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Elpis BioMed: Mastering the art of reprogramming human cells




Dr Mark Kotter, CEO of Elpis BioMed, at the Anne McLaren Laboratory for Regenerative Medicine Forvie Site on Robinson Way. Picture: Keith Heppell
Dr Mark Kotter, CEO of Elpis BioMed, at the Anne McLaren Laboratory for Regenerative Medicine Forvie Site on Robinson Way. Picture: Keith Heppell

The development of the Cambridge Biomedical Campus now speaks of a world-class scientific healthcare hub - and its newest arrival is Elpis BioMed, who have moved in to the Abcam building.

But while the nuts and bolts are astonishing of the new premises – the current vogue for see-through offices has extended to see-through labs which are as far from the dour labs of yesteryear as you could imagine – it’s the science that is driving all this, and in particular the rapid shift in our understanding of human biology.

This shift will soon allow us to do things with the building blocks of life which could eventually mean redesigning who we are as a species – or inventing a whole new type of species, if we want.

‘Do we want?’ is a question worth considering, but the fact is that the city's life sciences economy is at the forefront of this particular scientific and academic citadel and Elpis BioMed now is more deeply embedded than it was last month.

The reason for that is not speculative: the company is making significant progress in the vector where synthetic biology meets stem cell biology.

Dr Mark Kotter is founder and CEO of Elpis BioMed, winner of 'start-up of the year' at the 2018 Cambridge Independent Science and Technology Awards.

Mark was born in Calgary, Canada, and grew up mainly in the German-speaking world. He completed his medical training in Austria, did a masters and then a PhD in stem cell biology in Cambridge, then was a junior doctor abroad, became a research group leader at the Max Planck Institute for Experimental Medicine before “building a lab” at the university’s Department of Clinical Neurosciences.

He also founded Cambridge-based Myleopathy.org, the first charity dedicated to degenerative cervical myelopathy. He’s a consultant neurosurgeon who founded Elpis BioMed in 2016, and is also co-founder of Meatable, which builds non-animal steaks. A curious sideline, you might think, but what Meatable and Elpis share is technology that will help alleviate animals suffering for our wellbeing.

The company’s science involves “a synthetic biology approach in which you change the cell by rebooting the stem cell with a new programme”.

New Abcam buiding Discovery Drive on the CUH Biomedical campus. Picture: Keith Heppell. (14024197)
New Abcam buiding Discovery Drive on the CUH Biomedical campus. Picture: Keith Heppell. (14024197)

A key purpose of this is to provide the best human cells for use in research and drug discovery – Elpis investor and biotech star Jonathan Milner has predicted the approach could replace animal experiments.

The technology also allows the control of advanced synthetic biology circuits for biomanufacturing and could open the door to new cell therapies.

Mark graciously talks me through the basics.

“So what is a stem cell?” he asks rhetorically – at least I hope so. “It’s a cell that divides very quickly, so itscales, it’s very open-minded and can produce any other cell – and eventually it produces us.”

To get from a cell to a human is quite a journey, but having stem cells programmed for diversity – into brain cells and heart cells, for example – has been the key to building the lifeforms around us.

“Diversity is deeply engrained in stem cells,” Mark continues, “and when nature wants diversity it introduces stochastic principles – chance. The process of going from a stem cell to brain cell or a heart cell involves multiple steps and at each point there’s a stochastic decision.

“During development the growing organism ensures that only the right kind of cells remain. However, if you base your production on a strategy with multiple steps where chance plays a role, you have inconsistency.”

The acceleration of synthetic biology began in 2012. The University of Cambridge’s John Gurdon and Shinya Yamanaka of Japan’s Kyoto University won the Nobel Prize in Physiology or Medicine that year – although the public was aware something was going on when Dolly the cloned sheep was born in 1997.

Synthetic biology – the application of engineering principles to biology – had the potential to strip out these stochastic processes and coach the reprogrammed cell through the development process without the decision-making pinch points/bottlenecks.

“We figured out the solution to the bottleneck is to introduce stem cells into the synthetic biology approach,” says Mark. “We think the manufacturing process is probably unprecedented in terms of consistency and quality.”

The key moment for Elpis Biomed occurred in 2016: they were “working hard to solve the inconsistencies, and suddenly every stem cell in our culture turned into what we wanted, in one week – one-tenth of the time of existing ‘directed differentiation’ approaches and in terms of purity we’re approaching 100 per cent”. How?

“We figured out the Y cells don’t reprogramme very well and we found out what the mechanism for that is – gene silencing. Where a cell doesn’t want a virus to replicate, or it faces being attacked, the cell shuts the foreign DNA introduced by the virus down.”

The new Abcam building on Discovery Drive offers Elpis BioMed an incredible working environment. Picture: Keith Heppell
The new Abcam building on Discovery Drive offers Elpis BioMed an incredible working environment. Picture: Keith Heppell

To evade this shutdown and allow activation of a new program is the goal.

Cell reprogramming is not a new concept. Dr Gurdon had demonstrated that cellular differentiation could work two ways, so it was theoretically possible to develop a cell whose clock was reset to its original state.

Dr Yamanaka proved that “the introduction of a small set of transcriptionfactors into a differentiated cell was sufficient to revert the cell to a pluripotent state”, according to his Nobel citation. He found 24 transcription factors, later whittled down to four, could reprogramme a nucleus when introduced into cells on the back of a virus. Subsequently, multiple groups around the world showed that many different cells can be converted into other cell types by activation of specific transcription factors.

“The concept of cell reprogramming thus seems to be generalisable, but the efficiency remained low,” continues Mark. “So to bypass gene silencing we had to trick the cells into accepting a new set of transcription factors, and once we’d tricked them – by circumventing the silencing mechanism in the genome – it started working really incredibly well, the entire process.

“We put a gene switch and the new transcription factor programme intosafe harbour sites – actually two safe harbour sites – which are privileged areas in the genome. They shouldn’t really exist, but they are there.

This provides “command line access to life, ie using a drug, we can now activate the new transcription factors like a line of code that has to be executed, and suddenly the radical change takes place in the phenotype of the cells. We use this approach to program stem cells to be the ones the companies – our clients – want them to be.”

Elpis BioMed win Start-up of the Yearat the Cambridge Independent Science and Technology Awards 2018. Picture: Richard Marsham
Elpis BioMed win Start-up of the Yearat the Cambridge Independent Science and Technology Awards 2018. Picture: Richard Marsham

It’s audacious science and it all stems from one single stem cell being replicated countless times.

“That’s why we love stem cells,” says Mark, “you can’t do this with any other cell. We embed our technology, produce one stem cell that has been integrated, and then start the entire manufacturing process.”

There are lots of questions that can’t be fully answered at the present time, such as whether the next step will be to move into therapeutics – having built the cell, the applications might actually be the easier part. But perhaps the suggestion is premature.

One question that is addressed today, however – others will be addressed in the coming weeks – concerns Mogrify, the start-up run by Dr Darrin Disley that reprogrammes cells without going through the stem cell process.

“I very much like Mogrify,” says Mark, “and I have huge respect for Darrin. The core difference is we do value the stem cell – that’s the starting point for us.

“It’s the merger of stem cell biology with synthetic biology that we’re really excited about.

“We are already providing highly consistent human cells for research and drug discovery.

“Using the same approach, we should be able to produce cell therapies at unprecedented low cost and so make them available for developing countries. Our ambition really is to democratise science, put cells more in the public domain, and make more cell therapies available.”

Watch this space. And when the non-animal steaks go on sale, we’ll let you know where you can buy one.


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