Reviews & Analysis

Early identification of at-risk people is critical in disease prevention, but current screening approaches are resource intensive and are often restricted to one disease at a time. We show how nuclear magnetic resonance (NMR) spectroscopy–derived metabolomics profiles can be used to predict multi-disease risk for the onset of 24 common conditions.

To accelerate the development of T cell–based immunotherapies that are effective for more patients with cancer, there is an urgent need to decipher the precise attributes of the ideal therapeutic T cell. In March 2021, the Parker Institute of Cancer Immunotherapy and 10x Genomics partnered to bring together a group of T cell immunotherapy researchers and single-cell-technology innovators for a day’s workshop. Participants evaluated the current cutting edge of knowledge, identified areas for focused technology development, and put forward a call to action to the field. Insights were provided on how to best leverage single-cell technologies and key areas for future development were proposed — with the goal of facilitating a better understanding of T cell research and translation of this research into effective cancer immunotherapies. The key points of discussion that emerged from this workshop are summarized here.

Using comprehensive single-cell profiling, two studies reveal the molecular phenotypes of CAR T cells associated with durable response in patients with lymphoma, and highlight the role of CAR regulatory T cells in mediating resistance.

Clinical evaluation of FMT is progressing without an adequate understanding of the underlying ecological dynamics; studies are now beginning to fill these gaps, but consensus will be needed on many fronts.

Multimodal artificial intelligence models could unlock many exciting applications in health and medicine; this Review outlines the most promising uses and the technical pitfalls to avoid.

Colorectal cancers expressing the mutant BRAF^V600E comprise 10% of all metastatic colorectal cancers, present with a poor prognosis, and are refractory to common therapies. We discovered that a subgroup of these tumors that carries loss-of-function RNF43 mutations is associated with significantly improved response to the current standard-of-care anti-BRAF–anti-EGFR combination therapy.

Assessment of tumor mutational burden through a simple blood test could help to identify which patients are most likely to benefit from immunotherapy, but optimal cutoffs are not well established.

A gene therapy product combines astrocyte replacement with stable delivery of a neuroprotective factor; a first-in-human study demonstrated safety and will inform the design of further clinical trials for this neurodegenerative disease.

Using population data on genetics and diseases and estimates of disability-adjusted life years, we generated a framework for estimating the effects of genetic factors on healthy life years, similar to the risk assessment framework for traditional modifiable epidemiological risk factors. This framework will help to inform the development and implementation of genetic-based clinical applications.

An engineered fusion protein exploits the efferocytosis pathway to clear amyloid-β (Aβ) from the brain without eliciting the severe inflammatory adverse effects associated with Aβ-targeting antibody-based immunotherapies. In mouse models of Alzheimer’s disease, this approach induced robust clearance of Aβ without inflammation, improved synapse protection, and decreased brain microhemorrhage, which result in superior behavioral recovery.

In patients with large B cell lymphomas, immune features of the tumor microenviroment predict clinical outcomes after CAR T cell therapy; as the number of patients treated with CAR T cells is set to increase, refinement of these and other biomarkers will be crucial.

We identified and mapped at high-resolution RNA structures in viral genomes that are essential for virus reproduction. We then rapidly designed potent antivirals with high barriers to resistance that prevent or treat severe infections of these viruses with pandemic potential — via development of what we term ‘programmable antivirals’.

A large cohort of non-hospitalized adults with confirmed SARS-CoV-2 infection and matched controls were studied to investigate the symptoms of long COVID. SARS-CoV-2 infection was associated with 62 symptoms (three clusters) that persisted beyond 12 weeks, and with a range of risk factors.

The commonly indolent chronic lymphocytic leukemia may evolve into Richter transformation (RT), a very aggressive large B cell lymphoma. We identified early seeding of RT cells decades before its final expansion, mapped the underlying (epi)genomic alterations driving this process, and validated in vitro potential actionable therapeutic pathways.

Cellular senescence has emerged as a promising therapeutic target for disorders across the lifespan; this Review highlights the most promising strategies for translating senescence-targeting interventions into clinical use in the near future.

The largest and most genetically diverse genome-wide association study thus far for coronary artery disease, a leading cause of death worldwide, identifies many new susceptibility loci and characterizes the genetic architecture in Black and Hispanic populations for the first time.

Incorporating genetic factors into risk models improves the prediction of severe obesity for survivors of childhood cancer, which could promote early interventions and better long-term care.

Infrequently dosed, longer-acting antiretroviral agents are making adherence to medication easier, leading to better outcomes for those living with HIV or at risk of infection.

Analysis of genomics data and medical records of over 40,000 patients with cancer identifies hundreds of mutations that are predictive of how well patients respond to specific cancer therapies. These predictive biomarkers could inform personalized treatment planning.