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Research Matters

By Terry Magnuson, January 4, 2021

Thinking back to how I rang in 2020, I was occupied with the goals and duties of UNCʼs Office of the Vice Chancellor (OVCR) as well as the work in my research laboratory. I just finished my term as president of the Genetics Society of America and was looking forward to serving as immediate past president. Whatever ideas and plans I had, along with everyone elseʼs, dramatically vanished as the pandemic engulfed our world.

And what has become absolutely clear is that the value of scientific research has never been more obvious. As pointed out in a recent Nature commentary, “The fastest any vaccine had previously been developed, from viral sampling to approval, was four years, for mumps in the 1960s.” Amazingly, it has been less than a year for several vaccines to show promising results in large trials. It was on December 2 that a vaccine made by Pfizer with the German biotech firm BioNTech became the first to be approved for emergency use in the United Kingdom with several countries to follow. Then a second vaccine, Moderna, received emergency use approval on December 18. As I write this column, a third vaccine from the University of Oxford and AstraZeneca has been approved in the U.K. and more will follow over the next few months.

An important point that Nature highlights is that the rapid development of vaccines against the new coronavirus depended on decades of research by academic and pharmaceutical scientists. Researchers like our own Ralph Baric, Timothy Sheahan, and Mark Heise had been paying attention to other coronaviruses, like those that cause SARS (severe acute respiratory syndrome) and MERS, for years and their work provided critical information for understanding SARS-Cov-2. Other researchers had been focusing on new ways to make vaccines using messenger RNA.

These years of fundamental, basic research paid off spectacularly well when the world needed tools to fight the SARS-Cov-2 pandemic. Of course, public funders, private philanthropists, and pharmaceutical funding meant that companies could start large-scale testing and manufacturing of candidates that might not work, which also played heavily in the rapid success of vaccine development. But no amount of money would have resulted in success without a solid platform of basic science on which to build. We have a way to go before any of the vaccines are widely available for all that want them. Thus, our best defense still is covering faces, washing hands, and keeping our space.

As applied to this pandemic, and looking ahead to future outbreaks, is that a rapid first-line defense depends on effective antiviral therapeutics. UNC investigators are taking the lead in this area. An idea began with a 2019 UNC Creativity Hub-funded team known as The Infectious Disease Drug Discover Program at UNC (ID3). Principal investigators Nathaniel Moorman and Ken Pearce brought together scientists from virology, proteomics, bioinformatics, chemical biology, and drug discovery to provide new antiviral therapeutics useful for treating multiple viral diseases. This group began work on anti-viral therapeutics before the pandemic and was already focusing on the three classes of viruses (coronavirus, alphavirus, flavivirus). Their work has led to a major UNC initiative known as the Rapidly Emerging Antiviral Drug Discovery Initiative, or READDI. The ID3/READDI team is focused on preparing today for outbreaks tomorrow. Their goal is to develop five broad-spectrum antiviral drugs in five years by focusing on antiviral drugs that target the cellular proteins pandemic viruses need to replicate and cause disease.

When the world most needed it, we were inspired by the resilience of our research community as the pandemic unfolded. And then, George Floyd was murdered. The world was yet again jolted by our collective acceptance of systemic racism, even within our own academic institutions that we have helped to build. Although equity, inclusion, and belonging were already priorities at UNC, it hasnʼt been enough. UNCʼs chancellor, provost and interim chief diversity officer issued a message to our community on June 11 that ends with: “We stand in solidarity with our faculty, students, and alumni in denouncing systemic racism, hate speech, and white supremacy. And we will continue to listen, engage, and demonstrate through actions our commitment to build a lasting culture of respect, inclusivity. and belonging among our community.”

UNCʼs leadership is committed to “Building Our Community Together” as the first initiative of the strategic plan known as Carolina Next: Innovations for Public Good. The university has committed to moving faster and more effectively to address racism. Steps forward can be followed through actions taken by the University Diversity, Equity, and Inclusion (DEI) Council. All of us must take a more active role. But many of us donʼt feel qualified or prepared to launch into discussions about complex topics with ethical and social dimensions. The DEI Councilʼs activity is critical in helping our community learn how to engage in these conversations in an open and inclusive way.

Last week, NPR reported on how the Black Lives Matter movement became an international phenomenon in 2020. As protesters took to the streets in cities across the U.S. in the aftermath of the murder of George Floyd, so did demonstrators in other countries — unfortunately, all with a similar message: There is a George Floyd in every country. Black Lives Matter inspired, for example, an “AllPapuanLivesMatter” movement in Indonesia, as well as many others for repressed communities across the globe.

