Neurosurgery_Research_Group_01-13-2016_2

What Your Support Gives to Researchers: An Interview with Dr. James Connor

Meet Dr. James Connor, an ALS researcher who leads a team at Penn State Hershey Medical Center in Hershey, PA that recently received an ALS Association Investigator-Initiated grant to move his exciting research forward. The ALS Association spoke with Dr. Connor about his investigations into how a therapeutic iron solution is potentially protective in ALS and how collaboration at Hershey bridges the lab and the ALS clinic.

What has the support from The ALS Association meant to you and how has your Investigator-Initiated grant pushed your project forward?

The support helps us on so many levels. It excites us, invigorates us and validates us. But at same time, there is a strong sense of responsibility because this is money from someone that was most likely touched by this devastating disease. That level of trust means a lot and heightens our work. It is a privilege to work on the brain and ALS and to have some ideas that could potentially help someone that is suffering. When we are working 60 hours a week and are tired and working on a weekend to do an experiment, knowing where that award money came from to do our work invigorates us.

Do you have a message for the donors that helped make this project possible?

We always tell our donors that our job is to provide the hope. When a person goes into the doctor’s office and gets the devastating diagnosis, clinicians are obviously wonderful working with the person to deal with the disease. We want to be the element of hope to come in and say that our study is working and hopefully this will be relevant and helpful to the patient. In return, donors are instilling their hope in us, which is a tremendous gift and honor. Also, we have lots of great ideas, but without the funding, they are just ideas. So donors are part of our implementation team. Donors join our team! When we receive a grant, we get excited to go work to do our experiments. Otherwise, people get frustrated because they cannot afford to do the experiments they want to do.

What is your academic background?

I received my Ph.D. at University of California Berkeley in Neuroscience under Dr. Marian Diamond looking at plasticity in the brain, meaning how the brain adapts to the environment. Then I went on to Boston University for my postdoctoral fellowship, where my interest in iron began. I then ended up at Penn State Hershey Medical Center and have been here for 29 years this summer.

Dr. Connor
Dr. James Connor

How did you get involved in ALS research?

I am a fan of baseball and of Lou Gehrig. I have always had an interest in ALS research and was looking for an opportunity to get involved. I was already interested in iron, and it was a natural fit because iron is the most potent inducer of oxidative stress. I also knew that super oxide dismutase (SOD1) helps cells handle oxidative stress and that there is a familial ALS mutation in SOD1. It is not the mutation in SOD1 that causes the disease, but its inability to do its job which is to minimize oxidative stress. And for oxidative stress to occur, iron has to be around. With all this in mind, I started asking the question: What is happening with iron in ALS?

What is the importance of iron in the brain and why is it so important to keep iron levels tightly regulated?

Iron is involved in 2 ways in cells: 1) Your cells need iron present to make energy (iron and oxygen are key components in this process); 2) If iron gets out of balance, too much iron promotes oxidative stress and neuroinflammation to cause cell damage. It does not make energy but makes free radicals, a type of reactive oxygen species that damages the cell. Here is an analogy to understand what oxidative stress looks like: If you crack an egg and look at the egg whites, it is clear. You can imagine that cell membranes look similar. They are nice and gooey and a clear fluid that proteins can freely move around in and get where want to be. When you heat the egg to cook it, the egg whites get white and harden. The cooking represents an oxidative stress reaction in that the cell membranes harden and proteins get stuck and cannot move around freely, causing cell damage.

Please describe your neuroinflammation project funded by The ALS Association.

We have this idea that if we could provide a protective and nourishing solution to the right places to the brain and spinal cord of people living with ALS, we could maybe limit the damage caused by neuroinflammation and oxidative stress. The protein we are most interested in is called ferritin, which is known for is its ability to bind and sequester iron.

So if a lot of ferritin is around to bind iron, the body and cells do not have to worry about oxidative stress. Our goal is to get ferritin into the cells in the cerebral spinal fluid (CSF), the fluid that surrounds our brain and spinal cord, with hopes to see an improvement in the survival and behavior of our SOD1 G93A mouse model. (SOD1 G93A is a common mutation and this model is classically used to study ALS.)

To do this, we made a “therapeutic solution.” To that solution, we thought that in addition to adding ferritin to limit cell damage, we would also provide nutrients, like glucose and other metabolites that cells need to be healthy and thrive. Dr. Amanda Synder, a talented research associate in our group, led this effort and came up with the final “therapeutic solution” that we are infusing into our mouse model to see if the solution affects its survival and behavior. To get the solution into the CSF, we are using a pump, like a pain pump used to get morphine into the spinal cord for chronic pain.

Our grant just started but right now, our survival results look promising and we are encouraged by our findings. For example, one thing that got us excited is that if we only infuse a plain solution (without ferritin and the added nutrients), it does not affect survival or behavior – meaning that the ferritin and nutrients are playing a role in improving survival and behavior in the mice. It is exciting because through infusing the solution, we delivered something that the cells really need and not just providing a cleansing solution!

What is the overall impact of your funded project on ALS and how can it lead to potential ALS treatments?

Another part that is exciting about our project is that the “therapeutic solution” does not contain any drugs or secret ingredients. It contains ferritin, glucose, vitamins and minerals. It contains nothing that is not already in your CSF and blood. There is no need to formulate the ingredients for drug development. So if our project works, we are hoping that FDA approval should move quickly to test our solution in people. Also, the device we use to infuse the solution is a common pain pump that is widely accepted and available.

