Pathogen protein modularity enables elaborate mimicry of a host phosphatase.

Pathogens produce diverse effector proteins to manipulate host cellular processes. However, how functional diversity is generated in an effector repertoire is poorly understood. Many effectors in the devastating plant pathogen Phytophthora contain tandem repeats of the "(L)WY" motif, which are structurally conserved but variable in sequences. Here, we discovered a functional module formed by a specific (L)WY-LWY combination in multiple Phytophthora effectors, which efficiently recruits the serine/threonine protein phosphatase 2A (PP2A) core enzyme in plant hosts. Crystal structure of an effector-PP2A complex shows that the (L)WY-LWY module enables hijacking of the host PP2A core enzyme to form functional holoenzymes. While sharing the PP2A-interacting module at the amino terminus, these effectors possess divergent C-terminal LWY units and regulate distinct sets of phosphoproteins in the host. Our results highlight the appropriation of an essential host phosphatase through molecular mimicry by pathogens and diversification promoted by protein modularity in an effector repertoire.

Two distinct host-parasite associations mediate seasonal ecosystem linkages.

Nematomorph parasites manipulate terrestrial arthropods to enter streams where the parasites reproduce. These manipulated arthropods become a substantial prey subsidy for stream salmonids, causing cross-ecosystem energy flow. Diverse nematomorph-arthropod associations underlie the energy flow, but it remains unknown whether they can mediate the magnitude and temporal attributes of the energy flow. Here, we investigated whether distinct phylogenetic groups of nematomorphs manipulate different arthropod hosts and mediate seasonal prey subsidy for stream salmonids. The results of our molecular-based diagnoses show that Gordionus and Gordius nematomorphs infected ground beetle and orthopteran hosts, respectively. The presumable ground beetle hosts subsidized salmonid individuals in spring, whereas the presumable orthopteran hosts did so in autumn. Maintaining the two distinct nematomorph-arthropod associations thus resulted in the parasite-mediated prey subsidy in both spring and autumn in the study streams. Manipulative parasites are common, and often associated with a range of host lineages, suggesting that similar effects of phylogenetic variation in host-parasite associations on energy flow might be widespread in nature.

Littorina snails and Microphallus trematodes: Diverse consequences of the trematode-induced metabolic shifts.

The intricate relationships between parasites and hosts encompass a wide range of levels, from molecular interactions to population dynamics. Parasites influence not only the physiological processes in the host organism, but also the entire ecosystem, affecting mortality of individuals, the number of offspring through parasitic castration, and matter and energy cycles. Understanding the molecular mechanisms that govern host-parasite relationships and their impact on host physiology and environment remains challenging. In this study, we analyzed how infection with Microphallus trematodes affects the metabolome of two Littorina snail species inhabiting different intertidal zone shore levels. We applied non-targeted GC-MS-based metabolomics to analyze biochemical shifts induced by trematode infection in a host organism. We have identified changes in energy, amino acid, sugar, and lipid metabolism. In particular, we observed intensified amino acid catabolism and nitrogenous catabolites (glutamine, urea) production. These changes primarily correlated with infection and interspecies differences of the hosts rather than shore level. The changes detected in the host metabolism indicate that other aspects of life may have been affected, both within the host organism and at a supra-organismal level. Therefore, we explored changes in microbiota composition, deviations in the host molluscs behavior, and acetylcholinesterase activity (ACE, an enzyme involved in neuromuscular transmission) in relation to infection. Infected snails displayed changes in their microbiome composition. Decreased ACE activity in snails was associated with reduced mobility, but whether it is associated with trematode infection remains unclear. The authors suggest a connection between the identified biochemical changes and the deformation of the shell of molluscs, changes in their behavior, and the associated microbiome. The role of parasitic systems formed by microphallid trematodes and Littorina snails in the nitrogen cycle at the ecosystem level is also assumed.

Parasite-mediated manipulation? Toxoplasma gondii infection increases risk behaviour towards culling in red deer.

