It’s not enough to just publish a great scientific paper.
Somebody else has to think it’s great too and include the work in the references at the end of their paper, the citations. The more citations a paper gets, presumably the more important and influential it is. That’s how science works — you know, the whole standing-on-the-shoulders-of-giants thing.
So it always comes as a chest swelling affirmation for Dukies when we read all those Duke names on the annual list of Most Cited Scientists, compiled by the folks at Clarivate.
This year is another great haul for our thought-leaders. Duke has 30 scientists among the nearly 7,000 authors on the global list, meaning their work is among the top 1 percent of citations by scientific field and year, according to Clarivate’s Web of Science citation index.
As befits Duke’s culture of mixing and matching the sciences in bold new ways, most of the highly cited are from “cross-field” work.
Duke’s Most Cited Are:
Biology and Biochemistry
Charles A. Gersbach
Robert J. Lefkowitz
Clinical Medicine
Scott Antonia
Christopher Bull Granger
Pamela S. Douglas
Adrian F. Hernandez
Manesh R. Patel
Eric D. Peterson
Cross-Field
Chris Beyrer
Stefano Curtarolo
Renate Houts
Tony Jun Huang
Ru-Rong Ji
Jie Liu
Jason Locasale
Edward A. Miao
David B. Mitzi
Christopher B. Newgard
John F. Rawls
Drew T. Shindell
Pratiksha I. Thakore
Mark R. Wiesner
Microbiology
Barton F. Haynes
Neuroscience and Behavior
Quinn T. Ostrom
Pharmacology and Toxicology
Evan D. Kharasch
Plant and Animal Science
Xinnian Dong
Sheng Yang He
Psychiatry and Psychology
Avshalom Caspi
William E. Copeland
E. Jane Costello
Terrie E. Moffitt
Social Sciences
Michael J. Pencina
John W. Williams
Congratulations, one and all! You’ve done us proud again.
Hello, my name is Jakaiyah Franklin, and I am a sophomore here at Duke University. In terms of my major, I am undecided, but I do know my passion lies in biology, science communication, and environmental science.
Outside of classes, I am the treasurer for the Duke Chapter of the NAACP and LLC leader for the Stem Pathways for Inclusion, Readiness, and Excellence (SPIRE) program. Last year I was the stage manager for two Hoof n Horn productions.
This is the Rocky Horror Picture Show company after finishing our last show.
This year, I will start a research position along with this research blogging position.
In a more personal sense, I am the youngest of three and a proud aunt. Right now, I say I am from Texas, even though I have lived in Georgia, South Carolina, Germany, and presently North Carolina. If someone ever asked me, I would say that Germany holds my most memorable memories; however, I have grown into a better version of myself in each place I have lived. Other than school, I like to read and watch House of the Dragon and the earlier seasons of The Game of Thrones. I prefer to study outside or in a place where natural light is abundant. I also love learning new things pertaining to science, specifically infectious diseases.
My view of Muhuru Bay, Kenya, where I spent the summer after my first year at Duke. That’s Lake Victoria in the distance.
I find diseases fascinating, and I believe they are our natural predators. I want to be able to not only understand them, but also, I want to help prevent them. If one were to have a favorite type of disease to study, mine would be zoonotic diseases. They are interesting because the act of a virus being able to jump from a host like a rat to a human is captivating to me.
After graduating from Duke, I want to earn a master’s in public health or a Ph.D. in epidemiology, virology, or infectious disease to feed my curiosity about diseases. However, before I can even decide what Ph.D. or master’s I want to earn, my current goal is to decide on my major.
Jakaiyah Franklin
I do like to think ahead, so, for my very distant career, I know I want to be able to see infectious diseases in both the lab and in the places where they are infecting populations. I want my research to be digestible for the general population because, as seen with both COVID and Monkeypox, science can be easily misinterpreted if not delivered appropriately. I want to prevent this occurrence from happening to me by learning more about science communication and actively improving my communication skills.
