Following the people and events that make up the research community at Duke

Author: Lawrence Carin

Duke’s Fundamental Research Can Turn Viruses Into Marvels

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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.

Gregory Gray, MD MPH
Gregory Gray, MD MPH

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.

Barton Haynes,MD
Barton Haynes, MD

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. 

David Ashley, Ph.D.
David Ashley, Ph.D.

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

On ‘Things We Already Know,’ Checklists and Mindfulness

I recently spoke to the Academic Council about my new role overseeing Duke’s entire research enterprise – medical and campus –  and I reiterated for them the messages in my first blog post: that all of us should take part in the quality and rigor of Duke’s research efforts and that everyone should participate in activities like Responsible Conduct of Research (RCR) training and other activities that will help us to improve.

Not all the faculty are persuaded, I soon learned.

“I read your recent blog post about quality. Clearly that was not meant for me,” one senior faculty member said to me. He suggested that my reminding the community of such matters was beneath him, and probably beneath many other faculty. “Of course we treat people with respect! Of course we always do research the right way!”

In response, let me share with you an important lesson from a book I read recently, “The Checklist Manifesto,” by Atul Gawande. He’s a general and endocrine surgeon at Brigham and Women’s Hospital in Boston who advocates the use of checklists for surgeons, just as pilots and space programs have used.

Dr. Atul Gawande

Checklists impose structure, they force us to think more slowly and carefully, and to systematically address specific questions of relevance to the mission, even if it’s a procedure we’ve done countless times before. Pilots and astronauts aren’t insulted by them.

At the end of his book, Gawande writes about his personal use of checklists in his surgical practice and a very important lesson he learned by using them.

When he first started thinking about checklists, Gawande thought it was an interesting subject, and that it was highly relevant to the average surgeon. However, with respect to himself, a top-flight surgeon, a former Rhodes Scholar and a MacArthur Fellow, he felt the exercise was probably redundant.

But since he had written and spoken so much about checklists, Gawande always went through the motions, just to avoid looking like a hypocrite. That is, until a particular surgery humbled and changed his perspective on checklists forever.

Gawande was about to perform a surgery, and the head nurse was going down the list of items needed for this particular procedure. All items checked off as expected until they came to the need for a substantial supply of blood in case of a rare complication that could cause severe bleeding.

This item surely was added after a prior disaster and a root-cause analysis that refined the checklist for this type of surgery. But as they went down the checklist, the extra blood was absent. So the team quickly got the blood, and the surgery commenced.

To Gawande’s horror, this particular surgery triggered that rare complication. But because they had the substantial supply of extra blood on hand, the surgical team was able – with great effort — to save the patient’s life.

Gawande says he was chastened by this experience. Without attention to the checklist, this patient would have died on the table.

But academic research isn’t anything like flying a plane or opening an abdomen, or is it? I think the stakes for university research are very high. Duke just settled a case related to research misconduct that cost the university more than $100 million, and damaged our reputation. It might have been prevented.

Pilots routinely use checklists before and during flight.

We have a responsibility to be good stewards of the more than $1 billion in annual funding that allows us to do this important work. The organizations that entrust us with those resources (often the federal government) are counting on us to use those resources well, and to engage in research of the highest quality. The stakes are high, and so should be our responsibilities.

While they aren’t a perfect analogue to things like RCR training, safety checklists address predictable human fallibility, which is often a result of thinking instinctually rather than carefully. RCR training, conflict of interest forms, institutional review boards and other research controls seek to address issues in the same way, by identifying problems that have come up in the past at Duke or other institutions and trying to prevent these lessons from having to be learned again (analogous to the need for extra blood).

I also think it’s important that another key component of checklists is cultural: Anyone on the surgical team is allowed to question anything before or during the surgery. This means that a junior nurse on the team can challenge the lead surgeon if they see something that is in conflict with best practice or the checklist. If you see something, say something.

Anyone at Duke who sees behavior that challenges the values connected to the principles of our checklists – conflict of interest, institutional review board, responsible conduct of research — has the right, and the responsibility, to say something.

Inviting faculty, trainees and staff to engage with training does not mean we feel our people are unaware of these issues. It does not mean we feel that Duke researchers lack integrity. It is just that we are all very busy and focused on many things, and we are human.

I’m asking all of us to slow down for a moment, and to remind ourselves of our responsibility to ourselves, to the broader Duke community, and to our research sponsors. We want to set a tone and a culture that will help all of us push the Duke research enterprise to even higher levels of excellence.

Post by Larry Carin, Vice President for Research

A Community Dedicated to the Highest Quality: Duke

When I was named to the new position of Vice President for Research at Duke last month, it was the culmination of an extensive process that examined how Duke performs all aspects of research. But rather than being seen as an end-point, I hope that everyone will view this as a beginning.

