Dr. Huda Yahya Zoghbi’s career spans decades; her Wikipedia page sports an “Awards and Honors” section that takes up my entire computer screen. She is a geneticist, neuroscientist, pediatric neurologist, pharmaceutical executive, and literature lover. Her presentation kicked off 2022 Research Week with a discussion of her work on Rett Syndrome. (View the session)
Rett Syndrome is a rare genetic disorder. The gene that researchers identified as the driver of the syndrome is MeCP2, which is especially active in brain cells. Certain mutations of this one gene can be responsible for a loss of speech, development issues, and persistent fidgeting.
Children with Rett Syndrome faced chronic misdiagnosis, and even with proper care were limited by a lack of research.
Duke’s Dr. Robert Lefkowitz introduced Zoghbi at the beginning of the seminar and explained how she came to become the leading expert on this relatively unknown disorder. After completing medical school in Beirut in the midst of the ravaging Lebanese Civil War, she came to Texas Children’s Hospital, where she was able to observe and diagnose her first case of the syndrome, a process spurred by a simple interest in a newly-published journal article.
Holistic knowledge of Rett Syndrome is completely dependent on genetic research. A mutation on the MeCP2 gene causes errors in transcription, the reading out of DNA in your cells which leads to the production of proteins.
The mutated gene’s MeCP2 protein is then lacking the ability to do its job, which is helping other genes be expressed, or actively transcribed.
It’s a vicious cycle; like when you go to sleep late one night, so you sleep in the next day, then go to sleep late the next night, then sleep in the next day, and so forth.
In order to simulate and measure the effect of different kind of mutations on the MeCP2 gene, Zoghbi and her team studied genetically modified mice. While Rett Syndrome is caused by a lack of MeCP2 function, an overactive MeCP2 gene causes MeCP2 duplication syndrome. Varying degrees of gene efficiency then produce varying degrees of severity in the syndrome’s traits, with fatality at either end of the curve.
Varying degrees of phenotype severity.
Zoghbi’s talk focused mainly on the mechanics of the disorder on a genetic level, familiar territory to both Nobel Laureate Lefkowitz and Duke Medicine Dean Mary Klotman, who shared some discussion with Zoghbi.
This medicine on a microscale is applicable to treating genetic disorders, not just identifying them. Zoghbi has been able to experimentally correct MeCP2 duplication disorder in mice by modifying receptors in a way that reverses the effects of the disorder.
The symptoms of Rett Syndrome are physical; they present themselves as distinct phenotypes of a subtle difference in genotype that’s too small to see. The field of genetics in medicine is responsible for making that connection.
Everything in our world is made from materials, meaning life is enabled by material development and efficiency. In today’s society, from constant technological revolution to the global pandemic, life as we know it is always evolving. But as the world around us evolves, the materials around us also need to evolve to keep up with current demands. But how? As a part of Duke University’s annual Research Week on Feb. 3, researchers from a multitude of practices offered their wisdom and research.
Moderated by Dr. Catherine L. Brinson, Ph.D., the panel hosted three Duke Scholars and their research on ‘Materials for a Changing World’. “The development of new materials can really be key in solving some of the more critical challenges of our time,” Brinson maintained.
Dr. David Beratan explaining his research on bio-machines and their material efficiency.
The first scholar to present was R.J Reynolds distinguished professor of chemistry, Dr. David N Beratan, Ph.D. His research concerns the transition from soft, wet, and tiny research machines to more durable, long-term research machines in the science field. “The machines of biology tend to be stochastic and floppy rather than deterministic and hard,” Beratan began. “They’re messy and there are lots of moving parts. They’re intrinsically noisy and error-prone, etc…They’re very different from the kinds of things you see under the hood of your car, and we’d really like to understand how they work and what lessons we might derive from them for our world.” His complex research and research group have aided in bridging the gap in knowledge regarding the transition of biological functional machines to synthetic ones.
Dr.Rubinstein presenting his research on materials at Duke’s Pratt School of Engineering in 2019.
The panel continued with Aleksandar S. Vesic Distinguished Professor in mechanical engineering, Dr. Michael Rubinstein, Ph.D. His research involves the development of self-healing materials across multiple spectrums. “What you want to think about is materials that can heal themselves,” he stated. “If there’s a crack or a failure in a material, we would like the material to heal itself without external perturbation involvement. So it could be done by the other diffusion of molecules across some physical approaches, or by a chemical approach where you have bonds that were broken to the form.” His research on this possibility has made strides in the scientific field, especially in a time of such ecological stress and demand for materials.
