SCHATTEN.Pptx

Should we be alarmed that designer babies walk among us?

PROFESSOR GERALD SCHATTEN UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE [email protected] Should we be alarmed that designer babies walk among us?

YES, URGENTLY… THOUGH NOT FOR THE OBVIOUS REASONS

PROFESSOR GERALD SCHATTEN UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE [email protected]

11/7/2019 Genetically Modified People Are Walking Among Us - The New York Times

NEWS ANALYSIS Genetically Modified People Are Walking AmongUs And, so far, theyʼre just fine. America needs a sober debate about the pros and cons of Crispr instead of a paranoid ban on the technology.

By Carl Zimmer Mr. Zimmer is a science columnist for The New York Times.

Dec. 1, 2018

It felt as if humanity had crossed an important line: In China, a scientist named He Jiankui announced on Monday that twins had been born in November with a gene that he had edited when they were embryos.

But in some ways this news is not new at all. A few genetically modiﬁed people already walk among us.

In the mid-1990s, fertility doctors in New Jersey got an idea for how to help women have children. They suspected that some women struggled to become pregnant because of defective material in their eggs.

To rejuvenate them, the doctors drew off some of the jellylike ﬁlling in eggs donated by healthy women and injected itinto the eggs of their patients before performing in vitro fertilization.

The researchers did not ask the Food and Drug Administration for permission to try out the procedure. Only after their patients started having healthy children did they share the news that it seemed to work. Once the word gotaround, would- be parents streamed into clinics to try the procedure themselves.

https://www.nytimes.com/2018/12/01/sunday-review/crispr-china-babies-gene-editing.html?action=click&module=RelatedLinks&pgtype=Article

ETTERS Letters to the Editor L Letters (~300 words) discuss material published in Science in the previous 6 months or issues of general interest. They can be submitted by Cloning Claim Is Science ered by some to be either irreproducible or e-mail ([email protected]), the Web worse. However, scientific rigor has con- (www.letter2science.org), or regular mail Fiction, Not Science firmed and extended somatic cell nuclear (1200 New York Ave., NW, Washington, transfer to seven species, and previously FANTASTIC CLAIMS OF BIRTHS OF CLONED unorthodox concepts are now being inten- babies have recently been made in the sively investigated. Infertility therapies, media. In the absence of any evidence for already responsible for the birth of more these claims, this destructive hoax must end. than 1 million babies, are blurring the pre- Suspicion is an appropriate reaction viously strict distinction between funda- because Clonaid, the company making mental developmental biology and clinical reproductive technologies bring precious these claims, has not described any labora- reproductive medicine. gifts to the infertile. Stem cell therapies for tory and clinical facilities,skilled person- Certainly in the United States, bioethi- devastating diseases are envisioned. The nel, proof of specialized knowledge, or cal deliberations are barely keeping abreast scientific and medical potential of stem prior accomplishments. of medical innovations. Against this back- cells derived after nuclear transfer should Legitimate scientists submit evidence, ground, self-described human cloners were not be ignored, because they may over- sufficiently substantial to withstand rigor- invited to speak to the National Academy come immune incompatibilities—although ous expert review, to be considered for of Sciences (NAS), the U.S. Senate, and

an ethical consensus on using human Downloaded from publication in reputable journals. For the media. Perhaps giving them such embryonic stem cells is difficult to Clonaid’s offspring claims (of which there prominence was, in retrospect, unwise. achieve, even among the three authors of are now two, with another three births said From safety considerations alone, human this letter. to be imminent), minimum requirements reproductive cloning is unwarranted because This appalling episode diverts our atten- include one table—summarizing oocyte animal cloning so far results in high rates of tionDC from20005weighty, USA)deliberations. Letters areregardingnot

numbers; success rates after enucleation, humanacknowledgedeggs ex uponuteroreceipt,. The currentnor aremediaauthorscir- http://science.sciencemag.org/ http://science.sciencemag.org/ after nuclear fusion or injection, and after cusgenerallymight beconentertaining- sulted beforewere itpublicationnot for the. oocyte activation; and data on pre- and potentiallyWhether publisheddestructivein fullconsequencesor in part, lettersforarenas- postimplantation development—and one In the absence of centsubjectresearchto editinginforhumanclarity andreproductionspace. and figure—verifying enucleation, cells used any evidence for these developmental biomedicine. Debates over the for transfer, activated oocyte with trans- ethics of such approaches, as well as their ferred nucleus, cleavage-stage constructs, [cloning] claims, potential scientific and clinical merit, should and fetal ultrasounds. Protocols for obtain- “ be separated from the fantasy currently occu- this destructive hoax ing oocytes, number of donors and their pying news reports. ages, micromanipulation and electrofusion must end.” We call for three actions: First, all news procedures, activation and culture meth- coverage should cease unless scientific ods, and the mode and timing of embryo –SCHATTEN ET AL. evidence is provided. Second, the NAS on December transfers are required. The purported abor- (and/or the American Association for the tions and other fetal losses, the number and Advancement of Science) should intervene fate of supernumerary embryos, and pedi- abortions and neonatal losses. Attempts to to oversee essential independent tests on atric health assessment should also be produce children by the present methods of the alleged offspring. Third, we call for all described. Genetic tests of the alleged off- nuclear transfer would be grossly irresponsi-

nations to enact responsible legislation to 5 , spring and their nuclear, cytoplasmic, and ble because the outcome would almost cer- prevent human reproductive cloning. 2018 tainly include late abortions, stillbirths, and surrogate parents for both nuclear DNA G. SCHATTEN,1 R. PRATHER,2 I. WILMUT3 and mitochondrial DNA must be per- children with abnormalities that would pre- 1Pittsburgh Development Center of Magee- formed by independent qualified molecu- vent them from leading a normal life. Many Womens Research Institute and Departments of lar biology labs and overseen by prominent cloned animals display birth defects, includ- Obstetrics-Gynecology-Reproductive Sciences authorities. Let others threatening similar ing respiratory failure, immune deficiency, and Cell Biology-Physiology at the University of travesties be forewarned: Provide evidence and inadequate renal function—all leading Pittsburgh, Pittsburgh, PA 15213, USA. E-mail: to premature deaths. These problems may be or keep silent. [email protected]. 2Department of Animal a consequence of inappropriate gene expres- Enormous difficulties in generating just Science, University of Missouri, Columbia, MO sion resulting from incomplete “reprogram- a single somatic cell nuclear transfer off- 65211, USA. E-mail: [email protected]. ming” of the adult cell used in cloning (8). spring demanded years of dedicated efforts 3Roslin Institute, Roslin, Midlothian EH25 9PS, UK. There is absolutely no reason to expect the in accomplished labs (1–5) [including our E-mail: [email protected] respective labs with sheep (1) and pigs (5), situation to be different in humans. References Furthermore, human brain development is 1. I.Wilmut et al., Nature 385, 810 (1997). but not yet rhesus monkeys (6, 7)]. far more complex than that of animals, and 2. A. Onishi et al., Science 289, 1188 (2000). the neuropsychiatric consequences for 3. I. A. Polejaeva et al., Nature 406, 505 (2000). Consequently, the Christmas-time syn- 4.T. Wakayama et al.,Nature 394, 369 (1998). chrony of these alleged five births from cloned children are predicted to be devastat- 5. L. Lai et al., Science 295, 1089(2002). ing. This was the conclusion of a recent 6. T. Dominko et al., Cloning Stem Cells 3, 143 (1999). this messianic group with success rates far 7. C. Simerly et al., in preparation. in excess of the world’s best infertility clin- study by the NAS (9) and would not be 8. D. Humpherys et al., Proc. Natl. Acad. Sci. U.S.A. 99, ics is truly unbelievable. changed by the birth of a small number of 12889 (2002). healthy cloned children. 9. National Research Council, Scientific and Medical To avoid future fiascos, let’s retrace Aspects of Human Reproductive Cloning (National some of the steps that brought us here. At Hard science is the foundation of Academies Press,Washington, DC, 2002). first, the cloned sheep “Dolly” was consid- somatic cell nuclear transfer. Assisted

