RESEARCH NEWS & VIEWS
specific T-cell-driven immune response that is
normally seen during organ rejection. To test
this possibility, Zhao and co-workers injected
iPS cells into mice lacking subsets of T cells —
either CD4+ T-helper cells or CD8+ cytotoxic
T cells. Under these conditions, teratomas
could grow. The authors also show that the
immunogenicity of iPS-cell-derived terato-
mas results from a specific T-cell response to
products of Hormad1 and Zg16.
The observation that even autologous
mouse iPS cells are rejected by a specific
immune response in matched hosts is quite
unexpected. But although these findings
serve as a cautionary note for the ultimate
therapeutic use of iPS cells, many questions
remain.
For example, it is unclear why and how the
nine genes become activated in iPS cells but
not in ES cells. It has recently been suggested3
that the reprogramming process introduces
epigenetic and genetic abnormalities into iPS
cells, which is one conceivable way in which
gene-expression patterns could be perturbed.
In addition, an influence of the cell type of ori-
gin on the immunogenic properties of result-
ant iPS cells must be explored, given that iPS
cells from different somatic cells can exhibit
distinct molecular and functional properties5,6.
Most importantly, it should be determined
whether the different types of differentiated
cells derived from iPS cells will also elicit an
immune response after transplantation.
Indeed, immature iPS cells as used in this
study4 would never be used for transplan-
tation in a clinical setting, and it is unclear
whether tumour antigens would continue to
be expressed after differentiation into thera-
peutically relevant cell types. Notably, previous
work has shown7 that haematopoietic progeni-
tors derived from iPS cells and matured in vitro
can successfully engraft in genetically matched
mice without obvious rejection, although the
recipient animals had to be irradiated first.
Another key question is to what extent the
reprogramming method might influence the
immunogenicity of resultant iPS cells. The
authors’ observation that iPS cells generated
using the episomal approach are less immuno-
genic than those generated using viral vectors
is promising, because it suggests that alternative
methods may entirely prevent immunogenicity.
Lastly, whether human iPS cells trigger
immunogenicity must be investigated. A way
to do this is to test whether teratomas derived
from human iPS cells are rejected in mice
carrying a genetically matched, humanized
immune system.
Regardless of the answers to the outstanding
questions, this and other recent studies reach
one common conclusion: researchers must
learn more about the mechanisms underlying
cellular reprogramming and the inherent simi-
larities and differences between ES cells and
iPS cells. Only on careful examination of these
issues can we know whether such differences
1 6 6 | NAT U R E | VO L 4 7 4 | 9 J U N E 2 0 1 1
pose an impediment to the potential therapeu-
tic use of iPS cells, and how to address them.
In any case, these findings should not affect
the utility of iPS-cell technology for studying
diseases and discovering drugs in vitro3. ■
Effie Apostolou and Konrad Hochedlinger
are at the Howard Hughes Medical Institute,
Center for Regenerative Medicine and Cancer
Center, Massachusetts General Hospital,
Boston, Massachusetts 02114, USA. They
are also in the Department of Stem Cell and
Regenerative Biology, and at the Harvard Stem
Cell Institute, Harvard University.
EPI D EM I O LOGY
How common is
autism?
Autism spectrum disorders vary greatly in severity. By including children in
regular education who received no special help, an epidemiological study has
found these disorders to be up to three times more prevalent than thought.
C AT H E R I N E L O R D
A
utism spectrum disorders (ASDs)
encompass autism, Asperger’s syn-
drome and other related conditions.
Core features include difficulties in basic
social and communicative behaviours such as
eye contact, intonation and facial expressions;
and repetitive behaviours and restricted inter-
ests, from finger mannerisms to preoccupation
with heating vents. The prevalence of ASDs
has been considered to be just over 1% (ref. 1).
However, in a provocative, carefully executed
study published in The American Journal of
Psychiatry, Kim et al.2 present evidence for
surprisingly high rates of these disorders —
3.74% in males and 1.47% in females — in
school-age children in a South Korean com-
munity. Remarkably, more than two-thirds
of the children diagnosed with an ASD in
this study were receiving no special help and
had no previous psychiatric or developmental
diagnoses.
Although ASDs are defined by the shared
difficulties mentioned above, anyone who
has met more than one person with an ASD is
struck by the differences between these indi-
viduals. With eye contact, for example, there
may be active avoidance, staring for too long
or a lack of the usual timing of gaze. Variations
in autism severity, cognitive skills and language
levels are apparent even between family mem-
bers — including identical twins — who have
autism3. In the search for explanations for this
variation, epidemiological studies are essen-
tial and can also identify factors that might
© 2011 Macmillan Publishers Limited. All rights reserved
e-mail: khochedlinger@helix.mgh.harvard.edu
1. Takahashi, K. & Yamanaka, S. Cell 126, 663–676
(2006).
2. Stadtfeld, M. & Hochedlinger, K. Genes Dev. 24,
2239–2263 (2010).
3. Wu, S. M. & Hochedlinger, K. Nature Cell Biol. 13,
497–505 (2011).
4. Zhao, T., Zhang, Z.-N., Rong, Z. & Xu, Y. Nature 474,
212–215 (2011).
5. Kim, K. et al. Nature 467, 285–290 (2010).
6. Polo, J. M. et al. Nature Biotechnol. 28, 848–855
(2010).
7. Hanna, J. et al. Science 318, 1920–1923
(2007).
K.H. declares competing financial interests. See
go.nature.com/w6v7kl for details.
increase the risk of developing an ASD —
especially given that, despite several hypoth­eses
about neurobiological pathways underlying
these disorders4, no diagnostic biomarkers
have been identified. Knowing the prevalence
of autism in different geographical regions and
cultures is important for comparing variation
and sources of risk .
However, epidemiological research in
autism faces many challenges. To recruit
subjects for a study of this kind, research-
ers depend either on medical or educational
records, or on behavioural descriptions —
usually measured through parent or teacher
questionnaires. To minimize the stigma asso-
ciated with ASDs, Kim et al.2 described their
project to parents and teachers as being about
“difficulties in social relationships”.
Most children with poor social relation-
ships do not have an ASD. Consequently,
ASD screening questionnaires typically mis­
identify substantial numbers of children who
have other difficulties, but not an ASD5. The
authors addressed this concern by provid-
ing comprehensive diagnostic assessments
for children who screened positive, using
Korean translations of internationally accepted
diagnostic interviews and observations.
Moreover, they paid substantial attention to
cross-cultural issues in translations, and to
documenting consistent, standard behav-
ioural coding across examiners. What’s more,
North American team members used their
judgement to confirm the South Korean diag-
noses. However, the translated scales were not
pre-tested by independent experts in South

