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Ectosomes from platelets, endothelia cytokines, in particular interleukin 1b,

and leukocytes are discharged directly are pro-inflammatory; others, however, Primer
into the blood where they can release are anti-inflammatory. Monocyte and
their content rapidly or persist in endothelial ectosomes are often rich
the circulation for quite some time. in tissue factor, a potent activator The optimism bias
Ectosomes discharged to the tissue of the coagulation cascade, and
intercellular space can also release can therefore trigger coagulation, Tali Sharot
their content there, remain trapped thrombosis and also angiogenesis.
locally or diffuse some distance. Effects Platelet ectosomes, however, contain The ability to anticipate is a hallmark
are triggered when ectosomes (or low levels of tissue factor, and of cognition. Inferences about what
their released molecules) reach their therefore work differently. Ectosomes will occur in the future are critical
targets, often in cell types distinct derived from leukocytes and platelets to decision making, enabling us
from the cells of origin. Released have profound effects on innate to prepare our actions so as to
molecules activate key cell-surface immunity and also on the induction avoid harm and gain reward. Given
molecules, such as receptors and of adaptive immunity, reprogramming the importance of these future
enzymes. Intact ectosomes can either macrophages and dendritic cells toward projections, one might expect the
fuse with target cells (with the ensuing immunosuppression. brain to possess accurate, unbiased
incorporation of their membrane in the foresight. Humans, however, exhibit a
plasma membrane and release of the What about ectosomes and disease? pervasive and surprising bias: when it
segregated package to the cytosol) Great interest has been raised by comes to predicting what will happen
or be taken up by endocytosis. The the increased levels of endothelial to us tomorrow, next week, or fifty
fate of the latter is variable: fusion with ectosomes in the blood of patients years from now, we overestimate
lysosomes; release of contents in the affected by acute coronary syndromes, the likelihood of positive events,
cytosol; or discharge to the extracellular atherosclerosis and stroke, a finding and underestimate the likelihood of
space by transcytosis (Figure 1). now considered for the development negative events. For example, we
of new diagnostic tests. Ectosomes underrate our chances of getting
What is the role of ectosomes in cell of specific origin are also being divorced, being in a car accident, or
biology, physiology and pathology? studied as a target of new therapies suffering from cancer. We also expect
Ectosomes are specific, multi-purpose for rheumatoid arthritis and multiple to live longer than objective measures
carriers that expand the borders of sclerosis, where ectosomes are would warrant, overestimate our
cells away from the plasma membrane, believed to promote inflammation and success in the job market, and
establishing communication networks cell death, and for cancer, in which believe that our children will be
by which specific properties and ectosomes play a role in invasion especially talented. This phenomenon
information can be shared among and metastasis. The mechanisms of is known as the optimism bias, and
cells. By delivering their molecules at the effects on cancer are multiple. In it is one of the most consistent,
distance without dilution or degradation addition to the above-mentioned roles prevalent, and robust biases
they reproduce effects otherwise in digestion of the intercellular matrix documented in psychology and
induced by direct cell–cell contact, and immunosuppression, ectosomes behavioral economics.
playing major roles in the integrated can induce the horizontal transfer The optimism bias is defined as
functioning of tissues and organs. among tumor cells of critical molecules the difference between a person’s
Digestion of the intercellular matrix such as proteins (e.g. P-glycoprotein expectation and the outcome that
by metalloproteinases activated by (which confers multidrug resistance to follows. If expectations are better
ectosomes can induce profound the cells), glutaminase, and fibronectin), than reality, the bias is optimistic; if
changes to the cell environment. mRNAs and miRNAs. This transfer is reality is better than expected, the
Fusion of ectosomes at the surface considered to be greatly important for bias is pessimistic. The extent of
of target cells delivers exogenous cancer progression. the optimism bias is thus measured
antigens, enzymes and other proteins to empirically by recording an
discrete sites of the plasma membrane. Where can I learn more? individual’s expectations before an
Concomitantly, release of the Cocucci, E., Racchetti, G., and Meldolesi, J. (2009).
