Reflections on the National Science Foundation's Understanding the Rules of Life Program Proceedings of a Workshop Series (2023) / Chapter Skim
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3 URoL: Building a Synthetic Cell
Pages 37-49

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From page 37...
... The charge from NSF to researchers submitting the full proposal was as follows: Full proposals derived from the Ideas Lab must include ideas that could lead to a step change, rather than to incremental advances in our knowledge. It is expected that these full proposals will be generated by multidisciplinary teams; the teams may include researchers with expertise in biology, physics, biophysics, mathematical modeling, statistics, chemistry, engineering, computer science, or any other discipline suited to shed light on the topic.
From page 38...
... leads a team of seven PIs who are working to build synthetic structures with the electrical properties of neurons.3 Whereas some members of the group are taking a top-down approach, introducing neuronal ion channels into non-neuronal cells, Liu's project involves building a synthetic neuron from the bottom up, reconstituting the minimum set of ion channels needed to generate an action potential in a cell-free system. Liu uses a HeLa-based cell-free expression system4 to assemble four types of channel proteins (ligand-gated channel and voltage-gated Na+, K+, and Ca+ channels)
From page 39...
... Liu is doing similar work in living cells, expressing ion channels in non-electrically active cells to see whether he can make these cells electrically active, which is an extension of previous work in this field. Liu has been able to change cells' spiking activities by expressing different types of voltage-gated channels.
From page 40...
... in collaboration with Adamala seeks to engineer and produce biomolecules that have mirror chirality to their naturally derived counterparts, with one goal being to chemically synthesize D-proteins and encode D-amino acids at the ribosome. Their long-term vision is to construct synthetic mirror cells whose nucleic acids and proteins exist in the opposite chiral states, creating "an entire mirror system that can coexist almost orthogonally from the natural living world," said Isaacs.
From page 41...
... applies tools of theoretical physics, evolutionary biology, and development to elucidate the constraints that govern the design of bacterial cells and small organisms, by searching for "theories that allow us to take the diversity of life and project those onto simple axes or extract general laws." Kempes described how he turned these efforts to the problem of engineering synthetic cells. Theoretical approaches to the diversity of life tend to fall at either of two extremes, he said, either "everything's the same" when viewed from a broad
From page 42...
... Noting that "a scaling law is really just cell size … to some exponent," he said, the researchers have found strong scaling relationships that relate key physiological and metabolic processes to bacterial cell size. In many cases, they have derived theories to predict the values of these exponents, with organisms "evolving to hard and fast physical constraints … really, it's physics predicting what you should see in the physiology," he said.
From page 43...
... If researchers succeed in demonstrating that the propagation of electrical information can be mediated purely by ion channels -- itself a rule, perhaps -- then they will be in a position to explore this process at a fundamental level. Similarly, by developing a toolkit that enables generation of a strong contractile force ectopically, in a cell that normally does not contract in that way, Elting and colleagues seek to build a system for interrogating the rules of life that govern mechanical force generation: "How can cells generate mechanical force across evolution, and how many different ways have cells evolved to generate mechanical force?
From page 44...
... One rule emerging from his group, said Isaacs, is that the machinery responsible for producing proteins is flexible in its stereoisomeric preference. "I think there's a lot of potential," he said, "to go beyond just what we're talking about in this context and open up a new possibility of repurposing ribosomes to create entirely new kinds of polymers and materials." Adamala concurred, noting "how generalizable the technology is … we're basically learning all the skills and technologies we need, not only for the opposite chirality building blocks but also for all different kinds of unnatural monomers, including different kinds of amino acid chemistries." The researchers' explorations of nonclassical systems of motility and wound repair, including Spirostomum's ATP-independent contractions and Stentor's twisting and folding, have opened up new potential pathways for designing synthetic cells.
From page 45...
... This work revealed that the ratios of ion channels matter more than their absolute concentrations when it comes to shaping spikes, which he suggested may be an emerging rule. MULTIDISCIPLINARY RESEARCH/MULTI-TEAM RESEARCH: EXAMPLES OF CHALLENGES AND STRATEGIES FOR SUCCESS Gaucher asked participants to share examples of particular challenges posed by multidisciplinary research and strategies they used to address them.
From page 46...
... "I think the students do learn a lot about how different science works," he said, noting that "I personally have learned a great deal about thinking about how synthetic cells might benefit society." Elting concurred, noting the "great opportunity for students to really learn how to talk across disciplinary boundaries." "You have to make the effort to understand the other discipline, how they think, what they are interested in," said Noireaux, adding that in his team's case, it has been a very positive experience for both trainees and PIs. NSF contributed significantly to the success of these projects; Ideas Lab activities taught "really helpful skills," said Elting, which she and the other PIs in her group passed on to their trainees.
From page 47...
... Noting that trainees in Adamala's laboratory would email him to propose ideas, share drafts, and ask hard questions, he said, "I think that's a really good sign that the trainees have become invested and feel some ownership over the project." This is also a sign that PIs have created a comfortable environment conducive to such efforts, noted Gaucher. SOCIETAL IMPACT AND SIGNIFICANCE OF WORK Noting that his own synthetic biology research tends to be received with a mixture of awe and terror -- and that how society perceives this work is important -- Wilson asked participants to briefly discuss the significance of their research to society and to address the social issues raised by these innovative projects.
From page 48...
... One long-term societal impact of her project, said Elting, would be to broaden the general understanding of biology across the breadth of the evolutionary tree, beyond its current focus on "a few narrow branches." Technological Advances to Benefit Society Manipulating biological molecules to do unnatural things "lends itself to the development of powerful technologies," said Isaacs, including systems for engineering new types of drugs that could address "long-standing challenges" such as antibiotic resistance and instability. Tang's group is seeking to identify laws regarding wound repair mechanisms, which could be applied to synthetic cells or soft micro-robots, to make them more robust and enable self-repair in harsh environments.
From page 49...
... When communicating about research, it is important to recognize how language can evoke an emotional response in people who lack the scientific context for these words, she said. Social scientists on Liu's team conducted interviews with members of the public to gauge their responses to the development of synthetic neurons.


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