Target population
55,266
Special-needs schools
Potential participants
294
Responded
103
Consented
84
Assessed
52
ASD diagnosis
49
×100 ×1,000 ×10,000
Figure 1 | Kim and colleagues’ study2.  Although the authors set out to investigate a large target
population of 7–12-year-old children from two groups in a South Korean community, the number of
children they eventually assessed for autism spectrum disorders (ASDs) gradually decreased, as is typical
of such studies.
Korea, to show that they could differentiate
children diagnosed with ASDs from those
without — the standard way in which the
methods are evaluated in other cultures.
The study is remarkable in its attempt to
identify ASDs in children in mainstream
schools, as well as in children receiving
special care. The overall response rate was
about 60% (Fig. 1). Although 7% of the main-
stream schoolchildren screened positive, only
13.4% of these could be further evaluated,
primarily because families did not consent to,
or did not attend, subsequent assessments. In
the end, Kim and colleagues assessed a total
of 286 children, and used a range of statistical
measures to reach estimates for a population
of more than 55,000. In such research, preva-
lence rates depend on data from the screening
questionnaires, which are necessary to make
inferences about children not seen. The prior-
ity is that no case should be missed. The nega-
tive consequences — both clinical and political
— of low rates are often assumed to be much
greater than those of overestimating.
Yet a larger question arises. Should individu-
als who are without impairment or disability
— that is, without any suffering, limitations
or restrictions in daily functioning — be
NEWS & VIEWS RESEARCH
Regular schools
Agreed to participate
36,592
50 Years Ago
Responded ‘[A Symposium on] Solar
23,234 Variations, Climatic Change and
Related Geophysical Problems’ —
It became abundantly clear how
Screened positive
large a number of investigators are
1,742 patiently accumulating evidence
of the amplitude, character, effects
Sampled
and especially the dating of climatic
fluctuations all over the world.
1,111 Speculations regarding the causes
abound; supporters of each of the
Consented popular theories — solar variation,
785 atmospheric turbidity, carbon
dioxide, ozone, variations in the
Earth’s orbital elements — find their
Assessed several gods alternately set up and
234 cast down … It now seems almost
certain that no one simple panacea
is in any way adequate to explain
ASD diagnosis
the intriguing patterns of climatic
152 fluctuation to which the evidence
points.
From Nature 10 June 1961
100 Years Ago
diagnosed with an ASD? In many areas of In the meteorological charts of
medicine, diagnosis with a disease (for the North Atlantic and Indian
instance, diabetes) can be clearly separated Oceans for the month of June …
from the associated disability (from no effect there is an interesting article on
to significant limitation in activity)6. By con- the phenomenon of St. Elmo’s Fire
trast, for a variety of reasons — including or corposants (corpus sanctum),
avoiding the unfortunate stigma of psychologi- the harmless luminous electricity
cal difficulties — standard-setting agencies7 of low intensity seen sometimes at
have typically required that definitions of night on ships’ masts, &c., during
ASDs include an impairment or, in the case unsettled weather. Many examples
of young children, a high risk of impairment of authenticated experiences
before a diagnosis is considered. in olden and modern times are
To identify the presence of impairment, quoted, e.g. one by Columbus in
many studies include a measure of adaptive October, 1495, during a severe
functioning that indicates children’s ability storm. It was then assumed that
to carry out everyday tasks; this is usually the light emanated from the saint’s
markedly impaired in those with ASDs, body, and was a sure sign that the
even in children of high intelligence8. In the gale was at its maximum … The
South Korean study, however, it was not clear phenomenon is not unfrequent on
whether the children identified as having an land; it was quoted by Caesar and
ASD needed help but were not receiving it, others. On the summit of Ben Nevis
or whether the mainstream school­children the observatory was at times ablaze
estimated to have considerable ASD symp- with it; the observers were not in
toms were otherwise without impairments. any way inconvenienced, except by
(The latter would possibly support propos- a slight tickling sensation in head
als by self-advocacy groups 9 and others10 and hands.
that ASDs are conditions not disorders, From Nature 8 June 1911
but contradicts norms for most standard
9 J U N E 2 0 1 1 | VO L 4 7 4 | NAT U R E | 1 6 7
© 2011 Macmillan Publishers Limited. All rights reserved
 RESEARCH NEWS & VIEWS