Shedding microvesicles: artefacts no more.
event unfolds and contrasting those
segregated protein/RNA packages to Trends Cell Biol. 19, 43–51. with the outcomes that transpire. This
target cells can alter gene expression. Mause, S.F. and Weber, C. (2010). Microparticles: methodology reveals, for instance,
protagonists of a novel communication network
This might explain, among other for intracellular information exchange. Circ. Res. that students expect to receive higher
events, the functional and phenotypic 107, 1047–1057. starting salaries and more job offers
changes taking place in stem cells Muralidharan-Chiari, V., Clancy, J.W., Sedgwick, A.,
and D’Souza-Schorey, C. (2010). Microvesicles:
than they end up getting. People
without transdifferentiation, sustained mediators of extracellular communication during tend to underestimate how long a
by genetic information transferred from cancer progression. J. Cell Sci. 123, 1603–1611. project will take to complete and how
Sadallah,S., Eken, C., and Schifferli, J.A. (2011).
tissue cells via ectosomes. Conversely, Ectosomes as immunomodulators. Semin. much it will cost. Most of us predict
transfer of genetic information from Immunopathol. 33, 487–496. deriving greater pleasure from a
stem cells to target cells may redirect vacation than we subsequently do,
altered functions, inducing repair of 1Department
and we anticipate encountering more
of Cell Biology, Harvard Medical
damaged tissues without replacement positive events in an upcoming month
School, Boston, MA 02115, USA. 2Department
of parenchymal cells. The heterogeneity of Neurosciences, San Raffaele Institute, (such as receiving a gift or enjoying a
of ectosomes can play different, even Milan, 20132 Italy. movie) than we end up experiencing
opposing roles. Ectosomes containing *E-mail: meldolesi.jacopo@hsr.it (Figure 1A). Across many different
Current Biology Vol 21 No 23
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A 60.00
Positive
motivated to press the correct lever,
Negative
because if they made a mistake they
50.00 Neutral
would not receive a reward at all. The
% Likelihood/occurrence

results reveal that a large percentage

of birds showed a bias towards
40.00 pressing the lever associated with an
immediate reward, suggesting that
30.00 they expected a positive outcome
although there was no objective
reason to do so. Interestingly, birds
20.00
that were kept in small cages without
access to water baths and toys did
10.00 not show optimistic tendencies.
Their actions indicated that their
0.00
expectations were unbiased rather
than optimistic (in response to a
Prediction Reality
medium length tone they pressed
B the green lever on only 50% of the
Optimistic 0.3 trials). Comparable results have
been reported in mice by Harding
r = -.35, p < .0001 and colleagues (2004) using a similar
0.2
N = 153 paradigm, indicating that positive
biases are shared by multiple other
0.1 species.
There is, however, at least one
Bias

0 group of humans who fail to show

positively biased expectations —
-0.1 individuals suffering from depression.
Strunk et al. (2006) have shown
-0.2
that while healthy humans expect
the future to be slightly better than
it ends up being, people with mild
-0.3
Low Middle High depression show no bias when
M = .01 M = -.02 M = -.06 predicting future events, and people
Pessimistic -0.4 with severe depression tend to
0 5 10 15 20 25 30 35 40 45 50
expect things to be worse than they
Beck Depression Inventory-II Scores turn out (Figure 1B). Thus, while
Current Biology
optimistic biases are common in the
majority of humans, optimism seems
Figure 1. Optimism bias in healthy individuals and lack of optimism bias in depression. to break down in major depression
In two studies participants were asked to predict the likelihood of different life events that
disorder (MDD), with pessimism being
might occur to them in an upcoming month (such as receiving a gift, burning dinner, getting
stuck in traffic). At the end of the month they reported back which events had occurred. one of its key symptoms according to
(A) Healthy individuals predicted positive events to be more likely than negative or neutral The Diagnostic and Statistical Manual
events. However, in reality the likelihood of positive, negative and neutral events to occur was of Mental Disorders (DSM IV).
equal (Sharot and Dudai, cited in Sharot 2011). (B) Greater pessimism bias was associated with
depressive symptoms as measured by BDI-II scores (bias is measured as the difference The puzzles of unrealistic optimism
between predicted and actual likelihood of positive events and the reverse for negative
The prevalence of the optimism
events). Individuals scoring low on depression symptoms showed an optimism bias (dark grey),
individuals showing no bias in either direction were mildly depressed (light grey), and individu- bias presents two puzzles. First, it
als exhibiting a pessimism bias scored high on depression symptoms (white). Adapted with is not obvious how optimism can
permission from Strunk et al. (2006). be maintained in the face of reality.