Dr. Segura talking with Dr. Brinson on her research involving self-healing materials.
The panel concluded with biomedical engineering professor Dr. Tatiana Segura, Ph.D. Segura talked about work they are doing at their lab regarding materials that can be used to heal the human body after damage or injury. She began by mentioning that “we are a materials lab and that’s what we’re interested in designing. So what are we inspired by? Well, we are really inspired by the ability of our body to heal.” At her lab, a primary motivation is healing disabilities after a stroke. “Sometimes you have something that you deal with for a long time no matter how your body healed. And that inspires us to consider how do we actually engage this process with materials to make it go better and actually make our body heal in a way that we can promote repair and regeneration.” Understanding this process is a complex one, she explained, but one that she believes is crucial in understanding the design of the material.
‘Materials for a Changing World’ was yet another extremely powerful speaker series offered this year during Duke Research Week. Our world is changing, and our materials need to keep up. With the help of these experts, material innovation has a bright future.
Cypress swamp, eastern North Carolina. Photo by Steve Anderson, Duke
DURHAM, N.C. — The Albemarle-Pamlico Peninsula covers more than 2,000 square miles on the North Carolina coastal plain, a vast expanse of forested swamps and tea-colored creeks. Many people would probably avoid this place, whose dense thickets of cane and shrubs and waterlogged soils can slow a hike to a crawl.
“It’s hard fieldwork,” says Duke researcher Steve Anderson. “It gets really dense and scratchy. That, plus the heat and humidity mixed with the smell of sulfur and the ticks and the poison ivy; it just kind of adds up.”
But to Anderson and colleagues from Duke and North Carolina State University, these bottomlands are more than impenetrable marsh and muck and mosquitoes. They’re also a barometer of change.
Researchers surveying plants in Alligator River National Wildlife Refuge in 2016. Photo by Mathew Stillwagon, North Carolina State University
Most of the area they study lies a mere two to three feet above sea level, which exposes it to surges of ocean water — 400 times saltier than freshwater — driven inland by storms and rising seas. The salt deposits left behind when these waters recede build up year after year, until eventually they become too much for some plants to cope with.
Trudging in hip waders through stunted shrubs and rotting tree stumps, Anderson snaps a picture with his phone of a carpet of partridge berry trailing along the forest floor. In some parts of the peninsula, he says, the soils are becoming so salty that plants like these can no longer reproduce or are dying off entirely.
Along the North Carolina coast, understory plants such as this partridge berry (left) are quickly ceding ground to species such as this bigleaf marsh-elder (right) as the soils become too salty for them to thrive. Credit: Steve Anderson
In a recent study the team, led by professors Justin Wright and Emily Bernhardt of Duke, and Marcelo Ardón of NC State, surveyed some 112 understory plants in the region, making note of where they were found and how abundant they were in relation to salt levels in the soil.
The researchers identified a ‘tipping point,’ around 265 parts per million sodium, where even tiny changes in salinity can set off disproportionately large changes in the plants that live there.
Above this critical threshold, the makeup of the marsh floor suddenly shifts, as plants such as wax myrtle, swamp bay and pennywort are taken over by rushes, reeds and other plants that can better tolerate salty soils.
Certain dwindling plants could be an early warning sign that salt is poisoning inland waters, researchers say. Credit: Steve Anderson
The hope is that monitoring indicator species like these could help researchers spot the early warning signs of salt stress, Anderson says.
This research was supported by grants from the National Science Foundation (DEB1713435, DEB 1713502, and Coastal SEES Collaborative Research Award Grant No. 1426802).
CITATION: “Salinity Thresholds for Understory Plants in Coastal Wetlands,” Anderson, S. M., E. A. Ury, P. J. Taillie, E. A. Ungberg, C. E. Moorman, B. Poulter, M. Ardón, E. S. Bernhardt, and J. P. Wright. Plant Ecology, Nov. 24, 2021. DOI: 10.1007/s11258-021-01209-2.
Salt is poisoning the soils past a point of no return for some marsh plants; one team is trying to pinpoint the early warning signs. By Steve Anderson.
Fauskee, who researches RNA editing sites in ferns, told me about the project that he’s been working on for the last several years. His research could push back against the idea that DNA is the end-all, be-all molecule for encoding life as we know it.