344 17 JANUARY 2003 VOL 299 SCIENCE www.sciencemag.org

Claim…Five couples lined up for CRISPR babies to avoid deafness

On June 3, 2019, Nature Medicine published research analyzing a U.K. genetic database and found that when people naturally have a trait similar to the one that He engineered into the babies' DNA, they have about a 21 percent greater risk of dying before the age of 76 than people who don't have this trait. INFOCUS NEWS

common than previously thought, she says. which are very closely related to very, very Virologist Ayato Takada at Hokkaido Three in the same family were discovered in dangerous pathogens,” she says. University in Sapporo, Japan, is also excited animals in the past year: the Mengla virus in It remains unknown whether these viruses about being able to study BSL-4 pathogens in Chinese bats and two Ebola-like viruses found can infect or harm humans, says Mühlberger. animals in Japan. Until now, researchers had to in fish in the East China Sea. “It is amazing But their diversity is “pretty scary”, she says. apply for access to BSL-4 labs overseas, which how many animals are infected with viruses “These viruses are everywhere.” are in high demand. ■

GENOMEEDITING Errors in CRISPR-baby study Geneticists retract paper that suggested first gene-edited babies might die early.

BY EWENCALLAWAY University of China in Shenzhen, said he predicted itshould —a signthat individualswith targeted CCR5 because people with a 32-DNA- two copies were dying earlier, on average, than study that raised questions over the letter deletion known as delta-32 in the gene the population at large,Weiand Nielsen argued. future health of the world’s first gene- are resistant to HIV but seem not to experience Questions over the conclusion emerged as soon Aedited babieshasbeen retracted because significant related health problems. as the paper was published. Sean Harrison, an ofkeyerrorsthat undermined its conclusion. He has not published data supporting his epidemiologist at the Universityof Bristol, UK, The research, published in June in Nature work, but his announcement — presented attempted to replicate the findings that night. Medicine1, had suggested that people with two at a scientific meeting — indicated that, for He did not have UK Biobank data on the gene copies ofa natural genetic mutation that confers one twin, both copies of CCR5 were altered, variant that Wei and Nielsen used to identify HIV resistance are at an increased risk of dying whereas the other twin carried edits in just one carriers of delta-32, so he analysed genetic earlier than other people. It was conducted of her two copies. None of the changes exactly variants near it on the genome that should have in the wake of controversial experiments by matched the delta-32 variation. given the same result (adjacent parts of the the Chinese scientist He Jiankui, who had genome tend to be inherited together, allow- attempted to recreate the effects of this muta- RESULTSNOTREPLICATED ing scientists to infer the presence or absence tion in the gene CCR5 by using the CRISPR Research has hinted that the delta-32 of a DNA sequence byanalysing neighbouring gene-editing techniquein human embryos. The mutation, which is relatively common in peo- variants). When they didn’t, he described his twin girls born last year as a result of the work ple of European ancestry, might carry down- findings in tweets and a blogpost. did not end up carrying this exact The discrepancy piqued the mutation, but the research attracted interest of David Reich, a popula-

TTY tion geneticist at Harvard Medical

E attention because of its potential G relevance to such experiments. School in Boston, Massachusetts, However, studies2–4 that looked whose lab is studying CCR5. Work- 2 anew at the Nature Medicine research ing with Nielsen, his team discovered find no evidence that people with the that Nielsen and Wei’s method had mutation die early. The erroneous caused them to undercount the num- conclusion about CCR5 was caused ber ofpeople in the UK Biobank with by errors in how the mutation was two copies of the delta-32 mutation, identified in a population-health because the probe that measured the database. variant they were tracking did not “I feel I have a responsibility to always identify its target sequence. put the record straight,” says Rasmus This —and not the supposed harmful Nielsen,a population geneticist at the effects of the mutation — explained University of California, Berkeley, the apparent absence of carriers from the UK Biobank database, says who led the study, which the authors Nielsen. retracted on 8 October. Nielsen A 32-letter deletionin the geneCCR5confers resistance to HIV. Researchers emphasize that the also co-authored one of the papers unravellingofWeiand Nielsen’sresults does not rebutting itsfindings. sides — one small study5 found that carriers mean it is a sound idea to target CCR5 for gene Someresearchersstressthat becausethetwins were more likely than other people to die from editing. “It’s very reasonable to expect that it did not receive exactly the same mutation that influenza. To tackle the question in larger might have a valuablefunction that we just don’t occurs naturally, the original research and its data sets, Nielsen and his Berkeley colleague know how to measure. It seems very unwise to retraction would not necessarily offer insights Xinzhu Wei looked at the UK Biobank data- edit it out,”says Reich. ■ into their health anyway. But the episoderaises base, which contains genome and health data questionsabout how best to assessthe safety of from 500,000people. 1. Wei, X. & Nielsen, R. Nature Med. 25, 909–910 (2019). 1 2. Maier, R. et al. Preprint at bioRxiv https://doi. future attempts to edit genesin humanembryos. Their paper reported that people with two org/10.1101/787986 (2019). He Jiankui shocked the scientific world copies of the delta-32 mutation were slightly 3. Gudbjartsson, D. et al. Preprint at bioRxiv when he announced, in November2018, that https://doi.org/10.1101/788117 (2019). more likely to die by the age of 76 than were 4. Karczewski,K. J.,Gauthier, L. D. & Daly, M. J. Preprint his team had used CRISPR to disable the CCR5 thosewithone orno copies.Theyalsofound that atbioRxiv https://doi.org/10.1101/784157(2019). gene in two babies born that month. He, who the database harboured fewer people with two 5. Falcon, A. et al. J. Gen. Virol. 96,2074–2078 (2015). was at the time a biophysicist at the Southern copiesofthe mutation than evolutionary theory

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r i A Holstein heifer will never grow horns thanks to gene-editing. Regulators have now found serious mistakes caused by the editing process. ALISON VAN EENENNAAM, UC DAVIS Bid for barnyard revolution is set back after regulators find celebrity “hornless” bovines contaminated by bacterial genes

Article Live birth derived from oocyte spindle transfer to prevent mitochondrial disease John Zhang a,b,*, Hui Liu b, Shiyu Luo c, Zhuo Lu b, Alejandro Chávez-Badiola a, Zitao Liu b, Mingxue Yang b, Zaher Merhi d, Sherman J Silber e, Santiago Munné f, Michalis Konstandinidis f, Dagan Wells f, Jian J Tan g, Taosheng Huang c,* a New Hope Fertility Center, Punto Sao Paulo, Lobby Corporativo, Américas 1545 Providencia, Guadalajara, Mexico b New Hope Fertility Center, 4 Columbus Circle, New York, NY 10019, USA c Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, OH 45229, USA d Department of Obstetrics and Gynecology, Division of Reproductive Biology, NYU School of Medicine, 180 Varick Street, New York, NY 10014, USA e Infertility Center of St Louis, St Luke’s Hospital, St Louis, MO 63017, USA f Reprogenetics, 3 Regent Street, Livingston, NJ 07078, USA g Department of Obstetrics and Gynecology, The Mount Sinai Hospital, E 101st Street, New York, NY 10029, USA

Dr John Zhang completed his medical degree at Zhejiang University School of Medicine in China, and subse- quently received his Master’s Degree at Birmingham University in the UK. In 1991, Dr Zhang earned his PhD in IVF, and, after researching the biology of mammalian reproduction and human embryology for nearly 10 years he completed his fellowship training in Reproductive Endocrinology and Infertility at New York University’s School of Medicine in 2001. Dr. Zhang continues his clinical research in minimal stimulation IVF, non-embryonic stem cell, long-term oocytecryopreservation,and oocytereconstructionby nucleartransfer.