UNCʼs Mark Peifer, an ardent supporter of diversity and equality, sent a note to a number of us pointing out an article published in Cell Mentor entitled, “1,000 inspiring Black scientists in America.” As Mark stated: “Representation matters, and this will be inspirational for the next generation of scientists — use it in your classes this spring. It is a great resource in the classroom, and for thinking about speakers and future faculty members.”

I encourage everyone to read the article.

So, as we leave 2020, my take home message is that you are the UNC community, and you have an obligation to “building our community together” in this new year and the ones that follow.

Inspiration for the title and this column comes from Denise Montellʼs goodbye message as her term as president of the Genetics Society of America during 2020 was coming to an end.

Permalink: Science, Society, and Thoughts on 2020

By Terry Magnuson, December 1, 2020

A genome is the complete DNA sequence of an organism that includes all of its genes and the DNA between genes. Genomics is the characterization, quantification, and interaction of how all genes influence the biology of an organism.

The Human Genome Project began 30 years ago with the goal of sequencing the DNA of the human genome. Now, the DNA of many, many organisms has been sequenced, revolutionizing research, medicine, and society. The Cancer Genome Atlas (TCGA), for example, brought together scientists from around the world to sequence DNA and RNA from over 20,000 cancer and matched normal samples to uncover the genetic differences for 33 cancer types. This approach, called structural genomics, has identified cancer-causing changes, allowing for a better understanding of the molecular basis of cancer growth, metastasis, and drug resistance. Putting large genomic datasets together and sharing them with researchers worldwide has become an important strategy for diagnosis and treatment.

UNCʼs Lineberger Comprehensive Cancer Center has been a leader in the TGCA project. Since 2016, faculty members Chuck Perou, Katie Hoadley, Joel Parker, and Corbin Jones have contributed to 48 TCGA publications. This work is exemplified in Hoadleyʼs first-authored pan-cancer analysis of the entire TCGA data set. Along with her colleagues, she estimated that at least one in 10 cancer patients might be classified or treated differently using a genomic and molecular taxonomy, rather than the current histopathology-based classification.

There are many other areas that have also benefited from DNA sequencing, some of which include prenatal genetic testing, forensics, direct-to-consumer ancestry, genetic disease diagnostics, and now, SARS-CoV-2 virus surveillance. Dirk Dittmer, for example, has been tracking the virus that causes COVID-19 by sequencing the genome of virus samples collected from patients. Genomic sequencing will help diagnose the novel coronavirus, identify mutations, and track its history.

The National Human Genome Research Institute (NHGRI) just published its 2020 Vision for whatʼs next for genomics over the coming decade, especially in applications to human health and disease. It outlines grand challenges such as understanding the roles and relationships of genes and regulatory elements; determining the genetic architecture of most human diseases and traits; studying diverse ancestral populations to enable scientific discoveries for all; and using genomics to understand health, disease, responsibility, identity, family, and community.

The vision also includes 10 bold predictions for human genomics that will occur by 2030:

  1. Generating and analyzing a complete human genome sequence will be routine for any research laboratory, becoming as straightforward as carrying out a DNA purification.
  2. The biological function(s) of every human gene will be known; for non-coding elements in the human genome, such knowledge will be the rule rather than the exception.
  3. The general features of the epigenetic landscape and transcriptional output will be routinely incorporated into predictive models of the effect of genotype on phenotype.
  4. Research in human genomics will have moved beyond population descriptors based on historic social constructs such as race.
  5. Studies that involve analyses of genome sequences and associated phenotypic information for millions of human participants will be regularly featured at school science fairs.
  6. The regular use of genomic information will have transitioned from boutique to mainstream in all clinical settings, making genomic testing as routine as complete blood counts.
  7. The clinical relevance of all encountered genomic variants will be readily predictable, rendering the diagnostic designation “variant of uncertain significance” obsolete.
  8. An individualʼs complete genome sequence along with informative annotations will, if desired, be securely and readily accessible on their smartphone.
  9. Individuals from ancestrally diverse backgrounds will benefit equitably from advances in human genomics.
  10. Breakthrough discoveries will lead to curative therapies involving genomic modifications for dozens of genetic diseases.
  11. NHGRI believes that these goals can be achieved with further detailed planning that includes input from the global community of scientists, funders, and research participants. The 2020 Vision also stresses that genomic advances during the coming decade will amplify questions related to the societal implications of genomics, which includes those related to social inequities and the ethical, legal, and social (ELSI) issues related to genomics.