Second, it is unclear whether and
methods and domains, studies to press a red lever whenever they why it would be adaptive to hold an
consistently report that a large heard a short (2 second) auditory optimism bias. Much recent work on
majority of the population (about 80% tone in order to receive an immediate optimism has addressed these two
according to most estimates) display reward (positive outcome), and issues.
an optimism bias. Optimistic errors a green lever when they heard a
seem to be an integral part of human long (10 second) auditory tone to The maintenance and breakdown
nature, observed across gender, race, receive a delayed reward (this is by of optimism
nationality and age. comparison a negative outcome Standard theories of learning hold
Optimistic biases are even reported as birds prefer immediate reward). that people adjust their expectations
in non-human animals such as rats Colour-reward-tone associations when faced with disconfirming
and birds. To study optimistic biases were counterbalanced. They then information. One puzzle of optimism
in birds, Matheson and colleagues tested them by presenting a medium is thus that people maintain overly
(2008) taught European starlings length auditory tone. The birds were positive expectations despite a
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lifetime of experience with reality.

There are many empirical examples
of this resistance to alter optimistic
expectations. For instance,
highlighting previously unknown risk
factors for diseases is surprisingly
ineffective at altering peoples’
optimistic perception of their medical
vulnerability. And although people
are aware that divorce rates are
nearing 50% in the Western World,
couples who are about to get married
estimate their own likelihood of
divorce as negligible. Even experts
show startlingly optimistic biases;
divorce lawyers underestimate the
negative consequences of divorce,
financial analysts expect improbably
high profits, and medical doctors
overestimate the effectiveness of Figure 2. How optimism is maintained in the face of reality.
(A) When given desirable information about the future (such as learning that the likelihood of
their treatment.
suffering from cancer is lower than anticipated) people updated their belief to a greater degree
Recent findings from our lab than when receiving undesirable information (such as learning that the likelihood of suffering
provide a mechanistic explanation of from cancer is greater than anticipated). This difference was related to how well regions of the
these observations. We have found frontal lobe tracked estimation errors (that is, the differences between prior beliefs about the
that an optimism bias is maintained future and information presented). (B) Activity in the left inferior frontal gyrus was correlated
in the face of disconfirming with the extent of errors that resulted from positive information equally well in highly optimistic
individuals and people low on optimism. (C) In the right inferior frontal gyrus activity correlated
evidence because people update
strongly with negative errors in people low on optimism, but less so in highly optimistic indi-
their beliefs more in response to viduals (trait optimism is measured independently by the LOT-R scale). Adapted with permis-
positive information about the sion from Sharot et al. (2011).
future than to negative information
about the future (Figure 2A). We This selectivity is mediated by one’s beliefs in response to negative
asked participants to estimate their a failure of frontal lobe regions to information contributes to a
likelihood of encountering different code errors in prediction that would pessimistic outlook that may result
aversive events in their lifetime (such reduce positive expectations. When in the low mood characteristic of
as Alzheimer’s disease and burglary) optimistic individuals are confronted depression. The causation, however,
and then presented them with the with unexpected statistics about the could point in the opposite direction:
average frequency of encountering likelihood of encountering negative low mood could cause depressed
those events. We next asked them to events, their right inferior frontal individuals to attend to negative
estimate their likelihoods once again gyrus exhibits reduced coding of information about the future that is
in order to test whether they used information that calls for a negative congruent with their current affective
the information provided to update update (Figure 2C). In particular, state. Further work is needed to
their beliefs. We found that when individuals who score high on a untangle these mechanisms.
