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COMMENTARY
Evolutionary algorithms and synthetic biology
for directed evolution: commentary on ‘‘on
the mapping of genotype to phenotype in evolutionary
algorithms’’ by Peter A. Whigham, Grant Dick,
and James Maclaurin
Douglas B. Kell1,2,3
 The Author(s) 2017. This article is an open access publication
Abstract I rehearse two issues around the commentary of Whigham and col-
leagues. (1) There really are many more reasons than those given as to why natural
evolution cannot reasonably find or select the ‘optimal’ individual. (2) A series of
experimental molecular biology programmes, known generically as directed evo-
lution, can use operators and selection schemes that natural evolution cannot. When
developed further using the methods of synthetic biology, there are no operators or
schemes for in silico evolution that cannot be applied precisely to directed evolu-
tion. The issues raised apply only to natural evolution but not to directed evolution.
Keywords Directed evolution  Synthetic biology  Navigating search spaces 
Intelligent operators
1 Introduction
The basic thesis of Whigham et al. [1] is that ‘molecular biology’, by which they
actually mean ‘mechanisms of natural evolution’, is a relatively poor guide to the
kinds of in silico optimisation problems that are typically the targets of evolutionary
algorithms. While I have no disagreement with that high-level sentiment (indeed I
This comment refers to the article available at doi:10.1007/s10710-017-9288-x.
& Douglas B. Kell
dbk@manchester.ac.uk
1 School of Chemistry, The University of Manchester, 131, Princess St,
Manchester, Lancs M1 7DN, UK
2 The Manchester Institute of Biotechnology, The University of Manchester, 131, Princess St,
Manchester, Lancs M1 7DN, UK
3 Centre for Synthetic Biology of Fine and Speciality Chemicals, The University of Manchester,
131, Princess St, Manchester, Lancs M1 7DN, UK
123
Genet Program Evolvable Mach
DOI 10.1007/s10710-017-9292-1
have argued that biological genotype-phenotype mapping is entirely analogous to
GP [2]!), they do omit some of the chief arguments as to why this is so. They also
entirely disregard a very large literature using ‘molecular biology’ that is not
‘natural’ evolution but is aimed at producing (optimising) biological products via a
set of processes typically referred to as ‘directed evolution’ (DE). These are
therefore the points that I cover. A more extended overview of modern directed
evolution may be found in [3].
2 Why natural evolution is not necessarily ‘optimal’ in the sense
of assuming that only the fittest survive
Whigham et al. [1] listed a series of reasons outlined by Dawkins [4] as to why this
is so. Natural evolution is based on the processes of (i) diversity creation within a
population (some or all of whom may interact and breed), (ii) ‘evaluation’ of
fitness(es) and (iii) selection. Each of these may contribute to the fact that, even over
an arbitrary time, populations do not converge such that they are populated only by
individuals of the highest possible fitness for that (nominally unchanging)
environment or objective function. Consequently there are many more reasons, at
different levels of detail, as to why this is the case. Some include:
At level (i) (populations and diversity):
• Populations are normally not panmictic (where all can breed with all) so global
optimality is then impossible.
• The size of the search space is so much greater than any population size that no
test of optimality (in the NP complete sense) is possible; even 30mers of
unmodified DNA have 1018 possible genotypes, which as 5 lm spots each
would cover 29 km2 [5].
• When the population size is too small, some individuals who may yet contribute
to optimality are simply squeezed out (especially in mutation-only organisms);
this is known as Muller’s ratchet (e.g. [6–8]).
• Weak mutation and strong selection (see [9–14]) is common in many
ecosystems, and traps individuals and populations in local minima (or maxima)
from which neutral evolution cannot help them escape.
• Given that 3/64 codons are stop codons [15], the required mutation or
recombination rates to explore the entire fitness landscape in a sensible time are
incompatible with the sustenance of the population, given that most mutations
are deleterious [16].