therapeutic or educational classifications.)
The diagnostic procedures Kim et al. used
have consistently been shown to distinguish
between children with ASDs and those with
other disorders11. However, systematic com-
parisons have not been made between children
diagnosed with an ASD by a clinician and chil-
dren thought to have social–communication
deficits on the basis of parent or teacher
reports, but whom experts consider not to
have an ASD.
It is possible that diagnostic instruments
are less effective in making this latter distinc-
tion than we might expect. So in breaking new
ground, Kim and co-workers’ study2 cries
out for replication. It provides a challenge to
expand research across cultures, to think criti-
cally about biases that could affect inferences
in the study of total population samples, and to
consider the possibility of undiagnosed ASDs
in children in ordinary classrooms, with or
without impairments. ■
Catherine Lord is in the University of Michigan
Autism and Communication Disorders Center,
Ann Arbor, Michigan 48109, USA.
e-mail: celord@umich.edu
1. Fombonne, E. Pediatr. Res. 65, 591–598 (2009).
2. Kim, Y. S. et al. Am. J. Psychiatry doi:10.1176/appi.
ajp.2011.10101532 (2011).
3. Le Couteur, A. et al. J. Child Psychol. Psychiatry 37,
785–801 (1996).
4. Moldin, S. O. & Rubenstein, J. L. R. (eds)
Understanding Autism (Taylor & Francis, 2006).
5. Ehlers, S., Gillberg, C. & Wing, L. J. Autism Dev.
Disord. 29, 129–141 (1999).
6. www.who.int/icidh
7. www.DSM5.org
8. Kanne, S. M. et al. J. Autism Dev. Disord.
doi:10.1007/s10803-010-1126-4 (2010).
9. www.aspiesforfreedom.com
10. Baron-Cohen, S. et al. Br. J. Psychiatry 194,
500–509 (2009).
11. Risi, S. et al. J. Am. Acad. Child Adolesc. Psychiatry
45, 1094–1103 (2006).
The author declares competing financial interests.
See go.nature.com/wdjx6a for details.