Parasites can modify host behaviour to increase their chances of survival and transmission. Toxoplasma gondii is a globally distributed protozoan whose ability to modify host behaviour is well known in taxa such as rats and humans. Less well known are the effects on the behaviour of wild species, with the exception of a few studies on primates and carnivores. Taking advantage of a culling activity conducted in Stelvio National Park (Italy), the serological status of T. gondii was studied in 260 individuals of red deer Cervus elaphus with respect to the risk of being culled. A temporal culling rank index was fitted as a response variable, and T. gondii serological status as the main explanatory variable in linear models, accounting for covariates such as sex, age, jaw length, bone marrow fat and culling location. The overall seroprevalence of T. gondii was 31.5%, and the selected models suggested that seropositive deer were culled earlier than seronegative ones, but this effect was only evident in females, in individuals with medium-good body condition, and in areas with greater human presence. Our results suggest that T. gondii may be involved in risk behaviour in large herbivores, supporting its role as a facilitator of predation risk.

Anatomical, phenological and genetic aspects of the host-parasite relationship between Andrena vaga (Hymenoptera) and Stylops ater (Strepsiptera).

Stylops ater is an endoparasite of the mining bee Andrena vaga with extreme sexual dimorphism and hypermetamorphosis. Its population structure, parasitization mode, genetic diversity and impact on host morphology were examined in nesting sites in Germany to better understand this highly specialized host­parasite interaction. The shift in host emergence due to stylopization was proven to be especially strong in A. vaga. Around 10% of bees hosted more than 1 Stylops, with at maximum 4. A trend in Stylops' preference for hosts of their own sex and a sex-specific position of extrusion from the host abdomen was found. Invasion of Andrena eggs by Stylops primary larvae was depicted for the first time. Cephalothoraces of female Stylops were smaller in male and pluristylopized hosts, likely due to lower nutrient supply. The genes H3, 18S and cytochrome c oxidase subunit 1 were highly conserved, revealing near-absence of local variation within Stylops. Ovaries of hosts with male Stylops contained poorly developed eggs while those of hosts with female Stylops were devoid of visible eggs, which might be due to a higher protein demand of female Stylops. Male Stylops, which might have a more energy-consuming development, led to a reduction in head width of their hosts. Host masculinization was present in the leaner shape of the metabasitarsus of stylopized females and is interpreted as a by-product of manipulation of the host's endocrine system to shift its emergence. Stylopization intensified tergal hairiness, most strongly in hosts with female Stylops, near the point of parasite extrusion, hinting towards substance-induced host manipulation.

Clonemate cotransmission supports a role for kin selection in a puppeteer parasite.

Host manipulation by parasites is a fascinating evolutionary outcome, but adaptive scenarios that often accompany even iconic examples in this popular field of study are speculative. Kin selection has been invoked as a means of explaining the evolution of an altruistic-based, host-manipulating behavior caused by larvae of the lancet fluke Dicrocoelium dendriticum in ants. Specifically, cotransmission of larval clonemates from a snail first host to an ant second host is presumed to lead to a puppeteer parasite in the ant's brain that has clonemates in the ant abdomen. Clonal relatedness between the actor (brain fluke) and recipients (abdomen flukes) enables kin selection of the parasite's host-manipulating trait, which facilitates transmission of the recipients to the final host. However, the hypothesis that asexual reproduction in the snail leads to a high abundance of clonemates in the same ant is untested. Clonal relationships between the manipulator in the brain and the nonmanipulators in the abdomen are also untested. We provide empirical data on the lancet fluke's clonal diversity within its ant host. In stark contrast to other trematodes, which do not exhibit the same host-manipulating behavioral trait, the lancet fluke has a high abundance of clonemates. Moreover, our data support existing theory that indicates that the altruistic behavior can evolve even in the presence of multiple clones within the same ant host. Importantly, our analyses conclusively show clonemate cotransmission into ants, and, as such, we find support for kin selection to drive the evolution and maintenance of this iconic host manipulation.

Is direct bodyguard manipulation a parasitoid-induced stress sleep? A new perspective.

Bodyguard manipulation is a behavioural manipulation in which the host's behaviour is altered to protect the inducer's offspring from imminent biotic threats. The behaviour of a post-parasitoid-egressed host resembles a quiescence state with a characteristic reduction in motor activities like feeding, locomotion, respiration, and metabolic rate. Yet, they respond aggressively through a defensive response when disturbed, which ensures better fitness for the parasitoid's offspring. The behavioural changes in the parasitized host appear after the parasitoid egression. Several hypotheses have been proposed to elucidate how the parasitized host's behaviour is manipulated for the fitness benefits of the inducers, but the exact mechanism is still unknown. We review evidence to explain the behavioural changes and their mechanism in the parasitized hosts. The evidence suggests that parasitoid pre-pupal egression may drive the host to stress-induced sleep. The elevated octopamine concentration also reflects the stress response in the host. Given the theoretical links between the behavioural and the physiological changes in the post-parasitoid-egressed host and stress-induced sleep of other invertebrates, we suggest that behavioural studies combined with functional genomics, proteomics, and histological analyses might give a better understanding of bodyguard manipulation.