At level (ii) (fitnesses):
• The linkage between genotype, fitness and phenotype may often be very weak
[17], for all kinds of reasons including epistasis [3] and the nonlinear properties
of biochemical networks [18, 19].
Genet Program Evolvable Mach
123
• Non-genetic factors may intervene, e.g. while reproductive fitness is normally
selected for, longevity may be preferred for social reasons (grandparents help
with childcare, etc.); there is not just one fitness (hence optimality).
At level (iii) (selection)
• At the population level, while selection is based on the offspring more than the
parents, simple stochastic events may blur the link between selection and fitness.
• For all kinds of reasons, selection is likely to (and does [20]) favour a
differentiated population.
3 Directed evolution (DE)
Directed evolution (a subset of closed loop optimisation [21]) refers to a set of
biochemical procedures that are akin to natural evolution (in that they involve
diversity creation and fitness-based selection). However, here the selection step is
performed not by the organisms within their environment (as in natural evolution)
but by an experimenter who has a specific goal, and thus selects individuals for
further improvement based on those in a given generation. This is a glorified form of
breeding (as in plant [22] and animal [23] breeding), but is typically done for
improving individual proteins (e.g. as biocatalysts [24, 25]), where it is indeed
sometimes known [17, 26, 27] as ‘molecular breeding’.
Classical methods of diversity generation used random in vitro methods of
mutagenesis (e.g. [24, 28, 29]), or recombination (known here as ‘DNA shuffling’
[30, 31]), and selection was typically done on the basis of screening via a target
biochemical assay (rather than true growth rate selection, e.g. as in [32, 33]).
Nowadays, the trend is to use the methods of synthetic biology, in which the
experimenter has complete (or statistical) control over precisely which amino acid is
expressed at which residue (e.g. [34]), literally by synthesising the encoding DNA,
coupled to sophisticated in silico sequence optimisation methods (e.g. [35]). This
synbio-based DE is formally equivalent to classical DE, but is typically cast in terms
of a Design-Build-Test-Learn cycle [36–38]. Knowledge of gene sequences can be
exploited directly [5, 39–41], and in some cases landscapes may be searched
exhaustively [42]. What we learn from this (see also [43]) is that protein fitness
landscapes are rugged but not pathologically so (e.g. [3, 44]), and that the
evolutionary landscape metaphor can provide insights into both innovation [45] and
science more generally [46].
This brings me nicely to my last point, elaborated in detail in Table 1 of [3],
where we point out that many aspects of ‘classical’ and synthetic biology-based
directed evolution differ massively from the same ones when they are compared to
natural evolution, e.g. in terms of selection (pressure), mutation rates and their
randomness, evolutionary ‘memory’, and the degree of epistasis allowed or
encouraged. Even where these are solely quantitative differences, the effective
emergent properties can make them appear to be qualitatively different. In
Genet Program Evolvable Mach
123
particular, by controlling explicitly (at least statistically) the protein sequences in
the population, we can combine the exploration and exploitation of fitness
landscapes in DE by keeping low-fitness members in the population in a manner
(arbitrarily long) that natural evolution would not be able to at any reasonable
selection pressure. Notwithstanding, all these methods involve ‘molecular biology’.
In conclusion, if ‘molecular biology’ methods are applied to synbio-based
directed evolution, any operator can be used, since any subsequent genetic sequence
can be based arbitrarily on what has been seen at any time before, because it can be
made de novo. These operators include very high mutation rates [16], three- (or
more-)way matings, matings based on information gain and the Pareto front [47],
complex crossover and mutation schemes such as ‘uniform’ crossover [48], explicit
coevolutions based on sequence alignments and 3D structures (e.g. [49]), and so on.
This, indeed, is precisely why the new methods of synthetic biology are so very
powerful [3, 50]. Consequently, while recognising that natural evolution may be a
rather poor guide to the utility of evolutionary algorithms in optimisation [1], we
would stress the field of directed evolution, especially that based on synthetic
biology, provides a highly productive domain for the cross-fertilisation of
evolutionary algorithms and molecular biology.
