Edited by Jennifer Sills

Germline gene therapy: We’re ready


RECENTLY, CHINESE researchers attempted

to modify embryos using “germline gene therapy.” If successful, this technique would create a heritable change and affect future generations, were those embryos to be used (1). A firestorm in the scientific community followed, with some researchers calling for an absolute ban on attempts to treat even lethal diseases with germline gene therapy. D. Baltimore, P. Berg, and a group of “interested stakeholders” met to discuss the issue and concluded: “At present, the potential safety and efficacy issues arising from the use of this technology must be thoroughly investigated and understood before any attempts at human engineering are sanctioned, if ever, for clinical testing” (“A prudent path forward for genomic engineering and germline gene modification,” D. Baltimore et al., Perspectives, 3 April, p. 36; published online 19 March). With apparent nostalgia, Baltimore et al. noted that the group “included some of the leaders in the original 1970s discussions about recombinant DNA research at Asilomar and elsewhere.” Many in the biomedical community do not regard the Asilomar experience as a success (2, 3). It exaggerated the potential risks of recombinant DNA technology, modern biotechnology’s core technique; gave rise to a years-long research moratorium; and

induced NIH to draft and promulgate “biosafety” guidelines. Those process-based guidelines, which were focused on the use of a single technique instead of on the risks of experiments, have plagued genetic engineering research ever since: Although NIH pared back the stringency of its guidelines, stultifying process-based approaches to regulation have remained at other federal agencies (4). A moratorium would once again be misguided, as are the arguments of those who advocate it. In his Letter “Eugenics lurk in the shadow of CRISPR” (22 May, p. 871), R. Pollack invokes abstract concerns about “eugenics,” showing remarkable insensitivity to the current suffering of patients with horrific genetic diseases. Rudolf Jaenisch, a biology professor at the Massachusetts Institute of Technology, has argued that gene editing is unethical for diseases such as Huntington’s (5), which is genetically dominant, meaning that only one defective gene copy causes the disease and only half of the parents’ embryos will inherit it. Jaenisch objects because the editing procedure must begin before we know whether the embryo has the Huntington’s gene, posing the unacceptable risk of altering a normal embryo. However, Jaenisch has knocked down a straw man. Nobody is proposing to modify normal embryos in the foreseeable future. An appropriate—and, indeed, compelling—application would be to correct the debilitating and ultimately lethal sickle cell anemia. In genetics terms, sickle cell anemia is an autosomal recessive disease, which means that every one of a patient’s chromosomes carries a defective gene (unlike Huntington’s disease). The sickle cell gene bears a mutation in one nucleotide of DNA, which in turn gives rise to a single amino

acid substitution in one discrete location of the protein chains of hemoglobin. Unlike Huntington’s disease, 100% percent of the offspring of two parents with sickle cell disease will be afflicted with the disease. The repair of this sort of molecular lesion has been performed successfully in animals for decades. Shouldn’t 21st-century medicine offer the possibility of repairing embryos that will become patients with sickle cell disease, and eliminate the disease from future generations? Technologies are seldom successful right out of the gate, but the concept of “perfecting” a technology seems to have eluded Harvard stem-cell researcher George Q. Daley, who recently said about germline gene therapy, “This is an unsafe procedure and should not be practiced at this time, and perhaps never” (5). Never? Maybe it has been a while since Dr. Daley has seen a patient like one I remember well—a 20-yearold with sickle cell anemia who had suffered three strokes, been crippled by hemorrhages into his major joints, and was in unrelenting pain from the arthritis that resulted. Germline gene therapy should be used sparingly and with scrutiny, to be sure, but we don’t need a moratorium. We do need to push the frontiers of medicine to rid families of monstrous genetic diseases. Henry I. Miller Robert Wesson Fellow in Scientifc Philosophy and Public Policy, Hoover Institution, Stanford University, Stanford, CA 94305, USA. E-mail: [email protected] stanford.edu REFERENCES

