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The Advent and Rise of Monoclonal Antibodies

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The Advent and Rise of Monoclonal Antibodies agreements is only a ceremonial first step; by 2010, and now the Antarctic ozone hole 1. Farman, J. C., Gardner, B. G. & Shanklin, J. D. Nature 315, they must subsequently be ratified and is slowly healing10. The protocol thus pre- 207–210 (1985). 5 19 2. Crutzen, P. J. Q. J. R. Meteorol. Soc. 96, 320–325 (1970). strengthened over time . I believe that Farman vented the ozone layer from collapsing and 3. National Research Council. Causes and Effects of and colleagues’ paper led to the remarkably is a signature success story for global environ- Changes in Stratospheric Ozone: Update 1983 (Natl Acad. fast ratification of the protocol in 1989, and mental policy. Because CFCs have atmospheric Press, 1984). 4. Molina, M. J. & Rowland, F. S. Nature 249, 810–812 (1974). to later amendments (beginning with the lifetimes of 50 years or more, the atmosphere 5. Benedick, R. A. Ozone Diplomacy: New Directions in London Amendment in 1990) that included will not fully recover until after 2050, even Safeguarding the Planet (Harvard Univ. Press, 1998). ever-tightening restrictions on the global pro- in the absence of further emissions. 6. de Zafra, R. L. et al. Nature 328, 408–411 (1987). 20 7. Solomon, S., Mount, G. H., Sanders, R. W. & duction and consumption of ozone-depleting However, recent work provides strong Schmeltekopf, A. L. J. Geophys. Res. Atmos. 92, substances. evidence of the continuing production and 8329–8338 (1987). So why was the ozone hole not seen in com- release of one type of CFC (trichlorofluoro- 8. Anderson, J. G. et al. J. Geophys. Res. Atmos. 94, 11480–11520 (1989). putational simulations of the stratosphere? methane). The source is not large enough to 9. Solomon, S. Nature 347, 347–354 (1990). It turned out that the models lacked a key reverse the healing of the ozone hole, but it 10. World Meteorological Organization. Scientic Assessment ingredient: by considering only gas-phase is slowing recovery and shows that there is of Ozone Depletion: 2018 – Report No. 58 (WMO, 2018). 11. Solomon, S., Garcia, R. R., Rowland, F. S. & Wuebbles, D. J. atmospheric chemistry, they overlooked still a need for scrutiny in this field. Research Nature 321, 755–758 (1986). the activation of ozone-destroying chlo- into, and policy to protect, the strato sphere 12. Tolbert, M. A., Rossi, M. J., Malhotra, R. & Golden, D. M. rine species that occurs on and within polar will thus continue to be inspired by Farman Science 238, 1258–1260 (1987). 13. Ravishankara, A. R. & Hanson, D. R. J. Geophys. Res. stratospheric cloud particles at extremely and colleagues’ research — and will probably Atmos. 101, 3885–3890 (1996). 11,12 low temperatures . The discovery of the do so until the ozone hole finally closes. 14. Peter, T. & Groos, J.-U. in Stratospheric Ozone Depletion missing ingredient drew physical chemists and Climate Change (ed. Muller, R.) Ch. 4, 108–144 (R. Soc. Chem., 2011). in increasing numbers to study the surface Susan Solomon is in the Department of 15. Pyle, J. A. et al. Geophys. Res. Lett. 21, 1191–1194 (1994). 13 chemistry involved . Previously unknown gas- Earth, Atmospheric and Planetary Sciences, 16. Frieler, K. et al. Geophys. Res. Lett. 33, L10812 (2006). phase reactions associated with ozone deple- Massachusetts Institute of Technology, 17. Eyring, V. et al. Atmos. Chem. Phys. 10, 9451–9472 (2010). 18. Thompson, D. W. J. et al. Nature Geosci. 4, 741–749 (2011). tion were also identified, particularly those Cambridge, Massachusetts 02139, USA. 19. Newman, P. A. Atmos. Chem. Phys. 9, 2113–2128 (2009). involving a ClO dimer (see ref. 10, for example). e-mail: [email protected] 20. Montzka, S. A. et al. Nature 557, 413–417 (2018). Laboratory and field studies were carried out, and microphysical models were developed Immunology (see ref. 14, for example), to determine what polar stratospheric clouds are made of: ice, nitric acid hydrates or supercooled liquids. The answer was that they could be all three, The advent and rise of depending on temperature and the histories of the sampled air parcels. monoclonal antibodies Ground-based and airborne missions to 15 understand Arctic ozone chemistry were also Klaus Rajewsky inspired by Farman and colleagues’ paper and related studies. It emerged that ozone loss in A 1975 Nature paper reported how cell lines could be made the Arctic is generally much less severe than in that produce an antibody of known specificity. This discovery the Antarctic, broadly because temperatures led to major biological insights and clinical successes in in the region are warmer as a result of meteor- ological differences between the two regions. treating autoimmunity and cancer. The coupling of chlorine-containing species