Acknowledgements I thank the Biotechnology and Biological Sciences Research Council for financial
support (Grant BB/M017702/1). This is a contribution from the Manchester Centre for Synthetic Biology
of Fine and Speciality Chemicals (SYNBIOCHEM).
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, dis-
tribution, and reproduction in any medium, provided you give appropriate credit to the original
author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were
made.
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Evolutionary algorithms and synthetic biology for directed evolution: commentary on “on the mapping of genotype to phenotype in evolutionary algorithms” by Peter A. Whigham, Grant Dick, and James Maclaurin

Noriomi Kuroki

Hiroko Kashiwagi

Miho Ota

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Toshio Ota

Brain structure differences among male schizophrenic patients with history of serious violent acts: an MRI voxel-based morphometric study

Journal of International
    Humanitarian Action
Sezgin Journal of International Humanitarian Action  (2017) 2:1 
DOI 10.1186/s41018-016-0017-5BOOK REVIEW Open AccessReview of “For Humanity or For the Umma?
Aid and Islam in Transnational Muslim
NGOs” by Marie Juul Petersen
Zeynep SezginBook details
Marie Juul Petersen, For Humanity or For the Umma? Aid and Islam in Transnational Muslim NGOs, London: Hurst
Publishers; 2014, 356 pages, ISBN-13: 978-1849044325, ISBN-10: 1849044325
Keywords: Muslim humanitarian and development NGOs, Gulf-based/UK-based NGOs, Sacred/Islamic aid cultures,
Sacralization/secularization of aidIn For Humanity or For the Umma? Aid and Islam in
Transnational Muslim NGOs, Marie Juul Petersen,
researcher at the Danish Institute for Human Rights,
provides a systematic empirical analysis of Muslim non-
governmental organizations (NGOs) and the role Islam
plays in their provision of humanitarian aid.
When people hear the word “humanitarian,” most of
them envision the various slogans and attention-grabbing
logos used by well-financed NGOs with headquarters in
Europe and North America, such as CARE and Médecins
Sans Frontières (MSF). Also, they might think of the Red
Cross or Red Crescent organizations, not to mention the
white Land Cruisers and tarps marked with the insignia of
United Nations (UN) agencies, such as the United Nations
High Commissioner for Refugees (UNHCR) and the
World Food Program (WFP). In some cases, the term
may even call to mind a few large donors, as represented
in the Development Assistance Committee (DAC) of the
Organisation for Economic Co-operation and Develop-
ment (OECD).
Together, these well-established actors “constitute the
multi-billion dollar visible face of humanitarianism. They
dominate international debates, coordination bodies,
advocacy campaigns, funding appeals and media atten-
tion, and thus dictate the principles of humanitarian
action.” In essence, they constitute a “Northern/Western
humanitarian movement, rooted in various traditions ofCorrespondence: zeynep.sezgin@univie.ac.at
Department of Development Studies, University of Vienna, Sensengasse 3/2/
2, 1090 Wien, Austria
© The Author(s). 2017 Open Access This article
International License (http://creativecommons.o
reproduction in any medium, provided you giv
the Creative Commons license, and indicate ifcharity and philanthropy and in the civilizing impulses
of the Enlightenment, as well as their subsequent
manifestations in the expanses of what we now call the
global south” (Donini 2010, p. 220).
In the shadow of this group, however, other types of ac-
tors often referred to as “non-traditional,” “new,” or
“emergent” humanitarians have been involved in humani-
tarian action. For example, faith-based organizations have
always provided aid to the needy. Yet, in recent years, the
number, size, and impact of especially Muslim NGOs,
many of which have a migrant background, have rapidly
grown. Today, these organizations make up a prominent
portion of the humanitarian community. In addition to
providing aid, protection, and advocacy, some also play
more political, economic, or security roles (Sezgin and
Dijkzeul 2016).