I hope this blogging position will expose me to infectious disease research or general public health research. With this new understanding of the research, I hope this position will also educate me on how to inform others so that they can enjoy and understand the science.
Dr. Bonnie L. Bassler, the Chair of Molecular Biology at Princeton University, is an advocate for diversity in science.
Bonnie Bassler of Princeton University
Throughout her presentation of the Ingrid Daubechies Lecture on Jan. 31 during Research Week, she emphasized that the diversity of her scientific team allowed every lab member to contribute to different steps of the process of studying quorum sensing, a form of microbial communication. (Watch her talk.)
Bacteria are everywhere. They’re sitting at the tables you sit at, burrowing in the clothes you wear and unfortunately, also crawling around on your skin. For a long time, they’ve had a pretty bad reputation, and for good reason! They have caused plagues that have wiped out masses across the globe, driven up breath mint sales by thriving in your mouth and mutated into every biologist’s Boogeyman when you try to kill them with antibiotics – super bugs!
However, the bacterial redemption arc is also quite compelling. “Good guy” bacteria in the gut help us break down food, produce essential vitamins and also sometimes fight off their evil siblings.
So, good or bad, the impact of bacteria in our daily lives is undeniable. But how does a microscopic little being have the capacity to influence the macroscopic world so greatly?
It doesn’t. At least, not by itself.
Lactococcus lactis is one of the starter bacteria in a cheese culture!
A bacterium never works alone because its strength lies in its numbers! Groupwork and communication (as any Pratt star going through recruiting season will swear to their interviewers) are what make bacteria so powerful. A bacterium by its lonesome will act differently than a bacterium surrounded by its daughters, sisters and cousins (bacterial family tree dynamics can get a little unusual).
Knowing that bacteria optimize their behaviors to work efficiently in a group answers the question of how they are so powerful, but it raises another.
How do bacteria know when they have company?
In a world where social media helps us stay connected, it is easy to take rapid status updates for granted. But for tech-deprived microbial colony, how does one member gauge the population of their surroundings? This question is one that Bassler’s lab answered: with a special chemical compound called autoinducers.
Autoinducers are little chemical signaling molecules that each bacterium sends out into its immediate environment. These molecules allow for quorum sensing, or cell-to-cell communication, to take place among bacteria.
Basic quorum sensing: How bacteria know who’s around them. (Nidhi Srivaths)
Every bacterium senses changes in the concentration of these autoinducers in their surroundings. Sensing a sudden increase in autoinducer concentration will change a bacterium’s gene expression, protein synthesis, and consequently, behavior. It will adapt to group behavior, while a bacterium that senses a drop in autoinducers will adapt to individual behavior.
Bacteria not only sense how many others are around them but also who their neighbors are. Autoinducers are universal to both Gram positive and negative bacteria and are unique to the type of bacteria that produce them.
This provides the bacterium with qualitative information on the population of its surroundings. Are they friends or foes?
Quorum sensing also includes nametags so bacteria can tell friend from foe. (Nidhi Srivaths)
In marine vibrio (a genus of Gram-negative bacteria), Bassler’s lab found that quorum sensing could perform intra-species, intra-genus and inter-species identification. This additional information helps the microbes adjust their behavior – from being friendly and supportive towards their relatives to being aggressive and competitive with their enemies.
Bassler provided a real-world perspective on quorum sensing. One species of the vibrio genus, Vibrio cholerae, is responsible for causing Cholera a deadly food and water-borne disease that has plagued low- and middle-income countries for centuries.
When the cholera bacteria enter the host, they are highly virulent and create a sticky biofilm around themselves that helps them clump into aggregates. Their cell density increases with bacterial division until the bacteria sense a certain concentration of autoinducers. Then their gene expression is modified to reduce virulence and biofilm production and the bacterial gene expression patterns shift to escape mechanisms. The bacteria soon break out in large numbers in search of a new host. (Their human host has voluminous, watery diarrhea in response and that becomes the vector for infecting new hosts.)
