The American Journal of Bioethics

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Germline Manipulation and Our Future Worlds

John Harris
To cite this article: John Harris (2015) Germline Manipulation and Our Future Worlds, The
American Journal of Bioethics, 15:12, 30-34, DOI: 10.1080/15265161.2015.1104163
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Date: 07 December 2016, At: 18:52

The American Journal of Bioethics, 15(12): 3034, 2015

Copyright Taylor & Francis Group, LLC
ISSN: 1526-5161 print / 1536-0075 online
DOI: 10.1080/15265161.2015.1104163

Target Article

Germline Manipulation and Our

Future Worlds1
John Harris, University of Manchester
Two genetic technologies capable of making heritable changes to the human genome have revived interest in, and in some
quarters a very familiar panic concerning, so-called germline interventions. These technologies are: most recently the use of
CRISPR/Cas9 to edit genes in non-viable IVF zygotes and Mitochondrial Replacement Therapy (MRT) the use of which was
approved in principle in a landmark vote earlier this year by the United Kingdom Parliament. The possibility of using either of
these techniques in humans has encountered the most violent hostility and suspicion. However it is important to be aware that
much of this hostility dates back to the fears associated with In Vitro Fertilization (IVF) and other reproductive technologies and
by cloning; fears which were baseless at the time concerning both IVF and cloning the use of both of which have proved to be
highly beneficial to humanity and which have been effectively regulated and controlled. This paper argues that CRISPR should
by pursued through researh until it is safe enough for use in humans but there is no reason to suppose at this stage that such
use will be unsafe or unethical (Collins 2015).
Keywords: Germline modification, CRISPR/Cas9, Mitochondrial Transfer, Epigenetics

Two new genetic technologies are capable of making heritable changes to the human genome. These technologies
have revived a very familiar panic concerning germline
interventions. These technologies are (1) the use of
CRISPR/Cas9 to edit genes in nonviable in vitro fertilization (IVF) zygotes and (2) mitochondrial replacement therapy (MRT) (Collins 2015). The possibility of using either of
these techniques in humans has generated vehement hostility and suspicion (Baltimore et al. 2015; Cyranoski 2015;
Cyranoski and Reardon 2015; Reardon 2015a; Vogel and
Stokstad 2015). Much of this hostility sounds familiar. It
echoes the fears associated with IVF, other reproductive
technologies, and cloning. Past lessons are instructive. The
fears about assisted reproduction and about cloning were
baseless. Both of these technologies have been effectively
regulated and controlled except perhaps in the United
States (Ollove 2015). Both have proven to be highly beneficial to humanity.
The birth of Louise Brown (the first IVF baby) on July
25, 1978, started this debate. In a paper I published in 1983
on IVF, I described the technique that would eventually

produce a live cloned creature (Harris 1983). I discussed

some possible advantages of human cloning in my 1985
book, The Value of Life (Harris 1990, 2004). A defining event
in the debate was the birth of another instantly famous
female baby in the United Kingdom, Dolly the sheep,
whose birth was announced in Nature on February 27,
1997 (Wilmut et al. 1997).
Louise and Dolly proved to be healthy and, as far as is
publicly known, happy individuals who, like the more than
5 million babies since born worldwide via IVF, owe their
existence to British science and in particular to the work of
Bob Edwards and Patrick Steptoe2 (Brian 2013). We may
hope that a very large proportion of these children are glad
to be alive and glad their births were not prevented by the
suppression of the science that made them possible.
Louise Brown and Dolly are related also by the unfortunate prejudice against them from those who objected and
continue to object to the birth of each. The form of this prejudice that engages us in the debate over germline modification was articulated by a very modest and unelected body
known as the UNESCO Bioethics Committee, in justification

