CRISPR-based diagnostics

CRISPR-based diagnostics research highlights DIAGNOSTICS INFeCTIOuS DISeASe brain-resident innate immune cells called Zika virus shedding in semen microglia and results in altered later Science 360, 436–439 (2018) development of neuropathologies in mice. N. Engl. J. Med. 378, 1377–1385 (2018) Science 360, 439–444 (2018) Previous exposure of myeloid cells to Zika virus RNA is commonly shed in the immune stimuli can result in immune training, Science 360, 444–448 (2018) semen of infected men, and in some of in which subsequent immune responses are these men, this occurs beyond 6 months Sensitive, specific and portable diagnostics exacerbated, or immune tolerance, in which can rapidly identify viral infections. after the first appearance of symptoms. later immune responses are inhibited. Shedding of infectious virus, however, Quick and reliable diagnosis of viral disease Wendeln et al. found that exposing a in the field can aid treatment and containment. appears to be limited to the month mouse engineered to develop Alzheimer’s immediately after illness onset. The recently developed specific high-sensitivity disease pathology to a peripheral immune enzymatic reporter unlocking platform Zika virus is transmitted by mosquitoes stimulus that results in immune training and during recent outbreaks has been (SHERLOCK) is based on the programmable increased Alzheimer’s neuropathology, and RNA cutting enzyme CRISPR–Cas13 and is linked to the development of congenital exposing this mouse to a peripheral immune microcephaly in the offspring of infected able to identify genetic signatures of viruses stimulus that induced tolerance decreased without the need for complex lab protocols. individuals. There have been reported cases Alzheimer’s neuropathology. These effects of male-to-partner sexual transmission, Gootenberg et al. have developed were mediated through epigenetic changes SHERLOCK version 2, which offers four but the duration of contagion is unknown. in the microglia. They also found that Mead et al. analyzed levels of Zika advances: quantitative detection, enhanced previous immune exposure modulated sensitivity, multiplex detection of up to virus RNA in semen samples from 184 stoke neuropathology. symptomatic men (1,327 total samples) four viruses (or other nucleic acid targets), In humans, it is possible that previous and a visual readout. SHERLOCKv2 can every 2 weeks over a period of 6 months. exposure to infection or other inflammatory Zika virus RNA was commonly detected, also detect specific mutations even at very conditions in the periphery might low frequencies, such as cancer-associated and the duration of shedding was linked mimic these immune memory effects on to ejaculatory frequency and joint pain. mutations found in liquid biopsies. neurological disease. HS Myhrvold et al. were able to add a step Detection of infectious virus in semen https://doi.org/10.1038/s41591-018-0076-9 was less common and was rarely observed named HUDSON to the initial SHERLOCK protocol that allows the detection of beyond the first few weeks of illness onset. Interruption of sexual activity during the viruses directly from body fluids, creating ReCOMBINANT PROTeIN THeRAPY a field-deployable diagnostic. early symptomatic phase of Zika in men could In utero correction of a be important in preventing transmission. HS Doudna and colleagues showed that genetic disorder the enzyme Cas12a has a target-activated https://doi.org/10.1038/s41591-018-0075-x N. Engl. J. Med. 378, 1604–1610 (2018) DNA cutting activity that can be leveraged to detect HPV in patient samples. The The genetic disorder X-linked hypohidrotic signal-amplifying property of Cas12a NeuRODe GeNeRATION ectodermal dysplasia (XLHED) results in a allows rapid and accurate point-of-care Training neuropathology lack of the protein ectodysplasin A in affected DNA detection. individuals, preventing the development Nature 556, 332–338 (2018) Together these tools will help to bring of sweat glands, and can be corrected by portable, accurate diagnostics to the field. HS The memory of previous immune stimuli amniotic delivery of the missing protein. https://doi.org/10.1038/s41591-018-0073-z peripheral to the brain is mediated by Individuals affected by XLHED can develop life-threatening hyperthermia after birth due to their inability to sweat. CANCeR eVOLuTION Researchers from the University of Erlangen Tracing clear cell renal carcinoma evolution injected the receptor-binding domain of EDA Cell 173, 595–610.e11 (2018) Cell 173, 611–623.e17 (2018) intraamniotically into two pregnant women, Cell 173, 581–594.e12 (2018) one with a single fetus and one with twins. These fetuses were known to be affected Three publications from the TRACERx consortium trace the evolution of clear cell renal by XLHED from noninvasive screening carcinoma (ccRCC), providing insights that can guide therapy in this cancer. and because they have affected siblings. In a whole-genome analysis of 95 biopsies from 33 patients with ccRCC, Swanton, Once born, the three infants were able to Campbell and colleagues gain insights into the landmark early genetic mechanisms sweat normally. Importantly, the authors’ in ccRCC development. mechanistic studies in mice show that the With regards to the further evolution of these tumors, Swanton, Larkin and colleagues protein had to be taken up systemically by analyzed genetic data from 1,206 primary tumor regions from 101 patients with ccRCC. They the developing offspring to be effective. find ccRCC evolution and outcome is determined by progressive, identifiable mutations. Although long-term follow-up has yet to be Similarly, Swanton and colleagues find in an analysis of 575 primary and 335 metastatic carried out, this study shows the effectiveness of biopsies across 100 patients with metastatic ccRCC that metastasis is largely driven by prenatal protein therapy for this genetic disease chromosomal aberrations. These create genetic drivers for either rapid progression to at critical time periods in development. HS metastasis or attenuated progression, which in turn influences patient mortality. In the future, genetic evolutionary analysis may aid in standard-of-care decisions. HS https://doi.org/10.1038/s41591-018-0077-8 https://doi.org/10.1038/s41591-018-0074-y Hannah Stower NATuRe MeDICINe | VOL 24 | JUNE 2018 | 702 | www.nature.com/naturemedicine © 2018 Nature America Inc., part of Springer Nature. All rights reserved. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Medicine Springer Journals

