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Research Matters

By Terry Magnuson, July 1, 2021

President Biden’s FY2022 discretionary budget request to Congress includes $6.5 billion for creating an Advanced Research Projects Agency for Health (ARPA-H) within the National Institutes of Health (NIH). Authorization for ARPA-H is also included in the Cures 2.0 bipartisan draft legislation that was released on June 22. The goal of the agency will be to “drive transformational innovation in health research and speed application and implementation of health breakthroughs.”

NIH Director Francis Collins, together with White House Office of Science and Technology Policy (OSTP) Director Eric Lander, OSTP’s Tara Schwetz, and NIH’s Larry Tabak published a commentary in Science outlining how ARPA-H would focus on time-limited projects with goals, benchmarks, and accountability to develop a flexible and nimble strategy for preventing, treating, and curing a range of diseases. The article was followed up with a webinar conducted on June 25, where Collins and Lander answered questions.

ARPA-H is a new model for NIH, which usually supports peer-reviewed fundamental research in university, non-profit, and government labs. Scientists funded by NIH have discovered molecular and cellular mechanisms underlying health and disease, which have led to new clinical treatments. The commentary cites two articles (1,2) showing that fundamental discoveries supported by NIH have been critical for new therapeutics approved by the US Food and Drug Administration. To be sure, the model by which NIH supports fundamental research will not change. But the authors argue that high risk/high yield innovative ideas do not always fit existing NIH support mechanisms — most proposals are directed at solving practical problems.

President Biden stated that ARPA-H should be modeled after the Defense Advanced Research Projects Agency (DARPA) that embraces a nimble, flexible research strategy that accepts failure. The DARPA approach has driven breakthrough advances for the Department of Defense for more than 60 years. Building on DARPA’s success, Collins et al. argue that an initial mission could be, “To make pivotal investments in breakthrough technologies and broadly applicable platforms, capabilities, resources, and solutions that have the potential to transform important areas of medicine and health for the benefit of all patients and that cannot readily be accomplished through traditional research or commercial activity.”  The commentary stresses that those projects supported by ARPA-H would develop solutions that foster breakthroughs to serve patients at levels ranging from the molecular to the societal and to drive those solutions to the point of adoption.

Although an exciting concept for NIH, Collins acknowledges a lot of work and community input are needed to organize this new approach. DARPA can serve as a model, but biological systems are much more complex than the engineered systems on which DARPA focuses. ARPA-H will need to pioneer new approaches.

It is important to note that ARPA-H is to be funded with new appropriations that will not cut into increasing base budgets for NIH’s 27 institutes and centers. And any new medical treatments that come out of ARPA-H will still need to go through the long road of clinical testing and regulatory approvals. Although there is widespread enthusiasm supporting opportunities to improve the way NIH operates, the authors acknowledge that a focus only on short-term results would undermine approaches that have made possible advances to technologies for detecting, treating, and curing diseases.

Permalink: NIH on a Path to Add a DARPA-Like Model

By Terry Magnuson, June 1, 2021

In April, Nature reported on the rules and regulations that U.S. universities and researchers must adhere to when reporting foreign financing and collaborations. While new, these rules do not represent a significant change from the past. U.S. funding agencies have required grantees to report funding from foreign sources for some time. What has changed is that since 2018, penalties — and, in some cases, criminal charges —  have been more frequently imposed on scientists who failed to report foreign activities. Most cases involved funding from the Chinese government, and the arrest or censure of many scientists of Chinese descent. Rightfully so, concerns were expressed by the scientific community that these actions amounted to racial profiling.

In 2019, the National Science and Technology Council (NSTC) launched an effort to clarify and strengthen national policies on research security by issuing a unified set of guidelines for universities to create teams devoted to all aspects of research security, including cybersecurity and export controls. These teams also provide training for faculty members in these areas and those who are considering participating in foreign talent programs that recruit and fund researchers for their expertise. Funding agencies were instructed to establish ways to vet foreign visitors. Along with the NSTC guidelines and memorandum, the National Defense Authorization Act (NDAA) included some broad research security requirements, such as federal agencies must have disclosure rules, and that the Office of Science and Technology Policy (OSTP) must ensure the rules are consistent across agencies.

The NSTC report was issued just days before President Biden was sworn in. On May 28, geneticist Eric Lander was confirmed by the Senate as the next director of OSTP, so follow-through on NSTC guidelines may be getting traction soon. In February, several university groups, including the Association of Public and Land-grant Universities (APLU) and the Association of American Universities, sent a letter to the Biden administration asking for a public comment period to air their views on the report, which is typical before major agency announcements. As of April 5, a response has not been received. It is still unclear how the new administration will approach the concerns of universities and scientists.