Blake Fauskee, third-year Biology PhD student
Fauskee broke down RNA editing for me. “RNA editing is this extra step in the whole central dogma, the whole gene expression process, that happens in plant organellar DNA,” he said. This process takes place in plant mitochondrial and chloroplast genomes.
Fauskee uses a lot of metaphors to describe his work, which I find both helpful and admirable. Science can often be dense and lack feasible connections to processes that most of us are familiar with. “Basically, in [plant] DNA, there are little typos almost. The wrong nucleotide is encoded at certain spots. When those genes are going to be expressed, they get turned into RNA and then other proteins from the nucleus come in and find the little typos so that in the end you get the correct protein.”
This image shows a simplified diagram of how RNA editing works.
Fauskee calls RNA editing an “interesting and strange process” that neither animals nor humans have. His work attempts to study the evolution of this process, the patterns of RNA editing, and why it came to be. He uses DNA and RNA sequence data and the help of computational tools to do his work. He explains that when sequencing DNA, you can think of the fragmented base pairs “as little puzzle pieces.”
“So, I take all those little puzzle pieces and try to put back together the chloroplast genome, which is about 150,000 base pairs. It’s like a thousand-piece puzzle.”
Next, he figures out where the fern’s gene sequences are on the DNA strands, making use of genomic databases that contain known genomes. He then aligns RNA sequences to the genes he has mapped. Fauskee looks for the “typos” or “little differences” between the DNA and RNA: “That’s how we find the RNA editing sites.” Finally, he evaluates how the proteins would be changed by the typos in the DNA if the RNA was not edited after being transcribed.
“So, a lot of these fern genes will have a STOP codon right in the middle, which is really, really bad if you don’t fix because you are only going to get half a protein,” Fauskee said. STOP codons signal to the protein-building ribosomes that the protein is finished once it reads this portion of the RNA. Fauskee explained that these types of errors are the ones would expect organisms to lose, but it turns out they are the ones that are conserved in ferns. “Is there an extra function there? Is it helpful? Is it adaptive?” Fauskee asked.
An image of different ferns.
Comparative analyses between fern species are important. By looking at whether there are common editing sites and common amino acid changes, Fauskee says, “we’re trying to understand if certain editing sites may be advantageous and what kinds of fluctuation we see between certain types of changes.”
Fauskee underscored the importance of his work. “RNA editing is a really interesting process that kind of undermines what I learned in molecular biology…They always tell you DNA is the bedrock, it’s the be-all, end-all. But what happens when the DNA is wrong? What’s the other added layer on this?”
Simply put, Fauskee, says that because of RNA editing, “We have to rethink central dogma a little bit.” In some plants, 10% of all their gene products contribute to RNA editing, Fauskee tells me. “That’s a big chunk and that’s got to be important,” Fauskee said, “Why would evolution keep such a burden going?”
Biology’s central dogma is the idea that DNA is transcribed into RNA and then translated into proteins. RNA editing adds an extra step before translation and protein production.
There may also be implications for how RNA editing sites affect the way that genetic relationships are mapped through phylogenetics. If differences between the DNA of different species at RNA editing sites, this could be misleading. Though the DNA indicates a change in base pair, RNA editing could lead to the same output in protein despite the seeming change. “If you took [RNA editing] into account,” Fauskee says, “does it give you a different answer?”
Fauskee studies ferns because of the amount of editing sites found in these plants. While flowering plants have lost editing sites over time, ferns have not. “For RNA editing, you can look at all angiosperms (flowering plants) and for the whole chloroplast genome, they might have 30-50 RNA editing sites. When you get into ferns, that number jumps up to 300-500 and I am trying to understand why.”
Botanical science first captured Fauskee’s interest while he completed his undergraduate degree in his home state at the University of Minnesota Duluth (UMD). As a sophomore at UMD, Fauskee was taken under the wing of Amanda Grusz (Ph.D.). Grusz received her PhD in biology from Duke and worked under Pryer during her own time at the university. “I’m like my advisor’s academic grandson, which is kind of funny.” Clara Howell, who is part of Fauskee’s PhD cohort and who I spoke with last Fall, is also an academic grandchild in her own lab.
Being an “academic grandson” has worked out well for Fauskee. His key advice to me for any person considering a PhD, “Make sure your advisor is not someone you just admire as a scientist, but as a person.” On a day-to-day basis, Fauskee says that advisor Katheen Pryer “is pretty hands off” but is also “one of the most supportive people ever. I’m pretty much the driver of my own ship. If I am falling off the road, she’ll push me back on the road, but she’ll give me freedom to swerve around on that road.”
