EXTENDING THE UNIVERSE OF CELL TYPES

Associate Professor of Systems Biology, Dr Owen Rackham’s field of research is so new that no one can agree on its name.

Variously known as ‘computational biology’, ‘biological generative AI’ and ‘computational stem cell biology’, “the name is evolving at the same rate as the field,” said Owen.

In its short existence, it has triggered an explosive growth in our understanding of stem cells and our ability to use them for disease modelling, regenerative medicine, and drug discovery. Potential applications include in immunotherapy and degenerative disease.

Owen, a world expert in the application of machinelearning in cell reprogramming and disease-gene association, joined the University of Southampton in 2020. He leads an interdisciplinary team working on combining artificial intelligence with highthroughput biology to identify key regulators that can control cell fate to find novel routes for cell conversion or targeted therapies.

He is also Theme Lead for Cell and Molecular Medicine at the Turing Institute, Adjunct Professor at Duke-NUS Medical School, Singapore, and Cofounder of Mogrify Limited.

As well as opening up new therapies, Owen believes this field has the potential to change the process of scientific discovery from, as he puts it, “guided trial and error at the bench” to a new kind of “biological engineering”.

An unconventional approach

As a computer scientist by training, Owen’s route into biological research has been unconventional.

A Masters in ‘Nature inspired computing’, which focused on writing algorithms inspired by processes that occur in nature, ignited his interest in both AI and Biology. A PhD in Computational Biology followed, despite, said Owen, “not having studied biology beyond GCSE.”

It was during his PhD that a Nobel prize-winning discovery by Shinya Yamanaka set him on the path to his current interdisciplinary work.

Our bodies are comprised of at least 400 different cell types, from neurons to heart, brain, and skin cells. These all begin life as embryonic stem cells, with the same genome. Embryonic stem cells are ‘pluripotent’ which means that they have the potential to develop into any cell type (except the amniotic sac and placenta). As the embryo develops, stem cells change into different cell types with distinct functions.

Yamanaka discovered that if you introduce just four regulatory genes or ‘transcription factors’ to any of these differentiated cells, they revert to this pluripotent state. This is called re-programming.

The discovery that it was possible to go from a differentiated cell back to an embryonic stem cell, suggested that any cell type could be converted into another cell type. This opened up a wide range of therapeutic possibilities.

Yamanaka’s methods required years of patient lab work trying out every combination until they found the four that worked. Owen, together with his PhD supervisor Professor Julian Gough, set out to streamline this process by creating an algorithm to predict what genes would need to be used in a cell type, depending on what properties you wanted it to have.

Dr Owen Rackham

Partnering with a clinical collaborator, Professor Jose Polo of Monash University, Australia, who was able to validate the algorithm, they “predicted how to turn fibroblasts from skin into three cell types that we’d never managed to make before, in just three months, where before it was taking three years to do one thing.”

That algorithm was published and spun out into a company, Mogrify, which is turning the technology into cell and gene therapies, addressing needs in ophthalmology, otology, metabolic and other areas of degenerative disease.

Fundamentally interdisciplinary

“My group is a computational-first group,” explained Owen. “Then we look for an expert in whatever our algorithm does to validate it.”

This agility allows Owen to apply these techniques to a wide range of fields.

“The computational infrastructure that I need for working on cancer is not very different to the computational infrastructure I need to work on ageing, which is not true for clinicians and biologists in cancer or ageing.”

“The privilege of being on the computational side is the opportunity to work on a problem with people with different expertise and understandings, being exposed to new problems and new ways of thinking.”

Owen is working with Professor Sean Lim, Professor of Haematology and

Translational Immunology, University Hospital Southampton, who is attempting to develop new immunotherapeutic approaches to blood cancer.

When cancer occurs, the body’s immune system will try to attack it using T cells. Eventually the T cells become ‘Exhausted’ and can no longer attack the tumour in the same way. Owen, Sean and PhD student Disha Mehta, are using Owen’s technologies to convert the Exhausted T cells back into non-Exhausted T cells, enabling the patient’s immune system to continue to attack the tumour.

Extending the universe of cell types

Until now, scientists have been working on converting one cell type to another, based on the cell types that occur in the body. According to Owen, this is unnecessarily limiting.

“I think that it’s probably possible to make cell types that our bodies don’t use, but which can be facilitated by the genome that we have.

“For example, when T cells are attacking a tumour, they become ‘cytotoxic’, which means that they can kill the cell they are attacking. The spectrum of how cytotoxic a T cell in the body is might go from zero to 10. There is no reason why I can’t work out what a T cell with cytotoxicity 13 looks like, it’s just that our body never makes it.”

But attempting to create an entirely novel cell type is a whole new level of challenge.

“At the moment we can observe the thing that we’re trying to make,” explained Owen. “The hard part now is saying, if I want a cell that has characteristic X, Y and Z, what will that look like, even though I’ve never seen it?”

In a new project funded by a BBSRC Pioneer award, ‘Using AI to extend the universe of cell types’, Owen’s Southampton group is using generative AI to address this challenge.

“The longer-term vision,” said Owen, “is that we try to make new cell types that are as useful as they possibly can be for treating a disease.”

Dr Owen Rackham’s work has received funding from the Biotechnology and Biological Sciences Research Council (BBSRC), the Medical Research Council and seed-funding from the Institute for Life Sciences at the University of Southampton.