Another project in your lab involves the Hfe gene mutation. Can you describe the Hfe gene mutation and how it impacts ALS?

This project is not a funded ALS grant, but it has been funded earlier and it formed the basis of some of the ideas for our current grant. A mutation in the Hfe gene is one of the ways that iron can get out of balance in our cells and causes neuroinflammation. I want to be clear that an Hfe mutation does not cause ALS, but is a disease modifier. This means that if I cross breed an Hfe mutated mouse with a ALS mouse, the disease gets worse = modifies the disease.

I think the Hfe gene mutation is important because we observed that 30% of our ALS patient population at Hershey Medical Center has this mutation. Similar studies in England, Italy and the Netherlands also reported that approximately 30% of their patients have the Hfe mutation. Most people agree with the personalized medicine approach that not one size fits all. The Hfe mutation ties back to neuroinflammation in that 30% of our patients have a different neuroinflammation baseline than others. Having this mutation may affect how a person responds to therapy.

We are now trying to carry out more studies in ALS patients to understand how the Hfe mutation carriers are affected in terms of disease progression and response to therapeutic strategies. All together, having a relatively high number of patients with the Hfe mutation in a clinical trial could impact overall outcomes, so it is important to study the impact of the Hfe mutation further.

What else do you think is exciting in ALS research? What are the bright spots on the horizon?

I think the most exciting thing is that the new wave of funding gives the opportunity to break out of some old ideas that can sort of box in researchers and instead, it allows the opportunity to try something new and innovative. With new funds, we bring in new thinkers and new ideas, so new insights are going happen to help the people living with ALS. It gives the OK to try something new and different!

Do you have any advise for young scientists just starting out in ALS research?

Since the Ice Bucket Challenge, a lot of people want to study ALS. Now more than ever, I think that more young scientists should join a lab that is doing unique research. Part of new funds bring in not only established researchers but encourage and bring in new young scientists to enter the ALS field.

From the funding we had for one of our ALS projects, one of my postdoc fellows wanted to work on ALS and successfully published a few papers and is now moving forward to the University of Pittsburgh to continue her career. Donors do not just fund projects, but fund people as well; now there is a new young scientist in the ALS field. A donor started a person down their ALS path that they will stay on for the rest of their career. We tell the donors that “You opened that door” and provided those opportunities for new scientists coming into the field. These funds are so important enable young scientists to get excited and to do unique research.

You have worked at Hershey Medical Center for 29 years. What do you think makes Hershey Medical Center a great and unique place to work and study ALS?

It is unique at Hershey. We work with Dr. Zachary Simmons, a neurologist specializing in ALS. He is a fantastic clinician and a wonderful man. We became good friends. He is very interested in the research side of things and does not want to just treat patients, but also wants to be involved in how to move the ALS field forward. We developed a great relationship in terms of sharing resources. Dr. Simmons sees the people living with ALS and asks how can we intervene, and we develop what questions to ask scientifically about how to study the disease. It is a great collaboration. We are not isolated in the lab at all. When we might be struggling with an experiment that did not work, I know that Zach is over in the clinic telling someone that they have ALS. It is a constant reminder that there is a person suffering at the end of this story.

Also, Zach and I go to the ALS meetings together. I go to the science sessions, and Zach goes to the clinical sessions, and we meet at lunch to go over what each other learned. That kind of interaction is what makes us unique and makes it fun.

What makes your lab unique and a great place to work?

We have 15 people in the lab on the research team. They come from a wide range of backgrounds. They are not all neuroscientists, but have clinical backgrounds, molecular biology backgrounds and chemistry backgrounds, among others. What is unique is that when we have group meetings, we are not all thinking about the problem from the same silo and that has helped us a lot. For example, we can come at the problem with all different angles, from people with expertise in oxidative stress, iron and inflammation. They had an idea to put together a solution (like Dr. Snyder did) that we can infuse in the mice. The neurosurgery team said yes we can do that with a pump. So we are unique in the breadth of how we can approach problems at all angles.

Does anyone in your lab work in the ALS clinic at Hershey Medical Center?

A primary example of this is a bright M.D., Ph.D., student interested in ALS, who carried out an ALS biomarker project that worked with both myself in the lab and with Dr. Simmons in the ALS clinic. He collected CSF and blood from people living with ALS in the clinic, and we would do the biomarker analysis in the lab. We were able to ask, “What are the clinical correlates to compare our lab results to?” It was a great opportunity! There is other crossover from the lab to the clinic. Dr. Simmons sits on multiple lab team member thesis committees. Dr. Simmons’ belief in our work and his medical expertise has also aided us in approaching pharmaceutical companies asking for their help in our clinical studies.

Is there something you would like to share with people living with ALS about your lab?

With the number of people in the lab and the number of ongoing projects, someone will always come up with something positive. There is almost never a day when nothing works, because so many different things are going on. Everyone can feel good at the end of the day that at least something is working. For example, to see your student doing the final set of experiments when they are wrapping up their Ph.D., to see junior faculty get a grant or get exciting results is energizing. I think a typical day is that something positive gets to happen everyday. It is a great science environment. I am fortunate to have very good people and have a great team!

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