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.
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.
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.
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.
Drew T. Shindell
Barton F. Haynes, Edward A. Miao
Barton F. Haynes
Plant and Animal Science:
Sheng Yang He
Psychiatry and Psychology:
Avshalom Caspi, E. Jane Costello, Renate M. Houts, Terrie E. Moffitt
Michael J. Pencina
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.
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.
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.
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.
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.
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.
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.
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.
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.
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)
The COVID-19 epidemic has impacted the Duke research enterprise in profound ways. Nearly all laboratory-based research has been temporarily halted, except for research directly connected to the fight against COVID-19. It will take much time to return to normal, and that process of renewal will be gradual and will be implemented carefully.
Trying to put this situation into a broader perspective, I thought of the 1939 essay by Abraham Flexner published in Harper’s magazine, entitled “The Usefulness of Useless Knowledge.” Flexner was the founding Director of the Institute for Advanced Study at Princeton, and in that essay, he ruminated on much of the type of knowledge acquired at research universities — knowledge motivated by no objective other than the basic human desire to understand. As Flexner said, the pursuit of this type of knowledge sometimes leads to surprises that transform the way we see that which was previously taken for granted, or for which we had previously given up hope. Such knowledge is sometimes very useful, in highly unintended ways.
The 1918 influenza pandemic led to 500 million confirmed cases, and 50 million deaths. In the Century since, consider how far we have come in our understanding of epidemics, and how that knowledge has impacted our ability to respond. People like Greg Gray, a professor of medicine and member of the Duke Global Health Institute (DGHI), have been quietly studying viruses for many years, including how viruses at domestic animal farms and food markets can leap from animals to humans. Many believe the COVID-19 virus started from a bat and was transferred to a human. Dr. Gray has been a global leader in studying this mechanism of a potential viral pandemic, doing much of his work in Asia, and that experience makes him uniquely positioned to provide understanding of our current predicament.
From the health-policy perspective, Mark McClellan, Director of the Duke Margolis Center for Health Policy, has been a leading voice in understanding viruses and the best policy responses to an epidemic. As a former FDA director, he has experience bringing policy to life, and his voice carries weight in the halls of Washington. Drawing on faculty from across Duke and its extensive applied policy research capacity, the Margolis Center has been at the forefront in guiding policymakers in responding to COVID-19.
Through knowledge accrued by academic leaders like Drs. Gray and McClellan, one notes with awe the difference in how the world has responded to a viral threat today, relative to 100 years ago. While there has been significant turmoil in many people’s lives today, as well as significant hardship, the number of global deaths caused by COVID-19 has been reduced substantially relative to 1918.
One of the seemingly unusual aspects of COVID-19 is that a substantial fraction of the population infected by the virus has no symptoms. However, those asymptomatic individuals shed the virus and infect others. While most people have no or mild symptoms, other people have very adverse effects to COVID-19, some dying quickly.
This heterogeneous response to COVID-19 is a characteristic of viruses studied by Chris Woods, a professor medicine in infectious diseases. Dr. Woods, and his colleagues in the Schools of Medicine and Engineering, have investigated this phenomenon for years, long before the current crisis, focusing their studies on the genomic response of the human host to a virus. This knowledge of viruses has made Dr. Woods and his colleagues leading voices in understanding COVID-19, and guiding the clinical response.
A team led by Greg Sempowski, a professor of pathology in the Human Vaccine Institute is working to isolate protective antibodies from SARS-CoV-2-infected individuals to see if they may be used as drugs to prevent or treat COVID-19. They’re seeking antibodies that can neutralize or kill the virus, which are called neutralizing antibodies.
Many believe that only a vaccine for COVID-19 can truly return life to normal. Human Vaccine Institute Director Barton Haynes, and his colleagues are at the forefront of developing that vaccine to provide human resistance to COVID-19. Dr. Haynes has been focusing on vaccine research for numerous years, and now that work is at the forefront in the fight against COVID-19.
Engineering and materials science have also advanced significantly since 1918. Ken Gall, a professor of mechanical engineering and materials science has led Duke’s novel application of 3D printing to develop methods for creatively designing personal protective equipment (PPE). These PPE are being used in the Duke hospital, and throughout the world to protect healthcare providers in the fight against COVID-19.
