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Research Matters

By Terry Magnuson, March 31, 2021

I am a member of the National Academies Forum on Regenerative Medicine, which was established in 2016. The forum convenes people from academia, industry, government, patient and provider organizations, regulators, foundations, and others to address the challenges facing the applications and opportunities for regenerative medicine. The charge to forum members is to identify barriers to scientific advances and to examine the impact of current policies on advancing discovery, development, and translation of effective therapies.

We meet four times a year, and agenda topics span a range of issues using public workshops, discussions, and commissioned papers to inform the field. I’d like to share the highlights from the four previous forum workshops.

  1. Exploring the State of the Science in the Field of Regenerative Medicine: Challenges of and Opportunities for Cellular Therapies (October 2016)

Several themes emerged from the workshop that highlighted challenges and areas of opportunity, as well as future innovation including understanding and characterizing cells, improving model systems, clinical translation, navigating regulatory pathways, and more.

  1. Navigating the Manufacturing Process and Enduring the Quality of Regenerative Medicine Therapies (June 2017)

This workshop focused on the challenges, opportunities, and best practices for defining and measuring the quality of cell and tissue products, as well as the raw materials in research and manufacturing of regenerative medicine therapies.

  1. Exploring Sources of Variability Related to the Clinical Translation of Regenerative Medicine Products (October 2018)

The forum used the Regenerative Engineering Society’s definition of regenerative engineering as the convergence of advanced materials sciences, stem cell science, physics, developmental biology, and clinical translation for the regeneration of complex tissues and organ systems.

Forum speakers highlighted the many factors that can affect the variability of regenerative engineering products, including the immune system, disease state, and other characteristics of the patient and the donor, the manufacturing process, and preservation techniques.

  1. Exploring Novel Clinical Trial Designs for Gene-Based Therapies (November 2019)

The workshop focused on gaining an understanding of the design complexities and ethical issues associated with clinical trials for gene-based therapies.

This workshop drew attention to a few points. First, that clinically meaningful, reliable, and rigorous endpoints are important for gene therapy trials, where trials may be smaller, and treatments are irreversible. Additionally, long-term follow-up is critical to identifying and mitigating delayed risks to patients who receive investigational gene therapies.

The forum continues its work and has established a working group on systems thinking, with a goal to examine systems-based analytical methods that could advance the mechanistic understanding of regenerative medicine products to overcome challenges with manufacturing and patient outcomes.

Additional workshop perspectives will be forthcoming. It has been an amazing and rewarding opportunity for me to participate in the Academies Forum on Regenerative Medicine.

Permalink: Regenerative Medicine: Advances and Challenges for Development of Effective Therapies

By Terry Magnuson, March 1, 2021

The UNC Carolina Population Center (CPC) recently received notice of a $38.2 million award to continue to lead the National Longitudinal Study of Adolescent to Adult Health (Add Health), now entering its sixth wave of data collection. This award from the National Institutes of Health is on top of the already impressive $114,165,158 in funding the Add Health team has collected since March 1994.

Professor Kathleen Mullan Harris directed the Add Health study from 2004 to 2021, and this year, professor Robert Hummer assumes leadership. The Add Health team includes sociologists, psychologists, epidemiologists, geneticists, physicians, and research methodologists. They collaborate on study design, data collection, and making study results available to researchers all over the world. Based at CPC, these researchers work closely with RTI International, the University of Vermont, and Exam One. Currently, the study has over 50,000 registered users of Add Health data, and a bibliography of over 8,000 journal articles, presentations, manuscripts, books, book chapters, and dissertations using the survey’s findings — all catalogued by the CPC.

This study is a nationally representative, longitudinal survey of over 20,000 individuals born between 1976 through 1982. The cohort was first interviewed as adolescents in grades 7-12 (ages 12-19) between 1994 and 1995. Since then, four waves of additional data have been collected at ages 13-20 (1996, Wave II), 18-26 (2001-2002, Wave III), 24-32 (2008, Wave IV), and 32 to 42 (2016-2018, Wave V). The survey design yields a sample representative of United States schools according to region, urbanicity, school size, school type, and ethnicity. The study includes oversamples of underrepresented racial and ethnic groups, as well as individuals differing by immigrant generation status and family structure, such as two-parent, single-parent, or stepparent familes.

