Publication highlights

Researchers at the Crick, Stockholm University, the University of Aberdeen and the University of East Anglia analysed two 3,000-5,000-year-old wolf remains found in the Stora Förvar cave on the Swedish island of Stora Karlsö. A small, isolated island, Stora Karlsö has no native land mammals, meaning that any animals found must have been brought there by people. Genomic analysis of the two canid remains confirmed they were wolves, not dogs, with no evidence of dog ancestry. However, they exhibited several traits typically associated with life alongside humans, such as a diet aligned with the humans on the island, a size smaller than typical mainland wolves, and low genetic diversity, a common result of isolation or controlled breeding. The finding challenges the conventional understanding of wolf-human dynamics and the process of dog domestication.

Researchers at the Crick examined unusually large and abnormal cells called polyploid giant cancer cells (PGCCs) in ten pleomorphic sarcomas, types of soft-tissue cancers known to be highly aggressive and genetically complex. Using advanced single-cell DNA sequencing, they analysed the genetic material of individual PGCCs to see how they differ from the rest of the tumour. They found that PGCCs were scattered randomly rather than forming groups in the tumour, suggesting that they arise spontaneously. They appeared to come from the main tumour cell population but had more genetic variation and many had signs of chromosomal instability. Chromothripis, where chromosomes shatter and reassemble in a chaotic pattern, was frequently seen in PGCCs. This ongoing genomic reshaping may explain why pleomorphic sarcomas often behave aggressively and are difficult to treat.

Researchers at the Crick have identified a signalling feedback loop which they think may have been vital to the evolution of insect wings and therefore flight. They found that, as concentrations of a morphogen called Dpp decrease across the wing tissue, another molecule called Brinker forms a reverse gradient. The Brinker gene is repressed by Dpp and is therefore increasingly expressed as the Dpp signal becomes weaker. They then found that Brinker is only found in insects and not in closely related crustaceans, and that it is found in a wingless insect called a firebrat, but doesn't form a gradient and is as yet unconnected to the Dpp signal transduction. This suggests that the Brinker-mediated feedback circuit may have been an evolutionary innovation of winged insects.

Gene regulatory networks play a central role in shaping spatial patterns: the lines that eventually give rise to segments, organs or markings like stripes and spots. Researchers at the Crick explored whether specific types of mutations in patterning networks accelerate the evolution of new patterns, and if any of these changes yield predictable evolutionary outcomes. Using a computer simulation that models how small networks of genes evolve under natural selection, they found that adjusting an existing boundary needed only small tweaks to the strengths of existing gene interactions. But creating new boundaries was far more difficult, demanding multiple changes at once. They also found that certain mutations radically shift the predicted evolutionary outcome, suggesting that a mutation introduces a fork in the road early on which reliably redirects evolution to a specific destination.

COVID-19 restrictions including social distancing were lifted in the UK in 2021 after the majority of the population had two doses of vaccine. Researchers at the Crick analysed data from the Legacy study to find out if either infection or vaccine as a third exposure generated different immunity. We found overall that both antibody-mediated and cellular immunity was similar, but when T cells were exposed to spike protein challenge in vitro, infection exposure drove production of more innate immune cytokines from T cells and expansion of mucosal-homing T cells, whereas vaccine-only exposed cells led to expansion of the T cell memory population that produced more inflammatory cytokines.

Researchers from the Francis Crick Institute and the Gulbenkian Institute for Molecular Medicine (GIMM) have shown that the evolution of a family of exported proteins in the malaria-causing parasite Plasmodium falciparum enabled it to infect humans. The team looked at over two thousand P. falciparum samples from people infected with malaria, finding that out of 21 FIKK kinases, 18 were protected against harmful mutations, suggesting they are necessary for the parasite to infect humans and likely helped it evolve. The researchers then expressed the FIKK kinases in bacteria to see what each one does. This experiment showed that the FIKK kinases all had different protein targets in the cell. Finally, the team showed that the specificity of FIKK kinases is linked to small changes in a flexible loop region, and that two molecules could block most FIKK kinases in a test tube. Blocking all FIKK kinases could be a promising treatment strategy for malaria.

Researchers at the Crick, the UCL Cancer Institute and UCLH have shown that a test called ORACLE can predict lung cancer survival at the point of diagnosis better than currently used clinical risk factors. This could help doctors make more informed treatment decisions for people with stage 1 lung cancer, potentially reducing the risk of the cancer returning or spreading. ORACLE was developed in 2019 to overcome the lack of biological markers in lung cancer, which is important for people with stage 1 lung cancer, who are normally given surgery without chemotherapy. In this study ORACLE was validated in 158 people with lung cancer in the Cancer Research UK-funded TRACERx study. The team found that ORACLE could predict which patients with stage 1 lung cancer had a lower chance of survival, and might benefit from chemotherapy as well as surgery. The researchers also found that high ORACLE risk scores were linked to regions of the tumour that were more likely to spread to another part of the body.

Humans intuitively tend to attribute agency to living things and to interpret their behaviour in teleological terms. A number of scientists have recently proposed that the agency of organisms is an important phenomenon for evolutionary biology to study. Proponents claim that agency—the capacity for goal-directed, self-determining activity—is not explainable by physiological or developmental mechanisms, or by adaptation via natural selection. This paper shows that this idea is theoretically unsound and unsupported by current biology. Instead, we argue, agency in simple organisms is a cognitive illusion, and the phenomena that the agency perspective purports to make sense of are better explained using the well-established idea that feedback mechanisms evolve through natural selection.

Researchers at the Francis Crick Institute and UCL, funded by Cancer Research UK, have unveiled the first computer algorithm capable of identifying which cell populations within a tumour drive aggressive growth. The innovative algorithm, called SPRINTER, analyses individual cells within a tumour to identify those that are growing the most rapidly. The algorithm was used to analyse nearly 15,000 cancer cells from a patient with non-small cell lung cancer (in TRACERx and PEACE studies). SPRINTER revealed that the cells that were growing the fastest were responsible for spreading the cancer to other parts of the body, even from other metasasised tumours. It also showed that these cells shed more of their DNA into the bloodstream. The possibility of detecting aggressive cancer cell populations early and monitoring them over time offers a new avenue for more proactive and personalised cancer care.

One of the major hallmarks of amyotrophic lateral sclerosis (ALS), also known as motor neurone disease, is the loss of function of the RNA-binding protein TDP-43 in diseased neurons. TDP-43 dysfunction causes errors in the assembly of RNAs and is a key driver of disease. The Fratta lab and collaborators have developed a method that takes advantage of these RNA assembly errors and uses them to selectively express therapeutic constructs only in the cells that have lost TDP-43. The research is an important step towards safer precision medicine, and work to further develop gene therapies for ALS using this system is being supported by the Crick Translation Fund