Hannah Stower

Toward understanding and exploiting tumor heterogeneity

The extent of tumor heterogeneity is an emerging theme that researchers are only beginning to understand. How genetic and epigenetic heterogeneity affects tumor evolution and clinical progression is unknown. The precise nature of the environmental factors that influence this heterogeneity is also yet to be characterized. Nature Medicine, Nature Biotechnology and the Volkswagen Foundation organized a meeting focused on identifying the obstacles that need to be overcome to advance translational research in and tumor heterogeneity. Once these key questions were established, the attendees devised potential solutions. Their ideas are presented here.

Searching for Alzheimer’s disease therapies

The pathological hallmarks of Alzheimer’s disease (AD) include extracellular beta-amyloid plaques, neurofibrillary tangles, neuronal loss and tau deposits in brain. Therapies targeting these known hallmarks are yet to yield any meaningful benefit in clinical trials. We spoke to four researchers in the fields of AD research and therapy development to find out where they think the fields should head next.

A wasted early warning

Wasting of peripheral tissue is an early sign of pancreatic ductal adenocarcinoma and could be used to aid early diagnosis of the disease. Pancreatic ductal adenocarcinoma (PDAC) is associated with peripheral tissue wasting resulting in a severe reduction in quality of life in affected individuals, but its cause and role in mortality are unclear. Researchers based in Boston find in mouse models of PDAC and in humans that both adipose and muscle wasting occurs at early stages of the disease. They attribute this to pancreatic enzyme secretion loss in mice, but surprisingly in both mouse models and humans, this doesn’t seem to contribute to mortality. The tissue wasting could potentially be used as an early diagnostic for the disease.

Cell therapy for spinal cord injury

Transplantation of human spinal cord– derived neural stem cells is safe and may be of therapeutic benefit in individuals with chronic spinal cord injury (CSI). For individuals with CSI, currently no therapy exists that results in improvement of motor or sensory function, although some cell therapies have shown promise. Joseph Ciacci and colleagues show for the first time in four individuals with CSI that injection with human spinal cord–derived neural stem cells is safe. Furthermore, three of the individuals that received the treatment saw some improvement in motor or sensory function. The study provides promise for development of stem cell therapies for CSI.

Identifying atrial fibrillation

The wearing of a diagnostic device increases the diagnosis of atrial fibrillation (AF) and subsequent engagement with appropriate healthcare. AF is the most common sustained arrhythmia, and it substantially increases the risk of stroke in affected individuals. Its diagnosis is important for correct prescription of anticoagulants to reduce the risk of stroke and is currently made during screening at regular medical checks. In a clinical trial, participants at high risk for AF wore a self-applied wearable electrocardiogram (ECG) patch that could diagnose AF. The rate of AF diagnosis and engagement with healthcare were higher among individuals who wore the device. HS

Early immune development

The deltaE50-MD dog model of Duchenne muscular dystrophy (DMD) can be treated with systemic delivery of CRISPR gene editing components that restore the expression of the dystrophin gene. DMD is characterized by progressive muscle degeneration and atrophy and is caused by mutations in the dystrophin gene that result in its decreased expression. It has been shown that the gene can be targeted with CRISPR–Cas9 to restore its expression in mice and muscle stem cells. The deltaE50-MD dog model of DMD has a mutation in the dystrophin gene that corresponds with a mutational hotspot in humans. Researchers were able to restore its expression in this model using CRISPR– Cas9, showing the potential for translation in humans. HS

Live bacterial therapies for metabolic disease

The deltaE50-MD dog model of Duchenne muscular dystrophy (DMD) can be treated with systemic delivery of CRISPR gene editing components that restore the expression of the dystrophin gene. DMD is characterized by progressive muscle degeneration and atrophy and is caused by mutations in the dystrophin gene that result in its decreased expression. It has been shown that the gene can be targeted with CRISPR–Cas9 to restore its expression in mice and muscle stem cells. The deltaE50-MD dog model of DMD has a mutation in the dystrophin gene that corresponds with a mutational hotspot in humans. Researchers were able to restore its expression in this model using CRISPR– Cas9, showing the potential for translation in humans. HS

Towards poliovirus eradication

The deltaE50-MD dog model of Duchenne muscular dystrophy (DMD) can be treated with systemic delivery of CRISPR gene editing components that restore the expression of the dystrophin gene. DMD is characterized by progressive muscle degeneration and atrophy and is caused by mutations in the dystrophin gene that result in its decreased expression. It has been shown that the gene can be targeted with CRISPR–Cas9 to restore its expression in mice and muscle stem cells. The deltaE50-MD dog model of DMD has a mutation in the dystrophin gene that corresponds with a mutational hotspot in humans. Researchers were able to restore its expression in this model using CRISPR– Cas9, showing the potential for translation in humans. HS

An antiviral for smallpox

The antiviral tecovirimat is a promising candidate for therapy in the case of a smallpox outbreak. Smallpox has been eradicated, but the variola virus still exists, and there are fears of an outbreak due to bioterrorism or warfare. Just one infection would be a worldwide public health emergency. Because of its infectious and pathogenic nature, it is unethical to expose humans deliberately to variola. Scientists from SIGA Technologies established the efficacy of the antismallpox therapy tecovirimat in two animal models of smallpox infection. They determined its safety in uninfected individuals. Tecovirimat was approved as a smallpox therapy by the Food and Drug Administration on July 13, 2018.

CRISPR-based diagnostics

Sensitive, specific and portable diagnostics can rapidly identify viral infections. Quick and reliable diagnosis of viral disease in the field can aid treatment and containment. The recently developed specific high-sensitivity enzymatic reporter unlocking platform (SHERLOCK) is based on the programmable RNA cutting enzyme CRISPR–Cas13 and is able to identify genetic signatures of viruses without the need for complex lab protocols. Gootenberg et al. have developed SHERLOCK version 2, which offers four advances: quantitative detection, enhanced sensitivity, multiplex detection of up to four viruses (or other nucleic acid targets), and a visual readout. SHERLOCKv2 can also detect specific mutations even at very low frequencies, such as cancer-associated mutations found in liquid biopsies. Myhrvold et al. were able to add a step named HUDSON to the initial SHERLOCK protocol that allows the detection of viruses directly from body fluids, creating a field-deployable diagnostic. Doudna and colleagues showed that the enzyme Cas12a has a target-activated DNA cutting activity that can be leveraged to detect HPV in patient samples. The signal-amplifying property of Cas12a allows rapid and accurate point-of-care DNA detection. Together these tools will help to bring portable, accurate diagnostics to the field. HS