High-resolution analysis of baculovirus-induced host manipulation in the domestic silkworm, Bombyx mori.

Many parasites manipulate host behaviour to enhance their transmission. Baculoviruses induce enhanced locomotory activity (ELA) combined with subsequent climbing behaviour in lepidopteran larvae, which facilitates viral dispersal. However, the mechanisms underlying host manipulation system are largely unknown. Previously, larval locomotion during ELA was summarized as the distance travelled for a few minutes at several time points, which are unlikely to characterize ELA precisely, as ELA typically persists for several hours. In this study, we modified a recently developed method using time-lapse recording to characterize locomotion of Bombyx mori larvae infected with Bombyx mori nucleopolyhedrovirus (BmNPV) for 24 h at 3 s resolution. Our data showed that the locomotion of the mock-infected larvae was restricted to a small area, whereas the BmNPV-infected larvae exhibited a large locomotory area. These results indicate that BmNPV dysregulates the locomotory pattern of host larvae. Furthermore, both the mock- and BmNPV-infected larvae showed periodic cycles of movement and stationary behavior with a similar frequency, suggesting the physiological mechanisms that induce locomotion are unaffected by BmNPV infection. In contrast, the BmNPV-infected larvae exhibited fast and long-lasting locomotion compared with mock-infected larvae, which indicates that locomotory speed and duration are manipulated by BmNPV.

SARS/CoV-2: Behavioral Host Manipulation.

INTRODUCTION: Though it has not been extensively studied, host manipulation has been documented for various pathogens. Examples of this phenomenon can be seen in cases of toxoplasmosis, rabies, and the influenza virus. An examination of the possible means by which SARS/CoV-2 alters the behavior of its host to spread among populations is elaborated. Indirect evidence that serves as indicators of this phenomenon is presented. METHODS: This is primarily a theoretical document. Many of the ideas raised are not amenable to direct testing due to ethical concerns. However, several indirect means by which to test the hypothesis are discussed. Primary data from cell phones regarding miles traveled, number of times leaving home, etc., are among the possible indirect measures. RESULTS: The rapid ability of the SARS/CoV-2 virus to spread through society suggests that it may cause behavioral changes of the host to increase its transmission. Numerous cases of super spreader events are noted that have provided meaningful measures of host manipulation. CONCLUSION: In the case of SARS/CoV-2, the largest advantage of the pathogen is likely that between 50% and 70% of those infected are asymptomatic (John's Hopkins Coronavirus Resource Center, John's Hopkins University Corona Virus Resource Center. Available at https://coronavirus.jhu.edu/map.html , 2020). This component is a threat to elderly individuals and those immunocompromised who are more likely to have severe complications from the virus and die. To spread within these groups, a seemingly healthy host is necessary to carry the virus to them. The goal of the virus is not to kill the host, but to survive and reproduce.

Host Manipulation Mechanisms of SARS-CoV-2.

Viruses are the simplest of pathogens, but possess sophisticated molecular mechanisms to manipulate host behavior, frequently utilizing molecular mimicry. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been shown to bind to the host receptor neuropilin-1 in order to gain entry into the cell. To do this, the virus utilizes its spike protein polybasic cleavage site (PCS), which mimics the CendR motif of neuropilin-1's endogenous ligands. In addition to facilitating cell entry, binding to neuropilin-1 has analgesic effects. We discuss the potential impact of neuropilin-1 binding by SARS-CoV-2 in ameliorating sickness behavior of the host, and identify a convergent evolutionary strategy of PCS cleavage and subsequent neuropilin binding in other human viruses. In addition, we discuss the evolutionary leap of the ancestor of SARS-COV-2, which involved acquisition of the PCS thus faciliting binding to the neuropilin-1 receptor. Acquisition of the PCS by the ancestor of SARS-CoV-2 appears to have led to pleiotropic beneficial effects including enhancement of cell entry via binding to ACE2, facilitation of cell entry via binding to neuropilin-1, promotion of analgesia, and potentially the formation of decoy epitopes via enhanced shedding of the S1 subunit. Lastly, other potential neuromanipulation strategies employed by SARS-CoV-2 are discussed, including interferon suppression and the resulting reduction in sickness behavior, enhanced transmission through neurally mediated cough induction, and reduction in sense of smell.