While the sequence of events that occurred in a cholera infection was known, the discovery of quorum sensing in V. cholerae opens doors for possible treatments, Bassler said. As bacterial communication sets the cycle of infection and division in motion, interfering with the autoinducers produced or disrupting bacteria’s ability to sense them sets the stage for innovative therapies for several infectious diseases.
Quorum sensing is another step towards understanding the world of the tiny microorganisms that influence our world and Bassler and her team are another example of the incredible research that can come from diverse teams in science.
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.
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!
Five of the ten Duke women included in the most highly-cited list this year. Their scholarly publications are viewed as important and influential by their peers. (Clockwise from upper left: Costello, Curtis, Dawson, Bernhardt, Moffitt)
Thirty-seven Duke faculty were named to the list this year, based on the number of highly cited papers they produced over an 11-year period from January 2009 to December 2019. Citation rate, as tracked by Clarivate’s Web of Science, is an approximate measure of a study’s influence and importance.
Barton Haynes
Two Duke researchers appear in two categories: Human Vaccine Institute Director Barton Haynes, and Michael Pencina, vice dean of data science and information technology in the School of Medicine.
And two of the Duke names listed are new faculty, recruited as part of the Science & Technology initiative: Edward Miao in Immunology and Sheng Yang He in Biology.
Michael Pencina
This year, 6,127 researchers from 60 countries are being recognized by the listing. The United States still dominates, with 41 percent of the names on the list, but China continues to grow its influence, with 12 percent of the names.
Clinical Medicine:
Robert M. Califf, Lesley H. Curtis, Pamela S. Douglas, Christopher Bull Granger, Adrian F. Hernandez, L. Kristen Newby, Erik Magnus Ohman, Manesh R. Patel, Michael J. Pencina, Eric D. Peterson.
Environment and Ecology:
Emily S. Bernhardt, Stuart L. Pimm, Mark R. Weisner.
Geosciences:
Drew T. Shindell
Immunology:
Barton F. Haynes, Edward A. Miao
Microbiology:
Barton F. Haynes
Plant and Animal Science:
Sheng Yang He
Psychiatry and Psychology:
Avshalom Caspi, E. Jane Costello, Renate M. Houts, Terrie E. Moffitt
Social Sciences:
Michael J. Pencina
Cross-Field:
Dan Ariely, Geraldine Dawson, Xinnian Dong, Charles A. Gersbach, Ru-Rong Ji, Robert J. Lefkowitz, Sarah H. Lisanby, Jie Liu, Jason W. Locasale, David B. Mitzi, Christopher B. Newgard, Ram Oren, David R. Smith, Avner Vengosh.
As multiple drug companies in the United States speed towards Phase 3 trials for Covid-19 vaccinations, there remain many unanswered questions about these vaccines.
Moderated by Professor of Law and Philosophy, Nita Farahany (J.D., Ph.D), principal investigators Cynthia Gay (M.D., M.P.H) and Emmanuel (Chip) Walter (M.D.) explored these lingering anxieties in a Science and Society hosted Coronavirus Conversation Thursday, November 6th. Dr. Gay is an Associate Professor of Medicine at the University of North Carolia Chapel Hill (UNC) and Medical Director of the UNC HIV Cure Center. Dr. Walter is a professor of Pediatrics with Duke’s Global Health Institute, as well as a member in the Duke Clinical Research Institute and Duke Human Vaccine Institute. Both Gay and Walter are currently overseeing trials for SARS-COV-2 vaccines.
Moderator Nita Farahany (left) and panelists Cynthia Gay (middle) and Emmanuel (Chip) Walter (right)
Farahany began the conversation by pointing out that though the previous ideal of a vaccine by the US presidential election did not come to fruition, Phizer and Moderna just reached full enrollment for their Phase 3 trials. “[The timeline question] is a million-dollar question,” said Dr. Gay, who is overseeing the Moderna trials at UNC. She said that soon statisticians who have no conflicts of interest with the trials will have a look at the unblinded trial data to see if there are any differences between those who received placebo injections and those who received vaccines. Gay believes this first “peek” may be too early to see a significant signal indicating success of the vaccines. Dr. Walter weighed in, saying that though he hopes “we’ll see something,” he concurs that Dr. Gay’s estimate that no significant signal will be present until January is an accurate one.