KEY MESSAGE We report a live birth after oocyte spindle transfer to prevent transmission of the mitochondrial disease, Leigh syndrome.

A B S T R A C T

Mutations in mitochondrial DNA (mtDNA) are maternally inherited and can cause fatal or debilitating mitochondrial disorders. The severity of clinical symptoms is often associated with the level of mtDNA mutation load or degree of heteroplasmy. Current clinical options to prevent transmission of mtDNA mutations to offspring are limited. Experimental spindle transfer in metaphase II oocytes, also called mitochondrial replacement therapy, isa novel technology for preventing mtDNA transmission from oocytes to pre-implantation embryos. Here, we report a female carrier of Leigh syndrome (mtDNA mutation 8993T > G), with a long history of multiple undiagnosed pregnancy losses and deaths of offspring as a result of this disease, who underwent IVF after reconstitution of her oocytes by spindle transfer into the cytoplasm of enucleated donor oocytes. A male euploid blastocyst was

Spontaneous emergence of cell-like organization in Xenopus egg extracts Xianrui Cheng1,*, James E. Ferrell Jr.1,2,* Science 01 Nov 2019: Vol. 366, Issue 6465, pp. 631-637 DOI: 10.1126/science.aav7793 Matters arising https://doi.org/10.1038/s41586-019-1623-3 Reversion after replacementof mitochondrial DNA gavin Hudson1*, Yuko takeda1 & Mary Herbert1,2*

arising from: E. Kang et al. Nature https://doi.org/10.1038/nature20592 (2016).

The risk of transmitting deleterious mutations in mitochondrial DNA They therefore concluded that mitochondrial genomes that carry (mtDNA) from mother to child may be reduced by mitochondrial pathogenic mutations were efficiently eliminated by spindle transfer2. replacement, which involves transplanting the nuclear DNA from Analysis of the mtDNA sequence data published in Kang et al.2 the egg of a woman containing such a mutation into an enucleated indicates that one of the egg donors (ED5, of haplogroup U5a) included egg from an unaffected donor1. Although embryonic stem cell lines in the control group is homoplasmic for a pathogenic mtDNA muta- derived from mitochondrial replacement embryos can revert to the tion. The mutation (m.14484T>C)is in the MT-ND6gene (Fig. 1) and mitochondrial genome of the nuclear donor1, a study that involved causes Leber’s hereditary optic neuropathy (LHON)5,6.The authors eggs from women who carry pathogenic mutations reported that derived three ES cell lines from mitochondrial replacement embryos, mutant mtDNA was efficiently eliminated and did not re-emerge in in which the eggs of this woman were used as nuclear donors. Crucially, embryonic stem cell lines2. Contrary to this, we find that two embry- these cell lines included two of the ES lines (ST-ES7 and ST-ES8) in onic stem cell lines derived by Kang et al.2 exhibited reversion to a which reversion to the mitochondrial genome of the nuclear donor was pathogenic variant, which was present in the mitochondrial genome observed (Fig. 1b). The authors reported that by passage 2–3 the kary- of a nuclear donor assigned to the control group. Although the clinical oplast mitochondrial genome accounted for 81% and 94% of the total relevance is unclear, reversion in embryonic stem cell lines remains a mtDNA in ST-ES7 and ST-ES8 respectively, and that both lines were consideration for therapeutic applications of mitochondrial homoplasmic for the U5a haplogroup by passage 9–10 (ref. 2). Thus, replacement, and accurate reporting of the research that both ES lines became homoplasmic for the mitochondrial genome that underpins these applications is thereforeessential. carries the m.14484T>C mutation during proliferation in vitro. The mitochondrial replacement procedure involves The m.14484T>C mutation is one of three common primary muta- transplanting the nuclear genome in a karyoplast containing a tions that are known to cause LHON7. LHON was first described in small amount of cytoplasm. The small amount of mtDNA 18718 and, just over a century later, became the first disease that was contained in the karyoplast generally accounts for less than 2% of the proven to be caused by a point mutation in mtDNA9. The phenotypic mtDNA content of mitochondrial replacement embryos2–4. Despite hallmark of LHONis a degeneration of retinal ganglion cellsthat results this, around 15% of embryonic stem (ES) cell lines derived from in an acute loss of central vision7. Unlike most pathogenic mutations of such embryos show complete reversion to the mitochondrial mtDNA,the mutations that cause LHON are typically homoplasmic7,10. genome of the nuclear donor during proliferation in vitro2–4. However,penetrance of the disease is variable. It shows a strong gender Because the majority of mitochondrial replacement studies are based bias; there is an approximately 50% chance of blindness in males, com- on mtDNA sequence variants that are not pathogenic, evidence for the pared with about 10% in females7. In addition, penetrance is thought fate of pathogenic variants in ES cell lines derived from mitochondrial to be modulated by factors such as environmental stressors and back- replacement embryos is limited. The study published by Kang et ground genetic effects, including mtDNA haplogroup10,11. Globally, the al.2 was therefore of considerable interest. These authors reported m.14484T>C mutation is the second-most common cause of LHON12; that three of the women who donated eggs for their study were however, there is considerable variation in the frequency worldwide. heteroplasmic for pathogenic mutations in their mtDNA. The For example, there is an unusually high frequency of the m.14484T>C study also included eggs from 11 women who were screened to con- mutation in cases of LHON among populations of French Canadian firm the absence of mtDNA mutations. Mitochondrial replacement descent, owing to a founder effect that dates from the 17th century11. was performed by transplanting the metaphase II spindle from eggs Kang et al.13 note in their corrections to their original paper, and in that carried pathogenic mtDNA mutations into enucleated eggs from the accompanying Reply, that the carrier of LHON was assigned to the unaffected donors, as well as between eggs that were donated bywomen control group because she had no symptoms or family history of this who were deemed to be free of pathogenic mutations. disease. However,clinical guidelines clearly indicate that the absence of Consistent with others3,4, Kang et al.2 found that reversion to the a family history of blindness does not preclude a diagnosis of LHON7. mitochondrial genome of the nuclear donor occurred in a minority Kang et al.2 also investigated the potential drivers of reversion in ES of ES cell lines (n = 3 out of 18). This included two lines (ST-ES7 and cell lines. They identified a candidate polymorphism in the mtDNA ST-ES8) that were reported to originate from mitochondrial replace- conserved sequence box II (CSBII), which contains sequences that are ment procedures involving eggs donated by women who did not carry involved in generating mtDNA replication primers14. In the case of the inherited pathogenic mtDNA mutations. The remaining reverted ES reverted ES cell lines ST-ES7 and ST-ES8,the authors proposed that the cell line (3243ST-ES1) was derived from a mitochondrial replacement CSBIIG6AG8 variant in the mtDNA of the nuclear donor conferred a procedure in which the nuclear donor was a carrier of the m.3243A>G replicative advantage, relative to the G5AG8 variant that was present mtDNA mutation. However, the authors reported that reversion in this in the mtDNA of the mitochondrial donor. They therefore proposed ES cell line involved the wild type, rather than the mutated mtDNA.

