vol. 353, i. 9167, page 1873
Abstract: Genetic manipulation of germ cells should
be prohibited. Alterations of the genetic code in sperm cells,
ova, and fertilized ova could be used to prevent disease or
to induce desired traits. In comparison to gene transfer in
other body cells, germ cell modification may produce effects
that were not predicted, and may not reveal themselves until
the child is grown, or in future generations. Germ cell modification
not only influence the single offspring, but create unique DNA
that will persist into subsequent generations. Prenatal diagnosis
permits specific pregnancies to be evaluated for genetic fitness.
Manipulation of germ-cell DNA is unnecessary and potentially
Human germline gene modification has been foreseen but not
yet accomplished.1-6 It can be defined as the genetic manipulation
of human germ cells, or of a conceptus, resulting in inherited
changes in DNA. With the development of advanced in-vitro fertilisation
(IVF) methods, preimplantation DNA analysis, improved techniques
for gene transfer, insertion, or conversion, and of embryo implantation
procedures, the technical barriers to such an intervention seem
easily surmountable. Unintended changes in DNA may occur when
gametes are manipulated or stored.7,8 Inadvertent germline mutations.
therefore, may have already occurred as a result of reproductive
technologies in current use, such as artificial insemination
and IVF. There are unpublished reports that researchers in the
USA have already carried out a manipulation involving the exchange
of a mitrochondrial genome in an IVF protocol. If true, this
human experimentation involving intentional hereditary changes
was probably conducted without federal oversight of safety,
since there are no discussions of this protocol in the available
Tsukui and colleagues9 used viral vectors in somatic gene therapy
protocols to infect mouse eggs in vitro, leading to germline
transmission of a transgene in the progeny. Although removal
of the zona pellucida is a prerequisite for infection of the
eggs in vitro, the early oocytes of postnatal ovaries also lack
zonas. These experiments thus raise the possibility that modification
of gametes may occur in vivo, and constitute a germline hazard
in the 200 or more somatic gene therapy protocols now in use.
Any such alterations would be difficult to detect. Intentional
or inadvertent germline modifications may pose significant burdens.
Although there are restrictions on experimentation that might
result in human modifications,10 and opposition to its implementation
has been voiced,11-15 some leading scientists and other commentators
have begun to advocate the development and application both
of techniques that may increase the risk of inadvertent alteration
of the germline, and of methods that would alter it deliberately.6,16-18
W French Anderson and his colleagues have developed an experimental
protocol for the treatment of adenosine deaminase deficiency
during fetal development; although their therapeutic intent
is directed towards somatic cells, they acknowledge that the
technique may modify germ cells as well. They have submitted
this proposal to the National Institutes of Health (NIH) for
review (panel). By introducing a genetic construct in utero,
which knowingly allows for the alteration of germinal tissue,
their attempt at a potentially transmissible correction could
be used to erode opposition to germline genetic manipulation
since germline modification would be achieved, though unintentionally.
Opposition to germline modification is based on several lines
of reasoning.19-22 First, as we have already suggested, germline
DNA modifications may affect gene function in ways that are
not immediately apparent, so their occurrence may not be recognised
for a generation or more-for example, germline introduction
in mice of an improperly regulated normal gene resulted in progeny
with unaffected development but high tumour incidence during
adult life.23 Furthermore, interactions among genes and their
products are highly integrated, have been refined over evolutionary
time scales, and often serve to stabilise developmental pathways
and physiological homoeostasis.24-26 Through experimental error,
unanticipated allelic interactions, or poorly understood regulatory
mechanisms such as imprinting, there is a risk that germline
genetic manipulation will alter sensitive biological equilibria.
Disruption of these interactive systems is likely to have complex
and uncertain biological effects, including some that appear
only during the development or functioning of specific cells
or tissues.27 Many of these effects could be undesirable.
Second, this sort of intervention is not needed. With available
methods of prenatal diagnosis, virtually all interested couples
can choose not to transmit specific identifiable genes. Other
reproductive options (artificial insemination, egg donation)
and adoption are available to those not able or willing to use
prenatal or preimplantation selection methods. An exception
might be when, rarely, two individuals have the same recessively
inherited disorder. If such couples chose to reproduce, it could
be argued that they would "need" germline or very
early genetic interventions since all their progeny might inherit
a disease-associated genotype. Yet, even these children may
differ genotypically and phenotypically from their parents and
the development of a new mode of treatment for this unusual
occurrence does not seem justifiable. Although available alternative
procedures are invasive, germline modifications would also require
similar interventions since they would probably involve IVF.