1. My most recent and complete work on this topic is Germ line modification and the burden of human existence, Cambridge
Quarterly of Healthcare Ethics Vol. 25 No 1 January 2016. Public interventions on this theme include a presentation at A workshop
of the United States Institute of Medicine of the National Academies Board on Health Sciences Policy, entitled Ethical and Social Policy
Considerations of Novel Techniques for Prevention of Maternal Transmission of Mitochondrial DNA Diseases. Washington,
http://www.iom.edu/Activities/Research/MitoEthics/2015-MAR-31.aspx, a presentation in the United Kingdom Parliament, Monday, February 2, 2015 (on the eve of the historic debate and vote in the U. Parliament that gave the go-ahead to mitochondrial transfer in
humans), and, most remotely, an article published in The Guardian newspaper on September 19, 2012, shortly after The UK Human Fertilization and Embryology Authority announced a public consultation on mitochondrial DNA transfer.
2. Both of whom I am very proud to say I knew personally.
Address correspondence to John Harris, DPhil, Institute for Science Ethics and Innovation, 3.614 Stopford Building, University of
Manchester, Oxford Road, Manchester M13 9PL, United Kingdom. E-mail: john.harris@manchester.ac.uk

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Germline Manipulation

of its condemnation of cloning. This resulted in the United

Nations Educational, Scientific and Cultural Organization
(UNESCO) publishing its infamous Universal Declaration
on the Human Genome and Human Rights, on November
11, 1997. This document absurdly endorses the preservation
of the human genome as common heritage of humanity as a
way of condemning cloning.
Why is that absurd? UNESCO (and many before and
since) conveniently ignores the fact that cloning is the only
reproductive method that actually preserves the human
genome intact. Indeed, cloning copies it (sometimes only
almost) exactly. Other forms of human reproduction, on the
other hand, randomly vary (often disastrously) the human
genome with each combination of the genetic material of two
or more different individuals. What human reproduction
does not do very well is improve it. As I argued in Enhancing
Evolution the human genome in its present state is a very
imperfect work in progress (Harris 2007). The problem is
that progress via Darwinian evolution is extremely slow and
the direction unpredictable, save only that it will facilitate
gene survival (Dawkins 1976). We surely need to accelerate
the development of better resistance to bacteria, disease,
viruses, or hostile environments, or of the technologies that
will be eventually necessary to find, and travel to, habitats
alternative to Earth.
Those who appeal to the common heritage of humanity
in this way see the present evolved state of the human
genome as a state that must be frozen, as far as is possible and in perpetuity, at this particular evolutionary stage.
That, I argue, is not a way to preserve the common heritage
of humanity, since that heritage only exists and can only
continue to exist if the human genome is allowed to continually evolve.
The consensus against germline interventions per se, I
have argued elsewhere long ago, is ill-conceived and it is
now crumbling (Harris 1992). The recent vote in the UK
Parliament to change the law concerning germline interventions, and the willingness of the U.S. Institute of Medicine of the National Academies, and indeed this journal
and other journals, to make a serious and objective reassessment of these issues are just two examples of the consensus crumbling (Institute of Medicine 2015; Vogel and
Stokstad 2015).
Recent papers in Nature and Science discuss possible
research and therapy using various genome modification
techniques, and were followed by the announcement that
a group in China had used such techniques in human
embryos (Cyranoski and Reardon 2015; Reardon 2015a). In
light of these and other developments, we urgently need
to reassess the safety, efficacy, and ethics of the use of such
techniques in humans and move toward a new consensus
as to the appropriate conditions for their ultimate acceptability (Baltimore et al. 2015; Cyranoski 2015; Lanphier
et al. 2015; Vogel 2015). David Baltimore and colleagues
rightly emphasize the need for such work to be carried out
in countries with a highly developed bioscience capacity
and ones in which tight regulation of such science exists
or can be established (Baltimore 2015).