As Gay and Walter explained, probed for clarification from Farahany, drug companies undertaking vaccine development enrolled portions of the population at higher risk for contracting Covid — typically on the basis of their form of employment. For example, someone working in healthcare statistically has a higher likelihood of contracting Covid because of increased exposure to environments where Covid-infected persons may be. Vaccine trial groups were either assigned to a placebo or to a vaccine. The drug companies will be able to test the success of the vaccines by evaluating whether those who received the vaccine contract Covid at some statistically significant lower amount than those who received the placebo.
But as Farahany pointed out, a drug company could receive an Emergency Use Authorization (EUA) for their vaccine before trials are complete, prompting the question: Will Phase 3 trial placebo participants receive the vaccine if their company receives an EUA? Dr. Walter offered that this could be problematic because there would be a lack of long-term data on vaccines and Dr. Gay suggested that because blinding is the best sort of study design, there is tension around this question. However, Walter and Gay both agreed that study participants should be honored for the role they stepped into for these trials. Thus, the timing for the EUA may be the biggest determinant on whether or not placebo-receiving Phase 3 participants will receive the vaccines as soon as they are available or not.
Other concerns focus on the overall safety of the vaccines. All of the current Covid vaccines in development are mRNA vaccines, which have never before been approved for use in humans. Dr. Walter offered that before Covid, some companies were actually poised to start an mRNA vaccine in children for other respiratory pathogens and that mRNA vaccines are “pretty well studied.” Dr. Gay reinforced these notions by stating that she doesn’t have concerns about the vaccine safety, but rather whether or not the vaccines will actually work for the particular strand of virus and “produce enough effective antibodies to have an impact.” If Covid vaccines are successful, they may actually change the direction of vaccinology in a promising way.
Walter and Gay also addressed the concerns of side effects and generally conceded that most of the side effects seen, such as low-grade fevers and injection-site tenderness, are merely side effects seen with any sort of vaccine. As Farahany pointed out, these sorts of symptoms are actually often just a signal that the immune system is working and responding to the vaccine. Dr. Gay said that a lot of the concerns over vaccine side-effects can be thought about as cost-benefit analysis. She says we make these sorts of analyses all day, every day — whether we realize it or not. For Gay, one day of muscle soreness and a slight fever is highly preferential to weeks of potential immobilization from contracting Coronavirus.
The concluding question: How do we ensure trials are met with public trust? “We have to remember we’re in the middle of a pandemic where things really have to move quickly,” Dr. Walter said. He also offered that though this has been the fastest vaccine development he’s ever seen – aside from H1N1 – all of the safety mechanisms in place have provided safety comparable to that we would normally see.
“This is a global tragedy we’re dealing with,” Dr. Gay said. “There is a time to step back and think, ‘Isn’t it amazing that all these [amazing, talented, expert] people are working day and night’ …They’re making it happen to try to get us an answer and some effective vaccines.”
Who will be the first company to secure an Emergency Use Authorization for a Covid-19 vaccine, and when? This question has circulated in the popular press for a few months and is at the forefront of many Americans’ minds with the upcoming presidential election on November 3rd.
Arti K. Rai (J.D.) moderated a dialogue between former FDA Commissioner and distinguished Professor of Cardiology, Robert Califf (M.D., M.A.C.C.), and Founder and Director of Scripps Research Translational Institute, Eric Topol (M.D.), in which the pair discussed emergency use authorization, public trust, and vaccines. The discussion was part of the Science & Society Initiative’s ongoing series of “Coronavirus Conversations.”
Arti Rai (J.D.)
Robert Califf (M.D., M.A.C.C.)
Eric Topol (M.D.)