Moreover, the associated risks with existing procedures are
not as serious as those created by introducing a hereditary
genetic "error" into a family. People who oppose prenatal
diagnosis on philosophical or religious grounds would be unlikely
to want to take part in germline modification if they were aware
of its intrinsically experimental nature and of the numbers
of human embryos that would have to be expended during the development
of the technology. No unmet need balances the risks of germline
interventions to mothers, fetuses, and future generations. Moreover,
the costs associated with the general development and implementation
of germline manipulation would be formidable.
If there is no clinical need for germline modifications, the
primary reason for using this intervention would be human enhancement.28
Apart from the uncertainties about its ultimate outcome, enhancement
is a form of eugenics. Though not a recrudescence of overtly
coercive, public-health-based eugenics popular earlier this
century, germline manipulations represent an individual or familial
form. Seemingly private personal decisions and "choices"
about medical or non-medical programmes for enhancement would,
nevertheless, reflect prejudices, socioeconomic and political
inequalities, and even current fashion. Though enhancement procedures
now in use (eg, cosmetic surgery or orthodontics) also change
according to fashion, germline intervention would intentionally
subject later generations to modifications undertaken on the
basis of existing values and conditions. The chance that "desirable"
manipulations might later be viewed as disastrous makes germline
enhancement "therapies" unacceptable.
Human germline interventions would necessarily alter the lives
of individuals who are yet to be born. Informed consent by the
affected individuals is not possible. Extension of the parental
right to consent for minors would be required.29 Such legal
permission to specifically alter the lives of generations of
unborn individuals would be unprecedented and unjustified.
If germline manipulation is attempted, there will be mistakes
or errors in its application. Neither social acceptance nor
the necessary range of protections and care for accidentally
damaged individuals can be guaranteed.30 Unexpected alterations
in family relationships will occur, and "wrongful life"
disputes could arise.31 Irrespective o whether such interventions
were to take place in research or clinical settings, these issues
mean that germline modifications cannot be approved by existing
standards for the protection of human beings.32 No benefits
to and future individual would justify abrogating or curtailing
For these biomedical reasons, as well as others based in legal,33
philosophical,19,34,35 cultural, and spiritual/religious traditions,36,37
human germline modifications should be opposed and prohibited.
Experimentation that may gradually make human germline modification
more feasible is under way; it may require further review. Further
study is needed of the safety of somatic gene therapy protocols
to ensure that they detect, with adequate sensitivity, germline
alterations. Many individuals and groups that monitor developments
in human genetics can be expected to mount vigorous opposition
to the development of human germline protocols, involving direct
action, legal manoeuvres, and organising among interested public
groups. Unlike man other countries, including those of the EU,
which have prohibited germline manipulation in principle,38,39
restrictions on the procedure in the USA are mainly based on
practical considerations (see, for example, the summary of the
January 1999, RAC-sponsored conference at http://www.nih.gov/od/orda/gtpcconc.htm.
Site accessed March 20, 1999) and are subject to revision as
the state of the science changes. Although debate about human
germline modifications should continue and, indeed, be broadened
to include representation of a diverse cross- section of viewpoints
and backgrounds, such discussion should not be construed as
suggesting that such a method would ever be appropriate or acceptable.
We thank Jacque Bradley for technical assistance, Jon Beckwith,
Felipe Cabello, Suzanne Bodor, Vernon Chong and Parris Burd
for helpful suggestions and critical comments on drafts of this
1. Splicing life. In: President's Commission for the Study
of Ethical Problems in Medicine and Biomedical and Behavioural
Research. Government Printing Office, Washington DC, 1982: 1-115.
2. Friedman T, ed. Therapy for genetic disease. Oxford: Oxford
University Press, 1991.
3. Fletcher JC, Anderson WF. Germ-like gene therapy: a new stage
of debate. Law Med
Healthcare 1992; 20: 2-39.
4. Wivel NA, Walters L. Germ-like gene modification and disease
prevention: some medical and ethical perspectives. Science 1993;
5. Cook-Deegan RM. Germ-like therapy: keep thewindow open a
crack. Pol Life Sci 1994; 3: 217-20.
6. Walters L, Palmer J. Ethics of human gene therapy New York:
Oxford University Press, 1997.
7. Bouquet M, Selva J, Auroux M. Cryopreservation of mouse oocytes:
mutagenic effects in the embryo? Biol Reprod 1993; 49: 764-69.
8. Vishwanath R, Shannon P. Do sperm cells age? A review of
the physiological changes in sperm during storage at ambient
temperature. Reprod Fertil Dev 1997; 9:321-31.
