armelagos, former professor of anthropology at Emory and a pioneer in bridging the disciplines of archeology and biology. While still a graduate student in the 1960s, Armelagos was part of a team that excavated ancient skeletons from Sudanese Nubia, so the bones would not be lost forever when the Nile was dammed. 

“Nubia was a place of human habitation for tens of thousands of years,” says Sirak, who is now a staff scientist at Harvard University. “This ancient genetic data helps fill in some major gaps in our understanding of who these people were.” 

The 66 individuals date back from 1,080 to 1,320 years ago, during the Christian Period of Sudanese Nubia, prior to the genetic and cultural changes that occurred along with the introduction of Islam. The analyses showed how the Kulubnarti gene pool formed over the course of a least a millennium through multiple waves of admixture, some local and some from distant places. They had ancestry seen today in some populations of Sudan, as well as ancestry that was ultimately West Eurasian in origin and likely introduced into Nubia through Egypt. 

“A key finding is that social status did not have a strong relationship to biological relatedness or to ancestry in this ancient population, who lived during a period of cultural and social change,” says Jessica Thompson, a co-senior author of the paper. Thompson, a former PhD supervisor of Sirak in Emory’s Department of Anthropology, is now at Yale University. 

During a field visit, Sirak took the above photo of a sunrise on the Nile River. The Nile Valley region "was, and still is, an incredibly important part of the world in terms of movement, meeting and mixing of people," she says.

The remains of the individuals came from two cemeteries with Christian-style burials that previous evidence indicated were socially stratified. In one cemetery, located on an island in the Nile, the skeletal remains bore more markers of stress, disease and malnutrition and the average age of those buried was just over 10 years old. By contrast, the average age at death in the other cemetery, located on the mainland, was 18 years. 

One hypothesis that grew out of this skeletal evidence was that the island cemetery was for a Kulubnarti “underclass,” possibly laborers for members of landowning families buried in the mainland cemetery. It was a mystery whether the social stratification may have developed because one population came from a different origin. 

A genome-wide analysis suggests that was not the case — the people buried in the separate cemeteries came from a single genetic population. 

“It seems that people in this area did not use biological ancestry as a basis for social differentiation,” Thompson says. “This reinforces the point that dividing people up socially on the basis of their genetic ancestry is a recent phenomenon, with no basis in universal human tendences.” 

Another key finding of the genetic analyses shows that some people as close as second-degree relatives were buried across the cemetery divide. Examples of second-degree relationships include grandparents to grandchildren, aunts and uncles to nieces and nephews, and half siblings. 

“That indicates that there was some fluidity among the two groups of people,” Sirak says. “There wasn’t an intergenerational caste system that meant someone was prescribed to being in the same social group as all of their relatives.” 

A further interesting twist is that much of the Eurasian-derived ancestry within the population came from women. “Often when you think of ancestry and how genes move, you think of males who are trading or conquering or spreading religion,” Sirak says. “But the genetic data here reveals that female mobility was really crucial to shaping the gene pool in Kulubnarti.” 

One possible explanation is that Kulubnarti was a patrilocal system, meaning that males tended to stay where they were born and females moved away from their homelands. 

“The Christian Period Nubians from Kulubnarti are fascinating,” Sirak says. “They survived in a barren, isolated, desolate region where life was never easy. I like to think that the ancient DNA research is giving a new life to these people from 1,000 years ago by providing a more nuanced view of them. Anytime you’re studying someone’s remains, their physical being, you owe it to them to tell the most accurate, respectful and meaningful story that you can.” 

The late George Armelagos during the 1980s. He and fellow faculty members built Emory's Department of Anthropology into a powerhouse of the biocultural approach to the field.

Sirak came to Emory as a graduate student in 2012 to study human bones and paleopathology under Armelagos. By that time, he and fellow faculty members had built Emory’s Department of Anthropology into a powerhouse of the biocultural approach to the field. In particular, Armelagos, his colleagues and graduate students studied the remains of the Sudanese Nubians to learn about patterns of health, illness and death in the past. 

A long missing piece in the studies of this population, however, was genetic analysis. So, in 2013, Armelagos sent Sirak to one of the best ancient DNA labs in the world, University College Dublin, with samples of the Nubian bones. 

“I had no interest in genetics,” Sirak recalls, “but George was a visionary who believed that DNA was going to become a critical part of anthropological research.” 

Sirak soon became hooked when she saw how she could combine her interest in ancient bones with insights from DNA. She formed collaborations not just in Dublin but at Harvard Medical School’s Department of Genetics and elsewhere, investigating mysteries surrounding deaths going back anywhere from decades to ancient times. 