1Wellcome Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. 2Newcastle Fertility Centre, Newcastle upon Tyne, UK. *e-mail: [email protected]; [email protected]

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11/7/2019 Opinion | This Editorial Is Not About Designer Babies - The New York Times

This Editorial Is Not About DesignerBabies A procedure called mitochondrial replacement therapy could eliminate devastating diseases. It would not enable parents to ʻdesignʼ their children.

By The Editorial Board April 12, 2019

Leigh syndrome is a terrible disease. In the worst cases, it emerges shortly after birth and claims one major organ after another. Movement becomes difﬁcult, and then impossible. A tracheotomy and feeding tube are often necessary by toddlerhood, and as the disease progresses, lungs frequently have to be suctioned manually. Most children with thecondition die by the age of 5 or6.

Leigh syndrome is one of hundreds of so-called mitochondrial diseases, which are caused by defects in the specialized cellular compartments — called mitochondria — that produce 90 percent of the body’s energy. These disorders are rare; about 1,000 to 4,000 babies in the United States are born with one every year. But they are devastating. They can result in grave impairment of nearly any bodily system. They are largely untreatable, uniformly incurable and very difﬁcult to screen for.

Some might also be preventable. Scientists have devised a procedure called mitochondrial replacement therapy(M.R.T.) that involves transplanting the nucleus of an affected egg — mitochondrial diseases are passed down from the mother’s side — into an unaffected one whose nucleus has been removed. (The procedure is sometimes called “three-parent I.V.F.” — in vitro 32/4

https://www.nytimes.com/2019/04/12/opinion/three-parent-babies-mitochondria.html?searchResultPosition=1 ICSI first manufactured zygotes Now Manufactured Gametes and Manufactured Embryos Haploid Cells are Generated from hPSCs Cultured in SSC Conditions

Prof Chas Easley U Georgia

fertility supplement c o m m e n t a r i e s Safeguarding ART Gerald P. Schatten

Pittsburgh Development Center, Magee Womens Research Institute, Departments of Obstetrics, Gynecology & Reproductive Sciences and of Cell Biology- Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA

e-mail: [email protected]

Assisted reproductive technologies (ART) are exceptional among clinical therapies, as unlike most medical procedures, ART have generational consequences. Further, human embryo research in the US has been sponsored solely by the private sec- tor and, until recent biotechnology forays into human embryonic stem cell (hESC) and cloning research, exclusively by infertility clinics. Additionally, the relatively brief clinical history of ART has made it difficult for practitioners and researchers to agree on criteria for its safety and success. Against this backdrop, market pressure on biotechnology companies to create InvestigatorhESC lines and on clinical practices to occupy vs. the innovative Practitionerforefront has resulted in arguably risky experiments with human embryo cloning, as well as in unintentional germ-line genetic modifications during ART and perhaps during gene therapy. Reproduction, once governed largely by passions and instinct, now seems to need further governance. Some argue that it could now be time for the biomedical community, especially in the US, to take further steps to safeguard ART.

rom its roots in in vitro fertilization (IVF), replication cycle is retarded2 and the orien- PGD has expanded ART beyond infertil- ART (Fig. 1) has matured over the past tation of the male and female pronuclei ity therapies: not only can potential parents twenty-five years to include other sophisti- (decondensed sperm and egg nuclei, respec- bear offspring, but they can also ensure that catedprotocols,such as ICSI(intracytoplas- tively) is perpendicular to that after IVF (C. the offspring do not carry genetic disease. mic sperm injection) and PGD (preimplan- Simerly and D. Takahashi, personal com- PGD involves the removal of one or two tation genetic diagnosis).The high fertiliza- munication). Compelling discoveries on cells from the early embryo (Fig. 1c) that tion rate of ART now far exceeds the ~25% mammalian body axis specification have then undergo chromosome analysis, usually Frate during natural human reproduction1, demonstrated that unfertilized murine and by fluorescence in situ hybridization (FISH) but many challenges remain. Oocyte num- human oocytes have an intrinsic polarity2–4 or DNA analysis by PCR for specific genetic bers sufficient for ART are usually obtained and that the sperm entry site establishes the diseases (for example, cystic fibrosis, after ovarian stimulation, although egg second axis in mice5. Extrapolation to Huntington’s disease, sickle-cell disease, X- quality, maternal age, environmental expo- humans suggests that the region of the egg linked disorders and Duchenne’s muscular sures and even the stimulating hormones chosen for sperm deposition determines the dystrophy). Recent improvements in themselves may compromisesuccess. future left–right bodyaxis. embryo culture now permit routine in vitro Fertilization by ICSI differs from IVF in A second partially understood area of blastocyst development. This provides an several fundamental ways (Fig. 1a). Men human reproductive biology with impor- extra day or two for PGD, so that embryos with abnormal sperm or a low sperm tant implications for ART is extranuclear with a normal chromosome complement count, and even those with no sperm in genetic transmission. Mitochondria, inher- are ultimately selected fortransfer. their ejaculates, can now father children ited by exclusive maternal origin6, deviate Reproductive ageing is a growing chal- through ICSI. Unlike natural fertilization from the norm during cytoplasmic transfer lenge for ART as more couples delay pro- or IVF, in which the sperm is chosen by (CT)7,8. Foreign DNA that adheres to the creation. The ability of women in their six- competition (for example, swimming, injected sperm is transmitted to transgenic ties to deliver healthy children using acrosome reaction, zona pellucida passage mice9 and is introduced during ICSI oocytes obtained from younger donors or fusion with the plasma membrane of the (though perhaps not during IVF) in non- suggests that reproductive ageing occurs egg), the sperm for ICSI is selected by the human primates10. The mitotic spindle of within the cytoplasm of the egg in vivo. The subjective criteria of the embryologist. The the zygote poles typically require the sperm meiotic spindles of oocytes from women in ICSI needle is carefully inserted to avoid centrosome, and centrosome dysfunction is their twenties are better organized, with damaging the meiotic spindle of the egg, one form of male infertility11–15. Ooplasmic more tightly aligned chromosomes than and membrane healing, egg activation and endomembranes, sperm RNA16 and epige- those from the oocytes of women in their the trigger and propagation of the cortical netic alterations of the nuclear genome, forties19,20. Aneuploidy screening (AS; or reaction can be all expected to differ from including genomic imprinting17,18, are preimplantation genetic screening (PGS); IVF. Decondensation of sperm DNA dur- other unipaternal contributions worthy of Fig. 1c, inset)21 shows promise for couples ing ICSI is non-uniform, the first DNA further investigation. with a maternal age in excessof 38 years. In