Information on many topics has been collected, including educational experiences, social relationships, personality and psychological characteristics, stressors, employment, children and parenting, and cognitive function. In addition, contextual data are linked to other data such as school and neighborhood characteristics, high school transcripts, and pollutant information. The most recent Wave V study collected genetic information and measures that capture metabolic, immune, cardiovascular, and renal function as well as inflammation.

The objectives for Wave VI will focus on the cognitive, mental, and physical health of Add Health participants, with particular attention given to disparities in health outcomes across racial and ethnic, socioeconomic, and gender subgroups of the population. The new wave of data will inform current trends, including rising health risks in middle-age and participants’ exposure to COVID-19.

Add Health has begun to answer important questions about the links between adolescent experiences with adult health outcomes. For example, as outlined by RTI , data from the study has correlated middle and high school students who have problems with homework being at increased risk for issues with drinking and smoking. In addition, adolescents embedded within social networks of friends, family, and school have better cardiovascular and metabolic health 15 years later than adolescents without strong network connections. Analysis on the ways the environment affects genetic influence on health and health behaviors in adulthood is underway.

Other examples include a recent study from PhD student Audrey Renson and colleagues that showed biomarkers of inflammation, metabolism, and macromolecular damage are early signs of gut microbiome aging in young adults, likely beginning as early as age 30. Another study by sociologist Taylor Hargrove and team found that women reported more depressive symptoms than men, and underrepresented racial and ethnic groups reported more depressive symptoms than their white peers. Results also exposed a difference in depression symptoms by race and ethnicity within each gender group and at varying times in the life course. By highlighting these vulnerable populations and understanding the age trajectories for depressive symptoms, it is easier to determine when interventions would be best suited in the life course.

These are just a few examples of how social, economic, and biological factors during adolescence and young adulthood can affect health outcomes later in life. Answers on how best to intervene and when can only be derived by a longitudinal study like Add Health that tracks individuals over decades. And while Add Health has garnered international recognition and many awards, including the 2016 Golden Goose, it is just one impressive research program of the many within social and behavioral sciences at UNC. Our programs in these disciplines were recently ranked number-one in the U.S. I look forward to following the continued findings from Add Health, and the survey’s critical contributions to society, for years to come.

Permalink: Harvesting Data from a Decades-Old, 20,000-Strong Cohort

By Terry Magnuson, February 2, 2021

We have truly experienced a year like no other. The loss of normality has left us missing human contact with friends and family. The loss of life due to the COVID-19 pandemic has been unprecedented. The 1619 project outlined the history of white supremacy in our country while continued violence against people of color made headlines. And the frightening attack on the U.S. Capitol in January highlights continued American extremism and racism.

But, through all of the turbulence, researchers continued to discover and innovate. Iʼd like to share how the work of researchers has been so important for the world by reflecting on this yearʼs research breakthroughs, selected by the journal Science, and to highlight how researchers at UNC are already working in those spaces.

The breakthrough of the year was, unsurprisingly, research on SARS-Cov-2 and COVID-19. While the world struggled, advances in research to understand the new virus and efforts to put a halt to the global pandemic were extraordinary. More than 200,000 peer-reviewed papers on this subject were published during 2020. The World Health Organization and the Centers for Disease Control also offered perspectives on COVID-19 science and research.

The rapid response to the pandemic demonstrated the critical need for a robust research infrastructure. A call for U.S. research infrastructure is outlined in NIHʼs Office of Research Infrastructure Programs (ORIP) 2021-2025 strategic plan entitled Infrastructure for Innovation. It is comforting that President Biden recognizes the importance of scientific research as demonstrated by the appointment of Eric Lander as the new director of the Office of Science and Technology Policy (OSTP) and by elevating the office to a cabinet-level position.

Runners-up for Scienceʼs breakthrough of the year include several important advances across the fields of gene editing, the global climate crisis, astronomy, artificial intelligence (AI), infectious diseases, the origins of human civilization, and how our current civilization is still reckoning with racism and equity.

Thanks to the basic science work of Emmanuelle Carpenter and Jennifer Doudna, both of whom won the 2020 Nobel Prize in Chemistry, the use of CRISPR-Cas9 gene editing to fix gene mutations causing disease continues to make advancements in treatments. Researchers in UNCʼs clinical immunotherapy program use this tool to re-engineer cells from a patientʼs immune system and create modified cells that recognize and direct a specific attack against that patientʼs cancer. Patient-specific treatments are employed by scientists in UNCʼs Precision Medicine program, using genomics to identify gene variants that could be targets of CRISPR editing. Last year, we highlighted CRISPR genome editing and the impact of this technology on individuals and society during 2020 University Research Week.