1. The Economist,“To the crack of doom” (2 May 2015); www.economist.com/news/ science-and-technology/21649607-scientists-china-havejust-crossed-one-biotechnologys-red-lines-crack. 2. DNA Learning Center,“Initial feelings on Asilomar meeting, James Watson” (www.dnalc.org/view/15423-Initialfeelings-on-Asilomar-meeting-James-Watson.html). 3. “Trying to Bury Asilomar,”James Watson Papers (1978); http://wellcomelibrary.org/player/b19847051#?asi=0&ai= 7&z=0%2C0.1956%2C1.0001%2C0.8925. 4. D. L. Kershen, H. I. Miller, Iss. Sci. Technol. XXXI, 2 (2015); http://issues.org/31-2/miller-5/. 5. G. Kolata,“Chinese scientists edit genes of human embryos, raising concerns,” The New York Times (23 April 2015); www. nytimes.com/2015/04/24/health/chinese-scientists-editgenes-of-human-embryos-raising-concerns.html.

Research ethics and health care reform A. FINKELSTEIN AND S. Taubman report on

Sickle cell anemia.

SCIENCE sciencemag.org

the underuse of randomized controlled trials for U.S. health care reform (“Randomize evaluations to improve health care delivery” Policy Forum, 13 February, p. 720). This reliance on suboptimal research compromises information needed for policy. However, a second problem about health reform decision-making is more serious, 19 JUNE 2015 • VOL 348 ISSUE 6241

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constituting a major ethical breach. The principles of research with humans require that deviations from the standard of care are allowable only if there is real uncertainty regarding which intervention is better. This is called the “principle of equipoise”; only when we don’t know which strategy yields the best results is it acceptable to compare them (1). Yet for health care reform writ large—i.e., the basic payment system—there is no equipoise. Research from dozens of developed countries demonstrates convincingly that single-payer financing reduces costs, assures access, and improves outcomes (2, 3). To ignore this compelling evidence risks lives in the United States as we experiment with partial fixes to the multi-payer system. This experimentation would be rejected by any responsible university institutional review board as violating the principle of equipoise and causing unacceptable patient harm. James G. Kahn1* and Paul Hofmann2 1

University of California, San Francisco, San Francisco, CA 94104, USA. 2Moraga, CA 94556, USA. *Corresponding author. E-mail: [email protected]


1. B. Freedman, N. Engl. J. Med. 317, 141 (1987). 2. K. Davis, K. Stremikis, D. Squires, C. Schoen, “Mirror, Mirror on the Wall, 2014 Update: How the U.S. Health Care System Compares Internationally” (The Commonwealth Fund, 2014); www.commonwealthfund.org/publications/ fund-reports/2014/jun/mirror-mirror. 3. World Health Organization,“The World Health Report 2000; Health Systems: Improving Performance” (WHO, Geneva, 2000).

Spitzer’s stellar work IN THE NEWS Feature “After Hubble” (24

April, p. 388), D. Clery inappropriately characterizes the Spitzer Space Telescope as “now largely blind.” In fact, Spitzer is alive and well and continuing to make substantial contributions to the advancement of astrophysics and to scientific preparations for the James Webb Space Telescope (JWST). The exhaustion of Spitzer’s cryogen in mid-2009 left the observatory with two functioning imaging arrays at wavelengths of 3.6 and 4.5 μm. The performance of what is now called “Warm” Spitzer at these wavelengths matches that achieved during the cryogenic mission. Despite its small size, Spitzer is by far the most sensitive telescope, space or ground, available at these wavelengths. The science community has used Warm Spitzer for important scientific investigations, including studies of exoplanets, the early universe, variable stars to define better the cosmic distance ladder, clusters of galaxies, near-Earth asteroids, and comets. Spitzer remains very much in demand; for the past 1326