Left to right: Moderator Arti Rai and Panelists Robert Califf and Eric Topol
Emergency Use Authorizations (EUAs) strengthen American public health protections by speeding the availability and use of medical countermeasures during public health emergencies. Dr. Califf explained that in addition to events like nuclear catastrophes that EUAs were designed to provide protections for, pandemics were also thought about in conceiving the emergency measure. “[The pandemic] is not a surprise,” Califf said, “We knew it was going to happen at some point.”
The panelists examined the possible use of EUAs for a Covid vaccine and monoclonal antibody treatments given the EUAs issued earlier this year for hydroxycholoroquine and convalescent plasma, the former of which was revoked due to proven risks. Both of these experimental treatments lacked sufficient evidence at the time the EUAs were approved.
Dr. Topol said that the EUA case for the antibodies treatment is a good one with growing evidence that suggests their effectiveness as a viable treatment measure. Dr. Califf concurred, saying that with 1,000 people predicted to die every day in the U.S. through the end of December, there’s a strong case for the FDA to exert its judgment. One issue with antibodies, however, is that they cannot be made in large quantities and are very expensive, meaning they would be inaccessible for many.
The question of EUA use for vaccines is less straightforward. Dr. Topol argued that though the protocols released by four drug companies, including Moderna and Pfizer, are pretty far along, “there is a very questionable ethical story here.” He continued, “How can we say it’s good enough to give to essential workers, healthcare works, high-risk individuals, but they won’t even give it to trial participants? They received placebo vaccines.” Across the board, the trials currently underway only include about 150 individuals.
These initial trials are only the first hurdles to the production of a vaccine, according to both Califf and Topol. Dr. Califf pointed out that there will be issues of manufacturing and distributing, lots of concerns with post-market assessments, and how to determine which vaccines will be the best. Dr. Topol reinforced these ideas, suggesting that because no single company will be able to fill the vaccine demands, we need multiple vaccines to be successful. Further, Dr. Topol admitted his concern about the major extrapolations of data we will face, going from trials of 150 individuals to potential distribution numbers of vaccines reaching the hundreds of millions, if not billions of people.
And even once an initial round of vaccines is developed, Dr. Califf inserted the question, “What happens after people get vaccinated?” The simple truth is, the vaccination will probably not completely eradicate the virus, there could be late post-vaccination reactions, and the vaccine could potentially end up creating asymptomatic carriers. Both doctors agreed, masks and social distancing will be needed for at least the next year.
The potential of a Covid-19 vaccination has been popular in the media over the last few months.
Public opinion and politics are also key players in vaccine debates and development. “The point of public trust is essential because if something happens with the first vaccine that gets out,” Dr. Topol said, “it’s going to be a real damaging blow to vaccine rollout.” Like mask-wearing, Topol suggested that vaccines are part of a larger social contract in which these sorts of preventative measures not only help oneself but those around them.
Rai pointed out that as tensions between the FDA and the U.S. department of Health and Human Services grow, as well as between the FDA and the Trump administration, we could face “doomsday” scenarios where the FDA is coerced into certain actions and their powers become limited. However, new FDA guidelines for vaccine development have extended the potential timeline for a Covid vaccine, meaning that the chances of a EUA being issued before the election and being utilized as a political tool for Trump’s reelection are quite unlikely at this point.
Dr. Califf closed by emphasizing the need for solidarity among the biomedical community as influential to the success or failure of potential vaccines and public trust. Dr. Topol offered that we “need education, government that supports science, and need to get [support from] people of all diverse backgrounds to get [the public] to buy in.”
While Dr. Topol maintained a more skeptical and sometimes grim tone, Dr. Califf said that though he’s worried about “everything,” he’s “preparing for the worst but hoping for the best.”
It seems that as many people grow both accustomed to and tired of our new normal, most of us are caught somewhere in the middle of these outlooks.
Imagine: you wake on a chilly November morning, alarm blaring, for your 8:30 am class. You toss aside the blankets and grab your phone. Shutting the alarm off reveals a Washington Post notification. But this isn’t your standard election headline. You almost drop your phone in shock. It can’t be, you think. This is too good to be true. It’s not — a second later, you get a text from the SymMon app, notifying you of your upcoming appointment in the Bryan Center.
