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Argument Technology for Debating with Humans generate double-strand breaks (DSBs) in specifically impairs the interferon response. Nandhitha Uma Naresh and Cole M. Haynes mtDNA. They used RNA sequencing to analyse The study highlights an immunostimu- are in the Department of Molecular, Cell and changes in gene expression in cells treated latory role for mtRNA. However, questions Cancer Biology, University of Massachusetts with mTLNs, and found increased transcrip- remain. For instance, mtRNA molecules are Medical School, Worcester, Massachusetts tion of nuclear genes involved in the innate highly unstable in nature11 — how are mtRNAs 01605, USA. immune response; these included inter- stabilized so that they accumulate in the cyto- e-mail: [email protected] feron-response genes, which are typically sol, as was observed in the current study? involved in combating viral infections. The Another avenue for further investigation is 1. Shpilka, T. & Haynes, C. M. Nature Rev. Mol. Cell Biol. 19, authors also found that the transcription the factors that stimulate the formation of 109–120 (2018). factor STAT1 was modified by phosphate BAK–BAX pores following mtDNA breaks. It 2. Guo, X. et al. Nature 579, 427–432 (2020). groups and relocated to the nucleus — a key would be of broad interest to study whether 3. Tigano, M., Vargas, D. C., Tremblay-Belzile, S., Fu, Y. & 8 Sfeir, A. Nature 591, 477–481 (2021). part of the interferon response . drugs that inhibit this pore formation can 4. McArthur, K. et al. Science 359, eaao6047 (2018). Breaks in mtDNA that occur through suppress an inflammatory immune response. 5. White, M. J. et al. Cell 159, 1549–1562 (2014). other means, such as treatment with toxic, The discovery of a mechanism by which cells 6. West, A. P. et al. Nature 520, 553–557 (2015). 7. Dhir, A. et al. Nature 560, 238–242 (2018). DNA-damaging agents or errors in replication, recognize self-RNAs from mitochondria to 8. Majoros, A. et al. Front. Immunol. 8, 29 (2017). often lead to compromised organelle func- initiate an immune response also raises the 9. Alexeyev, M., Shokolenko, I., Wilson, G. & LeDoux, S. tion9. But Tigano and colleagues found that question of whether this pathway might be Cold Spring Harb. Perspect. Biol. 5, a012641 (2013). 10. Rehwinkel, J. & Gack, M. U. Nature Rev. Immunol. 20, the mTLN treatment reduced the number of involved in autoimmune disease. Finally, it 537–551 (2020). mtDNAs by only around 60%, which did not would be exciting to explore whether artifi- 11. Borowski, L. S., Dziembowski, A., Hejnowicz, M. S., seem to have an immediate impact on mito- cially induced mtDNA damage could be used Stepien, P. P. & Szczesny, R. J. Nucleic Acids Res. 41, 1223–1240 (2013). chondrial function. The group observed no to increase the efficacy of targeted immuno- changes in key indicators of normal mitochon- therapies for cancer. This article was published online on 24 February 2021. drial function, such as morphology, the gradi- + ent of protons (H ions) across the membrane, Artificial intelligence and the generation of reactive oxygen species. These data indicate that mtDNA cleavage is a key trigger of antiviral responses. Next, Tigano et al. set out to identify the Argument technology signalling molecules that relay the message of mtDNA instability to the nucleus. Although the for debating with humans mTLN-treated cells had intact mitochondrial function and were not apoptotic, the group Chris Reed showed that BAK–BAX pores did form on the membrane, consistent with mitochondrial A fully autonomous computer system has been developed herniation. The authors found that mtRNA — that can take part in live debates with people. The findings hint but not mtDNA — accumulated in the cytosol at a future in which artificial intelligence can help humans to of these cells. The mtRNA molecules were detected by an RNA-sensing protein called RIG- formulate and make sense of complex arguments. See p.379 I, which is better known as a sensor of viral RNA in the cytosol10. Working with its adaptor pro- tein on the mitochondrial outer membrane, The study of arguments has an academic pedi- maturity in the engineering of argument dubbed mitochondrial antiviral signalling gree stretching back to the ancient Greeks, and technology, coupled with intense commer- (MAVS), RIG-I triggers a signalling pathway spans disciplines from theoretical philosophy cial demand, has led to rapid expansion of the that activates interferon-response genes in to computational engineering. Developing field. More than 50 laboratories worldwide are the nucleus10. These findings point to a frame- computer systems that can recognize argu- working on the problem, including teams at all work by which cells engage mitochondrial ments in natural human language is one of the large software corporations. signalling molecules in immune-surveillance the most demanding challenges in the field of One of the reasons for the explosion of work mechanisms (Fig. 1). artificial