Armelagos was 77 and still mentoring Sirak, his last graduate student, when he died of pancreatic cancer in 2014. Dennis Van Gerven, an emeritus professor of anthropology at the University of Colorado at Boulder, took over Sirak’s mentorship, along with Thompson. Van Gerven was among Armelagos’ first group of students, and he also spent decades studying the Sudanese Nubians. 

Sirak stuck with her PhD dissertation project of trying to collect enough ancient DNA from the Nubian remains for analysis. 

“Ancient DNA is difficult to recover from areas that are extremely hot, because DNA tends to degrade in heat,” she explains. 

Genetic sequencing techniques kept improving, however, and Sirak was working at the forefront of the effort. In 2015, while still an Emory graduate student, she was among the researchers who realized that a particular part of the petrous bone consistently yielded the most DNA. This pyramid-shaped bone houses several parts of the inner ear related to hearing and balance. In addition, Sirak developed a technique to drill into a skull and reach this particular part of the petrous bone in the most non-invasive way possible, while also getting enough bone powder for DNA analysis. The use of this part of the petrous bone is now the gold standard in ancient DNA analysis. 

In 2018, Sirak received her PhD from Emory and went on to work in the lab of David Reich, a geneticist at Harvard Medical School who specializes in the population genetics of ancient humans. 

She and her colleagues continued to push the boundaries of what’s possible with ancient DNA sequencing. They managed to get whole-genome samples from the petrous bones of 66 of the Sudanese Nubians, ushering in a whole new era of bioarchaeology for the Nile Valley. “I don’t think we would have succeeded in this work had we not known to focus on the specific part of the petrous bone,” Sirak says. 

“It’s incredible to me that George asked me to focus on ancient DNA back in 2012, long before these techniques were developed,” she adds. “He had a way of making anyone who was working with him really feel important and powerful and that gave me the confidence to strike out on a pioneering path.”

“George Armelagos’ influence is everywhere,” adds Thompson, explaining that he also advised many senior people who mentored her early in her career. 

Funded by National Geographic Explorer grants, Sirak is now working with Sudanese colleagues to gather and analyze ancient DNA samples from other geographic locations in the Nile Valley, going even deeper into its past, to add more details to the story of how people moved, mixed and thrived in the region across millennia. 

As the last graduate student of Armelagos — and then a mentee of Van Gerven, one of Armelagos’ first students — Sirak feels like she is completing a circle. The publication of the current paper is the realization of Armelagos’ last wishes for the project. 

“It’s really special for me to be able to use ancient DNA to build on decades of anthropological and archeological research for the region,” Sirak says. “I know that George would be proud and thrilled. I’m part of this amazing lineage of researchers now. And the desire to continue what they started is a huge motivation for me.” 

In addition to Reich, Thompson and Van Gerven, senior authors of the Nature Communications paper include Nick Patterson (Broad Institute of Harvard and MIT) and Ron Pinhasi (University College, Dublin). Co-authors include researchers from these institutions as well as the University of Vienna, the University of Coimbra in Portugal, the Howard Hughes Medical Institute, the University of Pompeu Fabra in Barcelona, the University of Georgia, the University of California, Santa Cruz, and the University of Michigan.


Emory students help unravel prehistoric mysteries

Malawi yields oldest-known DNA from Africa

Pioneering techniques in anthropological genetics

Ancient DNA lab maps little-explored human lineages

Tuesday, January 11, 2022

International trade bans on endangered species tend to help mammals but hurt reptiles

Emory economist Hugo Mialon led a major study on the impact of international trade bans on the status of endangered species, such as Madagascar's Antsingy leaf chameleon, above, once popular in the pet trade. (Photo by Bernard Dupont, via Wikipedia).

By Carol Clark

International trade bans on endangered species generally help mammals improve their status but hurt reptiles, finds a major economics study led by Emory University. 

Science Advances published the research on the impact of international trade bans by the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES). 

“We find large spikes in legal trade in anticipation of the bans on reptilian species but not in anticipation of the bans on mammalian species, potentially explaining the differential effect of the bans,” says Hugo Mialon, professor of economics at Emory University and lead author of the study. 

The work is the largest-scale study of its kind, spanning nearly four decades and including all mammalian and reptilian species for which threat-level assessments are available from the International Union for the Conservation of Nature (IUCN). 

Co-authors include economists Tilman Klumpp, from the University of Alberta, Canada; and Michael Williams, from the Berkeley Research Group and Competition Economics LLC in Emeryville, California. 

Their findings have significant implications for policymakers. Since CITES does not operate in secrecy, increased trading activity in anticipation of impending trading bans is generally not preventable. 