Risky business: influence of eye flukes on use of risky microhabitats and conspicuousness of a fish host.

A prerequisite for a parasitic manipulation to be considered adaptive is that it confers a fitness benefit to the parasite, such as increased transmission to another host. These manipulations can involve alterations to a wide range of host phenotypic traits, including microhabitat choice. Eye flukes of the trematode family Diplostomidae use fish as intermediate hosts and must be transmitted by predation to a piscivorous bird. In New Zealand, the diplostomid Tylodelphys darbyi infects the eyes of a widespread endemic freshwater fish, the common bully Gobiomorphus cotidianus. Within the eye, T. darbyi metacercariae achieve large sizes and move freely about the aqueous and vitreous humors of the eye. We hypothesized that higher intensities of T. darbyi would (i) cause bullies to show increased activity and spend more time moving about in open space (i.e., more conspicuous, risky microhabitat) and (ii) reduce their ability to compete for shelter with fish harboring lower infection levels. Our experiments showed that heavily infected fish were more active and spent more time in the open, although the effect was age-dependent, with immature fish displaying decreases in activity and time spent in the open with increasing intensities of infection. We also demonstrated that heavily infected female bullies have a lower probability of using shelter, but males show the opposite pattern. It is possible that using more risky microhabitats increases the likelihood of the fish being eaten by the parasite's predatory avian definitive hosts. However, our findings indicate that age- and sex-dependent effects call for a more nuanced interpretation.

Experimental evolution of parasitic host manipulation.

Host manipulation is a parasite-induced alteration of a host's phenotype that increases parasite fitness. However, if genetically encoded in the parasite, it should be under selection in the parasite. Such host manipulation has often been assumed to be energetically costly, which should restrict its evolution. Evidence of such costs, however, remains elusive. The trophically transmitted cestode Schistocephalus solidus manipulates the activity of its first intermediate copepod host to reduce its predation susceptibility before the parasite is ready for transmission. Thereafter, S. solidus increases host activity to facilitate transmission to its subsequent fish host. I selected S. solidus for or against host manipulation over three generations to investigate the evolvability of manipulation and identify potential trade-offs. Host manipulation responded to selection, confirming that this trait is heritable in the parasite and hence can present an extended phenotype. Changes in host manipulation were not restrained by any obvious costs.

Tapeworm manipulation of copepod behaviour: parasite genotype has a larger effect than host genotype.

Compared with uninfected individuals, infected animals can exhibit altered phenotypes. The changes often appear beneficial to parasites, leading to the notion that modified host phenotypes are extended parasite phenotypes, shaped by parasite genes. However, the phenotype of a parasitized individual may reflect parasitic manipulation, host responses to infection or both, and disentangling the contribution of parasite genes versus host genes to these altered phenotypes is challenging. Using a tapeworm (Schistocephalus solidus) infecting its copepod first intermediate host, I performed a full-factorial, cross-infection experiment with five host and five parasite genotypes. I found that a behavioural trait modified by infection, copepod activity, was affected by both host and parasite genotype. There was no clear evidence for host genotype by parasite genotype interactions. Several observations indicated that host behaviour was chiefly determined by parasite genes: (i) all infected copepods, regardless of host or parasite genotype, exhibited behavioural changes, (ii) parasitism reduced the differences among copepod genotypes, and (iii) within infected copepods, parasite genotype had twice as large an effect on behaviour as host genotype. I conclude that the altered behaviour of infected copepods primarily represents an extended parasite phenotype, and I discuss how genetic variation in parasitic host manipulation could be maintained.

Let's go swimming: mermithid-infected earwigs exhibit positive hydrotaxis.

