How can we model human metabolic diseases with
CRISPR-Based genome editing?

It’s no secret that CRISPR/Cas9 technology has revolutionised gene editing capabilities for scientists in academia and pharmaceutical industries. Being simpler to engineer compared to conventional gene editing methods such as zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), the CRISPR/Cas9 technique facilitates efficient, precise gene editing. The capability of CRISPR/Cas9 technology to target multiple genomic sites simultaneously makes it particularly useful to study disease models where multiple genes are at play.

At CRISPR in Drug Discovery 2020, 4-5 March, Cambridge, Dr Chad Cowan, Assistant Professor, Harvard Medical School, will share how his team has successfully used CRISPR to generate functional disease models that have advanced their research into metabolic diseases. We caught up with Chad ahead of the event to hear more about this fascinating area ahead of his talk.

Creating in vitro disease models with genome editing

CRISPR has been essential for creating translational disease models in Chad’s research. “By using CRISPR to modulate the expression of disease-related genes in human pluripotent stem cells (hPSCs), scientists can generate functional disease models to understand the pathophysiology of complex diseases,” Chad describes. “The ability of hPSCs to differentiate into any human cell type offers limitless potential to model diseases in vitro, especially in the absence of primary tissues from patients. While genome-wide association studies (GWAS) reveal candidate genes linked to diseases, a deeper understanding of the underlying molecular mechanisms in a particular disease can be obtained by targeted manipulation of the implicated genes in hPSC-based cellular models.”

Using a combination of GWAS-derived data, genome engineering and hPSC-based in vitro models, Chad, studies the molecular underpinnings of metabolic diseases such as obesity, type 2 diabetes and coronary artery disease. Although a leading cause of death in the world, there is a general lack of understanding of key molecular players in these metabolic diseases. “In our lab, we try to understand how naturally occurring genetic variations in humans can make some people more vulnerable to cardiovascular and metabolic diseases,” explains Chad. “With cellular models, we can learn more about the molecular pathways involved in these diseases to help develop therapies for a large population of individuals.”

Genetic modulation of hPSC-based disease models

Focusing on how genetic variation influences cardiovascular disease, Chad’s lab uses human cell-based models and mouse models to understand the effect of DNA variants on gene and protein function related to metabolic disease. “We use hPSCs to create human-derived tissues containing specific DNA variants as genetic disease models in which environmental and epigenetic influences have been minimized,” describes Chad. To minimize variability in the cell-based model, the Cowan lab generates isogenic cell lines from hPSCs. Sparing the differences in the disease-causing mutation, these isogenic cells are similar in all aspects, with the exact same genetic and epigenetic background. Such an experimental design provides a more reliable connection between the genotype and resulting phenotype.

Linking genotype and phenotype in complex diseases

In studying metabolic diseases, the Cowan lab links genetic function with phenotypic traits in three key steps. First, using genome editing, the members of the Cowan lab introduce mutations related to obesity and cardiovascular disease into hPSCs. Next, they differentiate and engineer the hPSCs into tissue types relevant to the disease, developing ex vivo disease models. Finally, functional assays on the genetically modified differentiated tissues offer insights into the disease biology, revealing characteristic disease phenotypes. The human cell-based disease models can also be used to screen for novel drug targets.

Advancements in CRISPR/Cas9 technology

Having used the CRISPR/Cas9 technology to genetically modulate cells for over 5 years, Chad notes how gene editing has become more accessible to researchers in recent times. “Originally, CRISPR was a bit of an intimidating technique that only experts could perform,” he says. “Now, CRISPR/Cas9 kits are simpler to use and easier to obtain.”

The availability of CRISPR technology as an open-access technique has accelerated its advancement and broadened its application across different disciplines. For Chad, using CRISPR/Cas9 techniques to study obesity not only answers important research questions but also helps make a difference and have a positive impact on the people affected by cardiovascular conditions. “For me, it’s really important that we understand obesity itself and not just the disease it causes,” says Chad. “For instance, we’re starting to understand why some people are hungrier than others.”

Keynote presentation at the CRISPR in Drug Discovery 2020 conference

Chad will present his latest research findings in a talk titled, ‘Investigating metabolic disease using human pluripotent stem cells’ at the CRISPR in Drug Discovery 2020 conference. Now in its second year, the CRISPR in Drug Discovery conference taking place at the Babraham Institute in Cambridge on 4th and 5th March 2020, will bring together researchers with similar interests i.e. applying genome engineering methods to advance drug discovery. With inspiring talks delivered by gene editing experts, lab-based workshops, technology showcase by exhibitors, poster presentation sessions and networking opportunities, the delegates will gain a broad perspective about CRISPR-based methods and emerging applications.

A plenary keynote speaker this year, Chad believes that attending conferences can expand one’s knowledge as well as offer interesting viewpoints that can inform research decisions. “You hear ideas from peers that challenge your own understanding and make you dig deeper. You discover new technologies, techniques, and systems that can solve your own research challenges,” explains Chad. “Honestly, whether you’re just starting out or have been in the field for 20+ years, there’s always something you’ll learn.”

The CRISPR in Drug Discovery conference highlights the theme ‘from targets to therapeutics,’ focusing on how large scale CRISPR-based functional genomics studies can help identify novel drug targets and how in vitro and in vivo disease models can advance target validation. Hosted by ELRIG, the event unites scientists from academia, pharma, biotech and CROs to participate in discussions related to CRISPR. “The ELRIG events are rare because they are free to attend,” notes Chad. “To me, this is important as it helps reduce budget barriers and encourages attendance.”

To watch Dr Chad Cowan’s talk on ‘Investigating metabolic disease using human pluripotent stem cells’ as well as other talks by CRISPR pioneers, register for the CRISPR in Drug Discovery 2020 conference. Use this fantastic opportunity to meet like-minded researchers, discover cutting-edge technologies poised to accelerate gene editing and become a part of the important conversation about CRISPR.

As with all ELRIG conferences, attendance is completely free. Don’t miss out Register today!