Fauskee also emphasized a piece of wisdom that Pryer passed down to him. “If whatever you’ve got going on is working and everyone else is doing something different, who cares?” he said.
Though Fauskee says that “lab work can be frustrating,” getting his long analyses to run after wrangling lots of data is very rewarding. Fauskee, who does not have a background in coding or computer languages, likes to “tell people that [his] floor of biology combined is one competent coder.” When he’s not stealing bits of his biology neighbor’s code, Fauskee loves to attend Duke Basketball games and is a fan of the television show Survivor.
Emily Levy studies how the physical and social environments that baboons experience affect their physiology and life outcomes. The Massachusetts native, who works under advisor Susan Alberts (PhD), is in the final year of her Biology PhD and will defend her thesis later this Spring.
Though Duke’s in-person classes have been delayed until next week, I caught up with Levy over Zoom. The wall of her home office displays a fascinating Russian map of Chicago from the cold war era that shows bridges with their weight capacity. Levy tells me that she had no idea how her husband, who is from Evanston, found the map.
Emily Levy, an almost-PhD in Duke Biology
Levy’s research stems from the Amboseli Baboon Research Project – a nearly 50-year-old, ongoing study of wild baboons in Kenya. Duke’s Alberts has been studying these baboons for over 35 years and is a renowned primatologist involved with the project. Alberts’ lab collaborates with field researchers in Kenya to receive data and samples that are imperative to much of their work.
“Something that I really appreciate about Susan and the way she runs the lab is that she starts first-year grad students on a starter project,” Levy told me. Following a discussion about Levy’s interests, this project led to her first work on dominance rank, stress levels, and what this means physiologically for baboons. Levy also “poked around” at how scientists study dominance rank and found that the methods used for assessing rank “matter a lot.”
In her more recent project, Levy is trying to figure out what early life environments mean for adulthood in baboons. “So, we know that baboons that experience a really harsh early life, if they survive to adulthood, have really, really reduced lifespans as adults – like half as long – as baboons that had no adverse events,” Levy said.
“I’m focusing on two hypotheses to get at what might be happening under the skin that could have something to do with longer term effects on health and mortality.” One hypothesis is that a tough early life environment, especially nutritional stress, could stunt baboon growth and impinge adult activities like foraging or maintaining dominance rank. The other hypothesis proposes that early life adversity disrupts immune development, leading to an immune system that is either always inflamed or produces an overpowering inflammatory response when a baboon does get sick.
The second hypothesis is one that has been supported by human research, but Levy’s preliminary results “are the exact opposite.” This highlights one facet of the importance of her research: Its implications and parallels to human health and mortality. But Levy says her research is also “cool because it’s just cool” and appreciates what her work may add to basic science beyond human application.
Images from Scientific American’s article about the Amboseli Baboon Research Project.
In her journey to Duke, Levy said that she “tried a few ways of studying” animals before arriving at the work she conducts now. Levy, who really liked animals, enjoyed time outside, and was “hooked on biology” in high school, began her undergraduate career at Williams College with this in mind. “In college, I took biology and neuroscience and then took animal behavior my sophomore year and was like Oooo, this is cool!,” Levy exclaimed with a big smile on her face, “And it felt sort of light-bulby.”
Along the journey to her PhD, Levy studied plants and insect pollinators and spent a few weeks in Madagascar in a tent filled with fleas. Though Levy said that these experiences of field work became “one of my favorite things about my job,” they also helped shape her trajectory as a scientist as she figured out which model systems and research questions “did and did not spark her joy.”
It was during her undergraduate thesis assessing social behavior in rats that she felt a strong “click” for studying social behavior in animals. Taking a couple years to work in a clinical research lab that conducted work on autism in humans, Levy enjoyed working on research to aid in special needs people. “But pretty quickly,” Levy said, “I was like, Alright, I don’t want to study humans for my whole life.”
“I’d basically been crossing things off my list up until this point,” Levy continued, “I now knew I wanted to study social animal behavior in non-human animals.” In her year away from research, Levy worked as an outdoor educator in Wyoming while she applied to grad school with this study plan in mind. Her time in Jackson Hole, Wyoming narrowed her interests even more, pushing her towards behavioral ecology because of her observation of an amazing, unbroken natural ecosystem.
