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NEWS & VIEWS RESEARCH
E NV IRO NMENTAL SCIENCE

Eating ourselves dry
Do human consumption habits affect groundwater depletion as a result of
international food trade? A global analysis indicates that they do, and shows
which products and countries have the biggest impact. See Letter p.700
M A I T E M . A L D AYA

G

roundwater levels are being depleted at
alarming rates in the world’s arid and
semi-arid regions, mostly because of
farm irrigation that has been implemented
over the past 50 years with little planning
or control by governmental agencies1. Such
irrigation measures have brought numerous
socio-economic benefits and are generally less
prone to corruption than are surface-water
irrigation projects, but they have also led to
ecological damage such as land subsidence,
seawater intrusion into coastal areas and the
loss of springs and wetlands2. These problems
seem to be partly related to the inter­national
export and consumption of commodities3,4.
On page 700, Dalin and colleagues5 report the
first quantification of global, non-renewable
groundwater depletion associated with irrigation that is embedded in the world’s food trade.
The concept of virtual water trade — the
water used to produce traded goods — was
introduced to explain how food imports can
save water in the Middle East6. The idea was
that food imports allow the Middle East to use
less of its own water for crop production than
it would do if it grew all of its own food. Morerecent studies have quantified the volumes
of virtual water embedded in food trade as a
way of linking food consumption and water
scarcity in the producing regions3,4,7,8.
Dalin and colleagues now deepen the analysis of the virtual water trade by revealing the
non-renewable depletion of groundwater that
was embodied in food trade for the period
from 2000 to 2010. Their research correlates
the amount of irrigation water taken from
non-renewable groundwater resources with
the related amount of trade. The analysis is
likely to influence both integrated management schemes for global water resources and
the rapidly evolving research field that studies
the socio-economic ‘footprints’ of global trade
(see ref. 9, for example).
The authors show that approximately 11%
of global non-renewable groundwater use was
exported through agricultural trade during
the period studied. Of this, about two-thirds
was accounted for by the combined exports of
Pakistan (29%), the United States (27%) and
India (12%) (Fig. 1). The researchers also find
that the vast majority of the world’s population lives in countries that source nearly all of
their imported staple food from partners that

consume non-renewable groundwater. Some
countries — such as the United States, Mexico,
Iran and China — are particularly exposed
to water- and food-security risks related to
groundwater depletion, because they both
produce and import food irrigated using water
from rapidly depleting aquifers.
This work is based mainly on big data and
global-scale studies. The numbers reported
by Dalin and colleagues are therefore generally average values, and have a wide range of
uncertainty. Groundwater evaluations per se
are quite uncertain, because the properties of
the atmosphere and soil are all highly variable, particularly in arid and semi-arid areas10.
This uncertainty explains why results found
in different reports can vary, sometimes
greatly. One should therefore always be cautious when drawing conclusions from global
ground­w ater-focused studies, especially
bearing in mind that the individual
uncertainties for quantities estimated in
such studies combine to generate even bigger
overall uncertainties.
Dalin and co-workers’ analysis assumes
that technological and social factors affecting
groundwater use will not change. The implications of their paper — that ground­water
depletion associated with global food trade is
unsustainable — might therefore represent a
worst-case scenario. Reality is more complex.

Exporters

So even though agriculture often accounts for
70% of groundwater use today2, it is difficult
to predict how this will change in the next
hundred years.
Global water assessments are useful in
highlighting the international need to respond
to groundwater depletion, but water is also a
local resource that moves within specific river
basins or aquifer systems. Smaller-scale studies
are therefore needed to make policy-relevant
decisions, because the details of local situations
are key to understanding the context, drivers
and influencing factors that affect ground­water
stocks. Hydrogeology is one factor, but the
economic, social, cultural and environmental
aspects of groundwater use must also be
considered10.
For example, in southeastern Spain, intensive
groundwater use and mining — continuous
groundwater depletion that often exceeds
replenishment of supplies — to irrigate cash
crops, and increasingly to supply water for
tourism, have cumulatively reduced groundwater stocks by about 15 cubic kilometres
(ref. 10). This has occasionally caused serious administrative, legal and environmental
problems, but has also fostered huge economic
and social development10. Such market-driven
use of an exhaustible vital resource raises ethical concerns that point to the need for a sea
change in the governance of environmental
resources.
Dalin and colleagues’ study identifies
regions and agricultural products most at risk
from groundwater depletion. It should serve
as a wake-up call for nations and river-basin
authorities to consider the influence of agricultural trade on non-renewable groundwater
depletion, and on the related sustainability of
national consumption. It should also focus the
minds of the end-consumers of these products, who typically turn a blind eye to supply