2 years, the oversubscription for requested observing time has been the highest of the mission. Much of the Spitzer work anticipating JWST is done jointly with the Hubble Space Telescope (HST). To take just one example, the two telescopes together are carrying out a “Frontier Fields” imaging study of half a dozen dense clusters of galaxies, using their gravitational lensing properties to uncover distant galaxies seen as they were when the universe was less than 5% of its current age. The two observatories work together to determine the distance, stellar masses, and stellar ages of these objects; neither HST nor Spitzer could do this alone. Galaxies studied by HST and Spitzer in the distant universe are faint enough to be challenging—but important—targets for spectroscopic study from JWST. These targets will allow JWST to begin spectroscopy at the start of the mission without awaiting results from its own survey programs. Lastly, Spitzer has been an important technical and engineering pathfinder for JWST. In particular, Spitzer successfully pioneered the passive, radiative cooling that allows it to remain very cold and thus highly sensitive even without stored cryogen, and which is essential for the success of JWST. We indeed celebrate the significance and success of HST. However, we feel that Spitzer has been and will continue to be a vital collaborator with HST in establishing the scientific landscape for JWST. M. W. Werner,1* B. T. Soifer,2 L. Storrie Lombardi,2 G. Helou2 1 Spitzer Space Telescope, Jet Propulsion Laboratory/ California Institute of Technology, Pasadena, CA 91109, USA. 2Spitzer Science Center, California Institute of Technology, Pasadena, CA 91125, USA.

*Corresponding author. E-mail: [email protected]

TECHNICAL COMMENT ABSTRACTS Comment on “Early Homo at 2.8 Ma from Ledi-Geraru, Afar, Ethiopia” John Hawks, Darryl J. de Ruiter, Lee R. Berger

Villmoare et al. (Reports, 20 March 2015, p. 1352) report on a hominin mandible from the Ledi-Geraru research area, Ethiopia, which they claim to be the earliest known representative of the genus Homo. However, certain measurements and observations for Australopithecus sediba mandibles presented are incorrect or are not included in critical aspects of the study. When correctly used, these data demonstrate that specimen LD 350-1 cannot be unequivocally assigned to the genus Homo. Full text at http://dx.doi.org/10.1126/science. aab0591

Response to Comment on “Early Homo at 2.8 Ma from Ledi-Geraru, Afar, Ethiopia” Brian Villmoare, William H. Kimbel, Chalachew Seyoum, Christopher J. Campisano, Erin DiMaggio, John Rowan, David R. Braun, J. Ramon Arrowsmith, Kaye E. Reed

Hawks et al. argue that our analysis of Australopithecus sediba mandibles is flawed and that specimen LD 350-1 cannot be distinguished from this, or any other, Australopithecus species. Our reexamination of the evidence confirms that LD 350-1 falls outside of the pattern that A. sediba shares with Australopithecus and thus is reasonably assigned to the genus Homo. Full text at http://dx.doi.org/10.1126/science. aab1122

Comment on “Missing gas-phase source of HONO inferred from Zeppelin measurements in the troposphere” Chunxiang Ye, Xianliang Zhou, Dennis Pu, Jochen Stutz, James Festa, Max Spolaor, Christopher Cantrell, Roy L. Mauldin, Andrew Weinheimer, Julie Haggerty

Li et al. (Reports, 18 April 2014, p. 292) proposed a unity nitrous acid (HONO) yield for reaction between nitrogen dioxide and the hydroperoxyl-water complex and suggested a substantial overestimation in HONO photolysis contribution to hydroxyl radical budget. Based on airborne observations of all parameters in this chemical system, we have determined an upper-limit HONO yield of 0.03 for the reaction. Full text at http://dx.doi.org/10.1126/science. aaa1992

Response to Comment on “Missing gas-phase source of HONO inferred from Zeppelin measurements in the troposphere” Xin Li, Franz Rohrer, Andreas Hofzumahaus, Theo Brauers, Rolf Häseler, Birger Bohn, Sebastian Broch, Hendrik Fuchs, Sebastian Gomm, Frank Holland, Julia Jäger, Jennifer Kaiser, Frank N. Keutsch, Insa Lohse, Keding Lu, Ralf Tillmann, Robert Wegener, Glenn M. Wolfe, Thomas F. Mentel, Astrid KiendlerScharr, Andreas Wahner

Ye et al. have determined a maximum nitrous acid (HONO) yield of 3% for the reaction HO2·H2O + NO2, which is much lower than the yield used in our work. This finding, however, does not affect our main result that HONO in the investigated Po Valley region is mainly from a gas-phase source that consumes nitrogen oxides. Full text at http://dx.doi.org/10.1126/science. aaa3777 sciencemag.org SCIENCE

19 JUNE 2015 • VOL 348 ISSUE 6241

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Research ethics and health care reform.

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