Using bioengineering to turn genes from a flower into a promising treatment for type 2 diabetes

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Using bioengineering to turn genes from a flower into a promising treatment for type 2 diabetes

Type 2 diabetes (T2D) is affecting a growing number of people worldwide, leading researchers to look for new ways to help patients maintain healthy blood sugar levels to avoid the most dangerous outcomes of the disease. Contributing to this work has been a newer area of focus for the lab of Dr. Jörg Bohlmann (Michael Smith Laboratories, Botany, Forest and Conservation Sciences) in recent years.

A potential new avenue for diabetes treatment was discovered when a team of researchers led by Dr. Stephen Withers (Michael Smith Laboratories, UBC Chemistry) found a natural plant metabolite that slows down the digestion of sugars in our gut. The metabolite, Montbretin A (MbA), does this by inhibiting a key human starch digestive enzyme. Found in the montbretia plant, MbA quickly became an exciting target for helping treat T2D, and is already undergoing clinical trials to see if it is a viable treatment option.

There are several challenges, however, with relying on naturally occurring MbA. Firstly, montbretia is the only plant that MbA has been found in, restricting potential sources of the molecule. Additionally, in the northern hemisphere the montbretia plant can only grow for a few months each year, meaning there would be no year-round supply. To add a further challenge, MbA is only found in below ground parts of the plant (known to gardeners as corms) – which means to harvest it, the entire plant needs to be dug up. Altogether, these challenges make it impossible to use MbA from montbretia plants as a regular, reliable treatment option for individuals with T2D.

PhD student Samuel Oguntimehin, Dr. Jörg Bohlmann, and postdoctoral fellow Dr. Lars Kruse are pictured in the lab, holding small potted plants from their research.

The Bohlmann lab is working to bioengineer a year-round solution for producing MbA in large quantities. From left to right: PhD student Samuel Oguntimehin, Dr. Jörg Bohlmann, and postdoctoral fellow Dr. Lars Kruse.

This is where bioengineering can play a role

Dr. Bohlmann’s lab, with help from Dr. Withers’ group and other collaborators, has been working to overcome these challenges by identifying the genes in the montbretia plant that produce MbA, and bioengineering those genes into other organisms to produce MbA there instead. This work was initiated by a former PhD student in the lab, Christopher Roach, who was later joined by former postdoc Dr. Sandra Irmisch (now Associate Professor at the University of Leiden, Netherlands).

The group had success in the lab getting yeast to produce MbA, and even more excitingly, a plant that would be easier to harvest MbA from – Nicotiana benthamiana, a close relative of tobacco.

“N. benthamiana has already been established as a discovery tool for producing metabolites from other systems, so it made sense for us to try that approach with MbA,” explains Dr. Bohlmann. “There’s still a lot of work for us to do now to optimize this system.”

In this bioengineered version of the plant, the MbA can be produced in the leaves instead of the roots, making it easier to harvest many times over without killing the plant. Additionally, this plant can be grown at the industrial scale in commercial greenhouses and vertical farming facilities year-round. Commercialization has been of particular interest to Bohlmann lab postdocs Drs. Lars Kruse and Michael Easson, as well as PhD student Samuel Oguntimehin, as they’ve helped to advance the bioengineering work on MbA.

“We’re excited by the potential for what we’re doing in the lab to be scaled up in a way that makes this a tangible treatment option for type 2 diabetes in the future,” shares Dr. Kruse

Graduate student Samuel Oguntimehin pushes a liquid from a syringe into the leaf of a plant on a lab bench in the Bohlmann lab.

Graduate student Samuel Oguntimehin introduces the MbA-producing genes to the Nicotiana benthamiana plant.

Advancing through clinical trials

Finding a way to produce MbA on a larger scale remains important as the metabolite moves forward in clinical trials. Drs. Bohlmann and Withers have been working with Drs. Michelle Storms and Robert Petrella (UBC Family Practice) at the Vancouver Coastal Health Research Institute on this clinical trial, which has been using naturally occurring MbA from montbretia plants.

The team is just wrapping up the first part of a phase 1 trial, which focused on safety and tolerability when giving healthy individuals MbA as a supplement. After they are done analysing their data to confirm that MbA is safe, the next part of phase 1 will then dive into how effective it is at slowing the digestion of starch to lower blood sugar levels in humans.

Continuing to move forward both parts of this research in parallel – finding ways to scale up production in the lab, while also evaluating its effectiveness in patients – will hopefully help the team to more quickly reach a viable treatment option using MbA.

Research driven forward with the support of research funding

Support in the form of research grants has been essential to the project so far, and also stands as evidence of the recognized importance of this research.

GlycoNet and Michael Smith Health Research BC have long been funding partners of the discovery research and clinical trial for this project, and have both also provided more recent funding support for the bioengineering work. The research team also received a prestigious Murdock Charitable Trust Scientific Research Grant, as well as support from Genome BC through their Genomics Innovation Fund.

The most recent grants have offered over $600,000 in research support for the work being done in the lab to optimize MbA production.

“The funding we’ve received so far has been critical and central to the project reaching the point we are at now,” shares Dr. Bohlmann. “This will remain an important part as we push towards our goal of producing a viable new treatment for type 2 diabetes patients.”

We look forward to seeing where the next steps of this research project lead, and how it will create a positive impact for T2D patients in the future.

 

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