individuals received information that scale measuring trait optimism An absence of optimism in
was worse than their estimate (for have a weaker correlation between depressed individuals may also
example, when someone estimated activity in this region and the extent relate to how future scenarios are
their probability of suffering from of negative errors in estimation. But mentally constructed. When healthy
cancer as 10% and then learned when the information presented is people imagine their future they tend
that the average probability was better than expected, regions of the to form positively biased scenarios,
30%) they did not update their prefrontal cortex code for it efficiently imagining positive events (such as
estimate much the second time both in highly optimistic and less winning a professional award) in
around. However, if a person initially optimistic individuals (Figure 2B). In more detail and as closer in time than
provided an estimate that was more other words, while coding for positive negative events (such as losing a
pessimistic than the information information about the future is large sum of money). Mentally, people
they were subsequently given intact, optimism is tied to a failure in ‘approach’ positive future scenarios
(for example, estimated their own updating from (and diminished neural and distance themselves from
probability of suffering from cancer coding of) undesirable information negative ones. We have shown that
at 40% and then learned that the regarding the future. this bias is associated with increased
average probability was 30%), they Although selective updating in activation of the amygdala (involved
substantially updated their estimate response to positive information is in emotional processing) and rostral
to more closely match the average consistently observed in healthy anterior cingulate (rACC, involved
probability. Selectively updating populations, this pattern seems to in emotion regulation) when people
beliefs in response to positive be abolished, and even reversed, in imagine positive future events relative
information produces optimism that is people suffering from depression. It to negative events. Furthermore, there
resistant to change. is possible that efficiently updating is increased functional connectivity
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between the two structures when The effects can be quite substantial, unwanted future outcomes (such as
healthy individuals imagine positive with one survey of 97,000 individuals lung cancer, bankruptcy and obesity)
scenarios relative to negative ones. reporting that optimists are 14% less are unlikely to materialize and that
We suggest that the rACC contributes likely to die between the ages of 50 positive future outcomes (such as
to optimism by biasing attention and 65, and 30% less likely to die earning larger amounts of money)
and vigilance towards positive from cardiac arrest. Optimism has are. Indeed, it has been reported that
associations and emotions when also been related to extended survival extreme optimists are more likely
imagining the future. Intriguingly, time of cancer and AIDS patients. to smoke and less likely to save
it is precisely these regions — the Optimism affects physical health money than are mild optimists. These
amygdala and the rACC — that show in at least two ways. First, expecting behaviours have traditionally been
abnormal function and impaired positive outcomes reduces stress attributed to temporal discounting
connectivity in depressed individuals. and anxiety. This is beneficial given (overvaluing the present over the
Further links between depression that chronic stress is detrimental to future), but studies show that when
and (a lack of) optimism come from health, causing over-activation of the optimistic expectations are abolished,
the notion that optimism relates to a autonomic nervous system and the these behaviours are reduced. This
person’s belief in their control over hypothalamic-pituitary-adrenocortical suggests that choosing to engage in
future outcomes. Overestimating axis. Optimists have been reported an act that is rewarding at present
ones’ control over events is thought to catch fewer infectious diseases but costly in the future (smoking,
to increase optimism, because and have a stronger immune system. unprotected sex, overeating) can be
people believe that if they have the Second, it has been suggested that partially explained by an excess of
ability to control future outcomes optimism facilitates health-promoting unrealistic optimism.