    UNC has many research programs that tie into the challenges listed by NHGRI. Eric Juengst, director of the UNC Center for Bioethics, has been a leader in ethical issues surrounding the human genome project. From 1990 to 1994, when the Human Genome Project began, Juengst served as the first chief of the ELSI branch of the National Center for Human Genome Research, which then became the NHGRI. His work continues to focus on the conceptual and ethical issues raised by advances in human genetics and genomics. He is examining the ethical and social implications of personalized genomic medicine as a paradigm for health care.

    Another example is the Integrative Program for Biological and Genome Sciences (IBGS), an integrated program between the College of Arts and Sciences and the School of Medicine. IBGS faculty conduct research into the mechanisms by which molecules and cells coordinate organism development and function using model systems and genomic approaches. The importance of model systems functional genomics was the subject of a recent workshop held by the National Academies.

    We at UNC agree with the NHGRI assessment that “the field, the fundamental sense of curiosity, marvel, and purpose associated with genome science seems to be timeless […] and we are ready to embark on the next exciting phase of the human genomics journey.”

    Permalink: The Future of Human Genomics Research Will Address Grand Challenges

By Terry Magnuson, November 3, 2020

Since 2018, the Office of the Vice Chancellor for Research (OVCR) has sponsored the Creativity Hubs initiative with the goal of changing how research and discovery happen at Carolina. The Creativity Hubs promote an environment where multidisciplinary investigators can nimbly leverage new advances that keep Carolina at the forefront of creativity and innovation.

The keys to successful Creativity Hubs include:

  • Innovation and Impact: The ability to provide solutions to important challenges and the generation of new fundamental knowledge and create impact to benefit society, culture, community, the environment, or the economy.
  • Convergence: Demonstration that the project takes advantage of expertise from multiple and diverse disciplines and promotes new ways of thinking that push disciplinary boundaries.
  • Sustainability: The likelihood that the project will lead to support of larger and sustained extramural funding from federal agencies, industry, venture groups, or nonprofit organizations.
  • Program Management Plan: Clearly articulated plan with description of feasibility, work-plan, milestones, project deliverables, evidence of alignment with large-scale extramural support, and timeline for soliciting external support.

In my September 2020 Research Matters post, I wrote about the success of the first two Creativity Hubs that completed their projects: Heterogeneity in Obesity and Sustainable Access to Safe Water.

This month, I want to highlight the success of a 2019-2020 winning Creativity Hub project, which after only one year of work has been successful in obtaining federal funding. The Dynamics of Extreme Events, People & Places (DEEPP) Hub is led by Elizabeth Frankenberg, director of the Carolina Population Center and the Cary C. Boshamer Distinguished Professor of Sociology, and brings together social and environmental scientists and engineers.

Their broad goal is to understand the environmental, economic, social, and psychological impacts of hurricanes and flooding in coastal Carolina communities. The team is combining survey information provided by people across the state with satellite imaging and flood mapping. They are developing a complete picture of impacts and recovery from hurricanes and floods – information that will inform effects of future hurricanes for a quicker and more complete recovery.

The DEEPP Hub researchers are using a three-pronged approach. The first is modelling and mapping exposure to risk. By comparing geophysical and flooding models with intensity measures, they will be able to develop an accurate picture of areas impacted from recent hurricanes in eastern North Carolina. The second part of their strategy involves aggregating administrative data from government agencies and non-governmental organizations. The third approach is to survey households about their own experiences.

As outlined in their proposal, the data obtained during the two-year project is laying the groundwork for a long-term project by:

  1. developing the measurement and sampling infrastructure for a cluster-based baseline survey of places and populations throughout eastern North Carolina that are at varying risk to extreme events;
  2. assembling and assessing extant “big data” resources that can be integrated to inform multi-scale analyses around the geographic distribution of hurricane physical impacts juxtaposed against the spatial and temporal variation in behaviors and outcomes of social-ecological systems affected by the physical impacts;
  3. developing fine-grained measures of response to hurricanes, within both natural and social systems using selected pilot sites;
  4. developing a conceptual framework and approach to predict how extreme events will affect social and ecological outcomes over the short and medium-term; and
  5. building interdisciplinary capacity to apply for external grants to support a large-scale long-term study of the impacts of extreme events on people and places, which integrates ground surveys with remote sensing and simulation models to understand social-ecological impacts of extreme events, predict responses to future events, and inform policies for impact mitigation and adaption.