CRISPR-based diagnostics

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Nature Publishing Group US
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Copyright © 2018 by The Publisher
Subject
Biomedicine; Biomedicine, general; Cancer Research; Metabolic Diseases; Infectious Diseases; Molecular Medicine; Neurosciences
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1078-8956
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1546-170X
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10.1038/s41591-018-0073-z
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Abstract

research highlights DIAGNOSTICS INFeCTIOuS DISeASe brain-resident innate immune cells called Zika virus shedding in semen microglia and results in altered later Science 360, 436–439 (2018) development of neuropathologies in mice. N. Engl. J. Med. 378, 1377–1385 (2018) Science 360, 439–444 (2018) Previous exposure of myeloid cells to Zika virus RNA is commonly shed in the immune stimuli can result in immune training, Science 360, 444–448 (2018) semen of infected men, and in some of in which subsequent immune responses are these men, this occurs beyond 6 months Sensitive, specific and portable diagnostics exacerbated, or immune tolerance, in which can rapidly identify viral infections. after the first appearance of symptoms. later immune responses are inhibited. Shedding of infectious virus, however, Quick and reliable diagnosis of viral disease Wendeln et al. found that exposing a in the field can aid treatment and containment. appears to be limited to the month mouse engineered to develop Alzheimer’s immediately after illness onset. The recently developed specific high-sensitivity disease pathology to a peripheral immune enzymatic reporter unlocking platform Zika virus is transmitted by mosquitoes stimulus that results in immune training and during recent outbreaks has been (SHERLOCK) is based on the programmable increased Alzheimer’s neuropathology, and RNA cutting enzyme CRISPR–Cas13 and is linked to the development of congenital exposing this mouse to a peripheral immune microcephaly in the offspring of infected able to identify genetic signatures of viruses stimulus that induced tolerance decreased without the need for complex lab protocols. individuals. There have been reported cases Alzheimer’s neuropathology. These effects of male-to-partner sexual transmission, Gootenberg et al. have developed were mediated through epigenetic changes SHERLOCK version 2, which offers four but the duration of contagion is unknown. in the microglia. They also found that Mead et al. analyzed levels of Zika advances: quantitative detection, enhanced previous immune exposure modulated sensitivity, multiplex detection of up to virus RNA in semen samples from 184 stoke neuropathology. symptomatic men (1,327 total samples) four viruses (or other nucleic acid targets), In humans, it is possible that previous and a visual readout. SHERLOCKv2 can every 2 weeks over a period of 6 months. exposure to infection or other inflammatory Zika virus RNA was commonly detected, also detect specific mutations even at very conditions in the periphery might low frequencies, such as cancer-associated and the duration of shedding was linked mimic these immune memory effects on to ejaculatory frequency and joint pain. mutations found in liquid biopsies. neurological disease. HS Myhrvold et al. were able to add a step Detection of infectious virus in semen https://doi.org/10.1038/s41591-018-0076-9 was less common and was rarely observed named HUDSON to the initial SHERLOCK