Certain species of parasites have the apparent ability to alter the behaviour of their host in order to facilitate the completion of their own life cycle. While documented in hairworms (phylum Nematomorpha), the ability for mermithid parasites (from the sister phylum Nematoda) to force hosts to enter water remains more enigmatic. Here, we present the first experimental evidence in a laboratory setting that an insect which normally never enters open water (the European earwig Forficula auricularia) will readily enter the water when infected with a mermithid nematode (Mermis nigrescens). Only adult mermithids appear capable of inducing this polarising shift in behaviour, with mermithid length being a very strong predictor of whether their host enters water. However, mermithid length was only weakly associated with how long it took an earwig to enter water following the beginning of a trial. Considering the evidence presented here and its alignment with a proteomic investigation on the same host-parasite system, this study provides strong evidence for adaptive behavioural manipulation and a foundational system for further behavioural and mechanistic exploration.

Inter-population variation in the intensity of host manipulation by the fish acanthocephalan Pomphorhynchus tereticollis: are differences driven by predation risk?

Many trophically-transmitted parasites induce behavioural alteration in their intermediate hosts that tend to increase host vulnerability to predation. Inter-population variability in parasite-induced alterations is expected to arise from variable local opportunities for trophic transmission. Yet, this hypothesis has not been investigated so far. We addressed the issue in four populations of the fish parasite Pomphorhynchus tereticollis (Acanthocephala), using variable fish biomass density as a proxy for transmission opportunities. We found variation in the intensity of parasite-induced changes in phototaxis and refuge use among populations. Two of the populations with the lowest predator biomass exhibited the highest levels of behavioural manipulation and prevalence, as expected at low transmission opportunities. They also exhibited micro-habitat segregation between infected and uninfected gammarids in the field. In addition, infection had variable effects on two physiological defence systems, immunity and antioxidant capacity, and on total protein content. Overall, our study brings partial support to the prediction that host manipulation and prevalence should be higher at low predator biomass. Although stronger evidence should be sought by increasing population replicates, our study points to the importance of the ecological context, specifically transmission opportunities brought about by predation pressure, for the evolution of parasite manipulation in trophically-transmitted parasites.

Behavior manipulation of mosquitoes by a mermithid nematode.

We examined manipulation of mosquito behavior by the parasitic mermithid nematode, Strelkovimermis spiculatus. This nematode species typically infects early instar host larvae and emerges after parasitic development to kill last-instar larvae. Parasitized adults, however, have occasionally been reported from field collections. We obtained low rates (1.7-11.5%) of parasitized adults in laboratory exposures only when Culex pipiens pipiens fourth-instar larvae nearing pupation were exposed to infective nematodes. This did not allow an adequate interval for parasitic development in immature host stages. Parasitized adult females in a multiple-choice assay were three times more likely to seek water than a blood source (63.1 vs. 20.5%), whereas uninfected females were twice as likely to seek blood than water (64%3.9 vs. 32.6%). This altered host behavior benefits the parasite by providing the only mechanism for dispersal and colonization of new host habitats while concurrently avoiding risks from the defensive behaviors associated with blood-feeding. Behavioral alternation in Cx. p. pipiens larval hosts was also examined using larvae infected as second instars to allow for a normal duration of parasitic development. As larvae neared pupation and parasite emergence, parasitized larvae became more spatially aggregated than unparasitized larvae. This altered host behavior benefits the parasite by providing a corresponding increase in post-parasite aggregation, which facilitates formation of large mating clusters and concomitantly reproductive success. Parasites derive fitness gains by overriding host autonomy, whereas hosts have zero fitness once parasitism is established, suggesting a coevolutionary response is inoperative and that the behavioral modifications may be adaptive.

Infection by the semi-persistently transmitted Tomato chlorosis virus alters the biology and behaviour of Bemisia tabaci on two potato clones.