9. Tsukui T, Kanegae Y, Saito I, Toyoda Y. Transgenesis by adenovirus-
mediated gene transfer into mouse zona-free eggs. Nat Biotechnol
1996; 14: 982-85.
10. McDonough PG. The ethics of somatic and germline gene therapy.
Ann NY Acad Sci 1997; 816: 378-82.
11. Krimsky S. Human gene therapy: must we know where to stop
before we start? Hum Gene Ther 1990; 1: 171-73.
12. Lippman A, Billings P, Bereano P, et al. Position paper
on human germ line manipulation. Hum Gene Ther 1993; 4: 35-37.
13. Bonnicksen AL. The politics of germline therapy. Nat Genet
1998; 19: 10-11.
14. Ewbank J. Problems of germline therapy. Nature 1998; 392:
15. McLaren A. Problems in germline therapy. Nature 1988; 392:
16. Anderson WF. Uses and abuses of human gene transfer. Hum
Genet Ther 1992; 3: 1-2.
17. Wadman M. Germline gene therapy "must be spared excessive
regulation". Nature 1998; 392: 317.
18. Kolata G. Scientists brace for changes in path of human
evolution. New York Times. March 21, 1998: A1.
19. Rifkin J. Algeny. New York: Viking Press, 1983.
20. Fowler G, Juengst ET, Zimmerman BK. Germ-line gene therapy
and the clinical ethos of medical genetics. Theor Med 1989;
21. Lappe M. Ethical issues in manipulating the human germ-line.
J Med Phil 1991; 16: 621-41.
22. Juengst ET. Can enhancement be distinguished from prevention
in genetic medicine. J Med Phil 1997; 22: 125-42.
23. Leder A, Pattengale PK, Kuo A, Stewart TA, Leder P. Consequences
of widespread deregulation of the c-myc gene in transgenic mice:
multiple neoplasms and normal development. Cell 1986; 45: 485-95.
24. Strohman R. Ancient genomes, wise bodies, unhealthy people:
limits of a genetic paradigm in biology and medicine. Persp
Biol Med 1993; 37: 112-45.
25. Newman SA. Interplay of genetics and physical processes
of tissue morphogenesis in development and evolution: the biological
fifth dimension. In: Beysens D, Forgacs G, Gaill F, eds. Interplay
of genetic and physical processes in the devlopment of biological
form. Singapore: World Scientific, 3-12.
26. Wilkins AS. Canalization: a molecular genetic perspective.
BioEssays 1997; 19: 257-62.
27. Jaenisch R, Breindl M, Harbers K, Jahner D, Lohler J. Retroviruses
and insertional mutagenesis. Cold Spring Harb Symp Quant Biol
1985; 50: 439-45.
28. Miller HI. Gene therapy for enhancement. Lancet 1994; 344:
29. Robertson JA. Children of choice: freedom and the new reproductive
technologies. Princeton: Princeton University Press, 1994.
30. Billings PR, Kohn MA, de Cuevas M, et al. Discrimination
as a consequence of genetic testing. Am J Hum Genet 1992; 50:
31. Cohen CB. "Give me children or I shall die!" New
reproductive technologies and harm to children. Hastings Cent
Rep 1996; 26: 19-27.
32. Protection of Human Subjects. Federal Register 1981; 46:
6386 and 1983; 48: 9269.
33. Annas GJ, Elias S. Somatic and germline therapy. In:Annas
GJ, Elias S, eds. Gene mapping: using law and ethics as guides.
New York: Oxford University Press, 1992: 142-54.
34. Davis BD. Germ-line therapy; evolutionary and moral considerations.
Hum Gene Ther 1992; 3: 361-63.
35. Neel JV. Germ-line gene therapy: another view. Hum Gene
Ther 1993; 4: 127-28.
36. World declaration on our responsibilities towards future
generations. In: Agius E, Busuttil S, eds. What future for future
generations? Valletta, Malta: Foundation for International Studies,
37. World Council of Churches. Manipulating life: ethical issues
in genetic engineering. Geneva: World Council of Churches, 1983.
38. Gene therapy in man. Recommendations of the European Medical
Research Councils. Lancet 1988; i:1271-72.
39. Wadman M. European states outlaw permanent changes. Nature
1998; 392: 317.
Lancet 1999; 353: 1873-75 Veterans Health Administration, Heart
of Texas Health Care System, 1901 North Highway 360 Grand Prairie,
(P R Billings MD); Biological Laboratories, Harvard University,
Cambridge, MA (R
Correspondence to: Dr Stuart A Newman (e-mail:[email protected])
Hubbard PhD); and Department of Cell Biology and Anatomy, New
College, Valhalla, NY, USA (S A Newman PhD)
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