With respect to point five, the DEEPP Hub, under the leadership of Frankenberg, Michael Piehler, and Rick Luettich, was just awarded a National Science Foundation (NSF) Growing Convergence Research Award based on the pilot data collected and the concepts outlined in their Creativity Hub proposal.

The DEEP Hub NSF award focuses on the concept that transformational adaptation and mitigation strategies for hazards in coastal regions require a convergent approach, integrating methods, insights, and data from the social sciences, the natural sciences, engineering, and geosciences. The results are intended to inform the design of effective strategies for mitigating impacts of extreme events for places and people. This is exactly the kind of research that the NSF is trying to stimulate, and the Creativity Hubs are providing pilot funding to generate foundational data for Carolinaʼs researchers to succeed in obtaining this type of external funding.

UNCʼs Creativity Hubs are research networks that concentrate talent and resources on bold ideas for defined periods of time – free from typical organizational boundaries, with the goal of moving new discoveries and ideas into practice. Congratulations to the DEEPP Hub for their success in obtaining an exciting NSF Growing Convergence Research Award.

Permalink: UNC’s Creativity Hubs Stimulate Convergence Research

By Terry Magnuson, October 5, 2020

During University Research Week, I will participate in a panel discussion titled “Editing Along Ethical Boundaries,” which will take place on October 21 at 11 a.m. We will discuss the documentary “Human Nature,” which explores the scientific breakthrough called CRISPR.

CRISPR allows for easy modification of DNA, creating new possibilities for improving human health. Already, advances are being made for using CRISPR to provide a cure for genetic disorders such as sickle cell anemia, as well as for many other diseases. In addition to human health, CRISPR has also opened a pathway to engineer the world around us for the benefit of agriculture and the environment. But it also presents ethical dilemmas for medicine, religion, and society at large.

To that end, the Personal Genetics Education Project, consisting of a team of scientists, social scientists, educators, and community organizers, has formed to address how genome editing impacts individuals and society. According to the teacher guide produced by the group, when used for genome editing, the CRISPR system has two main components:

Graphic: Mechanism of CRISPR gene editing system
  1. A targeting system that finds the right place in the genome to cut. This is achieved by a molecule called a guide RNA (gRNA), which has the same genetic sequence as the target site; and 
  2. a component for making the cut to the DNA. This consists of a DNA-cutting enzyme called Cas9.

“When both of these components are delivered into a cell, the gRNA will bind to the target genomic site through complementary base pairing,” states the teacher guide. “This pairing brings the Cas9 to the target site to make a cut to the DNA. The cell’s natural DNA repair mechanism will close the gap, but the process is not perfect, and a few DNA bases will be added or deleted, which renders the gene nonfunctional. CRISPR can also be used to replace a defective version of a gene that causes disease with the correct version. In this case, the desired version of the target gene can be placed into the cell along with the gRNA and Cas9. The cell will then use this desired sequence as a template to repair the broken DNA.”

It is clear the genome editing by CRISPR has potential significant benefits, but it also raises profound questions such as altering the germ line for “designer babies” and, potentially, the ecosystem to eradicate or change species of all kinds. Society needs to understand and seek a balance between the benefits of genome editing and unintended consequences of altering the genome. There is a need to have broad conversations that engage all communities and ensure that diverse values and voices are heard. Researchers, bioethicists, and policymakers have called for caution and the need for public consultation and dialogue that involves patients, faith leaders, environmental activists, and disability rights advocates.

I hope you will join us for this discussion on “Human Nature.” Panelists include myself, RENCI Director Stan Ahalt, and UNC Center for Bioethics Director Eric Juengst. We will explore how UNC researchers are leveraging this game-changing technology in their research, how data scientists are powering their breakthroughs, and the ethical implications all must consider. The movie is available to watch now on the links provided using your ONYEN credentials or PBS account information. We invite you to submit your questions for the panelists while you view the movie. We will begin the panel discussion with the questions that have already been submitted

Please visit the University Research Week website often over these next two weeks as information on the exciting event line-up is added daily. While we cannot participate in person this year, we have no shortage of engaging, informative, and inspiring events planned that celebrate UNC’s research excellence.