they can steer themselves in the right actions. For example, studies show The harmful influences of over-
direction. While healthy individuals that optimistic patients are more optimism likely extend to the
tend to overestimate the extent likely to eat healthily and engage in collective behaviour of groups. For
of control they have over events, exercise. It seems that the belief in instance, the optimism bias has
depressed individuals do not show recovery motivates the individual to been named by several economists
this tendency. Seminal work by act in ways that promote it. as one of the core causes of the
Martin Seligman (2006) suggests Optimism appears to be related financial downfall of 2008. Unrealistic
that learning that one does not have to success in the professional expectation of individuals, financial
control over the environment can domain as well. Duke economists analysts and government officials
induce depression. He has shown Puri and Robinson (2007) report that the market would continue
that when an animal is exposed to that optimists work harder and growing, despite evidence to the
an environment in which actions do longer hours, which may account for contrary, likely contributed to the
not influence outcomes, it quickly their higher pay. Indeed, optimism collapse. This example may be
begins to show signs of depression. has been linked to achievement indicative of a trend in which the
Seligman coined the effect “learned in education, business, sport and negative consequences of optimism
helplessness” and showed that, electoral politics. In a recent paper, are especially pronounced in the
even after being transferred to an Johnson and Fowler (2007) present a modern world. There are two reasons
environment in which the animal computational model suggesting that why this might be. First, models
can in fact determine outcomes, the overestimating one’s probability of of predictive bias (such as that of
animal assumes helplessness and success is advantageous in a world Johnson and Fowler) hold that the
fails to commit the actions needed to of uncertainty and competition. They extent of unrealistic optimism should
avoid negative outcomes. suggest that if contested resources increase with uncertainty. People will
were sufficiently valuable compared show the largest bias in situations
Is optimism optimal? to the costs of competing for them with the greatest unknowns. The
Given that the healthy brain exhibits during human evolutionary history, modern world presents us with many
mechanisms that create optimistic humans would have evolved a bias such situations — whether we are
beliefs, one can ask the teleological to overestimate their likelihood of dealing with unfamiliar cultures (for
question of why this is. While success. example, in political relations) or novel
classic theories in economics and In a recent review, McKay and technologies (for example, internet
psychology assert that correct beliefs Dennett (2009) conclude that and financial markets), modern life is
will maximize reward and minimize optimistic illusions are the only group rife with circumstances in which over
loss, many sources of evidence point of misbeliefs that are adaptive. While optimism is likely to arise. Second,
to the conclusion that optimism is this may indeed be the case, it is the modern world has increased
nonetheless advantageous compared important to note that excessive interactions between larger numbers
to unbiased predictions. optimism can also be hazardous. of individuals. Individuals’ biases that
As discussed above, the absence Underestimating risk may reduce are inconsequential on their own can
of positive expectations of the future precautionary behaviour such accumulate together to produce a
is associated with mild depression as safe sex, attending medical large bubble, such as in the case of
and anxiety, suggesting that optimism screenings or buying insurance. It the 2008 financial market fall.
is vital to mental health. However, could potentially promote harmful On balance, however, it seems that
optimism is also beneficial for behaviours such as smoking, over- the benefits of unrealistic optimism
physical health. All else being equal, spending, and unhealthy eating due may have outweighed the downfalls.
optimists live longer and are healthier. to the optimistic assumptions that The biologists Ajit Varki (2009), Danny
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Brower and others have argued that single-blind randomised experiment,

the evolution of mankind might have Correspondences 34 healthy naïve volunteers (21
come to a halt without optimistic females; mean ± SD age = 22.6 ± 2.5
illusions. With the emergence of years) underwent bilateral histamine
conscious foresight (the ability to The rubber hand applications under two different
imagine one’s future) came the
devastating understanding that old
illusion increases conditions. The RHI was induced in
seated participants using the usual
age, sickness, decline of mental histamine reactivity method [2]. After the illusion was
power, and oblivion await. Varki and established, participants closed their
Brower reason that this awareness in the real arm eyes. The skin was pricked (1 mm
on its own would have interfered standardized point) at standardized
with our daily function, bringing the N. Barnsley1,2, J.H. McAuley1,2, locations on the volar aspect of both
activities needed for survival to a R. Mohan1,2, A. Dey1,2, P. Thomas2,3, arms. Histamine, and antigen and
stop. However, if conscious foresight and G.L. Moseley1,4 saline controls, were applied to both
evolved alongside optimistic illusions, arms. Both forearms and the rubber
it would not have become an Most people are convinced that their arm were covered with a tissue so
evolutionary psychological barrier. body parts are in fact their own, but in the participant could not see the
some clinical conditions, this sense of topical reactions. Participants then
Conclusion ownership can be lost [1]. Perceptual opened their eyes. The illusion was
Research on the optimism bias illusions, most famously the rubber reestablished every three minutes
suggests an important divergence hand illusion (RHI) [2], demonstrate by 20 seconds of synchronous
from classic approaches to that a sense of ownership over a body stroking. For the control condition,
understanding mind and behaviour. It part (or an entire body [3]) that is not we also stroked for 20 seconds every
highlights the possibility that the mind in fact ours can be easily induced in three minutes. The vividness of the
has evolved learning mechanisms healthy volunteers. But does illusory illusion was monitored subjectively
to mis-predict future occurrences, ownership over an artificial body using Item 3 of the established
as in some cases they lead to better part have consequences for the real questionnaire [2], which is known to
outcomes than do unbiased beliefs. body part, the one that has been correlate tightly with proprioceptive
‘replaced’? Recent data show the drift, a behavioural index of the
Further reading RHI induces a small but robust drop illusion’s vividness [6]. We confirmed
Chang, E.C. (2000). Optimism & Pessimism:
Implications for Theory, Research, and in skin temperature of the real hand. this tight correlation in our pilot study
Practice. (American Psychological That is, blood flow to the ‘disowned’ (see Supplemental Information).