Although Muslim NGOs may have access, legitimacy,
and capacities in crisis zones, they are not seen as equals
and are thus excluded from the humanitarian system by
the more traditional humanitarian actors who see them-
selves as standard bearers (Labbé 2012). Similarly,
academic, public, and political discussions have often
portrayed Muslim NGOs as a monolithic bloc that
differs from the generally Christian, secular, liberal, and
democratic Northern/Western humanitarian NGOs.
Without doubt, the impression that the nature of
Muslim NGOs and of Northern/Western NGOs is
opposite and contradictory has led to a dualistic inter-
pretation that disregards the many nuances and excep-
tions of each group individually as well as the internalis distributed under the terms of the Creative Commons Attribution 4.0
rg/licenses/by/4.0/), which permits unrestricted use, distribution, and
e appropriate credit to the original author(s) and the source, provide a link to
changes were made.
Sezgin Journal of International Humanitarian Action  (2017) 2:1 Page 2 of 3heterogeneity of both Muslim and Northern/Western
NGOs.
Furthermore, the post-9/11 global security regime and
the so-called War on Terror have increasingly securitized
civil society and have cast a veil of suspicion and mistrust
over Muslim NGOs. In particular, these organizations are
often thought to be potentially susceptible to extremism,
radicalism, and terrorist abuse or to be political actors
who finance, participate in, or otherwise support militant
Islamic activism.
Studies that focus on faith-based NGOs and their re-
sponses to humanitarian crises, although broad-ranging,
have four shortcomings. First, most of these studies con-
centrate on humanitarian organizations run by Catholic
and Protestant Churches, often ignoring the role of
Islam and Muslim NGOs in humanitarian action (e.g.,
Ferris 2005; Thaut 2009). Second, various studies men-
tion the relevance of Muslim NGOs in humanitarian
crises, yet only a few offer a systematic empirical analysis
of their ideologies, aims, activities, and strategies (e.g.,
Beigbeder 1991; Savage and Harvey 2007). Third, sacred
and secular NGOs have often been represented as
contradictory actors that exist in parallel, unconnected
spheres, a belief that contributes to the “good NGO/bad
NGO” narrative (Wilson and Mavelli 2014). As a result,
a research gap continues to exist in terms of whether
and how Islamic NGOs can bridge sacred and secular
aid cultures and respond to diverse groups of actors
(including their own staff, volunteers, donors, govern-
mental agencies, and so on) whose expectations are
complex and sometimes contradictory and, in this
respect, whether and to what extent these organizations
differ from traditional humanitarian actors. And last but
not least, the literature on Muslim NGOs shares an
“instrumentalist” understanding of these organizations,
as Juul Petersen (2014, p. 4) points out, casting them as
tools either in struggles for the Islamization of society or
in the implementation of humanitarian and development
activities (as in the case of the cultural-proximity thesis)
(e.g., De Cordier 2009; Salehin 2016).
Because it is often not clear why and how Muslim
NGOs engage in humanitarian action, several questions
have become pertinent. How do these organizations
understand and present themselves, their religion, and
the aid they provide? What factors influence their
ideologies, aims, activities, and strategies? How do they
position themselves in relation to the Islamic and secular
aid cultures? How do they react to the securitization of
civil society and the growing sense of suspicion and
mistrust toward them? Whether and how do they differ
from the traditional humanitarian actors?
In her book For Humanity or For the Umma? Aid and
Islam in Transnational Muslim NGOs, Petersen
addresses these questions by choosing as case studiesfour of the biggest transnational Muslim NGOs: two Gulf-
based NGOs (International Islamic Charitable Organization
and International Islamic Relief Organization) and
two UK-based NGOs (Islamic Relief and Muslim
Aid). The author has drawn on extensive field research
conducted between 2007 and 2013 in Britain, Kuwait,
Saudi Arabia, Lebanon, Jordan, and Bangladesh, which in-
volved more than 100 interviews with participants in these
organizations. The book is divided into eight chapters.