Nature Cell Biology & Nature Medicine www.nature.com/fertility s19 fertility supplement c o m m e n t a r i e s Safeguarding ART Gerald P. Schatten

e-mail: [email protected]

rom its roots in in vitro fertilization (IVF), replication cycle is retarded2 and the orien- PGD has expanded ART beyond infertil- ART (Fig. 1) has matured over the past tation of the male and female pronuclei ity therapies: not only can potential parents twenty-five years to include other sophisti- (decondensed sperm and egg nuclei, respec- bear offspring, but they can also ensure that catedprotocols,such as ICSI(intracytoplas- tively) is perpendicular to that after IVF (C. the offspring do not carry genetic disease. Outcomes and Annuities:Simerly and D . Takahashi, Primatespersonal com- PGD involves the removalandof one or two Patients mic sperm injection) and PGD (preimplantation genetic diagnosis).The high fertiliza- munication). Compelling discoveries on cells from the early embryo (Fig. 1c) that tion rate of ART now far exceeds the ~25% mammalian body axis specification have then undergo chromosome analysis, usually Frate during natural human reproduction1, demonstrated that unfertilized murine and by fluorescence in situ hybridization (FISH) but many challenges remain. Oocyte num- human oocytes have an intrinsic polarity2–4 or DNA analysis by PCR for specific genetic bers sufficient for ART are usually obtained and that the sperm entry site establishes the diseases (for example, cystic fibrosis, after ovarian stimulation, although egg second axis in mice5. Extrapolation to Huntington’s disease, sickle-cell disease, X- quality, maternal age, environmental expo- humans suggests that the region of the egg linked disorders and Duchenne’s muscular sures and even the stimulating hormones chosen for sperm deposition determines the dystrophy). Recent improvements in themselves may compromisesuccess. future left–right bodyaxis. embryo culture now permit routine in vitro Fertilization by ICSI differs from IVF in A second partially understood area of blastocyst development. This provides an several fundamental ways (Fig. 1a). Men human reproductive biology with impor- extra day or two for PGD, so that embryos with abnormal sperm or a low sperm tant implications for ART is extranuclear with a normal chromosome complement count, and even those with no sperm in genetic transmission. Mitochondria, inher- are ultimately selected fortransfer. their ejaculates, can now father children ited by exclusive maternal origin6, deviate Reproductive ageing is a growing chal- through ICSI. Unlike natural fertilization from the norm during cytoplasmic transfer lenge for ART as more couples delay pro- or IVF, in which the sperm is chosen by (CT)7,8. Foreign DNA that adheres to the creation. The ability of women in their six- competition (for example, swimming, injected sperm is transmitted to transgenic ties to deliver healthy children using acrosome reaction, zona pellucida passage mice9 and is introduced during ICSI oocytes obtained from younger donors or fusion with the plasma membrane of the (though perhaps not during IVF) in non- suggests that reproductive ageing occurs egg), the sperm for ICSI is selected by the human primates10. The mitotic spindle of within the cytoplasm of the egg in vivo. The subjective criteria of the embryologist. The the zygote poles typically require the sperm meiotic spindles of oocytes from women in ICSI needle is carefully inserted to avoid centrosome, and centrosome dysfunction is their twenties are better organized, with damaging the meiotic spindle of the egg, one form of male infertility11–15. Ooplasmic more tightly aligned chromosomes than and membrane healing, egg activation and endomembranes, sperm RNA16 and epige- those from the oocytes of women in their the trigger and propagation of the cortical netic alterations of the nuclear genome, forties19,20. Aneuploidy screening (AS; or reaction can be all expected to differ from including genomic imprinting17,18, are preimplantation genetic screening (PGS); IVF. Decondensation of sperm DNA dur- other unipaternal contributions worthy of Fig. 1c, inset)21 shows promise for couples ing ICSI is non-uniform, the first DNA further investigation. with a maternal age in excessof 38 years. In

Nature Cell Biology & Nature Medicine www.nature.com/fertility s19 Asilomar 1975 ➔ ART-silomar Now? fertility supplement c o m m e n t a r i e s Safeguarding ART Gerald P. Schatten

e-mail: [email protected]

Assisted reproductive technologies (ART) are exceptional among clinical therapies, as unlike most medical procedures, ART have generational consequences. Further, human embryo research in the US has been sponsored solely by the private sec- tor and, until recent biotechnology forays into human embryonic stem cell (hESC) and cloning research, exclusively by infertility clinics. Additionally, the relatively brief clinical history of ART has made it difficult for practitioners and researchers to agree on criteria for its safety and success. Against this backdrop, market pressure on biotechnology companies to create InvestigatorhESC lines and on clinical practices to occupy the innovative vs. forefront Practitionerhas resulted in arguably risky experiments with human embryo cloning, as well as in unintentional germ-line genetic modifications during ART and perhaps during gene therapy. Reproduction, once governed largely by passions and instinct, now seems to need further governance. Some argue that it could now be time for the biomedical community, especially in the US, to take further steps to safeguard ART.

rom its roots in in vitro fertilization (IVF), replication cycle is retarded2 and the orien- PGD has expanded ART beyond infertil- ART (Fig. 1) has matured over the past tation of the male and female pronuclei ity therapies: not only can potential parents twenty-five years to include other sophisti- (decondensed sperm and egg nuclei, respec- bear offspring, but they can also ensure that catedprotocols,such as ICSI(intracytoplas- tively) is perpendicular to that after IVF (C. the offspring do not carry genetic disease. Outcomes and Annuities:Simerly and D. Takahashi, personalPrimatescom- PGD involves the removal of andone or two Patients mic sperm injection) and PGD (preimplantation genetic diagnosis).The high fertiliza- munication). Compelling discoveries on cells from the early embryo (Fig. 1c) that tion rate of ART now far exceeds the ~25% mammalian body axis specification have then undergo chromosome analysis, usually Frate during natural human reproduction1, demonstrated that unfertilized murine and by fluorescence in situ hybridization (FISH) but many challenges remain. Oocyte num- human oocytes have an intrinsic polarity2–4 or DNA analysis by PCR for specific genetic bers sufficient for ART are usually obtained and that the sperm entry site establishes the diseases (for example, cystic fibrosis, after ovarian stimulation, although egg second axis in mice5. Extrapolation to Huntington’s disease, sickle-cell disease, X- quality, maternal age, environmental expo- humans suggests that the region of the egg linked disorders and Duchenne’s muscular sures and even the stimulating hormones chosen for sperm deposition determines the dystrophy). Recent improvements in ARTsilomar? Inclusive,themselves Global,may compromisesuccess. Nonfuture left–right body-axisJudgmental. embryo culture now permit routine inSettingvitro for Discussions Fertilization by ICSI differs from IVF in A second partially understood area of blastocyst development. This provides an several fundamental ways (Fig. 1a). Men human reproductive biology with impor- extra day or two for PGD, so that embryos with abnormal sperm or a low sperm tant implications for ART is extranuclear with a normal chromosome complement count, and even those with no sperm in genetic transmission. Mitochondria, inher- are ultimately selected fortransfer. and Debate6 their ejaculates, can now father children ited by exclusive maternal origin , deviate Reproductive ageing is a growing chal- through ICSI. Unlike natural fertilization from the norm during cytoplasmic transfer lenge for ART as more couples delay pro- or IVF, in which the sperm is chosen by (CT)7,8. Foreign DNA that adheres to the creation. The ability of women in their six- competition (for example, swimming, injected sperm is transmitted to transgenic ties to deliver healthy children using acrosome reaction, zona pellucida passage mice9 and is introduced during ICSI oocytes obtained from younger donors or fusion with the plasma membrane of the (though perhaps not during IVF) in non- suggests that reproductive ageing occurs egg), the sperm for ICSI is selected by the human primates10. The mitotic spindle of within the cytoplasm of the egg in vivo. The subjective criteria of the embryologist. The the zygote poles typically require the sperm meiotic spindles of oocytes from women in ICSI needle is carefully inserted to avoid centrosome, and centrosome dysfunction is their twenties are better organized, with damaging the meiotic spindle of the egg, one form of male infertility11–15. Ooplasmic more tightly aligned chromosomes than and membrane healing, egg activation and endomembranes, sperm RNA16 and epige- those from the oocytes of women in their the trigger and propagation of the cortical netic alterations of the nuclear genome, forties19,20. Aneuploidy screening (AS; or reaction can be all expected to differ from including genomic imprinting17,18, are preimplantation genetic screening (PGS); IVF. Decondensation of sperm DNA dur- other unipaternal contributions worthy of Fig. 1c, inset)21 shows promise for couples ing ICSI is non-uniform, the first DNA further investigation. with a maternal age in excessof 38 years. In