Nonetheless, the National Institutes of Health (NIH) has moved ahead and is now asking for copies of contracts or agreements with foreign institutions when applying for or submitting updates on existing grants. The implementation of these changes has been delayed until January 25, 2022. The agency is also requiring scientists to certify by electronic signature that the information submitted in applications about foreign funding is accurate.

Few would argue the importance of preventing foreign espionage and intellectual theft on university campuses. However, universities are speaking out against overly burdensome regulations. In addition, immigration of thousands of students and scholars — which has been critically important to science and innovation — has come under threat in this country. There is no question that immigration of highly skilled scientists increases the economic, intellectual, moral, and public health of this country.

As AAU President Barbara R. Snyder recently stated: “We are pleased that President Biden has proposed a path for the best and brightest from around the world to stay and continue to contribute to our nation after finishing their graduate studies in the United States.” She adds that Congress must act now on implementing long-term immigration reform that will keep home-grown talent while attracting the world’s best and brightest scholars.

I ended last month’s Research Matters with the AAU’s recommendations for strengthening American higher education through opportunity, accountability, equity and inclusion, and safety. With the President’s proposed investment in research and ongoing congressional hearings supporting a stronger research budget, coupled with the acknowledgement of the importance of international science, the research community is ready for a research ramp-up.

Permalink: Foreign Influence, Immigration, and Funding

By Terry Magnuson, May 3, 2021

In 2014, the American Academy of Arts and Sciences published a report entitled, “Restoring the Foundation: The Vital Role of Research in Preserving the American Dream.” The conclusion of the report was that the research enterprise of the United States is at a “critical inflection point.” The trajectory of innovation in this country has been negatively impacted by past, present, and possibly future policy decisions. Innovation and breakthrough discoveries emerge from fundamental, curiosity-driven research in all fields.

In contrast, our corporate system rightfully values a market-driven focus on short-term results, thereby leaving the federal government as the primary funder of fundamental research, which by 2014 had dropped 13 percent from 10 years earlier as a percentage of our nation’s Gross Domestic Product. The report comments on how current funding mechanisms create instability, making it difficult for researchers to set long-term priorities. Three recommendations emerged from the report:

  • secure America’s leadership in science and engineering basic research by providing sustainable federal investments;
  • ensure that the country receives the maximum benefit from federal investment; and
  • regain America’s standing as an innovation leader, which would require a robust national government-university-industry research partnership.

In 2015, business leaders and hundreds of organizations emphasized the academy’s report by issuing further calls to action in a white paper addressed to Congress titled, “Innovation: An American Imperative.” The paper listed desired reforms and urged policy makers to take several actions, with the ultimate goal of renewing federal commitment to scientific discovery. In 2018, an encouraging progress report on the call was issued.

In May 2020, the academy issued a follow-up report to “Restoring the Foundation,” entitled, “The Perils of Complacency: America at a Tipping Point in Science & Engineering.” The report again emphasized that a significant majority of economic growth in the U.S. is attributable to advancements in science and technology, but that there was still a lack of understanding of the indispensability of innovation, competitiveness, and the know-how needed to address societal challenges. The report noted that the country had been through a period where security concerns resulted in significant restrictions on foreign researchers who consistently filled domestic talent gaps in science and engineering. Other countries had become more competitive at attracting research talent. With the acceleration of scientific and technological discoveries being measured in months rather than years, the report asked: “How does the United States compete?”

The report presented several recommendations for accelerating the need for the country to continue as a leader in the pace of innovation and translating discoveries and inventions from laboratory research to products. Industry, understandably, focuses R&D investments on immediate challenges, making it even more important that the federal government accelerate its own investment in research — especially basic research in the fields of science, engineering, medicine, and mathematics. Not every scientific discovery or technological innovation will have its origin in the U.S. Recognition of this fact makes international scientific cooperation absolutely vital. Unless the United States remains a leading contributor to the discovery of new knowledge and has the capacity and the will to translate that knowledge into applications, it will be left behind, isolated, and increasingly disadvantaged in a 21st-century world powered by science and technology.

With renewed national enthusiasm for innovation and research, there are now bright opportunities for prioritization of investment in research and higher education, cultivation of domestic and foreign talent, and productive partnerships between universities, corporations, and the federal government. In December 2020, the Association of American Universities outlined several recommendations to then President-Elect Biden that echoes the imperatives outlined by the American Academies assessment of innovation and research in this country. Now, President Biden’s first budget proposal includes $250 billion for research over the next several years. While the U.S. is sure to face budgetary pressures in the years ahead, a palpable optimism exists within our national research enterprise today.

Permalink: Renewing and Strengthening U.S. Government-University Partnerships

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