Following the Introduction, Petersen presents three
dichotomies between the traditional Islamic and secular
aid cultures—that is, the different contexts in which trans-
national Muslim NGOs emerged. The first dichotomy is
between solidarity with the umma (the community of
Muslims) and the universal notion of humanity. The
second dichotomy is between the notions of neutrality
and of justice. Finally (and to some extent underlying the
other two dichotomies) is the dichotomy between the
secularist and the religious.
Humanitarian NGOs, like all other types of organiza-
tions, address particular stakeholders in order to gain
and maintain legitimacy. An increase in organizational
legitimacy means an increase in support, resources, and
hence survival prospects (Meyer and Rowan 1977). The
more the aims and activities of an organization resonate
with the expectations of its stakeholders, the more legit-
imate an organization seems and the more support it
will get (Benford and Snow 2000). In the case of
humanitarian NGOs, access to those in need and the
security of their staff in crisis zones also increase in rela-
tion to greater legitimacy (Sezgin and Dijkzeul 2013).
Owing to the dichotomies noted above, secular and
traditional Islamic aid cultures provide fundamentally
different conditions of legitimacy in terms of the extent
to which their actions are perceived as desirable, proper,
or appropriate within their institutional environment
(Suchman 1995).
Local humanitarian NGOs draw on the ideologies, tra-
ditions, principles, and symbols of existing aid cultures,
their choices being shaped and constrained by the
particular cultural context in which they and their stake-
holders are situated. For transnational humanitarian
NGOs active in multiple cultural contexts, the condi-
tions for gaining and maintaining legitimacy are more
complex. These groups must justify themselves to di-
verse groups of actors who have complex and sometimes
contradictory expectations, including their own staff and
volunteers, donors, governments of the countries where
they are headquartered, governments in the humanitarian
crisis zones, other humanitarian organizations (local and
international), and the beneficiaries of their activities.
Accordingly, in Chapter 3, Petersen discusses the dif-
ferent ways in which these organizations have positioned
themselves relative to the two aid cultures. She presents
Sezgin Journal of International Humanitarian Action  (2017) 2:1 Page 3 of 3two main arguments: The first is that before 9/11 and
the War on Terror, transnational Muslim NGOs consid-
ered themselves part of an Islamic aid culture rather
than part of humanitarian aid culture, thus focusing on
fellow Muslim donors and recipients; the second is that
the situation changed after these events, and trans-
national Muslim NGOs were at once both encouraged
and forced to relate explicitly to the culture of humani-
tarian aid, thus transforming them into sites of cultural
encounter.
In Chapters 4, 5, 6, and 7, Petersen examines the
relationship between the case studies and the Islamic
and secular aid cultures, specifically the ways in which
these two distinct aid cultures shape these organizations’
identities and ideologies, and in turn how Muslim NGOs
are influencing the aid cultures from which they
emerged. She provides various examples of how the
analyzed Muslim NGOs navigate between the Islamic
and secular aid cultures to increase their autonomy and
resources, drawing on, accommodating, rejecting, or
bridging different cultural repertoires. Chapter 8 sum-
marizes the main research findings and the implications
for the field of aid provision.
This book is an important contribution to the aca-
demic, public, and political discourse on Muslim NGOs.
According to the findings presented therein, the domin-
ant notion that Muslim NGOs are a monolithic bloc
existing largely in parallel with and unconnected to
secular/Northern/Western humanitarian NGOs is often
in harsh contrast to the empirical realities on the
ground. The author does an admirable job of illustrating
how the four organizations chosen as case studies
present two different kinds of ideologies and rest on
different conceptions of aid and Islam and different
interpretations of the cultures of Islamic aid and devel-
opment: one is a sacralized aid ideology, the other a
secularized aid ideology. Their attempts to bridge
secular and Islamic aid cultures can be conceptualized
in terms of two overall strategies: “secularizing Islam”
and “sacralizing aid.” “By secularizing Islam, the two
Gulf-based NGOs seek to adjust their ideologies to
the culture of aid, thereby hoping to create resonance
with e.g. the UN and Western aid organizations. Likewise,
by sacralizing aid, the two UK-based NGOs hope to create
ideologies that simultaneously appeal to conservative
Muslim donors and secular aid agencies” (Juul Petersen
2014, pp. 15–16).