A vaccine for COVID-19 is finally available, and you’re getting one.
This scenario could be less far-fetched than one might think: the Centers for Disease Control and Prevention has told officials to prepare for a vaccine as soon as November 1st. To a country foundering due to the economic and social effects of COVID-19, this comes as incredible news — a bright spot on a bleak horizon. But to make a vaccine a reality, traditional phase 3 clinical trials may not be enough. What are challenge trials? Should they be used? What’s at stake, and what are the ethical implications of the path we choose?
Dr. Marc Lipsitch, Director of the Center for Communicable Disease Dynamics at the Harvard School of Public Health, began by comparing traditional phase 3 trials and challenge trials.
In both kinds of trials, vaccines are tested for their “safety and ability to provoke an immune response” in phases 1 and 2. In phase 3 trials, large numbers (typically thousands or tens of thousands) of individuals are randomly assigned either the vaccine being tested or a placebo. Scientists observe how many vaccinated individuals become infected compared to participants who received a placebo. This information enables scientists to assess the efficacy — as well as rarer side effects — of the vaccine.
Marc Lipsitch
In challenge trials, instead of random assignment, small numbers of low-risk individuals are deliberately infected in order to more directly study the efficacy of vaccine and treatment candidates. Though none are underway yet, the advocacy group 1Day Sooner has built a list of more than 35,000 volunteers willing to participate.
Dr. Cameron Wolfe, an Infectious Disease Specialist, Associate Professor of Medicine, and Clinical Expert In Respiratory and Infectious Disease at the Duke Medical School, provided an overview of the current vaccine landscape.
Cameron Wolfe
There are currently at least 150 potential vaccine candidates, from preclinical to approved stages of development. Two vaccines, developed by Russia’s Gamelaya Research Institute and China’s CanSinoBIO, have skipped phase 3, but are little more than an idiosyncrasy to Dr. Wolfe, as there is “minimal clarity about their safety and efficacy.” Three more vaccines of interest — Moderna’s mRNA vaccine, Pfizer’s mRNA vaccine, and Oxford and AstraZeneca’s adenovirus vaccine — are all in phase 3 trials with around 30,000 enrollees. Scientists will be watching for a “meaningful infection and a durable immune response.”
Dr. Nir Eyal, the Henry Rutgers Professor of Bioethics and Director of The Center for Population-Level Bioethics at Rutgers University, explained how challenge trials could fit into the vaccine roadmap.
According to Dr. Eyal, challenge trials would most likely be combined with phase 3 trials. One way this could look is the use of challenge trials to weed out vaccine candidates before undergoing more expensive phase 3 trials. Additionally, if phase 3 trials fail to produce meaningful results about efficacy, a challenge trial could be used to obtain information while still collecting safety data from the more comprehensive phase 3 trial.
Nir Eyal
Dr. Eyal emphasized the importance of challenge trials for expediting the arrival of the vaccine. According to his own calculations, getting a vaccine — and making it widely available — just one month sooner would avert the loss of 720,000 years of life and 40 million years of poverty, mostly concentrated in the developing world. (Dr. Eyal stressed that his estimate is extremely conservative as it neglects many factors, including loss of life from avoidance of child vaccines, cancer care, malaria treatment, etc.) Therefore, speed is of “great humanitarian value.”
Dr. Wolfe added that because phase 3 trials rely on a lot of transmission, if the US gets better at mitigating the virus, “the distinction between protective efficacy and simple placebo will take longer to see.” A challenge study, however, is “always a well defined time period… you can anticipate when you’ll get results.”
The panelists then discussed the ethics of challenge trials in the absence of effective treatment — as Krawiec put it, “making people sick without knowing if we can make them better.”
Dr. Wolfe pointed to the flu, citing challenge trialsthat havebeen conducted even though current treatments are not uniformly effective (“tamiflu is no panacea”). He then conceded that the biggest challenge is not a lack of effective therapies, but the current inability to “say to a patient, ‘you will not have a severe outcome.’ It varies so much from person to person, I guess.” (See one troubling example of that variance.)