December, Volume 15, Number 12, 2015

In the United Kingdom, any further such modifications

that would end up in the genome of an implanted human
embryo would have to be licensed by the UK regulatory
body, the Human Fertilization and Embryology Authority
(HFEA), which was established by Act of Parliament in
1990 (UK Parliament 1990, c.37; 2008, c.22). Such measures
would probably also need to be approved separately by
the UK Parliament, as has recently happened in the case of
MRT. In the United Kingdom we have so far had, for more
than 25 years, adequate and robust safeguards in place.
However, these follow prior years of wide public consultation, scholarly research, and authoritative reports (Department of Health and Social Security 1984), resulting in a
broad consensus on the way forward, established and continually reviewed by Parliament.
MITOCHONDRIAL REPLACEMENT THERAPY
MRT is considered by a broad consensus in the United
Kingdom as now safe enough for use in humans,
remembering that there is no such thing as safe. What is
safe enough is context relative and always involves risk
benefit analysis appropriate to the context. For example,
almost all chemical therapies used in the treatment of cancer are highly toxic, and as a result, unlike most other
pharmaceuticals licensed for human use, have never been
tested on healthy adults before clinical adoption. They
are, however, considered safe enough by cancer patients,
their families, and clinicians, in light of the lethal nature of
the alternatives.
MRT will enable some 2,500 women in the United
Kingdom to have children genetically related to them and
also avoid terrible diseases. Mitochondrial disease can be
very serious, causing conditions like Leighs disease, a
fatal infant encephalopathy, and others that waste muscles
or cause diabetes and deafness.
THE ALTERNATIVE TO MRT INVOLVES
GREATER KNOWN RISK
As I pointed out recently elsewhere in a comprehensive
discussion of these issues:
In the case of Mitochondrial disease we know that many
women will continue to desire their own genetically related
children and will continue to have them if denied or unable to
access MRT. The denial of access to MRT will not prevent serious disease being transmitted indefinitely through the generations whereas access to MRT can be expected significantly to
reduce this risk. The choice here is not between a germline
intervention which might go wrong and as a result perpetuate
a problem indefinitely and a safe alternative. It is between such
a technique and no current alternative for women who want
their own genetically related offspring and who will also act so
as to perpetuate the occurrence of disease. (Harris 2016a)

THREE-PARENT FAMILIES
The popular press usually labels MRT as the three genetic
parents process despite the fact that the third-party DNA

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The American Journal of Bioethics

contained in the donated mitochondria comprises much

less than 1% of the total genetic contribution and does not
transmit any of the traits that confer the usual family
resemblances and distinctive personal features in which
both parents and children are interested. The mitochondria
provide energy to cells, and when they are diseased, cause
inheritable harmhence the need for mitochondria
replacement therapy. No identity-conferring features or
other familial traits are transmitted by the mitochondria.
In any event, to be a parent properly so called, as opposed
to a mere progenitor, involves much more than a genetic
contribution to the child and often not even a genetic
contribution.

FUTURE GENERATIONS
Many objections to germline interventions emphasize that
such interventions differ in affecting generations down
the line (Sample 2012). But this is true not only of all
assisted reproductive technologies, but of all reproduction
of whatever kind. This so-called uncharted territory of
course involves trade-offs between benefits to people now
and concerns about future dangers (Sample 2012). The
introduction of all new technologies involves uncertainty
about long-term and unforeseen events.
This is also true of normal sexual reproduction, a
very dangerous activity indeed, and one often described as
a genetic lottery.
Every year an estimated 7.9 million children6 percent of
total birth worldwideare born with a serious birth defect of
genetic or partially genetic origin. Additional hundreds of
thousands more are born with serious birth defects of postconception origin, including maternal exposure to environmental agents, (teratogens) such as alcohol, rubella, syphilis
and iodine deficiency that can harm a developing fetus. (The
March of Dimes Birth Defects Foundation 2006)