protocol that allows the detection of beyond the first few weeks of illness onset. Interruption of sexual activity during the viruses directly from body fluids, creating ReCOMBINANT PROTeIN THeRAPY a field-deployable diagnostic. early symptomatic phase of Zika in men could In utero correction of a be important in preventing transmission. HS Doudna and colleagues showed that genetic disorder the enzyme Cas12a has a target-activated https://doi.org/10.1038/s41591-018-0075-x N. Engl. J. Med. 378, 1604–1610 (2018) DNA cutting activity that can be leveraged to detect HPV in patient samples. The The genetic disorder X-linked hypohidrotic signal-amplifying property of Cas12a NeuRODe GeNeRATION ectodermal dysplasia (XLHED) results in a allows rapid and accurate point-of-care Training neuropathology lack of the protein ectodysplasin A in affected DNA detection. individuals, preventing the development Nature 556, 332–338 (2018) Together these tools will help to bring of sweat glands, and can be corrected by portable, accurate diagnostics to the field. HS The memory of previous immune stimuli amniotic delivery of the missing protein. https://doi.org/10.1038/s41591-018-0073-z peripheral to the brain is mediated by Individuals affected by XLHED can develop life-threatening hyperthermia after birth due to their inability to sweat. CANCeR eVOLuTION Researchers from the University of Erlangen Tracing clear cell renal carcinoma evolution injected the receptor-binding domain of EDA Cell 173, 595–610.e11 (2018) Cell 173, 611–623.e17 (2018) intraamniotically into two pregnant women, Cell 173, 581–594.e12 (2018) one with a single fetus and one with twins. These fetuses were known to be affected Three publications from the TRACERx consortium trace the evolution of clear cell renal by XLHED from noninvasive screening carcinoma (ccRCC), providing insights that can guide therapy in this cancer. and because they have affected siblings. In a whole-genome analysis of 95 biopsies from 33 patients with ccRCC, Swanton, Once born, the three infants were able to Campbell and colleagues gain insights into the landmark early genetic mechanisms sweat normally. Importantly, the authors’ in ccRCC development. mechanistic studies in mice show that the With regards to the further evolution of these tumors, Swanton, Larkin and colleagues protein had to be taken up systemically by analyzed genetic data from 1,206 primary tumor regions from 101 patients with ccRCC. They the developing offspring to be effective. find ccRCC evolution and outcome is determined by progressive, identifiable mutations. Although long-term follow-up has yet to be Similarly, Swanton and colleagues find in an analysis of 575 primary and 335 metastatic carried out, this study shows the effectiveness of biopsies across 100 patients with metastatic ccRCC that metastasis is largely driven by prenatal protein therapy for this genetic disease chromosomal aberrations. These create genetic drivers for either rapid progression to at critical time periods in development. HS metastasis or attenuated progression, which in turn influences patient mortality. In the future, genetic evolutionary analysis may aid in standard-of-care decisions. HS https://doi.org/10.1038/s41591-018-0077-8 https://doi.org/10.1038/s41591-018-0074-y Hannah Stower NATuRe MeDICINe | VOL 24 | JUNE 2018 | 702 | www.nature.com/naturemedicine © 2018 Nature America Inc., part of Springer Nature. All rights reserved.

Journal

Nature MedicineSpringer Journals

Published: Jun 6, 2018

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