CRISPR is an extremely useful tool for mouse models but is not ready for use on human embryos

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By IMPC

Published 28th November 2018

A researcher in China claims to have produced the first genome-edited babies through using CRISPR. The IMPC uses the CRISPR/Cas9 system to generate the required knockout mouse lines. The project moved to use this technology because of its speed and accuracy, yet those involved in controlling and implementing CRISPR are keen to stress there is a long way to go before this technology should be implemented in human embryos. A recent blog post and video highlight how and why the IMPC uses this technique: Two new articles highlight the usefulness and intricacies of CRISPR/Cas9 technology & CRISPR-Cas9 and mouse genomics

Dr Lydia Teboul, Head of Molecular and Cellular Biology at the Mary Lyon Centre at MRC Harwell said “We have been using the CRISPR/Cas9 system over the past four years to create over 200 mouse lines with new mutations as part of our work for the International Mouse Phenotyping Consortium. We have learned a lot about the technology in the process. A key feature of these genome editing tools is the unpredictability of the outcome of applying them to embryos. Because of this, it is clear that the technology is not ready for use for assisted reproduction in clinic.”

Vchal/Shutterstock

The below article is republished under a Creative Commons license and highlights some of the main issues with altering human embryo DNA.


By Joyce Harper, UCL

A scientist in China claims to have produced the world’s first genome-edited babies by altering their DNA to increase their resistance to HIV. Aside from the lack of verifiable evidence for this non peer-reviewed claim, this research is premature, dangerous and irresponsible.

He Jiankui from the Southern University of Science and Technology in Shenzhen (which has reportedly since suspended him) said he edited the DNA of seven embryos being used for fertility treatment, so far resulting in the birth of one set of twin girls. He says he used the tool known as CRISPR to delete the embryos’ CCR5 gene (C-C motif chemokine receptor 5), mutations in which are linked to resistance to HIV infection.

If true, this is a significant advance in genetic science, but there are some very serious problems with this news. First, the research has not yet been published in a peer-reviewed journal so we cannot be sure of the exact details of what has been done. Instead, the scientist made the claims to the Associated Press news organisation, and the journalists involved haven’t been able to independently verify them. The parents of the allegedly gene-edited babies declined to be interviewed or identified.

Second, we know there can be significant problems with using existing gene-editing technology on human embryos. The main two issues are mosaicism, where the edited DNA does not appear in every cell of the embryo, and off-target effects, where other parts of the genome may also have been edited with unknown consequences.

Before genome editing becomes a clinical treatment, it is essential that scientists resolve both of these issues and eliminate other potential adverse effects on the embryo. We need comprehensive studies to show that genome editing is not going to cause harm to the future people it helps create. Any children born as a result of genome editing will also need long-term follow up. It would be vital to see the preliminary work that He has done to confirm that his technique has eliminated mosaicism and off-target effects, and it is surprising that he has not published this.

 

There is also a question over why gene-editing was used to tackle the particular issue of HIV transmission in this case. The reports suggest that the couples involved in the study were made up of HIV-positive men who had the infection under control and HIV-negative women. The risk of transmission of HIV for these couples would have been negligible, and there are well-established ways to prevent HIV transmission to the offspring of HIV-positive couples.

Finally, there is the wider ethical debate, which the scientist in this case has chosen to ignore. I was a member of the Nuffield Council on Bioethics working group. We spent 20 months examining all aspects of genome editing and published our report this summer. Our conclusion was that we needed a public debate before gene editing on embryos was carried out because this procedure takes reproduction to a new level.

Do we really need gene editing?

Most reports suggest that the potential main use of genome editing would be therapeutic genome editing to prevent the transmission of genetic diseases, such as cystic fibrosis. In most cases, couples at risk of transmitting a genetic disease to their children are able to prevent transmission using established techniques of screening before birth or even before an embryo is implanted via IVF. So perhaps editing embryos for therapeutic reasons is not the way forward.

But genome editing could also more controversially used for genetic enhancements, such as ensuring children have a particular desirable characteristic such as a certain eye colour. This raises even more ethical questions.

We also need legislation. In the UK, for example, the use of genome editing would be regulated by the Human Fertilisation and Embryology Authority, and would currently be illegal. Before this technique becomes a treatment, governments need to pass laws that will control and regulate it otherwise it could easily be misused.

With all this in mind, any research in this area needs to be peer-reviewed and published in the scientific literature, with all the necessary preliminary work, so that we can make a valued analysis of the technique. In bypassing this process, He has made our job much harder.The Conversation

Joyce Harper, Professor of Reproductive Science, UCL

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Scientists from the University of Cambridge have identified a potential therapeutic target in the devastating genetic disease Hutchinson-Gilford Progeria Syndrome (HGPS), which is characterised by premature ageing. The research utilises IMPC resources through the use of mouse phenotypic data.