This book is also a great read, because it serves to help
us better understand the ways in which Muslim NGOs
bridge Islamic and secular aid cultures in an attempt to
fulfill their stakeholders’ diverse expectations. In
addition, the author shows that the degree to which an
organization is secular or religious remains an empirical
question and may change from (transnational) contextto context, often being based on pragmatic decisions
that these organizations make to increase their resources
and hence their survival prospects.
Abbreviations
DAC: Development Assistance Committee; MSF: Médecins Sans Frontières;
NGOs: Non-governmental organizations; OECD: Organisation for Economic
Co-operation and Development; UN: United Nations; UNHCR: United Nations
High Commissioner for Refugees; WFP: World food program
Acknowledgements
No acknowledgements.
Funding
No funding.
Availability of data and materials
Not applicable.
Competing interests
The author declares that she has no competing interests.
Received: 13 December 2016 Accepted: 22 December 2016
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Review of “For Humanity or For the Umma? Aid and Islam in Transnational Muslim NGOs” by Marie Juul Petersen

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G. A. Malik

N. P. Robertson

JOURNAL CLUB
Treatments in Alzheimer’s disease
G. A. Malik1 • N. P. Robertson1
Published online: 24 January 2017
 The Author(s) 2017. This article is published with open access at Springerlink.com
Introduction
Alzheimer’s disease (AD) is the commonest cause of
dementia worldwide. However, no treatment is yet avail-
able to halt or reverse the underlying pathology of estab-
lished disease. Advances in the management of other
common diseases and an improvement in general health
have resulted in an increasingly elderly population so that
the prevalence of AD is expected to increase significantly
over time. In 2015, almost 47 million people worldwide
were estimated to be affected by dementia, with estimates
of 75 million by 2030, and 131 million by 2050, with the
greatest increase expected in low-income and middle-in-
come countries. The socio-economic burden of dementia
has become immense and the development of effective
interventions has become one of the greatest priorities for
health care research in the twenty-first century.
Current treatments for AD include acetyl cholinesterase
inhibitors and the N-methyl-D-aspartate receptor antago-
nist Memantine, but offer only symptomatic rather than
disease-modifying benefits. In spite of the urgent require-
ment, disease-modifying therapies have so far proved
elusive, in particular with almost universally disappointing
results in late stage clinical trials for therapies that target
aspects of amyloid metabolism. However, results from a
recent phase 1b trial, published in 2016, have offered new
hope. Aducanumab, a human monoclonal antibody that
selectively targets aggregated Ab, has been shown to
remove the build-up of the Alzheimer’s protein amyloid in
the brain and slow the decline in memory and thinking
skills in people with AD. This month’s journal club looks
at this and two other papers reporting recent clinical trials
in AD which together offer a window into potential future
therapeutic directions in this devastating disorder.
The antibody aducanumab reduces Ab plaques
in Alzheimer’s disease
This paper provides interim results from a double-blind,
placebo- controlled phase 1b randomized trial (PRIME). Its
primary outcome was to investigate safety, tolerability,
pharmacokinetics, and pharmacodynamics of monthly
infusions of aducanumab in patients with prodromal or
mild AD with brain Ab pathology confirmed by molecular
positron emission tomography (PET) imaging. 165 partic-
ipants were randomized across 33 centres to receive
monthly infusions of placebo, or 1, 3, 6, or 10 mg/kg doses
of aducanumab for 12 months. 40 patients dropped out,
leaving between 21 and 32 individuals per group for
analysis. The primary outcome was reduction in brain Ab
plaques as measured by florbetapir PET imaging in a dose-
and time-dependent fashion at baseline, six months, and
12 months. Additional cognitive tests were also performed
but were exploratory as the study was not powered to
detect clinical change.