P H YS ICAL CHEMISTRY ideas have proven to be more durable in the

scientific literature. Indeed, there has been a

Water’s wafer-thin renaissance of the notion that long-range order

can be imposed on water by an interface of the
liquid with air or with another immiscible

surface
liquid, or by an interface with a solid such as
the containing vessel6.
Moreover, the dust has been blown off the
picture of bulk water as a mixture of regions of
A combination of vibrational spectroscopy and molecular calculations reveals two distinct liquid forms, a concept first pro-
that only the surface layer of water at the interface with air has a distinctly posed7 heuristically by Wilhelm Röntgen more
different structure from the bulk liquid. See Letter p.192 than a century ago. In the most recent variant
of this idea8, robust X-ray scattering data for
liquid water have been fitted into a micro-
PAV E L J U N G W I R T H long-range order across hundreds or even scopic version of Röntgen’s elderly model.
thousands of molecular layers can exist in And, in keeping with the theory that liquid

T
he next time you drink a glass of water, liquid water. An early incarnation of this idea water is structured by surfaces, it has been pro-
take a moment to consider the surface was the report4 of polywater — a syrupy liq- posed that long-range water patterning occurs
of the liquid. It might surprise you to uid apparently produced when water was around proteins and other biomolecules. This
learn that the molecular structure of this seem- repeatedly forced through capillary tubes, and in turn has led to the enigmatic concept of
ingly unremarkable air–water interface has which was thought to be polymerized water. ‘cellular water’9 — the idea that all water mol-
long been the subject of controversial theories. As with the ‘memory of water’, the existence ecules in cells are ordered, and that this order
On page 192 of this issue, Stiopkin et al.1 weigh of poly­water has been debunked5, but similar is crucial for biological function.
into the debate by reporting the results Stiopkin et al.1 have therefore per-
of spectroscopic and theoretical studies formed a valuable service by looking
of this interface. Their findings strongly Air Dangling in great detail and with little prejudice
Hydrogen bond
contradict the recurring idea that exter- bond at the structure of an archetypal aque-
nal interfaces with water, or compounds Surface ous interface, that between water and
dissolved in it, can generate long-range air. They posed a seemingly simple
molecular order in the liquid. question: how thick is this interface? In
There have been two popular, other words, how deep into bulk water
mutually interconnected miscon­cep­ Subsurface does the patterning imposed by the sur-
tions about liquid water. According face propagate? In fact, for liquid water,
to the first, water can ‘remember’, for with its highly dynamical and vola-
Bulk water
extended periods of time, patterns tile surface, this is a difficult question
imposed on it by the environment or to answer.
by solute molecules2. This idea, among The authors succeeded by applying
others, lent credence to a central tenet a combination of two state-of-the-art
of homeo­pathy: that solu­tions of com- techniques, which they also helped to
pounds could maintain biological Figure 1 | Structure of the interface between liquid water and develop. The first was experimental:
activity even when repeatedly diluted to air.  This image, taken from a classical molecular-dynamics they used a sensitive version of surface-
such an extent that effectively no mol- simulation, reveals the features of liquid water at an air–water selective vibrational spec­troscopy to
ecules of those compounds remained in interface. Most water molecules form hydrogen bonds to study oxygen–hydrogen bonds in water
solution. But the ‘memory of water’ effect each other, but some at the surface1
do not (these are known as
that stick out into the air, and that are
dangling bonds). Stiopkin et al. report evidence that the surface
is not reproducible3 and the idea is now has a depth of only one layer of molecules, contradicting theories therefore not hydrogen-bonded to
scientifically unacceptable — although that interfaces with water impose long-range order deep into the another water molecule. (Actually, for
this doesn’t yet seem to have affected bulk liquid. The surface layer of water molecules thus sits atop a technical reasons, they studied oxygen–
the commercial success of homeopathy. subsurface layer, the properties of which approach those of bulk deuterium bonds of water molecules
The second misconception is that water. Red atoms are oxygen, white ones are hydrogen. isotopically labelled once or twice with

1 6 8 | NAT U R E | VO L 4 7 4 | 9 J U N E 2 0 1 1
© 2011 Macmillan Publishers Limited. All rights reserved