Nature Cell Biology & Nature Medicine www.nature.com/fertility s19 By Ronald M. Green

The Oxford philosopher Julian Savulescu, among others, has argued that prospective parents engaging in embryo selection using preimplantation genetic diagnosis not only may seek to have genetically enhanced children but are morally obligated do so. (See, for example, his essay “Procreative Beneficence: Why We Should Select the Best Children,” Bioethics, 15, no.5/6, 2001.)

Iargue that Savulescu is wrong.

Savulescu defends a moral principle he calls the principle of procreative beneficence. He states that, under this principle, prospective parents choosing among embryos “should select the child, of the possible children they could have, who is expected to have the best life, or at least as good a life as the others, based on the relevant, available information.” Among the possible enhancements he identifies are intelligence, memory, self-discipline, impulse control, foresight, patience, and a sense of humor. Savulescu has not yet extended this principle beyond preimplantation genetic diagnosis to gene editing. He acknowledges that gene editing currently carries health risks not associated with embryo selection, and that these risks outweigh any obligation to try to bring about “the best life” for a child.

But given the speed with which CRISPR technology is advancing, it seems that we are not far away from safe, effective gene enhancements for some traits. So according to Savulescu’s principle, when sufficient levels of safety are reached, all parents with the means to afford gene editing for enhancement will have a moral obligation to do so.

Iwill specify my criticisms of Savulescu’s principle, but first Iwant to say that Ifully support the reproductive use of gene editing technology for the prevention and elimination of serious genetic diseases. If we could use gene editing to remove the gene sequences in an embryo that cause sickle cell disease or cystic fibrosis, Iwould say not only that we may do so, but in the case of such severe diseases, that we have a moral obligation to do so.

Ithink that parents and medical professionals should always try to give a child a healthy start in life. This principle underlies the very firm moral intuition that pregnant women should not take drugs or drink alcohol to excess during pregnancy. In an era of safe gene editing, Ibelieve it would extend to the obligation to use this technology to avoid transmitting grave inherited disease conditions. Do We Have a Moral Obligation to Genetically Enhance our Children?

https://www.thehastingscenter.org/moral-obligation-genetically-enhance-children/ SUSTAINABILITY The stories COMMENTZOOLOGYFrom pheromones to POLICY Recovery ofCanadian CLIMATE CHANGE Geoengineering that inspire tomorrow’s faeces: the world through cod is too small and slow glaciers could do more harm

environmentalists p.434 the nose of a dog p.435 to rampup fishing p.436 than goodp.436

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SINGAPORE,

INSTITUTE GENOME

Simplified3D brain organoidscan be grownin a dish using human stem cells as the starting material. The ethics of experimenting with human brain tissue Difficult questions will be raised as models of the human brain get closer to replicating its functions, explain NitaA. Farahany, Henry T. Greelyand 15 colleagues.

f researchers could create brain tissue to better understand the human brain, brain surrogates is such that abandoning in the laboratory that might appear including miniaturized, simplified versions them seems itself unethical, given the vast to have conscious experiences or of brain tissue grown in a dish from stem amount of human suffering caused by I 1,2 subjective phenomenal states, would cells — brain organoids . And advances neurological and psychiatric disorders, and that tissue deserve any of the protec- keep being made. given that most therapies for these diseases tions routinely given to human or animal These models could provide a much developed in animal models fail to work research subjects? more accurate representation of normal in people. Yet the closer the proxy gets This question might seem outlandish. and abnormal human brain function and to a functioning human brain, the more Certainly, today’s experimental models development than animal models can ethically problematic it becomes. are far from having such capabilities. But (although animal models will remain use- There is now a need for clear guidelines various models are nowbeing developed ful for many goals). In fact, the promise of for research, albeit ones that can be

2 6 A P R I L 2 0 1 8 | V O L 5 5 6 | N A T U R E | 4 2 9

r i from a set of isotopes—of helium, beryl- BIOMEDICINE lium, and aluminum—that form when cos- mic rays bombard surface rocks. The high abundances of these isotopes suggest the Taking‘baby plateaus shed only 1 meter of material every 10 million years; the surrounding land- scape, meanwhile, likely eroded at100 times steps’ to that rate, the group concludes. “They put together an erosional history that’s very human compelling and exceptional,” Dietrich says. “I don’t know something so cleverly dated.” The results raise a new question, says Jane organs in Willenbring, a geomorphologist at the Scripps Institution of Oceanography in San Diego, California: “What makes landscapes livestock persist for millions of years?” Until now, the oldest known surfaces had been found in Chimera experiments parched regions like the Atacama Desert in tackle basic Chile or the dry valleys of Antarctica, where water-driven erosion is slow. Paradoxically, interaction between the longevity of the Brazilian plateaus de- foreign and hostcells fromDownloaded pends on water, says Ken Farley, a geo- chemist at the California Institute of Tech- nology in Pasadena and a co-author of the By Kelly Servick paper. They are rich in a type of iron oxide called hematite, which reacts with quartz

dissolved in rainwater to form tough blocks he perpetual shortage of human or- Successful rodent chimera experiments, such as http://science.sciencemag.org/ of rock that armor the soil. “It’s just iron ox- gans for transplant has researchers this mouse embryoharboringrat heartcells (red), ide, nothing else there,” Farley says. turning to farm animals. Several bio- havebeenhard to re-create with humancells. Similar plateaus protected by iron or tech companies are genetically en- silica probably exist throughout the slow Tgineering pigs to make their organs faster and less costly approach, human or- lands. “Vasconcelos’s finding has the po- more compatible with the human gans could be grown in advance from cells tential to motivate other researchers to body. But some scientists are pursuing a dif- from other donors, matched for key immune come back to ancient and slow landforms,” ferent solution: growing fully human organs signaling proteins to prevent rejection. says Fabiano Pupim, a geomorphologist at in pigs, sheep, or other animals, which could So far, the feat has been modeled only in the Federal University of São Paulo in then be harvested for transplants. rodents. In 2010, stem cell biologist