Sexual reproduction, with its gross inefficiency in

terms of the death and destruction of embryos (estimated
to be one in three to one in five deaths per live birth),
involves significant harm to future generations but is not
usually objected to on these grounds.
If the appropriate gold standard test for permissible
risk of harm to future generations is sexual reproduction,
other germline changing techniques (other than sexual
reproduction, that is) would need to demonstrate severe
foreseeable dangers to fail. MRT will prevent serious mitochondrial disease and the suffering it causes for women
with mitochondrial disease, their own children, and countless future generations. This looks like a reasonable cost
benefit strategy to attempt.
THE USE OF CRISPR/CAS9 IN EMBRYOS
Many of the arguments rehearsed in the preceding also
apply to objections to other germline modification techniques. In a recent Statement on NIH Funding of Research

32 ajob

Using Gene-Editing Technologies in Human Embryos,

issued officially by the NIH, Francis S. Collins, MD, PhD,
Director, National Institutes of Health, stated:
The strong arguments against engaging in this activity
remain. These include the serious and unquantifiable safety
issues, ethical issues presented by altering the germline in a
way that affects the next generation without their consent.
(Collins 2015)

Serious and unquantifiable safety issues feature in

all new technologies. What is different here? Collins thinks
one important difference is absence of consent.
CONSENT
In my view, Collinss concern about consent is simply irrelevant here. It is irrelevant for the simple and sufficient reason that there are no relevant people in existence capable
of either giving or withholding consent to these sorts of
changes in their own germline. We all have to make decisions for future people without considering their inevitably absent consent. All who might be parents make
numerous decisions about issues that might affect their
future children all the time without thinking about consent
of their childrenhow could they not do so? First and
foremost, decisions in most cases of sexual reproduction
are about what genetic endowment is likely to result from
a particular pairing (or more complex combination) of sets
of chromosomes. George Bernard Shaw and Isadora Duncan were famous, but only partial and possibly apocryphal, exceptions. She, apparently, said to him something
like Why dont we have a child . . . with my looks and
your brains it cannot fail, and received Shaws more rational assessment: Yes but what if it has my looks and your
brains! Unlike most would-be parents, they did think
about what combination of their collective genes would be
advantageous or otherwise, but even they did not think
(unlike Collins) that their decision needed to wait for the
consent of the resulting child. Nobody does! All parents
decide for their present and future children until such children are capable of consenting for themselves. This is not,
of course, to say that parents and scientists should not
decide responsibly on the best available combination of
evidence and argument; this they must do. It is to say that
the basis of their decision making cannot, for obvious reasons, include the consent of the future children.
This recalls Derek Parfits famous nonidentity problem
(Parfit 1984), which shows (inter alia) that many reproductive
choices involve identity-changing interventions (e.g., different month of conception, different egg and sperm, therefore
different resulting embryo), disregarding the relevance of
such consents as this potential childs only chance of existence. Therefore, as long as the best guess is that the childs
eventual life would not be unacceptably awful, it would be
in that childs interests to be created.
Notice that those who raise issues of consent in relation
to nonexistent beings, or indeed in relation to beings

December, Volume 15, Number 12, 2015

Germline Manipulation

incapable of consent, only do so in circumstances when

they wish to claim that the relevant children would not, or
should not, have consented, rather than the reverse, and
therefore that those potential children should not be or
have been born.
If there is a discernable duty here, it is surely to create
the best possible child. That is what it is to act for the best,
all things considered (Harris 2016b). This we have moral
reasons to do, but they are not necessarily overriding reasons (Harris 2004; Harris and Soren 2000).