intelligence (AI). On page 379, Slonim in this area is that direct application of AI sys- DNA-damaging agents such as radiation, et al.1 report an impressive development in this tems that can recognize the statistical regular- which is used to treat cancer, elicit a systemic field: Project Debater, an AI system that can ities of language use in large bodies of text has immune response that is thought to be driven engage with humans in debating competi- been transformative in many applications of AI by DNA damage in the nucleus. Tigano and tions. The findings showcase how far research (see ref. 3, for example), but has not, on its own, colleagues found that radiation depleted in this area has come, and emphasize the been as successful in argument mining. This is mtDNA numbers by 40% and elicited the same importance of robust engineering that com- because argument structure is too varied, too immune response as mTLNs, suggesting that bines different components, each of which complex, too nuanced and often too veiled DSBs occur in mtDNA as well as in nuclear handles a particular task, in the development to be recognized as easily as, say, sentence DNA following irradiation. Strikingly, induc- of technology that can recognize, generate structure. Slonim et al. therefore decided to tion of the interferon response during irradi- and critique arguments in debates. initiate a grand challenge: to develop a fully ation was nearly completely abrogated in cells Less than a decade ago, the analysis of autonomous system that can take part in live lacking mtDNA. This observation indicates human discourse to identify the ways in debates with humans. Project Debater is the that mtDNA damage caused by radiation can which evidence is adduced to support con- culmination of this work. be a driver of interferon responses. Of note, clusions — a process now known as argument Project Debater is, first and foremost, the induction of several other innate immune mining2 — was firmly beyond the capabilities a tremendous engineering feat. It brings responses still occurred in cells lacking of state-of-the-art AI. Since then, a combina- together new approaches for harvesting mtDNA, suggesting that depletion of mtDNA tion of technical advances in AI and increasing and interpreting argumentatively relevant Nature | Vol 591 | 18 March 2021 | 373 ©2021 Spri nger Nature Li mited. All ri ghts reserved. ©2021 Spri nger Nature Li mited. All ri ghts reserved. News & views humans7,8. The problem is that humans are not at all good at that task, precisely because it is artificially engineered. In open discussions, a given stretch of discourse might be a claim in one context and a premise in another. Moreover, in the real world, there are no clear boundaries that delimit an argument: discourses that happen beyond debating chambers are not discrete, but connect with a web of cross-references, analogy, exempli- fication and generalization. Ideas about how such an argument web might be tackled by AI have been floated in theory9 and implemented using software — a system called DebateGraph (see go.nature.com/30g2ym4), for example, /REDUX/EYEVINE is an Internet platform that provides compu- NYT tational tools for visualizing and sharing com- plex, interconnected networks of thought. However, the theoretical challenges and JASON HENRY/ JASON socio-technical issues associated with these Figure 1 | Project Debater takes on a human opponent. Slonim et al.1 have developed Project Debater, an implementations are formidable: designing AI system that can take part in debating competitions with humans. compelling ways to attract large audiences to such systems is just as difficult as design- material from text with methods for repair- is that it struggles to emulate the coherence ing straightforward mechanisms that allow ing sentence syntax (which enable the system and flow of human debaters — a problem asso- them to interact with these complex webs of to redeploy extracted sentence fragments ciated with the highest level at which its pro- argument. when presenting its arguments; the role of cessing can select, abstract and choreograph Project Debater is a crucial step in the their syntax-repair technology is modestly arguments. Yet this limitation is hardly unique development of argument technology and underplayed by the authors). These compo- to Project Debater. The structure of argument in working with arguments as local phenom- nents of the debater system are combined is still poorly understood, despite two millen- ena. Its successes offer a tantalizing glimpse with information that was pre-prepared by nia of research. Depending on whether the of how an AI system could work with the web humans, grouped around key themes, to focus of argumentation research is language of arguments that humans interpret with such provide knowledge, arguments and counter- use, epistemology (the philosophical theory apparent ease. Given the wildfires of fake news, arguments about a wide range of topics.
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