“Anticipatory trade spikes may be especially detrimental when the bans are applied to critically endangered species, because market prices for the few remaining specimens tend to be high, so eleventh-hour trading may be more intense and post-ban recovery harder,” Mialon says. “This suggests that trade bans should be implemented at lower endangerment levels — in other words, when a species is near threatened rather than critically endangered.” 

The authors propose several possible explanations for why eleventh-hour trade spikes did not occur — or were less pronounced — for mammalian species. One possibility is logistics, since many of the mammalian species in their dataset were many times larger and heavier than most of the reptilian species, requiring greater effort to ship across international borders. In addition, many of the reptilian species, such as turtles and tortoises, are easier to catch than the mammals. Finally, reptilian species traded in the exotic pet trade are known to be less likely to survive physical relocation compared to mammals. 

The Bolson tortoise, the largest of North American tortoise species, lives in the Chihuahuan Desert in Mexico and is listed as "critically endangered" by the IUCN. (Photo by Mbtrap, via Wikipedia)

Mialon specializes in research at the boundaries between law and economics. 

“From a young age, I’ve been fascinated by wild animals and their importance to ecosystems,” he says. “The available IUCN data on endangered species and CITES bans offered a chance to apply my expertise to potentially help save animal species from extinction. As far as I know, we are the first economists to tackle this topic.” 

Direct evidence for the effectiveness of trade bans by CITES has been inconclusive. Several previous small-sample studies have found that CITES regulations had a marginal effect, or no measurable effect, on endangerment. 

Mialon and his colleagues took a more comprehensive approach to the question. They focused on the period starting in 1979, when data on CITES bans first became available, to 2018. Their analysis included all 41 mammalian and 20 reptilian species that have received CITES bans within the study period and the thousands of mammalian and reptilian species that have been assessed by IUCN during that period. 

The status of a majority of species has deteriorated over the past four decades, due to various threats such as hunting, habitat loss and climate change. The statistical methods used by the researchers compared how the status of species that received CITES trade bans changed compared to those that did not receive bans. 

Economic controls used in the study included data on GPD per capita, international trade volume as a percentage of GDP, and population density, by country and year. For each species and year, the researchers averaged each of these variables over all countries in the species’ distribution, as recorded by the IUCN. They also constructed a measure for scientific interest in a species. And the analysis controlled for factors that differ across species but do not change over time, such as a species’ average adult size.

The ocelot is among the mammals whose status improved after a trade ban. The wild cat is native to the southwestern United States, Mexico, Central and South America and parts of the Caribbean. (Photo by Joao Carlos Medau, Wikipedia).

The results indicate that, on average, trade bans work for mammals. A trade ban is associated with an average reduction in the probability that a species is assessed as endangered or worse of up to 17 percent, relative to species in which trade was not banned.

Mammalian species whose status eventually improved following a ban include the Guadalupe fur seal, the grey wolf, the northern bottle-nose whale, the ocelot, the margay, the sloth bear, the Samoan flying fox, the Pacific flying fox, Cuvier's gazelle and the slender-horned gazelle.

“The Cuvier’s gazelle and the slender-horned gazelle are clear examples,” Mialon says. “They were endangered in 2007 when they received a CITES ban and are ‘vulnerable’ and no longer ‘endangered’ today.” 

The Dorcas gazelle, however, which did not receive a CITES ban, was “vulnerable” in 2007 and remains “vulnerable” today, so it saw no improvement in status. 

“All three species are closely related, share a similar geographic distribution, and face overlapping threats,” Mialon says. “This provides an example of the trade bans working and may suggest that extending a trade ban to the Dorcas gazelle could be effective, too.” 

In the case of reptiles, the analysis found that an international trade ban is associated with an average increase in the probability that a species is assessed as endangered or worse of up to 42.6 percent, relative to species in which trade was not banned. 

Only the American and saltwater crocodiles saw their status improve following a CITES ban. The Bolson tortoise, Simony’s lizard, the bog turtle, Kleinmann’s tortoise, the Antsingy leaf chameleon, the flat-tailed tortoise, the spider tortoise and the big-headed turtle all saw their status deteriorate following the ban. 

One limitation to the study is that historical data on the use of other conservation measures besides CITES bans was unavailable so it could not be used as a control variable. Another limitation is that the analysis only looked at international bans. 

“Many threatened animal species are not traded in international markets but are still traded in local and national markets,” Mialon says. 

Mialon and his colleagues are currently working on another paper about the effects of CITES international trade bans on plant species. 

The research received support from Competition Economics LLC and the Social Sciences and Humanities Research Council of Canada.


Valuing 'natural capital' vital to avoid next pandemic, global experts warn

Great apes and COVID-19: Experts raise the alarm for endangered species