Levy says she ultimately ended up at Duke because “the Baboon Project is amazing,” “Susan Alberts is amazing,” and “the Duke Biology Department is really wonderful.”
Images of Emily Levy conducting field work. On right, Levy is conducting field work in the Amboseli National Park in Southern Kenya.
While Levy enjoys working with Alberts and mentoring undergraduates, as well as using grant writing as a “fun way to develop really exciting ideas and hypotheses,” she also shared some of her frustrations with me. “Science is very slow — often, not always — and a project from start to finish takes a long time. And the publication process is so long. I struggle with that pace sometimes” Additionally, as someone who was raised to never take herself too seriously, Levy also said that she has felt a lot of pressure in grad school to take herself more seriously than she should as part of academic culture.
Levy loves teaching and her hope is to become a faculty member at a small liberal arts college or undergraduate institution following a post-doc, for which she is currently in the application process. Through this future work, Levy aspires to “bring undergrads through the scientific process.”
In her time away from the lab and science, Emily is an avid baker. “One of my goals in grad school has been to acknowledge and own what I am good at, and I know I am good at baking,” Levy said with a grin. Chocolate chip cookies are her specialty.
If she could give any aspiring science PhDs a word of advice, Levy offered that you should have fun and “pay attention to the non-intellectual, as well as intellectual, things that you enjoy most.” As exemplified by her path to figuring out what exactly it was in science that inspired her, Levy says not to worry as much about figuring out where you are going, and when, but reaping the lessons and insights of the experiences along the way.
It’s common for a Pratt engineering student like me to be surrounded by incredible individuals who work hard on their revolutionary projects. I am always in awe when I speak to my peers about their designs and processes.
So, I couldn’t help but talk to sophomore Joanna Peng about her project: LowCostomy.
Rising from the EGR101 class during her freshman year, the project is about building a low-cost colostomy bag — a device that collects excrement outside the patient after they’ve had their colon removed in surgery. Her device is intended for use in under-resourced Sub-Saharan Africa.
“The rates in colorectal cancer are rising in Africa, making this a global health issue,” Peng says. “This is a project to promote health care equality.”
The solution? Multiple plastic bags with recycled cloth and water bottles attached, and a beeswax buffer.
“We had to meet two criteria: it had to be low cost; our max being five cents. And the second criteria was that it had to be environmentally friendly. We decided to make this bag out of recycled materials,” Peng says.
For now, the team’s device has succeeded in all of their testing phases. From using their professor’s dog feces for odor testing, to running around Duke with the device wrapped around them for stability testing, the team now look forward to improving their device and testing procedures.
“We are now looking into clinical testing with the beeswax buffer to see whether or not it truly is comfortable and doesn’t cause other health problems,” Peng explains.
Poster with details of the team’s testing and procedures
Peng’s group have worked long hours on their design, which didn’t go unnoticed by the National Institutes of Health (NIH). Out of the five prizes they give to university students to continue their research, the NIH awarded Peng and her peers a $15,000 prize for cancer device building. She is planning to use the money on clinical testing to take a step closer to their goal of bringing their device to Africa.
Peng shows an example of the beeswax port buffer (above). The design team of Amy Guan, Alanna Manfredini, Joanna Peng, and Darienne Rogers (L-R).
“All of us are still fiercely passionate about this project, so I’m excited,” Peng says. “There have been very few teams that have gotten this far, so we are in this no-man’s land where we are on our own.”
She and her team continue with their research in their EGR102 class, working diligently so that their ideas can become a reality and help those in need.
As Alec Morlote emphasizes, he’s a Biology major because “I’m really interested in it. I’d definitely be a Biology major whether I was pre-med or not.”
Morlote, a Trinity junior from northern New Jersey, works in the lab of Dr. Pelin Volkan studying the neurobiology of fruit flies. Why fruit flies, of all things? Well, Morlote initially signed up for a research fellowship program during the summer following his freshman year.
Of course, in March of that year, COVID-19 happened, so Morlote ended up postponing his work to this past summer. He got paired with the Volkan lab because he didn’t want to work in an area of research that was very familiar to him.
“I wanted to use research as an opportunity to learn something completely new,” he said. The neurobiology of fruit flies hit the nail on the head.
Alec Morlote
The Volkan Lab is a cell biology and neurobiology lab that studies how social behavior, specifically courting, is affected by stimuli, using fruit flies as a model organism. Morlote’s specific project has to do with olfactory stimuli – the things flies smell. In flies, as he explained, one gene is responsible for courtship behavior in male flies. If you take out the olfactory receptor of the fly, however, that gene won’t be active.