Lawrence Carin, Vice President for Research

This re-examination of Duke’s research was led by President Price and included many leaders from across Duke, including Provost Sally Kornbluth, Chancellor Eugene Washington, and the Dean of the School of Medicine, Mary Klotman. We also engaged the services of an External Advisory Panel that included Ann M. Arvin (chair), professor of pediatrics and microbiology and former vice provost and dean of research at Stanford University; Edward M. Stolper, William E. Leonhard Professor of Geology and former provost at Caltech; and Barry S. Coller, David Rockefeller Professor, physician-in-chief and vice president for medical affairs at Rockefeller University.

(L-R) Ann Arvin, Edward Stolper and Barry Coller

During the Advisory Panel’s visit to Duke, Dr. Coller made a comment that stuck with me. He said: “You can always tell the effectiveness of an organization by how anyone within it responds when they answer the phone and hear this request: `Please connect me to the quality department.’ ” At a high-functioning organization, Dr. Coller said, anyone answering that query would say that they are responsible for quality, as is everyone in our organization.

There is no separate department of quality; everyone is a member of the quality department. This, I think, is something that all of us working and studying at Duke should take to heart, concerning everything we do at Duke, including all aspects of research. We need to not only be in charge of quality within our own research, but also take the responsibility to each other and to the institution, to assure that everything throughout the Duke research enterprise is done with the highest quality. That means excellence in all its forms, including ethics and integrity.

Nursing students work with assistant professor Rémi Hueckel.

My hope is that the Duke research enterprise will be characterized as a highly functioning operation. Toward that end, if you should see something that can be improved, seek to improve it. Often this can be done directly, by utilizing the agency we may have in a given situation. If the issue requires broader engagement, communicate with your School leadership, or with the Duke Office of Scientific Integrity (DOSI). Let’s work as a team.

Duke’s move to a Vice President for Research position, with oversight over all aspects of our  research in both the School of Medicine and the schools and departments on the campus side, is a reflection of what many in the administration have been calling a “One Duke” philosophy.

WE NEED TO … TAKE THE RESPONSIBILITY TO EACH OTHER AND TO THE INSTITUTION, TO ASSURE THAT EVERYTHING THROUGHOUT THE DUKE RESEARCH ENTERPRISE IS DONE WITH THE HIGHEST QUALITY.

Lawrence Carin

We are increasingly one university, with the lines between different schools blurring, and when it comes to research, that is one of our great competitive advantages over peer institutions.

I hope we also can go beyond “One Duke” and emphasize “Our Duke.” While every member of the Duke research community must be a member of the Duke Research Quality Department, this is particularly true of our faculty. Faculty should not just feel that they are employees of Duke; as faculty, each of us has a leadership responsibility for stewardship of Duke as a whole.

Student Sabrina Tran studying algae at the Marine Lab.

Given the pressure faculty face to find and secure research funding and to publish high-quality research, it is natural that faculty tend to focus on their own relatively narrow part of Duke– their  lab and students. While this is to be expected for junior faculty, we must expect something more from our senior faculty.

Senior Duke faculty have a responsibility to foster an environment dedicated to the highest quality of ethics and integrity, if for no other reason than that the actions of a tiny minority can impact the reputation of the entire university, as we’ve seen in a few isolated but high-profile examples that affected  all of us individually, and our institution’s reputation nationally.

By Our Duke, I mean a culture that emphasizes that the research enterprise at Duke belongs to all of us, and all of us have a responsibility to care for it.

Barton Haynes, MD, Director of the Human Vaccine Institute (with gloves).

To help me with the expanded duties and responsibilities of being Vice President for Research, we have identified four faculty who will be  engaged on research challenges, helping me and my OVPR colleagues with direction and implementation.

Susan Alberts (Biology & Evolutionary Anthropology), Sonke Johnsen (Biology), Hashim Al-Hashimi (Biochemistry) and Andrew Muir (Division of Gastroenterology in Department of Medicine) have agreed to become regular members of the VPR team, meeting with me and other Duke leaders regularly.

We intend to pull in a larger group of Duke faculty to supplement and help us. Our goal is not to make every faculty member an administrator. Our goal is to have increasing faculty ownership of Duke’s overall research enterprise, providing inputs and guidance, and helping us set priorities.

To say everyone is a member of the Quality Department is easy; to make it happen is another thing. We will be engaging faculty extensively in this process. It is critical that we do this together, as a community dedicated to achieving the highest quality in everything we do at Duke.

I look forward to working with all of you to pursue this new vision of an integrated, caring, high-quality Duke research community.

A student in biomedical engineering.
Post by Lawrence Carin, Vice President for Research

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