Much of the work discussed above, in addition to being motivated by the desire to understand and adapt to viruses, is motivated from the perspective that viruses must be fought to extend human life.
In contrast, several years ago Jennifer Doudna and Emmanuelle Charpentier, academics at Berkeley and the Max Planck Institute, respectively, asked a seemingly useless question. They wanted to understand how bacteria defended themselves against a virus. What may have made this work seem even more useless is that the specific class of viruses (called phage) that infect bacteria do not cause human disease. Useless stuff! The kind of work that can only take place at a university. That basic research led to the discovery of clustered regularly interspaced short palindromic repeats (CRISPR), a bacterial defense system against viruses, as a tool for manipulating genome sequences. Unexpectedly, CRISPR manifested an almost unbelievable ability to edit the genome, with the potential to cure previously incurable genetic diseases.
Charles Gersbach, a professor of Biomedical Engineering, and his colleagues at Duke are at the forefront of CRISPR research for gene and cell therapy. In fact, he is working with Duke surgery professor and gene therapy expert Aravind Asokan to engineer another class of viruses, recently approved by the FDA for other gene therapies, to deliver CRISPR to diseased tissues. Far from a killer, the modified virus is essential to getting CRISPR to the right tissues to perform gene editing in a manner that was previously thought impossible. There is hope that CRISPR technology can lead to cures for sickle cell and other genetic blood disorders. It is also being used to fight cancer and muscular dystrophy, among many other diseases and it is being used at Duke by Dr. Gersbach in the fight against COVID-19.
In another seemingly bizarre use of a virus, a modified form of the polio virus is being used at Duke to fight glioblastoma, a brain tumor. That work is being pursued within the Preston Robert Tisch Brain Tumor Center, for which David Ashley is the Director. The use of modified polio virus excites the innate human immune system to fight glioblastoma, and extends life in ways that were previously unimaginable. But there are still many basic-science questions that must be overcome. The remarkable extension of life with polio-based immunotherapy occurs for only 20% of glioblastoma patients. Why? Recall from the work of Dr. Woods discussed above, and from our own observation of COVID-19, not all people respond to viruses in the same way. Could this explain the mixed effectiveness of immunotherapy for glioblastoma? It is not known at this time, although Dr. Ashley feels it is likely to be a key factor. Much research is required, to better understand the diversity in the host response to viruses, and to further improve immunotherapy.
The COVID-19 pandemic is a challenge that is disrupting all aspects of life. Through fundamental research being done at Duke, our understanding of such a pandemic has advanced markedly, speeding and improving our capacity to respond. By innovative partnerships between Duke engineers and clinicians, novel methods are being developed to protect frontline medical professionals. Further, via innovative technologies like CRISPR and immunotherapy — that could only seem like science fiction in 1918 (and as recently as 2010!) — viruses are being used to save lives for previously intractable diseases.
Viruses can be killers, but they are also scientific marvels. This is the promise of fundamental research; this is the impact of Duke research.
“We shall not cease from exploration And the end of all our exploring Will be to arrive where we started And know the place for the first time.”
T.S. Eliot, Four Quartets
Post by Lawrence Carin, Vice President for Research
University of North Carolina cell biologist Efra Rivera-Serrano says he doesn’t look like a stereotypical scientist: he’s gay, Puerto Rican, and a personal trainer.
Known on Twitter as @NakedCapsid or “the guy who looks totally buff & posts microscopy threads,” he tweets about virology and cell biology and aims to make science more accessible to the non-science public.
But science communication encompasses more than posting the
facts of viral transmission or sending virtual
valentines featuring virus-infected cells, Rivera-Serrano says. As a
science communicator, he’s also committed to conveying truths that are even
more rarely expressed in the science world today. He’s committed to diversity.
Rivera-Serrano’s path through academia has been far from linear — largely because of the microaggressions (which are sometimes not so micro) that he’s faced within educational institutions. He’s been approached while shopping by a construction work recruiter and told by a graduate adviser in biology to “stop talking like a Puerto Rican.”