Association).
Harding, E.J., Paul, E.S., and Mendl, M. (2004).
hand seems to be selectively reduced After ten minutes, the equipment
Cognitive bias and affective state. Nature 427, [1]. Such a finding is particularly was dismantled and a separate
312. relevant to the immune system investigator, who was blinded
Johnson, D.D.P, and Fowler, H.F. (2011). The
evolution of overconfidence. Nature 477, because a primary role of the immune to condition, arm and applied
317–320. system is to ‘discriminate self from substance, entered the room, marked
Matheson, S.M., Asher, L., and Bateson, M.
(2008). Larger, enriched cages are associated
non-self’ [4]. We predicted that the area of induration with a felt
with ‘optimistic’ response biases in captive the innate immune system may be pen, and photographed it from a
European starlings (Sturnus vulgaris). Appl. upregulated in a manner consistent standardized location 35 cm above
Anim. Behav. Sci. 109, 374–383.
McKay, R.T., and Dennett D.C. (2009). The with rejection of the replaced hand. the midpoint between the wrists of
evolution of misbelief. Behav. Brain Sci. 32, Consistent with this prediction, we the participant. Room lighting and
493–561.
Puri, M., and Robinson, D.T. (2007). Optimism and
report here that the RHI increases camera zoom were fixed. Both arms
economic choice. J. Fin. Econom. 86, 71–99. histamine reactivity, which is a key were in the one image. The size of
Seligman, M.E.P. (2006). Learned Optimism (New final pathway of the innate immune the wheal was measured by two
York: Vintage Books).
Sharot, T. (2011). The Optimism Bias (New York: response and has been implicated investigators, who were also blinded
Pantheon Books). in autoimmune disorders, including to subject, condition, arm and applied
Sharot, T., Korn, C.W., and Dolan, R.J. (2011).
How unrealistic optimism is maintained in the
multiple sclerosis [5]. Our finding has substance. Participants returned
face of reality. Nat. Neurosci. 14, 1475–1479. direct implications for autoimmune 10 ± 7 days later to perform the
Strunk, D.R., Lopez, H., and DeRubeis, R.J. (2006). disorders and a range of neurological second condition of the experiment.
Depressive symptoms are associated with
unrealistic negative predictions of future life and psychiatric conditions The experimental arm (left or right)
events. Behav. Res. Ther. 44, 861–882. characterised by a disrupted sense and the order of conditions were
Taylor, S.E., and Brown, J.D. (1988). Illusion and
well-being: a social psychological perspective
of ownership over one’s body (see randomized.
on mental health. Psychol. Bull. 103, 193–210. [1] for a list of conditions), and has Histamine always caused a wheal
Varki, A. (2009). Human uniqueness and the denial broader implications that extend well response, but the size of the wheal
of death. Nature. 460, 7256–684.
Weinstein, N.D. (1980). Unrealistic optimism beyond previous assertions about the depended on the arm involved and
about future life events. J. Pers. Soc. Psychol. mind-body link. on the experimental condition. That
39, 806–820.
We undertook an initial pilot study is, the wheal was bigger on the
that showed elevated histamine experimental arm during the illusion
Department of Cognitive, Perceptual and reactivity, measured by the size of the than it was on the control arm
Brain Sciences, Division of Psychology and
flare response, when the histamine during the illusion or on either arm
Language Sciences, University College
London, 26 Bedford Way, London WC1H was applied in conjunction with the during the control condition (arm x
0AP, UK. RHI (see Supplementary Information condition interaction (F(1,30) = 4.9,
E-mail: t.sharot@ucl.ac.uk for details). In the subsequent p = 0.034; post-hoc p < 0.05 for all;