Dr. Eyal acknowledged the trouble of informed consent when the implications are scarcely known, but argued that “in extraordinary times, business as usual is no longer the standard.” He asserted that if people volunteer with full understanding of what they are committing to, there is no reason to assume they are less informed than when making other decisions where the outcome is as yet unknown.
Dr. Lipsitch compared this to the military: “we are not cheating if we cannot provide a roadmap of future wars because they are not yet known to us.” Rather, we commend brave soldiers (and hope they come home safe).
Furthermore, Dr. Eyal asserted that “informed consent is not a comprehensive understanding of the disease,” lest much of the epidemiological research from the 1970s be called into question too. Instead, volunteers should be considered informed as long as they comprehend questions like, “‘we can’t give you an exact figure yet; do you understand?’”
Agreeing, Dr. Wolfe stated that when critics of challenge trials ask, isn’t your mission to do no harm?, he asks, “Do no harm in regards to whom?” “Who is in front of you matters,” Dr. Wolfe confirmed, “that’s why we put up safeguards. But as clinicians it can be problematic [to stop there]. It’s not just about the patient, but to do no harm in regards to the broader community.”
The experts then discussed what they’d like to see in challenge trials.
Dr. Wolfe said he’d like to see challenge trials carried out with a focus on immunology components, side effect profiles, and a “barrage” of biological safety and health standards for hospitals and facilities.
Dr. Eyal stated the need for exclusion criteria (young adults, perhaps age 20-25, with no risk factors), a “high high high” quality of informed consent ideally involving a third party, and access to therapies and critical care for all volunteers, even those without insurance.
Dr. Lipsitch stressed the scientific importance of assessing participants from a “virological, not symptom bent.” He mused that the issue of viral inoculum was a thorny one — should scientists “titrate down” to where many participants won’t get infected and more volunteers will be needed overall? Or should scientists keep it concentrated, and contend with the increased risk?
Like many questions pondered during the hour — from the ideal viral strain to use to the safest way to collect information about high risk patients — this one remained unanswered.
So don’t mark November 1st on your calendar just yet. But if you do get that life-changing notification, there’s a chance you’ll have human challenge trials to thank.
The novel coronavirus pandemic has now resulted in more than 3 million confirmed cases globally and is pushing scientists to share ideas quickly and figure out the best ways to collaborate and contribute to solutions.
SARS-CoV-2 surface proteins illustrated by We Are Covert, via Wikimedia Commons
Recently, Duke researchers across the School of Medicine came together for an online symposium consisting of several short presentations to summarize the latest of what is known about the novel coronavirus, SARS-CoV-2.
This daylong event was organized by faculty in the Department of Molecular Genetics and Microbiology and researchers from different fields to share what they know about the virus and immunity to guide vaccine design. This conference highlighted the myriad new research pathways that Duke researchers are launching to better understand this pandemic virus.
One neat area of research is understanding viral processes within cells to identify steps at which antivirals may block the virus. Stacy Horner’s Laboratory studies how RNA viruses replicate inside human cells. By figuring out how viruses and cells interact at the molecular level, Horner can inform development of antivirals and strategies to block viral replication. Antivirals stop infections by preventing the virus from generating more of copies of itself and spreading to other cells. This controls damage to our cells and allows the immune system to catch up and clear the infection.
At the symposium, Horner explained how the SARS-CoV viral genome consists of 29,891 ribonucleotides, which are the building blocks of the RNA strand. The viral genome contains 14 areas where the RNA code can be transcribed into shorter RNA sequences for viral protein production. Though each RNA transcript generally contains the code for a single protein, this virus is intriguing in that it uses RNA tricks to code for up to 27 proteins. Horner highlighted two interesting ways that SARS-CoV packs in additional proteins to produce all the necessary components for its replication and assembly into new viral progeny.
