Unraveling Mitochondrial Mysteries: An Interview with Dr. Neal Sondheimer
Dr. Neal Sondheimer
Staff Physician, Clinical and Metabolic Genetics, The Hospital for Sick Children
Associate Scientist, Genetics & Genome Biology, The Peter Gilgan Centre
Assistant Professor, Department of Pediatrics
By: Yousef Manialawy
When people hear the word ‘genetics’, their minds often turn to the DNA residing in the nucleus of virtually every cell in the body, having gradually evolved after being passed down through countless generations. However, there also exists an often over-looked evolutionary partner of the nuclear genome: mitochondrial DNA (mtDNA). Unlike its nuclear equivalent, mtDNA is exclusively inherited from the mother (i.e. matrilineally). Moreover, with only 13 protein-coding genes, the mitochondrial genome is dwarfed by the 20,000 or so protein-coding genes that make up the nuclear genome.1 Despite this, the pivotal role of mitochondria as the main energy source for the cell means that even minor disruptions of its tiny genome can have huge implications on human health. As a mitochondrial researcher and paediatric geneticist at SickKids hospital, Dr. Neal Sondheimer is a leading figure in the pursuit of novel techniques to characterize and treat diseases linked to mitochondrial mutations.
Dr. Sondheimer completed an MD/PhD at the University of Chicago, followed by clinical training in paediatrics, genetics and clinical biochemistry at the Children’s Hospital of Philadelphia before eventually joining SickKids in 2015. His interest in mitochondrial genetics stemmed from his experience working with patients who had rare mitochondrial mutations, and how their problems differed from those seen in patients affected by nuclear-encoded disorders. Dr. Sondheimer confesses that his interest is also largely due to his longstanding fascination with rare topics in biology. “In graduate school I worked on prion biology, so my joke is always that I’m the only geneticist who is terrified of the nuclear genome because I’ve always worked on stuff that causes phenotypes but is not subject to Mendelian inheritance.”
Dr. Sondheimer’s current research revolves around the inheritance of mtDNA in disease and its interaction with nuclear DNA to produce distinct phenotypes. One aim of his work is to identify a method to manipulate mitochondrial heteroplasmy–the balance of different mtDNA variants within the same cell. Unlike the nuclear genome, thousands of independent copies of mtDNA exist across the mitochondrial population of the cell, and a certain percentage of those copies may carry pathogenic variants. The ratio of pathogenic to healthy mtDNA can drift and manifest into a disease phenotype if it gets too high. “We’re trying to understand if we can use a sort of structural cue within the mtDNA as a selective filter to block the replication of mutated mtDNA and allow the replication of the good mtDNA,” he explains.
Dr. Sondheimer has also recently published a study outlining a system to quantitatively evaluate how mtDNA fits into the context of nuclear genomes, and how this might relate to preterm birth.2 He explains that, whereas nuclear DNA from both parents forms new combinations in an individual, their mtDNA is fixed based on their maternal ancestry. The study suggests that as the two have co-evolved over many generations, rapidly changing nuclear DNA in increasingly diverse populations might be disrupting crosstalk with mtDNA, potentially causing increased rates of preterm birth.
“If you look back a thousand years ago, people were born, lived and died in the same location and there was no opportunity for mitochondrial and nuclear polymorphisms to diverge. Now people are extremely mobile and have children with people of different backgrounds. Because of the way mtDNA is inherited, there actually may be a consequence to having your nuclear DNA drift too far away from it.”
Dr. Sondheimer is currently attempting to develop an animal model to demonstrate this, but researching mitochondrial genetics presents some unique challenges. Unfortunately, there is currently no way to make a specific, targeted mutation in mtDNA–a technique that is a cornerstone of nuclear genetic research. To study mtDNA mutations, mitochondria have to be taken from patients and transferred into tumor cell lines, which comes at the cost of losing nuclear-mitochondrial interactions.
The elusive nature of mitochondrial mutations also poses a challenge in the clinic. “For example, when we have a family who’s had a child with an inherited nuclear disorder like phenylketonuria, we can tell them the exact probability of having another affected child–it’s 25 percent. But for mtDNA, there are no firm rules like that,” he explains.
As it stands, the challenge of mitochondrial research means that effective long-term solutions for patients with mitochondrial disease simply do not exist. However, Dr. Sondheimer remains hopeful that these solutions are over the horizon in clinical care. “For very severe nuclear disorders we can use in vitro fertilization to help people not have an affected child, and that’s something that is just on the cusp of being possible for mitochondrial disease. Take a healthy egg [containing healthy mitochondria], remove its nucleus and stick the embryo’s nucleus in it. It’s called mitochondrial replacement therapy.”
Due to the novelty of the therapy, the procedure currently remains illegal in Canada and much of the world. Although the UK was the first to approve the therapy in 2015, the first announcement of the birth of a so-called “three-person baby” emerged the following year under more controversial circumstances. Being illegal in the US, a couple and their medical team travelled to Mexico to perform the procedure in an attempt to prevent their child from inheriting Leigh syndrome, a severe neurodegenerative disorder linked to mitochondrial mutations in approximately a quarter of cases.3 The experimental nature of the treatment and the controversy surrounding selective genetics has led many to question the approach. However, Dr. Sondheimer believes that the therapy is indeed the way forward.
“Scientifically it’s essential, and I’m actually trying to work with folks in Canada to see if we can develop the technical means to do it but also to change the laws. I don’t see anything ethically wrong as a geneticist. People who would like to use this method are trying to have healthy kids and their wishes are entirely inoffensive. We’re not recombining DNA, although ultimately the DNA for that child will come from three parents. It’s a healthy kid with normal mitochondrial DNA, that’s all anybody wants.” However, while he approves of the method, he takes issue with the aforementioned case. “It wasn’t done in a very regulated fashion, so I think there’s a lot of concerns because there are possibilities for abuse. In England there are groups who are doing it under appropriate supervision for the right reasons, and they’re picking the right patients and that’s what I think should be introduced in Canada.”
With much to discover, mitochondrial genetics undoubtedly remains an exciting frontier of research. It’s this drive that propels Dr. Sondheimer forward, and he believes this to be critical to the success of budding researchers. “The most important thing in all fields of science is to fundamentally be interested in the area that you’re working on. I think one of the things that’s helped me is that even on days, weeks, or even months where things are going badly, I at least realize that these are important problems that I want to resolve. And it helps me feel good about the things that I’m doing.”
- Reference GH. What is mitochondrial DNA? [Internet]. Genetics Home Reference. [cited 2018 Apr 29]. Available from: https://ghr. nlm.nih.gov/primer/basics/mtdna
- Crawford N, Prendergast D, Oehlert JW, et al. Divergent Patterns of Mitochondrial and Nuclear Ancestry Are Associated with the Risk for Preterm Birth. J Pediatr. 2018 Mar;194:40–46.e4.
- Reference GH. Leigh syndrome [Internet]. Genetics Home Reference. [cited 2018 Apr 29]. Available from: https://ghr.nlm.nih.gov/ condition/leigh-syndrome