INSIGHTS | PERSPECTIVES
The genetics approach to uncovering the causes of disease has focused mainly on finding the underlying primary mutations, with diseased individuals playing the leading role in this discovery. But as health care
begins to focus more on preventive therapies, an emphasis on understanding how
individuals remain healthy—“resilient” to
disease—may provide insights into disease
pathogenesis and new treatments. This view
underlies “The Resilience Project” (www.
resilienceproject.me), an effort to search
broadly for these apparently healthy people
(see the photo). There are, indeed, individuals whose genetics indicate exceptionally
high risk of disease, yet they never show any
signs of the disorder. What are the genetic
and environmental factors that buffer disease for them? How can such information
be gathered and harnessed most efficiently
For 127 catastrophic Mendelian diseases
(those caused by a single gene such as cystic
fibrosis and ataxia-telangiectasia), there are
presently 164 genes harboring 685 known
recurrent variants that are highly penetrant
and causal for deleterious traits, most typi-
cally manifesting in individuals before the
age of 18 (1). More generally, thousands of
variants spanning many hundreds of genes
have now been associated with common dis-
eases ranging from inflammatory bowel dis-
ease, rheumatoid arthritis, type 1 diabetes,
and cancer, to Alzheimer’s disease, schizo-
phrenia, and asthma (2). Yet, despite this
wealth of discoveries, few gene variants have
translated directly into diagnostic predictors
of disease risk and severity or into thera-
peutic interventions. For common diseases,
the observed small effect sizes of individual
gene variants limit diagnostic potential, and
given that most variants identified have an
unclear function, how to target the corre-
sponding gene for therapeutic intervention
is typically unclear. For rarer Mendelian dis-
orders, although genetics directly implicate
a specific gene in a disease, a majority of
such cases relate to loss-of-function muta-
tions. Designing small molecules to fix the
corresponding broken protein has proven
difficult. Compounds are effective in some
cases, such as potentiators of mutant (loss-
of-function) forms of the cystic fibrosis
transmembrane conductance regulator in
patients (3). However, sub-
stantial challenges remain
in delivering functional
versions of the aberrant
proteins to specific cell
types at the right time to
treat or prevent disease.
The prominent role of
second-site mutations and
environmental factors that
enable resistance to (or buffer against) disease traits
has been well established
in a multitude of model organisms from yeast to mice
(4–7). Screening for second-site mutations in
“resilient” individuals that prevent disease-causing alleles from manifesting their effects could identify targets to which drugs
would be designed to disrupt their function,
as opposed to targeting the disease-causing
gene directly. Genetic studies examining
seemingly healthy people have revealed, for
example, rare mutations in chemokine (C-C
motif) receptor type 5 (the co-receptor for
human immunodeficiency virus) that block
HIV infection (8), and secondary mutations
in fetal globin genes that modify the severity of sickle cell disease by buffering primary
mutations in β-globin genes (9). Even among
common diseases, examples of protective alleles are growing, such as mutations in the
gene encoding the enzyme proprotein con-
Clues from the resilient
Talk the talk. “The Resilience Project” is described in a Technology,
Entertainment, Design (TED) conference. See www.ted.com/talks/2004.
By Stephen H. Friend1,2 and Eric E. Schadt2
Genetic information from individuals who do not succumb to
disease may point to new therapies and ideas about wellness
1Sage Bionetworks, Seattle, WA, 98109 USA; 2 Icahn School
of Medicine at Mount Sinai, Department of Genetics and
Genomic Sciences and the Icahn Institute for Genomics and
Multiscale Biology, New York, NY 10029, USA. E-mail: friend@
sagebase.org; firstname.lastname@example.org P
the x-ray beam and the crystal will be completely dominated by the local geometry of
the chosen element. Bromine has a conveniently placed absorption edge accessible
for many synchrotron beam lines and distinct from those of lighter elements. Also,
bromine tends to form bonds to just one
of the carbon atoms in organic compounds
and represents the ideal probe.
The thiourea inclusion systems used by
Palmer et al. are well known for their structural diversity. The correlation between the
thiourea host network and the included guest
molecules is often strongly temperature dependent (3), and the guest bromocyclohexane is no exception. The high-temperature
form of the compound (4) features an effectively orientationally disordered guest, in
that this phase shows no x-ray birefringence.
The disorder creates an isotropic environment around the bromine atoms, but the
overall structure is still optically active and
displays the typical cyclic behavior with respect to transparency to polarized light.
In previous studies of x-ray birefringence
(5, 6), a small probe was used that allowed
the intensity of transmitted light to be measured. However, this approach would make
mapping impractical because it would require scanning the entire specimen for each
orientation. Palmer et al. used a wide beam
that illuminated the entire sample and created a map simply by using a detector with
good spatial resolution. In the ordered low-temperature phase, the Br–C bonds are antiparallel, and the crystals show birefringence
with respect to both x-rays and visible light.
Ordering of the bromocyclohexane resulted
in domain formation. These domains were
directly visible as light and dark regions in
the x-ray birefringence images.
The work of Palmer et al. provides proof-of-principle for the use of x-ray birefringence
imaging, both as a way of mapping local order and as an element-specific probe in partially disordered structures. The technique
may be used to address the whole specimen
simultaneously. This capability opens the
way for many interesting applications, perhaps the most alluring being the possibility
of studying domain boundary dynamics in
real time. ■
1. B.A.Palmer et al., Science 344, 1013(2014).
2. D. Templeton,L. Templeton, Phys. Rev. B 40,6505
3. K. D. M. Harries, Chem. Soc. Rev. 26, 279 (1997).
4. T. Ishibashi, M. Machida, N. Koyano, J. Korean Phys.
Soc. 46, 228 (2004).
5. B. A. Palmer, A. Morte-Ródenas, B. M. Kariuki, K. D. M.
Harris, S. P. Collins, J. Phys. Chem. Lett. 2, 2346 (2011).
6. Y. Joly, S. P. Collins, S. Grenier, H. C. N. Tolentino, De M.
Santis, Phys. Rev. B 86, 220101(R) (2012).