with bromine-containing ones was found to be a key ingredient in polar ozone depletion, In their 1975 Nature paper1, the immunologists their wide range of specificities, essentially especially in the Arctic16. Georges Köhler and César Milstein described covering the universe of chemical structures. Atmospheric modelling also progressed the production of monoclonal antibodies of This had stood out from early on as a major to simulate the newly discovered processes, predetermined specificity, each made by a genetic puzzle. How can our limited genome evolving from two dimensions (latitude– continuously growing cell line that had been encode a seemingly limitless repertoire of altitude) to three (latitude–altitude–longi- generated by the fusion of an antibody-pro- specificities? And in medical (and industrial) tude), to better represent global stratospheric ducing cell from an immunized mouse with practice, antibodies have been used ever since temperatures, winds and circulation17. Dynam- an immortal cancer cell specialized for anti- their discovery as the basis for serum therapy ical studies have shown that the ozone hole body secretion. Hearing from César about (the treatment of infectious diseases using influences Antarctic winds and temperatures this work before it was published, on the way blood serum from immunized animals), as not just in the stratosphere, but also in the to an obscure meeting in San Remo in Italy, I diagnostic tools to monitor infectious disease, underlying troposphere, and there is evidence knew immediately that our research field had and in innumerable other contexts. for climate connections at other latitudes18. reached a turning point. But antibodies specific for any given mol- Modern global climate models therefore Antibodies were discovered in 1890 by the ecule (called an antigen in the context of an include increasingly detailed representations physiologist Emil von Behring and the micro- antibody response) came, with a few notable of stratospheric chemistry and dynamics. The biologist Shibasaburo Kitasato as protective exceptions, as mixtures of antibodies, pro- ozone hole has thus inspired a new generation antitoxins in the blood of animals exposed to duced by thousands of antibody-producing of scientists to probe climate–chemistry diphtheria or tetanus toxin2. Ever since, anti- cells in an immunized animal or infected inter actions, forging connections between bodies have been a major research subject, person. Each of these cells produced an previously separate disciplines. given their key role in adaptive immunity antibody of its own kind, so that ‘antibody The Montreal Protocol led to global CFC (specific immune responses against, for exam- specificity’ usually referred to the properties production and consumption phase-outs ple, invading disease-causing agents) and of antibody populations rather than those Nature | Vol 575 | 7 November 2019 | 47 ©2019 Spri nger Nature Li mited. All ri ghts reserved. ©2019 Spri nger Nature Li mited. All ri ghts reserved. 10 extraordinary papers The impact of the Köhler–Milstein paper on biomedical and, specifically, immuno- Sheep red blood cells logical research was dramatic, propelled by Monoclonal antibody scientific developments that occurred around specific for sheep Spleen red blood cells the time the paper appeared. Thus, it became clear shortly afterwards that the variable and constant regions of antibodies are encoded by separate gene segments. Antibody diver- Antibody An antibody-producing spleen cell and a Addition of sity arises when somatic recombination joins myeloma cell fuse to sheep red create a hybridoma cell blood cells gene segments together, and when a subse- + quent process called somatic hypermutation operates, during the course of the antibody response, on the recombined gene segments Antibody- Myeloma cells producing Cells arising from a encoding antibody variable regions. Together, spleen cells single hybridoma cell these mechanisms generate a vast repertoire of antibody specificities, as well as distinct Figure 1 | The production of monoclonal antibodies. Köhler and Milstein’s 1975 Nature paper1 solved classes of antibody, which mediate their the problem of how to generate clones of continuously dividing cells that make antibodies of a known various roles (effector functions) through specificity. The ability to generate such monoclonal antibodies revolutionized antibody research and their differing constant regions. paved the way to clinical advances. The authors injected mice with sheep red blood cells and isolated spleen These insights were accompanied by the cells, including those that produce antibodies. Different antibody colours indicate antibodies specific explosive development of new molecular and for different molecules (antigens), and produced by different cells. The authors had the
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