At 6 and 12-month intervals there was a significant
dose-dependent reduction of Ab deposits. In the placebo
group, the florbetapir standardized average uptake value
ratio (SUVR) was 1.44, compared to 1.16 in the 10 mg/kg
group. The reduction in plaque load was seen in partici-
pants with both prodromal and mild AD, and regardless of
ApoE4 carrier status and reduced brain Ab in a dose- and
time-dependent manner. The most common adverse effects
& N. P. Robertson
robertsonnp@cardiff.ac.uk
1 Institute of Psychological Medicine and Clinical
Neurosciences, Cardiff University, Cardiff CF14 4XW, UK
123
J Neurol (2017) 264:416–418
DOI 10.1007/s00415-017-8395-1
were amyloid-related imaging abnormalities (ARIA),
headache, urinary tract infection and upper respiratory tract
infection. ARIA-vasogenic oedema occurred in no patients
in the placebo group but up to 41% of the high dose group.
ARIA although not fully understood, generally occurred
early in the course of treatment and is likely to be related to
increased extracellular fluid, however, no patient were
hospitalised for this and there were no drug related deaths.
Comment and conclusion. Based on its primary out-
comes the PRIME study shows that aducanumab penetrates
the brain and decreases Ab in patients with AD in a time and
dose-dependent manner. With only 165 participants the
study was not powered to detect clinical change so that the
preliminary findings of a slowing of clinical decline mea-
sured by Clinical Dementia Rating (Sum of Boxes and Mini
Mental State Examination scores versus placebo at
12 months) must be interpreted with some caution. The
greatest effect in reducing brain Ab plaques was observed in
the 10 mg/kg group (p\ 0.05 versus placebo), and whereas
significant Ab reduction was detectable by 6 months, any
clinical effects were not seen until 12 months. Analysis also
suggested that performance on the CDR-SB and the MMSE
stabilized only in patients who had a substantial reduction in
amyloid at one year. Patients for whom there was no
reduction in imaging correlates of Ab levels, declined
cognitively in a similar pattern to the placebo group.
The authors acknowledged several study limitations of
the PRIME phase 1b study, including staggered parallel-
group design, small sample sizes, limited region (USA only),
and possible partial unblinding due to the imaging frequency
required following ARIA. However, this study suggests that
a reduction of brain Abmay confer a clinical benefit, thereby
supporting the amyloid hypothesis and providing impetus to
research in this field, including unravelling the exact
molecular basis of clearance of Ab clearance from the brain
following aducanumab. The results from this Phase 1b study
support results from earlier preclinical trials demonstrating
aducanumab brain penetration, target engagement, and dose-
dependent clearance of Ab plaques, and if confirmed in
future studies powered to detect clinical benefit studies
would provide support for aducanumab as an Ab-removing,
disease-modifying therapy for AD.
Sevigny J et al (2016) Nature 537:50–56.
Efficacy and safety of tau-aggregation inhibitor
therapy in patients with mild or moderate
Alzheimer’s disease: a randomized, controlled,
double-blind, parallel-arm, phase 3 trial
Based on the previous potential efficacy of methylthion-
inium chloride in patients with AD, a modified stable re-
duced form of the methylthioninium moiety was identified
as a potential therapeutic agent. Leuco-methylthioninium
bishydromethanesulfonate (LMTM) acts as a selective
inhibitor of tau protein aggregation both in vitro and in
transgenic mouse models. The aim of this study was to
determine whether LMTM was safe and effective in
modifying disease progression in patients with mild to
moderate AD. The primary outcome measure was pro-
gression on the Alzheimer’s Disease Assessment Scale-
Cognitive Subscale (ADAS-Cog) and the AD Co-operative
Study-Activities of Daily Living Inventory (ADCS-ADL)
scales from baseline, assessed at week 65 in the modified
intention-to-treat population.