The global climate crisis was another notable breakthrough. The 2020 wildfire season was the largest recorded in Californiaʼs modern history with 4,257,863 acres burned. Additionally, an unprecedented number of Australia’s forests have burnt down. NASAʼs climate change website has an extensive collection of examples regarding global warming. President Biden has prioritized the climate crisis by naming John Kerry as the special presidential envoy for climate. The North Carolina Climate Risk Assessment and Resilience plan outlines warnings about the effects of climate change on the state, and it provides a roadmap to resilience. The UNC Institute for the Environment studies climate, extreme heat, air quality, and ways to change our current course. Researchers in the Gillings School of Global Public Healthʼs Department of Environmental Sciences and Engineering are focused on air quality and atmospheric processes, human exposure and health effects, and sustainable water resources.

The origins of fast radio bursts (FRBs) — short flashes of radio waves from distant galaxies — were also featured on Scienceʼs list. Astronomers studying FRBs believe they have finally found their source, but they still donʼt know exactly how magnetars produce such bursts. Carolina researchers have been studying the universe for over 100 years. The Morehead Planetarium and Science Center, the Department of Physics and Astronomy, and the CoSMS Institute have played pivotal roles to advance our understanding of the universe. In a recent Science article, our own Chris Clemens and co-investigators identified and measured lithium in the atmosphere of burned-out stars called white dwarfs. The study is important for tracking the galactic evolution of lithium.

Back on Earth, researchers have developed an AI program that predicts protein structures by modeling the amino acid interactions that govern its three-dimensional shape. A proteinʼs precise shape determines its biochemical functions, the knowledge of which is critical for researchers to uncover mechanisms of disease and develop new drugs. UNC researcher Michael Kosorok uses AI for decision-making and patient care.

A study of 64 HIV-infected people who have been healthy for years without antiretroviral drugs revealed a link between their success and where the virus is located in their genomes. Although this will not be a cure, the finding points to a strategy that may allow infected people to live without treatment. The UNC HIV Cure Center has developed a public/private partnership with Viiv Healthcare to form Qura Therapeutics. Current research at Qura centers on the concept of “induce and reduce,” a therapeutic approach that affects the virus while minimizing the impact on the body beyond the hidden infected cells. The UNC Center for AIDS Research provides infrastructure to support clinical research, behavioral research, research into mechanisms at the molecular level, and educational outreach. The Global HIV Prevention and Treatment Clinical Trials Unit is dedicated to developing and conducting research of HIV prevention, disease, associated opportunistic infections, and therapy complications.

In yet another breakthrough, researchers confirmed a series of animal-headed hunters sketched on cave walls in Indonesia is more than 40,000 years old. The age of the paintings makes them the oldest pictorial record of storytelling and the earliest figurative artwork in the world. As Michael Price quotes April Nowell, “the findings … help dispel … [the] mistaken notion that humanity first became fully modern in Europe and [this and other recent findings] continues to underscore … the importance of the record outside Europe.” A story from the April 2020 issue of Endeavors profiles UNC archeologists Benjamin Arbuckle and Heather Lapham, who study ancient animal remains, texts, and iconography to understand how relationships with animals changed peoplesʼ lives and the world — which highlights why the recently uncovered 40,000-year-old sketches are a breakthrough of the year.

Confronting racism and the journey toward reconciliation was as important a breakthrough in 2020 as research on COVID-19. As stated by Tanisha Williams of Bucknell University: “People of color across the board are struggling … Itʼs a systemic problem.” The events of 2020 have many of us in academia and research learning the ways that systemic racism pervades our community, and we are committed to addressing it. As Williams continues: “I definitely feel like our voices are being heard, and in a different way … But itʼs not going to be a quick fix … we have a long road.”

Across the board, we researchers have a passion to fix the world as illustrated by the scientific breakthroughs of 2020. But our passion is often myopic. My hope for 2021 is that what occurred in 2020 — and before — encourage us to mindfully address the pain that our colleagues have endured and work together to create a better research community for all, where our diverse perspectives and experiences fuel even greater breakthroughs.

Permalink: Breakthroughs, Passion, and the Way Forward

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