And the worst part is that he’s far from being the only one
in this kind of position. That’s why Rivera-Serrano holds one simple question
close to heart:
What would a cell do?
“I use this question to shape the way I tackle problems,” Rivera-Serrano
says. After all, a key component of virology is the importance of intercellular
communication in controlling disease spread. Similarly, a major goal of
diversity-related science communication is “priming” others to fight stereotypes
and biases about who belongs in science.
Virology’s “herd immunity” theory operates under the principle that higher vaccination rates mean fewer infections. For some viruses, a 90% vaccination rate is all it takes to completely eradicate an infection from existing in a population. Rivera-Serrano, therefore, hopes to use inclusive science communication as a vaccination tool of sorts to combat discriminatory practices and ideologies in science. He isn’t looking for 100% of the world to agree with him—only enough to make it work.
This desire for “inclusive science communication” led Rivera-Serrano to found Unique Scientists, a website that showcases and celebrates diverse scientists from across the globe. Scientists from underrepresented backgrounds can submit a biography and photo to the site and have them published for the world’s aspiring scientists to see.
Generating social herd immunity needs to start from an early
age, and Unique Scientists has proven itself useful for this purpose. Before introducing
the website, school teachers asked their students to draw a scientist. “It’s
usually a man who’s white with crazy hair,” according to Rivera-Serrano. Then, they
were given the same instructions after
browsing through the site, and the results were remarkable.
“Having kids understand pronouns or see an African American
in ecology—that’s all something you can do,” Rivera-Serrano explains. It doesn’t
take an insane amount of effort to tackle this virus.
What it does take, though, is cooperation. “It’s not a one-person job, for sure,” Rivera-Serrano says. But maybe we can get there together.
Countless hours of lost productivity also accompany the illness. Including hospitalization costs, estimates for the flu’s total economic burden range from 10 to 25 billion dollars each year.
Flu prevention efforts have yielded mixed results. For many viruses, vaccines provide protection that lasts a lifetime, building up a network of antibodies primed to neutralize future infections. Influenza viruses, however, mutate quickly, rendering vaccines from years past ineffective. As a result, new vaccines are constantly in development.
Every year, researchers predict which flu viruses are likely to dominate the upcoming flu season. Based on these predictions, new vaccines target these specific strains. Consequentially, the effectiveness of these vaccines vary with the prediction. When a vaccine is a good match for the dominant flu strain, it can lower rates of infection by 40-50%. When it isn’t, its preventative power is far lower; in 2014, for example, the yearly influenza vaccine was only 19% effective.
Peter Palese, Ph. D, might have a better solution. Working at the Icahn School of Medicine, Palese and his team are developing a vaccine that takes a new approach to flu prevention.
Just before classes ended last month, Palese spoke at the Duke Influenza Symposium, a showcase of Duke’s current research on influenza. The symposium is part of Duke’s larger push to improve the efficacy of flu vaccination.
Palese’s vaccines work by redirecting the immune response to the influenza virus. Traditional vaccines create antibodies that target hemagglutinins, proteins found on the outermost part of influenza viruses. Hemagglutinins are divided into two regions: a head domain and a stalk domain (Fig. 1).
In a traditional vaccination, the head domain is immunodominant—that is, the antibodies produced by vaccines preferentially target and neutralize the head domains. However, the head domain is highly prone to mutation and varies between different strains of influenza. As a result, antibodies for one strain of the virus provide no protection against other strains.
The new vaccines pioneered by Palese and his team instead target the stalk domain, a part of hemagglutinin that mutates far slower than the head domain. The stalk is also conserved across different subtypes of the influenza virus. As a result, these vaccines should theoretically provide long-lasting protection against most strains of influenza.
Testing in ferret, mice, and guinea pigs have produced promising results. And early human trials suggest that this new kind of vaccination grants broad immunity against influenza. But long-term results remain unclear—and more trials are underway. “We would love to say it works,” Palese says. “But give us 10 years.”
In the meantime, the seasonal flu vaccine is our best option.“The recommendation to vaccinate everyone is the right policy,” Palese tells us.
