Cell Transformation Breakthrough Could Revolutionise Regenerative Medicine

A breakthrough in the transformation of human cells by an international team led by researchers at the University of Bristol could open the door to a new range of treatments for a variety of medical conditions.

Their paper demonstrates the creation of a system that predicts how to create any human cell type from another cell type directly, without the need for experimental trial and error.

Julian Gough, professor of bioinformatics at the University of Bristol, said:

“The barrier to progress in this field is the very limited types of cells scientists are able to produce. Our system, Mogrify, is a bioinformatics resource that will allow experimental biologists to bypass the need to create stem cells.”

Pluripotent stem cells – or cells that have not yet ‘decided’ what to become – can be used to treat many different medical conditions and diseases.

Mogrify

The first human artificial pluripotent stem cells were created by Japanese researcher Shinya Yamanaka in 2007, through a process of educated trial and error that took a long time. In the nine years since, scientists have only been able to discover further conversions for human cells a handful of times.

Professor Gough said:

“Mogrify predicts how to create any human cell type from any other cell type directly. With Professor Jose Polo at Monash University in Australia, we tested it on two new human cell conversions, and succeeded first time for both. The speed with which this was achieved suggests Mogrify will enable the creation of a great number of human cell types in the lab.

The ability to produce numerous types of human cells will lead directly to tissue therapies of all kinds, to treat conditions from arthritis to macular degeneration, to heart disease. The fuller understanding, at the molecular level of cell production leading on from this, may allow us to grow whole organs from somebody’s own cells.

This represents a significant breakthrough in regenerative medicine, and paves the way for life-changing medical advances within a few years from now, and the possibility in the longer term of improving the quality of longer lives, as well as making them longer.”

To achieve this game-changing result, Professor Gough worked with then-PhD student Dr Owen Rackham (who now works at Duke-NUS Medical School in Singapore) for five years to develop a computational algorithm to predict the cellular factors for cell conversions.

The algorithm was conceived from data collected as a part of the FANTOM international consortium (based at RIKEN, Japan) of which Professor Gough is a long time member.

The algorithm, called Mogrify, has been made available online for other researchers and scientists, so that the field may advance rapidly.

Cell World Atlas

It is known that cell types are not fixed, and that one cell type can be reprogrammed, or converted, to become another cell type by the addition of a unique set of cellular factors. This approach was brought to the fore by Shinya Yamanaka, whose Nobel prize-winning work involved the reprogramming of fibroblast cells from the skin to induced pluripotent stem cells (iPS).

In theory, iPS could then be directly reprogrammed to become, for instance, retinal cells that could help treat macular or eye degeneration. In practice though, it seems there are technical and safety concerns with this approach of cell conversion due to the accumulation of cancerous mutations in the reprogrammed cells, therefore leading to unpredictable behaviour.

mogrify

Credit: Cherrie Kong

In addition, despite this breakthrough, determining the unique set of cellular factors that is needed to be manipulated for each cell conversion is a long and costly process that involved much trial and error. As a result, this first step of identifying the key set of cellular factors for cell conversion is the major obstacle researchers and doctors face in the field of cell reprogramming.

Explains Duke-NUS Senior Research Fellow Dr Owen Rackham:

“Mogrify acts like a ‘world atlas’ for the cell and allows us to map out new territories in cell conversions in humans.

One of the first clinical applications that we hope to achieve with this innovative approach would be to reprogramme ‘defective’ cells from patients into ‘functioning’ healthy cells, without the intermediate iPS step. These then can be re-implanted into patients, and should, in practice, effectively enable new regenerative medicine techniques.”

Associate Professor Enrico Petretto, co-author of the study and head of the Systems Genetics of Complex Disease Laboratory in the Centre for Computational Biology at Duke-NUS, highlighted that since Mogrify is completely data-driven, its robustness and accuracy can only continue to improve as more comprehensive data are collected and input into the framework.

“Mogrify is a game-changing method that leverages big-data and systems-biology; this will inspire new translational applications as the result of the work and expertise here at Duke-NUS,” said Assoc Prof Petretto.

Owen J L Rackham, et al.
A predictive computational framework for direct reprogramming between human cell types
Nature Genetics (2016) doi:10.1038/ng.3487

Illustration: the result of converting fibroblasts to keratinocytes using the Mogrify algorithm. In the image it can be seen that the converted keratinocytes, which are stained green, have a ‘cobble-stone’ pattern whilst fibroblasts have a long thin morphology. Credit: Nature Genetics & Rackham et al.