Importers

Pakistan

China

United States

United States

India

Iran

Mexico

Mexico

Iran

Japan

Italy

Saudi Arabia

Bulgaria

Canada

Saudi Arabia

Bangladesh

Romania

United Kingdom

Turkey

Iraq
0

2

4

6

8

0

2

4

6

8

Groundwater depletion (km3)

Figure 1 | Top ten exporters and importers of groundwater depletion embedded in the food trade. 
Groundwater stocks are being rapidly depleted, largely because of water withdrawals used for crop
irrigation. Crops that are imported and exported by countries involved in the international food trade
can be thought of as containing a virtual quantity of water that corresponds to a fraction of global,
non-renewable groundwater depletion. Dalin et al.5 have quantified the amount of groundwater depletion
that was embedded in international food trade between 2000 and 2010, revealing, among other things, the
top ten exporters and importers of such depletion in 2010. (Data taken from Extended Data Table 3 of ref. 5.)

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3 0 M A RC H 2 0 1 7 | VO L 5 4 3 | NAT U R E | 6 3 3

RESEARCH NEWS & VIEWS
chains and the impacts of imported goods.
Such global assessments are a first step
towards improving the sustainability of worldwide food production, because they provide
fresh data and perspectives on the big picture
and on the drivers of water use and abuse. A
consideration of trade-related environmental
concerns might also suggest new global watergovernance solutions, which could be applied
by introducing measures to ensure that existing
food-trade frameworks of the European Single

Market and the World Trade Organization
are effective, sustainable and equitable. ■
Maite M. Aldaya is at the Water Observatory,
Madrid 28001, Spain.
e-mail: maite.aldaya@unep.org
1. Famiglietti, J. S. Nature Clim. Change 4, 945–948
(2014).
2. Llamas, M. R. UNESCO Ser. Water and Ethics Essay 7
(UNESCO, 2004); see http://www.rac.es/ficheros/
doc/00010.pdf
3. Marston, L., Konar, M., Cai, X. & Troy, T. J. Proc. Natl

CANCE R THERAPY

The leukaemia
epigenome targeted
Modification of methyl groups attached to DNA alters gene expression, and
mutations that deregulate this methylation are common in some leukaemias.
Drugs that target aberrant methylation are emerging as promising therapeutics.
J U L I E- A U R O R E L O S M A N

O

nly 20–40% of adults who have acute
myeloid leukaemia (AML) survive
in the long term1. Several large-scale
genome-sequencing efforts have attempted to
define mutations associated with AML, with
a view to identifying new therapeutic strategies2. These analyses have uncovered many
recurrent mutations in epigenetic regulator
proteins, which modulate gene expression by
altering the 3D structure of chromosomes.
Epigenetic regulators include enzymes that
attach and remove molecular modifications on DNA. Writing in Cancer Discovery,
Yen et al.3 and Shih et al.4 present evidence
that mutations in two enzymes, IDH2 and
TET2, that lead to altered epigenetic regulation, can be targeted therapeutically in AML
cells, providing a compelling rationale for further development of epigenetically targeted
anticancer treatments.
The enzyme TET2 is a dioxygenase that
depends on the molecule a-ketoglutarate
(a-KG) for its activity (Fig. 1). It catalyses the
addition of a hydroxyl group to 5-methylcytosine (5mC) — a form of the DNA base cytosine
that has been modified by the attachment of
a methyl moiety — to produce 5-hydroxymethylcytosine (5hmC) 5. The formation
of 5hmC is an important step in converting
5mC into unmethylated cytosine. Inactivating mutations in the TET2 gene decrease
5hmC levels and lead to the accumulation
of 5mC. This DNA hyper­methylation leads
to changes in gene expression that promote
the proliferation of long-lived TET2-mutant
haematopoietic stem cells, and disrupt
their differentiation into various types