Influenza is ubiquitous. Every fall, we line up to get our flu shots with the hope that we will be protected from the virus that infects 10 to 20 percent of people worldwide each year. But some years, the vaccine is less effective than others.
Every year, CDC scientists engineer a new flu virus. By examining phylogenetic relationships, which are based on shared common ancestry and relatedness, researchers identify virus strains to target with a vaccine for the following flu season.
Sometimes, they do a good job predicting which strains will
flourish in the upcoming flu season; other times, they pick wrong.
Andrew Pekosz, PhD, is a researcher at Johns Hopkins who examines why we fail to predict strains to target with vaccines. In particular, he examines years when the vaccine was ineffective and the viruses that were most prevalent to identify properties of these strains.
A virus consists of RNA enclosed in a membrane. Vaccines function
by targeting membrane proteins that facilitate movement of the viral genome
into host cells that it is infecting. For the flu virus, this protein is
hemagglutinin (HA). An additional membrane protein called neuraminidase (NA) allows
the virus to release itself from a cell it has infected and prevents it from
returning to infected cells.
Studying the viruses that flourished in the 2014-2015 and
2016-2017 flu seasons, Pekosz and his team have identified mutations to these
surface proteins that allowed certain strains to evade the vaccine.
In the 2014-2015 season, a mutation in the HA receptor conferred an advantage to the virus, but only in the presence of the antibodies present in the vaccine. In the absence of these antibodies, this mutation was actually detrimental to the virus’s fitness. The strain was present in low numbers in the beginning of the flu season, but the selective pressure of the vaccine pushed it to become the dominant strain by the end.
The 2016-2017 flu season saw a similar pattern of mutation, but in the NA protein. The part of the virus membrane where the antibody binds, or the epitope, was covered in the mutated viral strain. Since the antibodies produced in response to the vaccine could not effectively identify the virus, the vaccine was ineffective for these mutated strains.
With the speed at which the flu virus evolves, and the fact that numerous strains can be active in any given flu season, engineering an effective vaccine is daunting. Pekosz’s findings on how these vaccines have previously failed will likely prove invaluable at combating such a persistent and common public health concern.
Margarethe (Meta) Kuehn studies vesicles — little bubbles that bud off bacterial membranes. All sorts of things may be tightly packed into these bubbles: viruses, antigens, and information a bacterium will need to make cells vulnerable to infection.
But why do bacteria produce these small membrane vesicles in the first place? Why not spread out to nearby cells themselves?
“The short answer is that we don’t know yet,” explains Kuehn, an associate professor of biochemistry at Duke. “But we speculate that it is due to their small size. These vesicles, which serve as delivery ‘bombs,’ can pass through pores that are too small for bacteria to fit through.”
Originally a chemistry major, Kuehn always had an interest in biochemistry. As an undergraduate, she worked in protein purification and then in the infectious disease division of a children’s hospital. There, she learned about pathogenic bacteria and how they secrete proteins to give themselves access to host cells.
Kuehn’s lab studies the mysterious world of bacterial vesicle production,focusing on the genetic, biochemical, and functional features of vesicles. So far, they have identified specific proteins and genes involved in the vesiculation process.
With a fine filter, they showed that vesicles can fit through holes to reach mammalian cells where a bacterium cannot.
Kuehn wonders why the bacteria don’t just use soluble proteins, which are even smaller than vesicles. They must have some reason for preferring the cell’s vesicles. Currently, they believe that vesicles can serve as nice packages — a whole bolus of information delivered together.
Not only will this new insight into extracellular vesicles of gram-negative bacteria aid in identifying new medicines, vesicles are also being used for vaccine delivery.
“They are really good antigen vehicles,” reveals Kuehn, “The more we know how they are made, the better we can design effective vaccines for humans.”
According to Kuehn, the amazing part about studying these pathogens is that, “You are never done. You never know it all. Every single pathogen, they each do things differently.” What keeps Kuehn going, she explains, is that the search never ends.
“There is never really a defined end point; you have to come to grips with the fact that you will never know that whole answer.”