Permalink: University Research Week: A Panel on CRISPR Genome Editing

By Terry Magnuson, September 1, 2020

Convergent research — a collaborative, cross-disciplinary approach that brings teams of researchers with divergent expertise together to generate new ideas and pursue groundbreaking studies — is the way to address societal problems as they become more complex.

In 2018, the Office of the Vice Chancellor (OVCR) began harnessing the power of a convergent approach to research by establishing Creativity Hubs.

The Hubs were envisioned to be evolving research networks that concentrate talent and resources on bold new ideas for defined periods. In consultation with research deans from the UNC schools and the College, as well as pan-campus center and institute directors, the OVCR identified strategic research priorities for Creativity Hubs. These priorities reflect UNC’s strengths where the convergence of social sciences, humanistic scholarship, foundational research, health science, and the natural sciences can accelerate discoveries and solutions to emerging challenges.

Without typical departmental constraints, discoveries and ideas can more easily move into practice to keep Carolina at the forefront of creativity and innovation. To achieve the goal of convergent research, the OVCR provides $250,000 per year for two years for each Creativity Hubs winning team. Since the award program’s start in 2018, six award-winning teams have yielded impressive results and millions in extramural funding.

The inaugural winning Hubs selected in 2018 were: Heterogeneity in Obesity: Transdisciplinary Approaches for Precision Research (Obesity Hub), and Treatment and Sustainable Access to Safe Water: Graphene-Polymer Nanocomposite Membranes for Water Purification, Energy Production, and Storage (The Sustainable Access to Safe Water Hub). I am happy to share that both have made tremendous progress.

The Obesity Hub, led by Penny Gordon-Larsen, is comprised of 25 faculty members from various departments across many fields. The goal of the project is to leverage UNC’s prowess in big data management by assessing the underlying causes of obesity. By developing an automated tool to analyze and integrate large data sets, the team will provide more personalized treatments that take into account a wide range of factors — from diet, to social influences, to genetics — that contribute to weight gain and loss.

The team has found that data using weight, body composition, and other phenotypes in mouse strains revealed subtypes of mice have differential response to weight gain and resistance to weight loss. This indicates the importance of genetic background. Next, the team will analyze a genetically diverse population of mice to pinpoint the combinations of regions of DNA that control this response.

The team also has been conducting parallel studies in humans. They are using population data to develop obesity subtypes in several datasets — notably the China Health and Nutrition Survey (CHNS), Coronary Artery Risk Development in Young Adults (CARDIA), Atherosclerosis Risk in Communities (ARIC), and Hispanic Community Health Survey (HCHS) — using identical phenotypic data to the mouse study.

Using this information, they have identified four obesity subclasses demonstrating the value of accounting for multiple measures of obesity duration and severity and changes in these measures over time, as opposed to simple consideration of obesity at one point in time.

Their next step was to be a three-month planned intervention study for 40 participants using their data tool.  Due to the COVID-19 pandemic, this study has been delayed, but plans are in place to complete the pilot study by mid-December.

The Sustainable Access to Safe Water Hub, led by Theo Dingemans and five others from different departments and institutions, addresses a need that affects over 1.8 billion people worldwide. This Hub assembled a unique team of scientists and engineers comprised of polymer chemists, computational modelers, and engineers to develop affordable membrane-based water purification tools that remove a broad range of water contaminants. Building on existing graphene and graphene oxide technologies that have shown promise as water purifiers, the team has been working to develop new membranes that make water purification more energy-efficient and to lay a foundation for large-scale, affordable membrane production. During the past two years, they have developed simulation models to refine membrane design with new polymer chemistry that is commercially scalable.

The result of their work was incorporated into a project within the new $12 million NIEHS Superfund Center to advance membrane-sorbent systems for the next five years. The team seeks to create a filtration system that removes contaminants better than existing in-home water treatment systems and minimizes contaminant re-entry into the environment. The hypothesized treatment system will serve as an intervention point between drinking water contaminants and human exposure, resulting in reduced risk of adverse health outcomes from exposure to inorganic arsenic and other contaminants. The group has also expanded the scope of their work to include not only water purification but also gas, solvent, and heavy metal filtration for commercial use, which includes ongoing discussions with companies to improve high-temperature gas separation.

These Creativity Hubs have achieved their goals by bringing together interdisciplinary researchers to address approaches focused on new world problems. Additional Creativity Hubs awards have been made for 2019 and 2020, and we will report on their progress at the end of their two-year funding period.

Permalink: Progress from the Inaugural 2018 Creativity Hubs