Morlote is interested in seeing how the olfactory receptor is critical to the expression of this gene.
To do this, he has been working on imaging the antennae of flies – work he describes as “cool, but tedious.” It’s incredibly detailed work to pick apart the antenna off of such a tiny creature. Once isolated, neurotransmitters in the antenna that have been tagged with green fluorescent protein (GFP) light up, thus showing the expression pattern of all cells expressing the neurotransmitter.
Humans clearly don’t have as simplistic a courtship behavior as fruit flies, but the simplicity of the fruit fly makes it an incredibly valuable organism for studying neurobiology. All discoveries in humans initially started with some sort of watered-down version of the human anatomy, whether mice or in this case, fruit flies. Discoveries into the neurobiology and neuroplasticity of fruit flies just might yield significant discoveries into the neurobiology and neuroplasticity of the human brain.
When asked about his favorite and least favorite parts about his research, Morlote laughed.
“I don’t like doing work for three months and getting no results at all,” he remarked in reference to the initial work he started on this summer – but alas, such is the nature of scientific research. But he adds that the best part of research is getting results, any at all. And even no results can mean something.
Morlote’s poster from his summer research
Research was a way for Morlote to narrow his post-graduation plans. He knows now that he wants to pursue an MD, or possibly an MD/PhD. But initially, research was a way for him to see whether this was the path for him at all. When asked why he chose to be pre-med, Morlote said that “it just seemed like the most practical way to apply a love for science.” Biology is the science that he loves the most, and so being pre-med seemed like a no-brainer.
It’s also a family business. Both of Morlote’s parents are doctors, so medicine “is not unfamiliar territory to me.” Being Latin American, both his parents have worked extensively with Latin communities in New Jersey, which is work he hopes to emulate in the future.
Whether or not benchwork stays a part of his life, Morlote knows that he wants his career to involve research somehow. The way he sees it, “you’re doing the bare minimum if you’re just a doctor but you’re not trying to better medicine in some way.”
Contributing to research just might become his way.
In 2011, Dr. Jennifer Doudna began studying an enzyme called Cas9. Little did she know, in 2020 she would go on to win the Nobel Prize in Chemistry along with Emmanuelle Charpentier for discovering the powerful gene-editing tool, CRISPR-Cas9. Today, Doudna is a decorated researcher, the Li Ka Shing Chancellors Chair, a Professor in the Department of Chemistry and Molecular as well as Cell Biology at the University of California Berkeley, and the founder of the Innovative Genomics Institute.
Doudna was also this year’s speaker for the MEDx Distinguished Lecture in October where she delivered presented on “CRISPR: Rewriting DNA and the Future of Humanity.”
“CRISPR is a system that originated in bacteria as an adaptive immune system” Doudna explained.
Dr. Jennifer Doudna holding the Nobel Prize in Chemistry
When bacterial cells are infected by viruses those viruses inject their genetic material into the cell. This discovery, a couple decades ago, was the first indication that there may be ways to apply bacteria’s ability to acquire genetic information from viruses.
CRISPR itself was discovered in 1987 and stands for “Clustered Regularly Interspaced Short Palindromic Repeats.” Doudna was initially studying RNA when she discovered Cas-9, a bacterial RNA-guided endonuclease and one of the enzymes produced by the CRISPR system. In 2012, Doudna and her colleagues found that Cas9 used base pairing to locate and splice target DNAs when combined with a guide RNA.
Essentially, they designed guide RNA to target specific cells. If those cells had a CRISPR system encoded in their genome, the cell is able to make an RNA copy of the CRISPR locus. Those RNA molecules are then processed into units that each include a sequence derived from a virus and then assemble with proteins. This RNA protein then looks for DNA sequences that match the sequence in the RNA guide. Once a match occurs, Cas9 is able to bind to and cut the DNA, leading to the destruction of the viral genome. The cutting of DNA then triggers DNA repair allowing gene editing to occur.
“This system has been harnessed as a technology for genome editing because of the ability of these proteins, these CRISPR Cas-p proteins, to be programmed by RNA molecules to cut any desired DNA sequence,” Doudna said.