The paper is published in Nature Communications, with preclinical data showing that chemical inhibition or genetic deregulation of the enzyme N-acetyltransferase 10 (NAT10) leads to significant health and lifespan gains in a mouse model of HGPS.

HGPS is a rare condition: patients have an average life expectancy of around 15 years, suffering a variety of symptoms including short stature, low body weight, hair loss, skin thickening, problems with fat storage, osteoporosis, and cardiovascular disease, typically dying of a heart attack.

The disease arises from specific mutations in the gene for the protein Lamin A, which lead to production of a shorter, dysfunctional protein that accumulates in cells, specifically in the membranes surrounding the nucleus. This causes disorganisation of chromatin (the ‘packaging’ around DNA), deregulated transcription, accumulation of DNA damage and defective cell proliferation.

By screening candidate molecules for an effect on nuclear membranes in human HGPS patient-derived cells in vitro, the authors have previously identified a small molecule called remodelin as an effective ameliorative agent. They then identified which component of the cells was being affected by remodelin: an enzyme with a variety of cell functions, called NAT10.

Their aim in the new study was to take these findings into a mouse model with the same genetic defect as HGPS patients, to see whether inhibiting NAT10 – either chemically by administration of remodelin or genetically by engineering reduced production of NAT10 – could ameliorate the disease. The results show that these approaches indeed significantly improved the health of the diseased mice, increased their lifespan, and reduced the effects of the HGPS mutation across a variety of measures in body tissues and at the cellular level.

The research was led by Dr Gabriel Balmus from the Wellcome Trust/ Cancer Research UK Gurdon Institute and Dr Delphine Larrieu from the Cambridge Institute for Medical Research, University of Cambridge; and Dr David Adams from the Wellcome Sanger Institute.

 

Senior author Professor Steve Jackson commented: “We’re very excited by the possibility that drugs targeting NAT10 may, in future, be tested on people suffering from HGPS. I like to describe this approach as a ‘re-balancing towards the healthy state’.

“We first studied the cell biology to understand how the disease affects cells, and then used those findings to identify ways to re-balance the defect at the whole-organism level. Our findings in mice suggest a therapeutic approach to HGPS and other premature ageing diseases.”

 

Research article: https://www.nature.com/articles/s41467-018-03770-3.pdf

Nat10 gene on the IMPC website: http://www.mousephenotype.org/data/genes/MGI:2138939

Nishanth Ulhas Nair discusses his recent article in Scientific Reports: Putative functional genes in idiopathic dilated cardiomyopathy

Link to article: https://www.nature.com/articles/s41598-017-18524-2

The International Mouse Phenotyping Consortium (IMPC) has been predominantly interested in using mouse models to understand human health and disease. In a new study in the journal Conservation Genetics researchers have found another intriguing use of IMPC data.

By comparing genetic functional data from the IMPC with other non-human animals, it may be possible to identify genes relevant for the normal development in those species. For example, by comparing mouse genetic functional data with genomic data for selected species with specific diseases, improved breeding management could be implemented.

To test this potential application researchers at the European Bioinformatics Institute (EMBL-EBI) and Queen Mary University London (QMUL), alongside colleagues from the IMPC, compared genetic functional data from mice with genomic data from gorillas, showing how such analyses could aid in the identification of genes essential for healthy development.

As well as gorillas, the researchers highlighted other examples, including cheetahs, polar bears, wolves, pandas and cattle. This type of analysis could improve the current management approaches to breeding endangered species, by allowing researchers to identify the matches that are most likely to produce healthy offspring or select breeders to preserve genetic variation relevant for adaptation.

Genes associated with fat metabolism can be a real asset for species like polar bears

Heart disease is a common cause of death for gorillas in captivity and cheetahs suffer from impaired fertility both in captivity and in the wild. By identifying gorilla genes linked to heart disease or cheetah genes linked to infertility, researchers could help better understand the cause for the condition, which is the first step to envisage ways to prevent it. Similarly, this type of data could help identify genes linked to adaptation in certain mammals. For example, genes associated with fat metabolism can be a real asset for species like polar bears, which have diets rich in fats in the extreme environment of the Arctic.

Impaired fertility is common in cheetahs both in captivity and in the wild

“When the number of individuals of a species dramatically decreases, loss of genetic variation also takes place”, explains Violeta Muñoz-Fuentes, Biologist at EMBL-EBI. “This can result in many offspring not surviving, or exhibiting genetic defects linked to fertility or health problems.”