of blood cell, thereby promoting AML.
Most other AML-associated mutations
in genes that encode epigenetic regulators
cause protein inactivation, but mutations in
IDH genes are an exception. Both IDH1 and
IDH2 are metabolic enzymes that normally
catalyse the interconversion of a-KG and
another molecule, isocitrate. But cancerassociated mutations alter their activity6 such
that they instead convert a-KG to (R)-2hydroxy­glutarate (2HG), which is structurally

Acad. Sci. USA 112, 8561–8566 (2015).
4. Mekonnen, M. M. & Hoekstra, A. Y. Hydrol. Earth Syst.
Sci. 14, 1259–1276 (2010).
5. Dalin, C., Wada, Y., Kastener, T. & Puma, M. J. Nature
543, 700–704 (2017).
6. Allan, J. Virtual Water: Tackling the Threat to Our
Planet’s Most Precious Resource (Tauris, 2011).
7. Dalin, C., Konar, M., Hanasaki, N., Rinaldo, A. &
Rodriguez-Iturbe, I. Proc. Natl Acad. Sci. USA 109,
5989–5994 (2012).
8. Hoekstra, A. Y. & Mekonnen, M. M. Proc. Natl Acad.
Sci. USA 109, 3232−3237 (2012).
9. Zhang, Q. et al. Nature 543, 705–709 (2017).
10. Custodio, E. et al. Sci. Tot. Environ. 559, 302–316
(2016).

similar to a-KG and can competitively inhibit
several a-KG-dependent enzymes7, including
TET2 (Fig. 1).
A previous study8 showed that the leukaemic
effects of mutant IDH enzymes require the
sustained production of 2HG. Furthermore,
drugs that inhibit the activity of mutant IDHs
lower intracellular levels of 2HG and promote
the differentiation of immature, IDH-mutant
AML cells into mature white blood cells, both
in vitro and in mice9. Mature white blood cells
have a limited capacity to proliferate and are
short-lived, so the inhibition of mutant IDH
reduces the leukaemia-cell pool. However,
these experiments were performed using ‘tool’
compounds, which, although highly potent,
have not been pharmacologically optimized
for use in humans.
In one of the two current studies, Yen et al.3
developed a drug called AG-221, which is the
first clinical-grade inhibitor that potently and
selectively inhibits mutant IDH2. Treating
patient-derived AML cells that harboured
IDH2 mutations with AG-221 reduced
their levels of 2HG and induced them to

Mutant
IDH2

α-KG

AG-221
2HG
5-Aza

TET2

DNA
methylation

Cytosine

Hydroxyl group

Methyl group

5mC

DNA
demethylation

5hmC

Figure 1 | The yin and yang of mutant IDH and TET2 proteins.  Covalent linking of a methyl group to
the DNA base cytosine by DNA-methylation enzymes produces 5-methylcytosine (5mC). The enzyme
TET2, with the co-factor molecule a-ketoglutarate (a-KG), converts 5mC to 5-hydroxymethylcytosine
(5hmC), which can be demethylated to form cytosine again. Mutations that cause the loss of TET2
function lead to accumulation of 5mc (not shown), which promotes acute myeloid leukaemia (AML).
Mutant forms of IDH enzymes also promote AML. The enzymes convert a-KG to the structurally similar
(R)-2-hydroxyglutarate (2HG), which competes with a-KG and so inhibits the activity of TET2. Yen et
al.3 developed a drug called AG-221 that inhibits mutant IDH2. The drug reduces 2HG levels and restores
TET2 activity, thereby reversing 5mC accumulation in mouse models of IDH-mutant AML. Shih et al.4
showed that a drug called 5-Aza has a similar effect in Tet2-mutant AML in mice. 5-Aza inhibits the
conversion of cytosine to 5mC, thereby preventing 5mC from accumulating.

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6 3 4 | NAT U R E | VO L 5 4 3 | 3 0 M A RC H 2 0 1 7


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