CRISPR-cas9 is also being applied in many clinical settings. In fact, when the COVID-19 pandemic hit, Doudna along with several colleagues organized a five-lab consortium including the labs of Dan Fletcher, Patrick Hsu, Melanie Ott, and David Savage. The focus was on developing the Cas13 system to detect COVID-19. Cas13 is a class of proteins, that are RNA guided, RNA targeting, CRISPR enzymes. This research was initially done by one of Doudna’s former graduate students, Alexandra East-Seletsky. They discovered that if the reporter RNA is is paired with enzymes that have a quenched fluorophore pair on the ends, when the target is activated, the reporter is cleaved and a fluorescent signal is released.
One study out of the Melanie Ott group demonstrated that Cas13 can be used to detect viral RNA. They are hoping to apply this as a point-of-care diagnostic by using a detector as well as a microfluidic chip which would allow for the conduction of these chemical reactions in much smaller volumes that can then be read out by a laser. Currently, the detection limit is similar to what one can get with a PCR reaction however it is significantly easier to run.
Graphical Abstract of Cas13 Research by the Melanie Ott lab
“And this is again, not fantasy, we’ve actually had just fabricated devices that will be sitting on a benchtop, and are able to use fabricated chips that will allow us to run the Cas13 chemistry with either nasal swab samples or saliva samples for detection of the virus,” Doudna added.
Another exciting development is the use of genome editing in somatic cells. This involves making changes in the cells of an individual as opposed to the germline. One example is sickle cell disease which is caused by a single base pair defect in a gene. Soon, clinicians will be able to target and correct this defect at the source of the mutation alleviating people from this devastating illness. Currently, there are multiple ongoing clinical trials including one at the Innovative Genomics Institute run by Doudna. In fact, one patient, Victoria Gray, has already been treated for her sickle cell disease using CRISPR.
Victoria Gray being treated for Sickle Cell Anemia Meredith Rizzo/NPR
“The results of these trials are incredibly exciting and encouraging to all of us in the field, with the knowledge that this technology is being deployed to have a positive impact on patient’s lives,” Doudna said.
Another important advancement was made last summer involving the use of CRISPR-based therapy to treat ATR, a rare genetic disease that primarily affects the liver. This is also the first time CRISPR molecules will be delivered in vivo.
In just 10 years CRISPR-cas9 has gone from an exciting discovery to being applied in several medical and agricultural settings.
“This powerful technology enables scientists to change DNA with precision only dreamed of a few years ago,” said MEDx director Geoffrey Ginsburg, a Professor of Medicine at Duke. “Labs worldwide have redirected the course of research programs to incorporate this new tool, creating a CRISPR revolution with huge implications across biology and medicine.”
Examples of further CRISPR-Cas9 research can also be found in the Charles Gersbach lab here at Duke.
Peak achievement in the sciences isn’t measured by stopwatches or goals scored, it goes by citations – the number of times other scientists have referenced your findings in their own academic papers. A high number of citations is an indication that a particular work was influential in moving the field forward.
Nobel laureate Bob Lefkowitz made the list in two categories this year.
And the peak of this peak is the annual “Highly Cited Researchers” list produced each year by the folks at Clarivate, who run the Institute for Scientific Information. The names on this list are drawn from publications that rank in the top 1% by citations for field and publication year in the Web of Science™ citation index – the most-cited of the cited.
Duke has 38 names on the highly cited list this year — including Bob Lefkowitz twice because he’s just that good — and two colleagues at the Duke NUS Medical School in Singapore. In all, the 2021 list includes 6,602 researchers from more than 70 countries.
The ISI says that US scientists are a little less than 40 percent of the highly cited list this year – and dropping. Chinese researchers are gaining, having nearly doubled their presence on the roster in the last four years.
“The headline story is one of sizeable gains for Mainland China and a decline for the United States, particularly when you look at the trends over the last four years,” said a statement from David Pendlebury, Senior Citation Analyst at the Institute for Scientific Information. “(This reflects) a transformational rebalancing of scientific and scholarly contributions at the top level through the globalization of the research enterprise.”
Without further ado, let’s see who our champions are!
Clara Howell and I meet to chat on a lovely October afternoon under the trees of the Bryan Center Plaza. In my final Fall at Duke as an undergraduate, I am happy to connect with Clara, a third-year PhD student in the biology department. We meet on the auspices that I want to learn more about her trek through academia and her current work in the Nowicki lab for this very profile piece. “I’ve never been written about before,” Clara says to me. I suspect that, though most grad students’ work is totally cool, most of them never have.