Insect-borne plant viruses usually alter the interactions between host plant and insect vector in ways conducive to their transmission ('host manipulation hypothesis'). Most studies have tested this hypothesis with persistently and non-persistently transmitted viruses, while few have examined semi-persistently transmitted viruses. The crinivirus Tomato chlorosis virus (ToCV) is semi-persistently transmitted virus by whiteflies, and has been recently reported infecting potato plants in Brazil, where Bemisia tabaci Middle East Asia Minor 1 (MEAM1) is a competent vector. We investigated how ToCV infection modifies the interaction between potato plants and B. tabaci in ways that increase the likelihood of ToCV transmission, in two clones, one susceptible ('Agata') and the other moderately resistant (Bach-4) to B. tabaci. Whiteflies alighted and laid more eggs on ToCV-infected plants than mock-inoculated plants of Bach-4. When non-viruliferous whiteflies were released on ToCV-infected plants near mock-inoculated plants, adults moved more intensely towards non-infected plants than in the reverse condition for both clones. Feeding on ToCV-infected plants reduced egg-incubation period in both clones, but the egg-adult cycle was similar for whiteflies fed on ToCV-infected and mock-inoculated plants. Our results demonstrated that ToCV infection in potato plants alters B. tabaci behaviour and development in distinct ways depending on the host clone, with potential implications for ToCV spread.

Insect-Borne Plant Pathogens and Their Vectors: Ecology, Evolution, and Complex Interactions.

The transmission of insect-borne plant pathogens, including viruses, bacteria, phytoplasmas, and fungi depends upon the abundance and behavior of their vectors. These pathogens should therefore be selected to influence their vectors to enhance their transmission, either indirectly, through the infected host plant, or directly, after acquisition of the pathogen by the vector. Accumulating evidence provides partial support for the occurrence of vector manipulation by plant pathogens, especially for plant viruses, for which a theoretical framework can explain patterns in the specific effects on vector behavior and performance depending on their modes of transmission. The variability in effects of pathogens on their vectors, however, suggests inconsistency in the occurrence of vector manipulation but also may reflect incomplete information about these systems. For example, manipulation can occur through combinations of specific effects, including direct and indirect effects on performance and behavior, and dynamics in those effects with disease progression or pathogen acquisition that together constitute syndromes that promote pathogen spread. Deciphering the prevalence and forms of vector manipulation by plant pathogens remains a compelling field of inquiry, but gaps and opportunities to advance it remain. A proposed research agenda includes examining vector manipulation syndromes comprehensively within pathosystems, expanding the taxonomic and genetic breadth of the systems studied, evaluating dynamic effects that occur during disease progression, incorporating the influence of biotic and abiotic environmental factors, evaluating the effectiveness of putative manipulation syndromes under field conditions, deciphering chemical and molecular mechanisms whereby pathogens can influence vectors, expanding the use of evolutionary and epidemiological models, and seeking opportunities to exploit these effects to improve management of insect-borne, economically important plant pathogens. We expect this field to remain vibrant and productive in its own right and as part of a wider inquiry concerning host and vector manipulation by plant and animal pathogens and parasites.

Differences between populations in host manipulation by the tapeworm Schistocephalus solidus - is there local adaptation?

Host manipulation whereby a parasite increases its transmission to a subsequent host by altering the behaviour of its current host is very far spread. It also occurs in host-parasite systems that are widely distributed. This offers the potential for local adaptation. The tapeworm Schistocephalus solidus modifies its first intermediate copepod host's predation susceptibility to suit its own needs by reducing its activity before it becomes infective and increasing it thereafter. To investigate potential differences in host manipulation between different populations and test for potential local adaptation with regard to host manipulation, I experimentally infected hosts from two distinct populations with parasites from either population in a fully crossed design. Host manipulation differed between populations mostly once the parasite had reached infectivity. These differences in infective parasites were mostly due to differences between different parasite populations. In not yet infective parasites, however, host population also had a significant effect on host manipulation. There was no evidence of local adaptation; parasites were able to manipulate foreign and local hosts equally well. Likewise, hosts were equally poor at resisting host manipulation by local and foreign parasites.

Host manipulation by cancer cells: Expectations, facts, and therapeutic implications.

Similar to parasites, cancer cells depend on their hosts for sustenance, proliferation and reproduction, exploiting the hosts for energy and resources, and thereby impairing their health and fitness. Because of this lifestyle similarity, it is predicted that cancer cells could, like numerous parasitic organisms, evolve the capacity to manipulate the phenotype of their hosts to increase their own fitness. We claim that the extent of this phenomenon and its therapeutic implications are, however, underappreciated. Here, we review and discuss what can be regarded as cases of host manipulation in the context of cancer development and progression. We elaborate on how acknowledging the applicability of these principles can offer novel therapeutic and preventive strategies. The manipulation of host phenotype by cancer cells is one more reason to adopt a Darwinian approach in cancer research.