The National Science Foundation’s Big Idea on Understanding the Rules of Life

In 2016, the National Science Foundation (NSF) unveiled a set of “Big Ideas”—10 bold, long-term questions to drive NSF’s research agenda and support its critical role in establishing U.S. leadership in science and engineering by creating innovations that drive the nation’s economy while educating the next generation of scientists and engineers. These Big Ideas define a set of cutting-edge research agendas and processes that bring together a diverse array of scientific disciplines, employing innovative approaches to solve some of the most pressing problems the world faces. One of NSF’s Big Ideas addresses what is perhaps the most significant gap in biological knowledge, which is our inability to predict an organism’s observable characteristics—its phenotype—from what is known about its genetic makeup and the nature of its environment. Many factors influence the traits of an organism, making this prediction extremely complex. To unravel these dynamics, NSF has undertaken an initiative that requires convergence of research across multiple disciplines. That initiative, Understanding the Rules of Life (URoL), seeks to develop a predictive understanding of how key properties of living systems emerge from dynamic interactions operating on multiple levels, including genomic,¹ epigenomic, metabolomic, organismal, and environmental.

Projects funded under the URoL initiative seek to identify “rules” operating at multiple levels by addressing fundamental questions in life sciences that cross different scales (spatial, temporal, or levels of biological organization); that produce broadly generalizable results to permit formulating a “rule”; and that enable prediction of change in biological systems. Additional goals of the URoL initiative include training the next generation of researchers to work across scales and scientific disciplines, building the capacity to approach increasingly complex questions in the life sciences, and fostering the collaboration and convergent research necessary to accomplish its scientific aims. Since its establishment, the URoL initiative has issued eight program announcements: Understanding the Rules of Life: Building a Synthetic Cell (2018); Understanding the Rules of Life: Epigenetics (2018 and 2019); Understanding the Rules of Life: Microbiome Theory and Mechanisms (2019); Understanding the Rules of Life: Microbiome Interactions and Mechanisms (2020); Understanding the Rules of Life: Emergent Networks (two in 2021); and Using the Rules of Life to Address Societal Challenges (2022) (see Figure T-1).²

To assess the progress of research funded under the URoL program NSF requested the National Academies of Sciences, Engineering, and Medicine (the National Academies) to conduct a retrospective review of the URoL program. The Statement of Task is provided in Box T-1.

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¹ These terms encapsulate various levels at which biological systems operate, starting with the genetic information encoded within an organism’s DNA (genomics) and moving up through increasing levels of complexity to include stable but reversible changes that alter how the information in DNA is expressed (epigenetics), the products that cells generate through metabolism (metabolomics), the interactions that underlie the structure, function, and diversity of entire organisms (organismal), and the interactions between populations of organisms and their habitats (environmental).

² Factual errors in the information provided to the workshop participants was corrected between the prepublication and final version of the proceedings.

As of December 2022, $86 million had been awarded under this program for the study of 63 biological systems, at levels of resolution ranging from the molecular to organismal to ecosystem. Principal investigators (PIs) represent 79 unique institutions, including six minority-serving institutions, distributed over 35 states. Of the 60 projects begun to date, 21 have been completed or are in their final year (see Figures T-2 and T-3).

As described by planning committee member Connie J. Mulligan (University of Florida), these virtual workshops aimed to develop a picture of scientific advancements and rules of life that were beginning to emerge from the funded projects; to learn how research groups incorporated multidisciplinary, systems-level approaches into their work, and how this informed findings and contributed to achievements; to identify opportunities for exploration through which future societal needs and scientific questions might be addressed by the URoL program; and to identify rules of life generalizable across fields and scales.

This workshop proceedings is the rapporteur’s summary of all four workshops, including moderated discussions with PIs, material submitted in writing from PIs prior to the workshop (including from several PIs who could not participate in the live discussions), and comments submitted by audience members via an online chat function. This proceedings summarizes discussions from a workshop series that focused on identifying “rules” or common principles identified by URoL researchers in three specific areas (epigenetics, microbiome, and synthetic cell) and highlighting principles that might apply across scales and systems. This proceedings also summarizes the discussions about societal benefits from URoL-funded research, education and training of next generation scientists, and strategies for successful multidisciplinary research. The National Academies staff reached out to all PIs and co-PIs of URoL-funded projects with assistance from NSF. For workshop planning purposes, URoL PIs and co-PIs were invited to respond to a set of initial questions, via an online questionnaire³ or a Zoom call with a National Academies staff member. After the dates for the field-specific (epigenetics, microbiome, and synthetic cell) and cross-cutting workshops were selected, the PIs or co-PIs were invited to serve as workshop participants. Some PIs agreed to participate, however, if they were unable to attend, their co-PI or one of their collaborators or students agreed to attend on their project team’s behalf. All participants were asked to provide responses to additional questions in preparation for the workshops. Information about the URoL program, responses to the initial set of questions and to the pre-workshop questions, which were presented at the beginning of each of the field-specific workshops and the cross-cutting workshop, provided the basis for discussion. Notification about the workshops were sent to NSF, all URoL PIs and co-PIs, and the broader scientific community to provide opportunities for interaction and engagement. This proceedings summarizes all the information provided to the National Academies that was presented and discussed during the workshop. The views of URoL researchers who did not respond to any of the questions or participate in any of the workshops are not included in this proceedings. Finally, this proceedings has been written for a technical audience, particularly NSF, URoL researchers, and others in the broader scientific community. Workshop agendas are provided in Appendix A, biographical sketches of workshop planning committee members and workshop participants are provided in Appendix B, and URoL-funded projects are listed in Appendix C. All webcasts have been archived online.⁴

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³ See https://survey.alchemer.com/s3/6989059/PI-Questionnaire-URoL.

⁴ See https://www.nationalacademies.org/our-work/understanding-the-rules-of-life-program-scientific-advancements-and-future-opportunities---a-workshop-series (accessed January 31, 2023).