Diadema, Brazil. The idea is biologically daunting and eth- Hiromitsu Nakauchi and his team at the on June One lure is the long histories they hold. ically fraught. But a few teams are chipping University of Tokyo reported growing rat “This surface has seen a lot of geochemical away at a key roadblock: getting stem cells pancreases in mice that couldn’t form pan-

processes,” Vasconcelos says. “If something of one species to thrive in the embryo of creases of their own. In 2017, Nakauchi and 27

very drastic happened on the entire planet, another. Last month, a U.S. group reported colleagues treated diabetes in mice by giv- , 2019 a signature should be left.” He’s developing in a preprint that it had grown chimpanzee ing them transplants of insulin-producing a technique to tease out rainfall and tem- stem cells in monkey embryos. And newly mouse pancreas tissue grown in a rat. perature histories from oxygen isotopes in loosened regulations in Japan have encour- But the success in rodents hasn’t held up goethite, an iron oxide that caps inselbergs aged researchers to seek approval for ex- between larger and more evolutionarily dis- in Brazil and Australia. These surfaces can periments to boost the survival of human tant animals. In 2017, cell biologist Jun Wu also help scientists judge how often rare, cells in the developing embryos of rodents at the Salk Institute for Biological Studies powerful intraplate earthquakes strike a and pigs. Insoo Hyun, a bioethicist at Case in San Diego, California, and colleagues re- region. If the ancient cap is unbroken, any Western Reserve University in Cleveland, ported that when they injected pig embryos faults found in the rock below it must be as- Ohio, says the work is being done responsi- with human IPS cells and implanted the sociated with even older earthquakes, says bly. Efforts such as the new chimp-monkey embryos into sows, about half of the result- Bierman, who recently used an isolated an- chimeras represent “baby steps forward, ing fetuses were stunted and slow growing. cient plateau in South Africa to judge the gathering data as you go,” he says. “And I Those that were normal size had very few hu- seismic hazard to a nuclear power plant. think that’s a wise approach.” man cells after a month of gestation.

Inselbergs hold another gift: deposits of Ultimately, the researchers envision re- Wu, who is now at the University of Texas STUDIES concentrated iron ore, protected from programming a person’s cells to a primitive Southwestern Medical Center in Dallas, has washing away by the impermeable surface. developmental state that can form most any since explored how human stem cells inter-

BIOLOGICAL Left alone, the Urucum might exist for an- tissue and injecting these induced pluripo- act in a lab dish with stem cells from non-

FOR FOR other 30 million years. But now, human- tent stem (IPS) cells into another species’s human primates, rats, mice, sheep, and cows. ity is doing the job much faster. When the embryo. The embryo would be implanted He’s found what he calls “a very exciting team visited earlier this decade, most of the in the uterus of a surrogate, and allowed to phenomenon: a competition between cells of

plateau’s surface had been lost to mining, grow to full size to serve as an organ do- different species.” Pitted against cells of a dis- SALK INSTITUTE INSTITUTE SALK Farley says. “If we went back there, I’m not nor. The IPS cells could come from the per- tantly related animals, human cells tend to

PHOTO: PHOTO: sure this material would be left.”j son awaiting transplant or, in a potentially die off, and the team is now trying to under-

SCIENCE sciencemag.org 28 JUNE 2019 • VOL 364 ISSUE 6447 1217

fertility supplement c o m m e n t a r i e s Safeguarding ART Gerald P. Schatten

e-mail: [email protected]

Assisted reproductive technologies (ART) are exceptional among clinical therapies, as unlike most medical procedures, ART have generational consequences. Further, human embryo research in the US has been sponsored solely by the private sec- tor and, until recent biotechnology forays into human embryonic stem cell (hESC) and cloning research, exclusively by infertility clinics. Additionally, the relatively brief clinical history of ART has made it difficult for practitioners and researchers to agree on criteria for its safety and success. Against this backdrop, market pressure on biotechnology companies to create InvestigatorhESC lines and on clinical practices to occupy the innovative vs. forefront Practitionerhas resulted in arguably risky experiments with human embryo cloning, as well as in unintentional germ-line genetic modifications during ART and perhaps during gene therapy. Reproduction, once governed largely by passions and instinct, now seems to need further governance. Some argue that it could now be time for the biomedical community, especially in the US, to take further steps to safeguard ART.

rom its roots in in vitro fertilization (IVF), replication cycle is retarded2 and the orien- PGD has expanded ART beyond infertil- ART (Fig. 1) has matured over the past tation of the male and female pronuclei ity therapies: not only can potential parents twenty-five years to include other sophisti- (decondensed sperm and egg nuclei, respec- bear offspring, but they can also ensure that catedprotocols,such as ICSI(intracytoplas- tively) is perpendicular to that after IVF (C. the offspring do not carry genetic disease. Outcomes and Annuities:Simerly and D. Takahashi, personalPrimatescom- PGD involves the removal of andone or two Patients mic sperm injection) and PGD (preimplantation genetic diagnosis).The high fertiliza- munication). Compelling discoveries on cells from the early embryo (Fig. 1c) that tion rate of ART now far exceeds the ~25% mammalian body axis specification have then undergo chromosome analysis, usually Frate during natural human reproduction1, demonstrated that unfertilized murine and by fluorescence in situ hybridization (FISH) but many challenges remain. Oocyte num- human oocytes have an intrinsic polarity2–4 or DNA analysis by PCR for specific genetic bers sufficient for ART are usually obtained and that the sperm entry site establishes the diseases (for example, cystic fibrosis, after ovarian stimulation, although egg second axis in mice5. Extrapolation to Huntington’s disease, sickle-cell disease, X- quality, maternal age, environmental expo- humans suggests that the region of the egg linked disorders and Duchenne’s muscular sures and even the stimulating hormones chosen for sperm deposition determines the dystrophy). Recent improvements in ARTsilomar? Inclusive,themselves Global,may compromisesuccess. Nonfuture left–right body-axisJudgmental. embryo culture now permit routine inSettingvitro for Discussions Fertilization by ICSI differs from IVF in A second partially understood area of blastocyst development. This provides an several fundamental ways (Fig. 1a). Men human reproductive biology with impor- extra day or two for PGD, so that embryos with abnormal sperm or a low sperm tant implications for ART is extranuclear with a normal chromosome complement count, and even those with no sperm in genetic transmission. Mitochondria, inher- are ultimately selected fortransfer. and Debate6 their ejaculates, can now father children ited by exclusive maternal origin , deviate Reproductive ageing is a growing chal- through ICSI. Unlike natural fertilization from the norm during cytoplasmic transfer lenge for ART as more couples delay pro- or IVF, in which the sperm is chosen by (CT)7,8. Foreign DNA that adheres to the creation. The ability of women in their six- competition (for example, swimming, injected sperm is transmitted to transgenic ties to deliver healthy children using acrosome reaction, zona pellucida passage mice9 and is introduced during ICSI oocytes obtained from younger donors or fusion with the plasma membrane of the (though perhaps not during IVF) in non- suggests that reproductive ageing occurs egg), the sperm for ICSI is selected by the human primates10. The mitotic spindle of within the cytoplasm of the egg in vivo. The subjective criteria of the embryologist. The the zygote poles typically require the sperm meiotic spindles of oocytes from women in ICSI needle is carefully inserted to avoid centrosome, and centrosome dysfunction is their twenties are better organized, with DON’T EXAGGERATE!damaging the meiotic spindle of the egg, one form of male infertility (11–e.g.15. Ooplasmic Organoids,more tightly aligned chromosomes than Chimera, and membrane healing, egg activation and endomembranes, sperm RNA16 and epige- those from the oocytes of women in their the trigger and propagation of the cortical netic alterations of the nuclear genome, forties19,20. Aneuploidy screening (AS; or Therapeuticreaction can be all expected to namediffer from including withoutgenomic imprinting17,18, areprovenpreimplantation genetic therapy;screening (PGS); IVF. Decondensation of sperm DNA dur- other unipaternal contributions worthy of Fig. 1c, inset)21 shows promise for couples ing ICSI is non-uniform, the first DNA further investigation. with a maternal age in excessof 38 years. In