Clara Howell, Ph.D. student, conducting field work.
Clara talks with her hands as she lays out her current work for me. Right now, she is studying sexual selection and infection in different bird species. Duke biology professor Steve Nowicki, one of Clara’s advisors, has done a lot of work on honesty in communication systems between animals. Most species, Clara tells me, rely on honest signals for mate choice, because it benefits females to be able to discern between low- and high-quality mates, and it benefits high quality males to be able to advertise their quality. In general, animal signals should be reliable. Clara’s other advisor, biology professor and chair of evolutionary anthropology Susan Alberts, specializes in life history trade-offs of signaling: Animals only have so many resources and they must make choices about how to use them. A male bird, that is, for example, fighting an infection, cannot devote as many resources to sexual signaling as an uninfected male.
“But,” Clara says, with an increasingly bright smile on her face, “There is an interesting period of time right after an animal is exposed to a potential pathogen where it’s not immediately clear if the bird’s sexual signals will be honest. This is because it could be most advantageous for animals – especially males – to continue devoting every resource possible for sexual signaling, even if it means ignoring a pathogen that will eventually kill them.”
The punchline is, the male swamp sparrows and zebra finches that Clara studies might benefit from “lying” about being sick. By ignoring an arising infection and devoting one’s energy to maintaining strong sexual signaling, these male birds may be tricking females into thinking they are perfectly healthy mates with no sickness in sight. So far, Clara has been recording the songs of male birds following an injection of bacterial cell walls to stimulate their immune response. “The real kicker will be when I test females and see how and if they discern between the songs of sick and healthy males.”
Zebra Finch (left) and Swamp Sparrow (right)
“When we started to social distance at the beginning of the pandemic in March 2020, before any of us knew how long this would last, I wondered whether other animals do the same thing,” Clara said. When COVID-19 put a pause to Clara’s original work, she found inspiration in the pandemic itself to think about cues of sickness in other animal species besides our own – an idea she saw other scientists starting to buzz about.
Before grad school, Clara studied neuroscience and English at Tulane University in New Orleans. She worked in an evolutionary biology lab with former Duke Ph.D. Elizabeth Derryberry beginning in sophomore year and did her honor’s thesis in Derryberry’s lab on connections between novel foraging tasks and mate preferences in zebra finches. And Clara loved her advisor so much that she decided to follow Derryberry to the University of Tennessee as a grad student in the same year she earned her bachelor’s degree.
“What about your English major?” I asked Clara. “I was a very nerdy, book-ish child,” she replied, “I wanted to read more in college.” Her background in English has turned out to be quite useful for her work in the sciences. “Having really great scientific ideas and not being able to tell people about them is pretty useless,” she said with a short laugh. These English skills have been useful for grant writing too. That’s right – I asked Clara to tell me about the less glamorous parts of being a grad student.
“The process of finding money is something I wish people talked about more,” Clara said as she wrapped her long ponytail through her hands. The through line: “If you want to do your own ideas, you have to find your own money,” she stated plainly. The process of finding money takes up a considerable amount of her time and most grants she has applied for she does not end up getting. But because she enjoys writing, she says it’s not so bad. Though Clara wishes departments were more open about research funding policies and that there were more internal grants, she’s never thought of grant writing as a waste of time. “A lot of the time when I write grants, I’m really clarifying ideas. It’s definitely helpful,” she tells me.
Grant writing takes up a considerable amount of time for most science Ph.D. students.
Clara’s advice to anyone interested in a science Ph.D. is to truly consider getting a master’s degree beforehand. “It might not be the right choice for everyone,” Clara said, “But I found the transition from undergrad to graduate school really difficult. I spent most of my master’s degree just learning how to be a grad student and figuring out how academia works, which meant that when I started my Ph.D. I could focus much more on what I wanted to research.” The time in her master’s program also helped her home in on her central interests in biology. And oh, she also recommends noise-canceling headphones, her “favorite possession.”
Although she says she is still working on figuring out her work-life balance, Clara likes being able to set her own schedule and how each week is so different from the next. Outside of lab, Clara claims she is the stereotype of ecology and evolutionary biology grad students: She enjoys rock-climbing, board games, and craft breweries. You might have to go to the Biological Sciences building to find Clara. “I haven’t broached the other areas of campus,” she said, “Undergrads are sort of scary. They use language I don’t understand, and they are all so stylish. They make me feel old.” Old at 26, the life of the biology Ph.D.
