Greg Cox Q & A

For our fourth Q & A instalment we have a special guest from the US Greg Cox who works in Spinal Muscular Atrophy with Respiratory Distress (SMARD).

What is SMARD?

SMARD stands for Spinal Muscular Atrophy with Respiratory Distress. It is a rare genetic variant of Spinal Muscular Atrophy (SMA) that is caused by mutations in a completely different gene (IGHMBP2 versus SMN1). This disease is apparent in young children before one year of age and progresses quite rapidly such that most children become paralysed and require respiratory and feeding support before the age of two. Like SMA, this is a recessive genetic disorder; this means that a child must inherit two independent mutations in the IGHMBP2 gene, one from each parent, to develop this disease. Also like SMA, the motor dysfunction is caused by the degeneration of motor neurons in the spinal cord. As the motor neurons die, the children lose innervation to their muscles and they become progressively weaker.

How did you come to work on SMARD?

We initially discovered that the Ighmbp2 gene was important for motor neuron health and maintenance from a spontaneous mouse mutation that I was studying in the lab. The mutation was named Neuromuscular Degeneration (nmd) based on the early onset and progressive paralysis the mice developed. I work at The Jackson Laboratory in the U.S., and one of the most amazing things about working here is the unique opportunity we have to discover new genetic mutations. Part of the mission of JAX (and the one it is most commonly known for) is to produce genetically defined research mice for investigators all over the globe. JAX ships over 3 million mice per year for biomedical research, and our animal caretakers are trained to look for 'deviants' that pop-up from time to time in their mouse colonies. Although spontaneous mutations are rare, if you produce over three million of anything - rare things show up. In fact, they occur frequently enough that every two weeks we have what is called the Deviant Search. The researchers gather to observe the deviant mice that have been collected from the production rooms over the previous two weeks and we attempt to determine if they might be caused by a heritable mutation that could be relevant to our particular area of research. It was through this process that the mutant nmd mice were first discovered. My role in this story began when I was able to genetically map and clone the gene and causative nmd mutation in 1998. Only later were human SMARD patients, with IGHMBP2 mutations, discovered by Katja Grohmann in Cristoph Hübner's lab in 2001. Thus, the mouse mutation directly aided in the eventual discovery of the human SMARD disease gene.

What SMARD research are you currently doing?

We are actively trying to determine the mechanisms causing motor neurons to degenerate in our mutant nmd mice, and by extension, the motor neurons of SMARD patients. If we can define the cellular and biochemical defects that lead to cell death, we hope to target those processes for a therapy.

One of the approaches we are taking arose from a serendipitous discovery I made while originally trying to map and clone the mouse nmd mutation. We typically work with completely inbred strains of mice in our research at JAX. All of the mice from an inbred strain are genetically identical to one another and this allows us to faithfully reproduce our research within our own labs and in labs across the world, as we know each group is working on exactly the same genetic model. However, you can't map gene mutations within an inbred strain of mice as the maternal and paternal chromosomes can't be distinguished from one another in the offspring. To get around this, we set up genetic crosses between different inbred strains to allow us to follow each of the chromosomes and find where the mutation is located. The nmd mutation was originally maintained on the C57BL/6J (B6) inbred strain background and these mice always present with the same early age of onset (2-3 weeks of age) and rapid disease progression. However, when I crossed the B6 mice with the nmd mutation to mice from the wild-derived CAST inbred strain, I found that not all of the offspring carrying the nmd mutation had the same disease severity. Some of the nmd mice had the same early onset of symptoms we expected while others had very mild motor symptoms that allowed the mice to run around the cage seemingly unaffected. I collected DNA from all of the severely and mildly affected nmd mice and found that a single location on mouse Chromosome 13 from the CAST strain background could suppress the nmddisease severity. We are attempting to identify the gene that is responsible for this genetic suppression, as we believe it may provide clues as to how we could similarly modify the severity of the SMARD disease in patients.

A second approach we are taking is to try and reproduce the nmd motor neuron disease in a tissue-culture dish. Motor neurons are very difficult to study in mice and humans because they are in an inaccessible location in the spinal cord and cannot be removed or examined in a living person or animal model. To get around this problem, we have developed embryonic stem cells from our nmd mice that we can differentiate into motor neurons in a dish. These isolated motor neurons will allow us to understand the disease process within the relevant cell type and hopefully give us a means for drug testing that can be scaled to identify effective pharmacological therapy strategies. We will next extend our mouse cell work to humans by deriving induced pluripotent stem (iPS) cells from patient skin biopsies to do the same thing with human motor neurons. If we can generate a 'disease in a dish' model system from either the nmd mouse or SMARD patient cells it will dramatically increase our ability to screen for potential therapies that can then be moved to clinical trials.

When and why did you first decide you wanted to be a scientist?

My love of science began as a child while watching all of the medical and science programs on television that described the latest discoveries and theories in a visual and exciting format. Programs such as Carl Sagan's "Cosmos" or the PBS series "Nova" which often contained science programs that originally aired on the BBC, fired my imagination and made me want to learn more on my own. So I suppose there are redeeming qualities to television programming after all.

What would you be if you weren’t a scientist?

I have a great passion for automobiles and working on all things mechanical, so I would have probably been an auto mechanic if I hadn't gone into science. I love doing maintenance work and repairs on my cars and truck, and I am currently rebuilding my 1964 Ford Mustang that I originally bought as a teenager.

If you are not in the lab you are...

At home with my wife and three children doing work around the house or just relaxing.

Describe yourself in three words

Curious, optimistic, and handy.

What has been the most important moment of your career so far?

As a graduate student I had published on the transgenic rescue of disease symptoms in a mouse model of Duchenne muscular dystrophy. This work provided the proof of principle for current gene therapy strategies in this disease and allowed me an invitation to be on the Jerry Lewis Muscular Dystrophy Telethon in Las Vegas, Nevada. I had never been on television before and it was an exciting and nerve-wracking experience for a student.

What is your most memorable finding relating to SMARD?

The initial identification of the Ighmbp2 mutation was incredibly exciting, but the realization that the gene identity didn't lead to an obvious disease mechanism was just as sobering.

What is your favourite conference location?

New Orleans, Louisiana. I love the city, the food and the jazz music...it doesn't get much better than that.

What is the best scientific advice you ever received?

It was actually in the form of a quote from William Bateson around the turn of the last century, "Treasure your exceptions". This is a guiding principle in science that instructs us to focus on the things that don't fit our expectations, as that is where the real discoveries will lie. In genetics, the exceptions are the mutations that can provide true insight into the workings of biological systems.

If you could start your career all over again, are there things you would do differently?

I would probably like to pursue a medical degree in addition to my PhD in Human Genetics. Being a pediatric geneticist would allow me to work directly with the patients that I am trying to model in my mouse genetic studies.

In your opinion, what makes a good scientist?

Tenacity and an optimistic disposition to recover from the inevitable setbacks and disappointments that come from primary research endeavors. We are constantly probing the unknown and are wrong more often than right as we test our various hypotheses.

Where do you see the SMARD research field in the next 10 years?

The discovery of the gene has allowed for a definitive diagnosis to be achieved. However, the move to therapeutic intervention is more daunting. I expect that the function of the IGHMBP2 protein will be known in the next 10 years and we will have access to several potential cell or drug-based therapies to try and stop the progression of symptoms. The bigger challenge will be to reverse the disease process once motor function is lost. I hope that cell-replacement therapies will be available to replace the motor neurons lost to the disease, as that would constitute a true 'cure'.