The first way is through slippery sequences on the RNA genome of the virus. A ribosome is a machine inside the cell that runs along a string of RNA to translate its code into proteins that have various functions. Each set of 3 ribonucleotides forms one amino acid, a building block of proteins. In turn, a string of amino acids assembles into a distinct structure that gives rise to a functional protein.
One way that SARS-CoV-2 packs in additional proteins is with regions of its RNA genome that make the ribosome machinery slip back by one ribonucleotide. Once the ribosome gets offset it reads a new grouping of 3 ribonucleotides and creates a different amino acid for the same RNA sequence. In this way, SARS-CoV-2 makes multiple proteins from the same piece of RNA and maximizes space on its genome for additional viral proteins.
An example of an RNA ‘hairpin’ structure, which might fool a ribosome to jump across the sequence rather than reading around the little cul de sac. (Ben Moore, via Wikimedia Commons)
Secondly, the RNA genome of SARS-CoV-2 has regions where the single strand of RNA twists over itself and connects with another segment of RNA farther along the code to form a new protein. These folds create structures that look like diverse trees made of repetitive hairpin-like shapes. If the ribosome runs into a fold, it can hop from one spot in the RNA to another disjoint piece and attach a new string of amino acids instead of the ones directly ahead of it on the linear RNA sequence. This is another way the SARS-CoV-2 packs in extra proteins with the same piece of RNA.
Horner said a step-by-step understanding of what the virus needs to survive at each step of its replication cycle will allow us to design molecules that are able to block these crucial steps.
Indeed, shapes of molecules can determine their function inside the cell. Three Duke teams are pursuing detailed investigation of SARS-CoV-2 protein structures that might guide development of complementarily shaped molecules that can serve as drugs by interfering with viral processes inside cells.
Some Duke faculty who participated in the virtual viral conference. (L-R from, top) Stacy Horner, Nick Heaton, Micah Luftig, Sallie Permar, Ed Miao and Georgia Tomaras. (image: Tulika Singh)
For example the laboratory of Hashim Al-Hashimi, develops computational models to predict the diversity of structures produced by these tree-like RNA folds to identify possible targets for new therapeutics. Currently, the Laboratories of Nicholas Heaton and Claire Smith are teaming up to identify novel restriction factors inside cells that can stop SARS-CoV-2.
However, it is not just the structures of viral components expressed inside the cells that matter, but also those on the outside of a virus particle. In Latin, corona means a crown or garland, and coronaviruses have been named for their distinctive crown-like spikes that envelop each virus particle. The viral protein that forms this corona is aptly named the “Spike” protein.
This Spike protein on the viral surface connects with a human cell surface protein (Angiotensin-converting enzyme 2, abbreviated as ACE2) to allow the virus to enter our cells and cause an infection. Heaton proposed that molecules designed to block this contact, by blocking either the human cell surface protein or the viral Spike protein, should also be tested as possible therapies.
One promising type of molecule to block this interaction is an antibody. Antibodies are “Y” shaped molecules that are developed as part of the immune response in the body by the second week of coronavirus infection. These molecules can detect viral proteins, bind with them, and prevent viruses from entering cells. Unlike several other components on our immune defense, antibodies are shaped to specifically latch on to one type of virus. Teams of scientists at Duke led by Dr. Sallie Permar, Dr. Georgia Tomaras, and Dr. Genevieve Fouda are working to characterize this antibody response to SARS-CoV-2 infection and identify the types of antibodies that confer protection.
Infectious disease specialist Dr. Chris Woods is leading an effort to test whether plasma with antibodies from people who have recovered can prevent severe coronavirus disease in acutely infected patients.
Indeed, there are several intriguing research questions to resolve in the months ahead. Duke scientists are forging new plans for research and actively launching new projects to unravel the mysteries of SARS-CoV-2. With Duke laboratory scientists rolling up their sleeves and gowning up to conduct research on the novel coronavirus, there will be soon be many more vaccine and therapeutic interventions to test.
Guest post by Tulika Singh, MPH, PhD Candidate in the Department of Molecular Genetics and Microbiology (T: @Singh_Tulika)