This was a large, multinational trial of 15 months
duration. It was a randomized, controlled, double-blind,
parallel-group trial involving 115 academic centres and
private research clinics in 16 countries in Europe, North
America, Asia, and Russia involving patients younger than
90 years with mild to moderate Alzheimer’s disease.
Patients taking other medicines for Alzheimer’s disease
were not excluded as the study group felt it infeasible not to
allow their inclusion. Participants were randomly assigned
(3:3:4) oral tablets to 75 mg LMTM twice a day, 125 mg
LMTM twice a day, or control (4 mg LMTM twice a day
to maintain blinding with respect to urine or faecal dis-
colouration). Randomisation was achieved via an interac-
tive web response system and all participants and all
assessors were masked to treatment assignment throughout
the study.
In total 891 participants were assigned to treatment (357
to control, 268–75 mg LMTM twice a day, and
266–125 mg LMTM twice a day). Neither co-primary
outcomes demonstrated treatment benefit at any dose:
ADAS-Cog score compared with control (n = 354, 6.32,
95% CI 5.31–7.34): 75 mg LMTM twice a day (n = 257)
-0.02, -1.60 to 1.56, p = 0.9834, 125 mg LMTM twice a
day (n = 250) -0.43, -2.06 to 1.20, p = 0.9323 and
change in ADCS-ADL score compared with control
(-8.22, 95% CI -9.63 to -6.82): 75 mg LMTM twice a
day -0.93, -3.12 to 1.26, p = 0.8659; 125 mg LMTM
twice a day -0.34, -2.61 to 1.93, p = 0.9479). The most
common adverse events were gastrointestinal and urinary
effects with both high doses of LMTM, and were the
commonest causes for discontinuation. Non-clinically sig-
nificant dose-dependent reductions in haemoglobin con-
centrations were the most commonly identified laboratory
abnormality. Amyloid-related imaging abnormalities were
noted in less than 1% (8/885) of participants.
Comment and conclusion. As with previous study’s
targeting tau protein accumulation analysis of the primary
outcomes for this study was negative and the results do not
suggest benefit of LMTM as an add-on treatment for
patients with mild to moderate Alzheimer’s disease.
Findings from a recently completed 18-month trial of
J Neurol (2017) 264:416–418 417
123
patients with mild Alzheimer’s disease are to be released in
the near future.
Gauthier S et al (2016) The Lancet 388(10062):
2873–2884.
Towards personalised intervention in Alzheimer’s
disease
This final paper by Peng et al. is a review of the current
understanding of risk factors and intervention strategies in
AD and provides a practical alternative approach in
addressing the considerable challenges of treating patients
with Alzheimer’s. The authors suggest that these chal-
lenges commonly occur as a result of the heterogeneity in
disease aetiology, which involves complex and divergent
pathways and that more detailed patient stratification is
required to inform intervention strategies which can be
tailored for individual patients. They argue that this
approach would provide improved patient management
more focussed clinical trials and would also have potential
for more personalised intervention in AD.
The authors suggest that the required information that
would allow improved patient stratification centres on
demographic and biological data. The demographic data
includes APOE genotype, age, gender, education, envi-
ronmental exposure, life style, and medical history,
whereas the biological data might include genome
sequencing, imaging, biomarkers and functional assays on
patient-specific induced pluripotent cells. Intervention
strategies based on physical activity, brain stimulation,
social communication, diet and drugs are reviewed as well
as a stage specific intervention strategy.
Comment and conclusion. Admittedly intervention
strategies are limited currently and this review paper offers
a practical approach to modify risk factors and better target
preventative treatments. It is proposed that the demo-
graphic and in-depth information can also generate focus-
sed preventive strategies to limit the rate of conversion
from mild cognitive impairment to dementia.
Peng X et al (2016) Genomics Proteomics Bioinfor-
matics 14:289–297.
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://crea
tivecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a
link to the Creative Commons license, and indicate if changes were
made.
418 J Neurol (2017) 264:416–418
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