‘Add-On’ CostsNature Cell Biology without & Nature Medicine www.nature.com/fertility proven benefits; Futile ARTs19 cycles)

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Conducting research that alters human embryos with the genome editor CRISPR (shown here) would not be banned if a proposed moratorium goes in place, but implanting altered human embryos would. MARK SCHIEFELBEIN/AP PHOTO New call to ban gene-edited babies divides biologists

By Jon Cohen Mar. 13, 2019 , 2:00 PM A prominent group of 18 scientists and bioethicists from seven countries has called for a global “moratorium” on introducing heritable changes into human sperm, eggs, or embryos—germline editing—to make genetically altered children. The group, which published a commentary in Nature today, hopes to influence a long-standing debate that dramatically intensified after China’s He Jiankui announced in November 2018 that he used the genome editor CRISPR to try to alter the genes of babies to be resistant to the AIDS virus.

Their call, which is endorsed in the same issue of Nature by Francis Collins, director of the U.S. National Institutes of Health, is a departure from statements issued by two global summits on genome editing in 2015 and 2018, a 2017 report from the U.S. National Academies of Sciences, Engineering, and Medicine (NASEM), and a 2018 report from the United Kingdom’s Nuffield Council on Bioethics. None has banned human germline editing, and most have stressed that it holds promise to help correct some heritable diseases. All have warned against using germline editing for cognitive or physical “enhancement” of people. Scientists including Nobel laureate David Baltimore of the California Institute of Technology in Pasadena remain opposed to a moratorium. Even in the wake of the He incident, Baltimore, who helped organize the summits, denounced such a ban as “draconian” and “antithetical to the goals of science.”

Any nation that wants to greenlight a human germline edit by its scientists, the 18 authors declare, should have to give public notice, engage in an international and transparent assessment of whether the intervention is justified, and make sure the work has broad support in their own nation. “Nations might well choose different paths, but they would agree to proceed openly and with due respect to the opinions of humankind on an issue that will ultimately affect the entire species,” they write. They strongly encourage that nonscientific perspectives, including those of people with disabilities and religious groups, be

fertility supplement c o m m e n t a r i e s Safeguarding ART Gerald P. Schatten

e-mail: [email protected]

Assisted reproductive technologies (ART) are exceptional among clinical therapies, as unlike most medical procedures, ART have generational consequences. Further, human embryo research in the US has been sponsored solely by the private sec- tor and, until recent biotechnology forays into human embryonic stem cell (hESC) and cloning research, exclusively by infertility clinics. Additionally, the relatively brief clinical history of ART has made it difficult for practitioners and researchers to agree on criteria for its safety and success. Against this backdrop, market pressure on biotechnology companies to create InvestigatorhESC lines and on clinical practices to occupy the innovative vs. forefront Practitionerhas resulted in arguably risky experiments with human embryo cloning, as well as in unintentional germ-line genetic modifications during ART and perhaps during gene therapy. Reproduction, once governed largely by passions and instinct, now seems to need further governance. Some argue that it could now be time for the biomedical community, especially in the US, to take further steps to safeguard ART.

rom its roots in in vitro fertilization (IVF), replication cycle is retarded2 and the orien- PGD has expanded ART beyond infertil- ART (Fig. 1) has matured over the past tation of the male and female pronuclei ity therapies: not only can potential parents twenty-five years to include other sophisti- (decondensed sperm and egg nuclei, respec- bear offspring, but they can also ensure that catedprotocols,such as ICSI(intracytoplas- tively) is perpendicular to that after IVF (C. the offspring do not carry genetic disease. Outcomes and Annuities:Simerly and D. Takahashi, personalPrimatescom- PGD involves the removal of andone or two Patients mic sperm injection) and PGD (preimplantation genetic diagnosis).The high fertiliza- munication). Compelling discoveries on cells from the early embryo (Fig. 1c) that tion rate of ART now far exceeds the ~25% mammalian body axis specification have then undergo chromosome analysis, usually Frate during natural human reproduction1, demonstrated that unfertilized murine and by fluorescence in situ hybridization (FISH) but many challenges remain. Oocyte num- human oocytes have an intrinsic polarity2–4 or DNA analysis by PCR for specific genetic bers sufficient for ART are usually obtained and that the sperm entry site establishes the diseases (for example, cystic fibrosis, after ovarian stimulation, although egg second axis in mice5. Extrapolation to Huntington’s disease, sickle-cell disease, X- quality, maternal age, environmental expo- humans suggests that the region of the egg linked disorders and Duchenne’s muscular sures and even the stimulating hormones chosen for sperm deposition determines the dystrophy). Recent improvements in ARTsilomar? Inclusive,themselves Global,may compromisesuccess. Nonfuture left–right body-axisJudgmental. embryo culture now permit routine inSettingvitro for Discussions Fertilization by ICSI differs from IVF in A second partially understood area of blastocyst development. This provides an several fundamental ways (Fig. 1a). Men human reproductive biology with impor- extra day or two for PGD, so that embryos with abnormal sperm or a low sperm tant implications for ART is extranuclear with a normal chromosome complement count, and even those with no sperm in genetic transmission. Mitochondria, inher- are ultimately selected fortransfer. and Debate6 their ejaculates, can now father children ited by exclusive maternal origin , deviate Reproductive ageing is a growing chal- through ICSI. Unlike natural fertilization from the norm during cytoplasmic transfer lenge for ART as more couples delay pro- or IVF, in which the sperm is chosen by (CT)7,8. Foreign DNA that adheres to the creation. The ability of women in their six- competition (for example, swimming, injected sperm is transmitted to transgenic ties to deliver healthy children using acrosome reaction, zona pellucida passage mice9 and is introduced during ICSI oocytes obtained from younger donors or fusion with the plasma membrane of the (though perhaps not during IVF) in non- suggests that reproductive ageing occurs egg), the sperm for ICSI is selected by the human primates10. The mitotic spindle of within the cytoplasm of the egg in vivo. The subjective criteria of the embryologist. The the zygote poles typically require the sperm meiotic spindles of oocytes from women in ICSI needle is carefully inserted to avoid centrosome, and centrosome dysfunction is their twenties are better organized, with DON’T EXAGGERATE!damaging the meiotic spindle of the egg, one form of male infertility (11–e.g.15. Ooplasmic Organoids,more tightly aligned chromosomes than Chimera, and membrane healing, egg activation and endomembranes, sperm RNA16 and epige- those from the oocytes of women in their the trigger and propagation of the cortical netic alterations of the nuclear genome, forties19,20. Aneuploidy screening (AS; or Therapeuticreaction can be all expected to namediffer from including withoutgenomic imprinting17,18, areprovenpreimplantation genetic therapy;screening (PGS); IVF. Decondensation of sperm DNA dur- other unipaternal contributions worthy of Fig. 1c, inset)21 shows promise for couples ing ICSI is non-uniform, the first DNA further investigation. with a maternal age in excessof 38 years. In

‘Add-On’ CostsNature Cell Biology without & Nature Medicine www.nature.com/fertility proven benefits; Futile ARTs19 cycles)