The Delicate Art of Editing Genes
BNC’s Conrad Nieduszynski explains his role in some incredible advances in genomics
Interview by Olivia Gordon, Oxford Today
Professor Conrad Nieduszynski is in his brightly lit laboratory, showing me a truly clever little device. It looks like a portable hard drive, but it’s actually a DNA sequencer attached to a USB port, which Nieduszynski’s team has on lease from Oxford Nanopore Technologies, a University spin-out company. The human genome was first sequenced in 2003, a process which took around 10 years and cost about $100 million. These days, scientists like Nieduszynski can sequence an entire human genome overnight for $1,000 using a device like this.
For Nieduszynski, who is Associate Professor of Cell Biology at The Sir William Dunn School of Pathology, sequencing genomes is a key tool in his quest to understand the pattern of how DNA is copied. For the last 16 years, since his PhD, he’s been fascinated by this process – and specifically, how DNA copying is regulated. The way the regulatory system works – and why it sometimes fails – could bring about world-changing new gene therapy treatments for cancer as well as other diseases and genetic conditions.
Back in his office down the hall, at a table strewn with science textbooks and research papers, Nieduszynski patiently explains the basics to me. New cells form continuously in our bodies: ‘a cell goes through an astronomical number of divisions to make a whole human.’ Cells routinely copy themselves and then divide, creating a ‘daughter’ cell, that receives a copy of the original. The cell must only make one copy, but it must be exactly one copy, and that’s not so easy for a cell to do.
Problems arise when a cell makes more than one copy, or if it doesn’t quite finish making a copy. Often mistakes are lethal, but minor errors can lead to genetic disorders like dwarfism or aneuploidies.
Mutations are, of course, also essential for the survival of our species – just look at the diseases which arise in inbred populations, or how sickle cell anemia gives some immunity in malarial areas. ‘Genetic diversity is really important - the differences between us are how an organism survives in ecological terms,’ stresses Nieduszynski. ‘So you need some level of mistakes.’ But mistakes can also cause diseases.
One of the main targets of this lab’s research is cancer. Nieduszynski explains that particular enzymes ensure cell replication only happens when it’s supposed to happen, in a process scientists call ‘once and only once’ or ‘licensing’. ‘Certain sites along our genome have a kind of permission slip to copy DNA. In the copying process, that permission slip is destroyed - until a new cell cycle starts and everything is reset.’ Crucially, research has found that the proteins involved in this licensing are often deregulated in cancer – ‘cancer is a cell proliferating uncontrollably; these regulating proteins are lost.’
Nieduszynski explains that people increasingly think of cancer as an evolution within an organism – and it’s a pretty scary evolution. ‘What the cancer wants - to become a successful cancer - is to accumulate more and more mutations. It can accumulate more mutations if it stops the correct regulation of DNA replication. In nature, you see two organisms where one preys on the other - within our body the cancer wants to mutate to escape the controls of our body and flourish and take over.’ Nieduszynski’s team, which currently has seven members but will soon grow to ten, is trying to identify these molecular mechanisms.
The diagnosis of disease could transform thanks to this research. For example, many of the proteins involved in copying DNA are already used as diagnostic markers for the early stages of cancer, since uncontrolled cell growth occurs before faulty cells spread around the body and actually become cancer. ‘In the future, we might have more sophisticated ways of quantifying this,’ says Nieduszynski.
But most extraordinary of all will be how this research could allow us to correct cell replication mistakes using gene editing. For example, Nieduszynski says, ‘with cancer, we know if the proteins that control regulation rise, it can lead to uncontrolled cell division - so in the future we might be able to develop inhibitors that would prevent that.’ We’re not far off, he says, a point where gene editing will be possible both during a person’s life and before birth - the major restrictions, he stresses, will be ethical.