TRANSGENERATIONAL EPIGENETIC INHERITANCE

One further possibility that has, I believe, so far entirely
escaped attention in this context is the fact that heritable
changes are not necessarily confined to conventional germline genetic effects (Reardon 2015b). As noted recently:
The transmission of epigenetic states across cell divisions
in somatic tissues is now well accepted and the mechanisms are starting to be unveiled. The extent to which epigenetic inheritance can occur across generations is less
clear (Transgenerational Epigenetic Inheritance Workshop 2015). How, for example, can UNESCOs claim
already noted concerning the obligation to preserve the
human genome as common heritage of humanity be
applied to epigenetic effects that may only be apparent
post hoc? Should we be alarmed or comforted by this
apparent crack in the armor?
For now, we need not panic. Rather, we need to recognize that we are the products of a germline-altering process called evolution, which uses a very hit-and-miss
experimental technology sometimes politely called sexual
reproduction (and sometimes not). That process is mindbogglingly slow but it has not stopped, and we cannot
stop it except by our own extinction. We know that in the
distant future there will be no more human beings and no
more planet Earth. Either we will have been wiped out by
our own foolishness or by brute forces of nature or, I hope,
we will have further evolved by a process more rational
and much quicker than Darwinian evolution (as described
in my book Enhancing Evolution: Harris 2007). Even more
certain is that there will be no more planet Earth. Our sun
will die and with it all possibility if life on this planet.
As I say in my new book How To Be Good (Harris
2016a):
By the time this happens, we may hope that our better
evolved successors will have developed the science and the
technology needed to survive and to enable us (them) to find
and colonise another planet or perhaps even to build another
planet; and in the meanwhile to cope better with the problems
presented by living on this planet. Most importantly perhaps
the problem of how to be good, or how to be good enough to
ensure the survival of what may be the only sorts of beings
anywhere in the universe capable of caring about their own
survival and the survival of others.

Steven Hawking initially predicted that we might have

about 7.6 billion years to go before the earth gives up on

December, Volume 15, Number 12, 2015

us, but he recently revised his position in relation to the

earths continuing habitability as opposed to its physical
survival: We must also continue to go into space for the
future of humanity, he said recently. I dont think we
will survive another thousand years without escaping
beyond our fragile planet3 (Big Think Editors 2010; Jha
2013; OMalley-James et al. 2012).
We will at some point have to escape beyond both our
fragile planet and our fragile nature. One way to enhance
our capacity to do both these things is by improving on
human nature where we can do so in ways that are safe
enough. The debate of which this article is a part is about
just that. It is about what methods are safe enough, given
what is at stake. This is a classic baby and bath-water
problem. An over-precautionary approach may stifle the
science that we need to make us safe; a reckless approach
will be equally disastrous.
THE WAY FORWARD
As noted in the preceding, I concur with the suggestion of
David Baltimore and colleagues that in countries with a
highly developed bioscience capacity and ones in which
tight regulation of such science exists or can be established, it should be possible to pursue the science to the
point at which safety and efficacy can be established (Baltimore et al. 2015). Once a new and beneficial technology
has been demonstrated to be safe enough for use in or
by humans, any decent society will wish to ensure that citizens are not denied the opportunity to choose for themselves whether they wish to avail themselves of these
benefits.
For IVF and other assisted reproductive technologies
and now for MRT, the UK model of a regulatory authority
like the HFEA plus parliamentary oversight has proven to
work well. In the case of CRISPR/Cas9 and other germline
modification technologies, once research and development
have progressed to the point where we can properly assess
their likely safety in humans, I hope and expect that in the
United Kingdom, these would, after public discussion and
wide consultation, also be put to Parliament (as was the
case with MRT) for debate as to whether they could also be
remitted to the HFEA or some similar body for license and
oversight. In the United States and elsewhere, such a process would need to be established and an acceptable and
accepted regulatory body brought into existence. This may
not be easy, but the UK experience has established proof
both of principle and of practice. &

3. Steven Hawking famously estimated we have about 7.6 billion

years to go: http://bigthink.com/dangerous-ideas/5-stephenhawkings-warning-abandon-earth-or-face-extinction.
Hawking
recently revised this estimate with a different event horizon:
http://www.theguardian.com/science/2013/nov/12/stephenhawking-physics-higgs-boson-particle. Different recent studies
indicate that a realistic figure would be 2.8 billion years: http://
arxiv.org/pdf/1210.5721v1.pdf.

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The American Journal of Bioethics

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