“Many zoos and wildlife conservation centres are seeing excellent results through their breeding programmes. Currently, many focus on minimising inbreeding. By adding a functional genetic dimension to the selective process, conservation geneticists can identify the crosses that would, for example, avoid a gene variant linked to disease in the offspring. It is nevertheless important to keep in mind that for a genetic rescue approach to be successful in the long term, the conditions that led to the decrease of individuals need to be removed; otherwise, the accumulation of deleterious alleles will likely take place again”.

Number of IMPC significant phenotypes for selected mammalian species (source: http://bit.ly/conservationarticle)

Although this type of research is still in its early stages, gene functional knowledge is a powerful tool for maximising adaptive genetic diversity within a species and even for reducing genetic variants that negatively affect an individuals’ health and survival. With the accumulation of gene function annotation by the IMPC, as well as technical advancements in gene editing such as CRISPR/Cas9, the hope is that this method of comparing genome information between laboratory mice and endangered wildlife will help in future conservation projects.

The IMPC aims to produce and phenotype knockout mouse lines for 20,000 genes

The IMPC would like to encourage conservation geneticists, conservation centres and zoos to get in touch if they are interested in using IMPC data for conservation purposes.

 

 

Amalio Telenti discusses his recent article in Nature: Human gene essentiality

Link to article: https://www.nature.com/articles/nrg.2017.75.pdf 

More information on this research can be found on Amalio’s website: https://www.stsiweb.org/about/faculty/telenti-amalio/

You can also follow Amalio on Twitter: https://twitter.com/atelentia

Melanie Samuel discusses her research in neural development and disease, and explains how she has used IMPC data.

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Dr. Tao Wang talks about his recent Nature Communications publication, in which he leverages the IMPC and Mutagenetix data to estimate the probability of phenotypically detectable protein damage predicted by various mutation effect prediction algorithms. His work further applied these estimated probabilities in addressing interesting questions in mouse genetics. Dr. Wang also talks about his related research in cancer genomics.

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Jesse Mager discusses his work in mammalian developmental genetics, and how he uses IMPC data for this research.

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Scientists have identified a network of genes that could play an important role in the development of metabolic diseases such as diabetes. A research team from the Helmholtz Center Munich and the International Mouse Phenotyping Consortium (IMPC) led the work that is published in ‘Nature Communications‘.

The development of metabolic diseases like diabetes is a complex process. As well as lifestyle and environmental factors, many different genes are responsible for the pathogenesis of both type 1 and type 2 diabetes. These genes encode information on how to assemble individual proteins that function in glucose metabolism.

Many genes that play an important role in the development of human diseases are still unknown. It is only by deciphering the causal genetic links that we can understand diseases, develop therapeutic interventions, or even prevent an outbreak. Thus, the new diabetes genes discovered in this study could be used, for example, as biomarkers for individual risk prediction, early diagnosis of the disease, or personalised approaches for treatment.

Twenty-three new candidate genes for diabetes in humans

As part of the IMPC, knockout mice – each lacking a specific gene – were examined for metabolic dysfunction. Using this method, researchers are trying to establish whether the missing gene is involved in important metabolic processes and can be linked to human diseases.

“Our analysis of the phenotyping data has identified a total of 974 genes whose loss has strong effects on glucose and lipid metabolism,” said Martin Hrabě de Angelis, who led the study and is the Chair of Experimental Genetics at the Technical University of Munich. “For more than a third of the genes no connection to metabolism was known previously.”

In addition, the researchers that teamed up with first author Dr. Jan Rozman, report that the functions of 51 of the discovered metabolic genes in the mouse were hitherto completely unknown. When compared with genome data collected in humans, they found that 23 of these also appear to play a role in human diabetes. “They are new candidate genes, and mice that lack these genes may be important models to investigate impaired glucose metabolism and diabetes,” explains Rozman, who coordinates the metabolic phenotyping at the German Mouse Clinic as part of the IMPC. One of these genes is C4orf22, which appears to be involved in insulin action in participants of the diabetes study “Tübingen Family Study (TÜF)”.

Interestingly, according to the bioinformatician and co-author Dr. Thomas Werner, these genes were also similar in their structure – many had common genetic elements. The scientists therefore assume that these genes belong to a network. In the future, they want to investigate these new regulatory structures and to explore to what extent they allow the prediction of gene functions of so-far unknown genes.

Publication
Rozman et al. Nature Communications 2018

Further links 
https://www.medizin.uni-tuebingen.de/en/Research/Collaborative+Research/…

To see the data, click here

This study in Nature Genetics reveals hundreds of new insights into gene function and human disease. The paper describes the analysis of 3,328 genes by the IMPC, representing approximately 15% of the mouse genome. 360 new disease models were identified. Moreover, the team identified new candidate genes for diseases with unknown molecular mechanisms. More than half of the genes analysed have never been investigated in a mouse before, and, for 1,092 genes no molecular function or biological process were previously known.

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By IMPC

Published 20th March 2018

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