When I Developed the Disease My Father Was Researching

During my freshman year in college, I never concerned myself with the daily work life of my father, Richard Mazzarella, Ph.D. He always kept that part of his life isolated from family life, and to be honest, I was more concerned with making new friends and tackling my Chinese courses. I knew he worked as a computational biologist at a large pharmaceutical company, but could not name a single disease he was studying. I thought my life would never intersect with the diseases he was researching, but by some quirk of fate, I would soon be proven wrong.

• What is Ulcerative Colitis?

While my introduction to inflammatory bowel disease (IBD) came during a bathroom session hunched over in pain, my father’s connection to these autoimmune diseases came much earlier. As the resident geneticist at his company, he was tasked with repositioning known drugs for use in managing chronic conditions such as IBD and rheumatoid arthritis. A recent example of this is the oral medication, Xeljanz. Xeljanz was originally developed and marketed for rheumatoid arthritis, but later repositioned to also treat ulcerative colitis.

Back in 2008, few pharmaceutical companies paid attention to IBD and other autoimmune diseases, preferring to focus on medications such as Viagra that would generate a substantial amount of revenue. However, the pharmaceutical company my father worked for saw a niche and profitable market for reprofiling certain drugs for autoimmune diseases. My father was soon brought onto the team tasked with researching two of these diseases: Crohn’s Disease and ulcerative colitis.

A year into his research, I began experiencing symptoms commonly associated with IBD: bloody and mucus-filled stool, constant fatigue, nonexistent appetite, abdominal pain and weight loss. Although no doctor I saw knew what was happening to me, my father’s research told him I most likely had either Crohn’s or ulcerative colitis. Confirming his suspicions, my gastroenterologist later diagnosed me with left-sided ulcerative colitis.

It took many years and validation that my disease was in a deep remission for my father to share with me the conflicted feelings he had of being both a scientist who researched the disease and a father who wanted to support his daughter through a tough diagnosis. He had a sense of deep guilt for winning an award for his work on IBD and a profound sense of sadness for me; he knew what IBD patients went through and understood the long struggle that was ahead of me.

It has been 10 years since my initial diagnosis and my father has been by my side playing the dual role of a scientist and a dad each step of the way. To commemorate how far we have come, I thought I would interview him to revisit how he felt and what he studied during those challenging days a decade ago, as well as get his perspective on the future of science and medicine in treating IBD.

KM: When were you first introduced to IBD? Did you know anything about it before this time?

RM: My primary job at the time was as a Computational Biologist in indication discovery. In short, I dealt with identifying and repositioning compounds. In drug discovery, we have all these compounds (or inhibitors) that sometimes fail for their primary indication. In some cases, these compounds were shown to be safe, but ultimately failed for what they were originally developed. I was tasked with finding new indications and hypotheses for these compounds. After searching through scientific literature and finding genetic evidence to prove my hypothesis, I discovered this compound might be able to be used to treat IBD. Prior to this discovery, I did not really know anything about the disease.

KM: How did the scientific community view these diseases at the time?

RM: When you were diagnosed with IBD in 2008, these diseases were known within the scientific community. However, the treatment options available at the time were limited. Many of the treatments used for IBD had been on the market for several years with few new treatment options in development. One of the treatment options at the time, mesalamine, had a long history of use in the treatment of IBD, but the delayed release Lialda tablet form of the medication had only been approved by the FDA a year before your diagnosis.

Your current treatment of 6-MP (mercaptopurine) combined with Allopurinol have both been used in the medical community for a long time, but were originally developed to treat other diseases. 6-MP (mercaptopurine) was developed to treat children with certain types of leukemia and Allopurinol was originally developed to treat gout. Using 6-MP amplified by Allopurinol to treat IBD is the perfect example of drug repositioning.

KM: When did you suspect I might have Crohn’s or ulcerative colitis?

RM: Around February of 2008, a few months before your diagnosis, I began studying potential drugs to reposition to treat IBD. By the end of the year, I had studied around 29 drugs for use in the treatment of different diseases, with your disease being the first I studied. I received an indication discovery performance award in my unit for proposing a drug to treat IBD long before your diagnosis. When you started experiencing symptoms of IBD, I noticed they matched up with the symptoms for Crohn’s and ulcerative colitis I had been studying less than a year earlier. I was 98 percent certain it was IBD with a 2 percent chance it might be colon cancer, which was rare for people your age (20) but does happen on occasion.

KM: How did you pitch the idea for IBD research to the pharmaceutical company?

RM: Based on the mechanism of action and genetic evidence I found, I believed this mechanism was involved in the disease. The mechanism for IBD is particularly complicated, so it was not as straightforward as most drugs I studied. Once I found genetic evidence of this mechanism, I pitched the idea to my company.

KM: How do you separate your role as a scientist and researcher verses your role as a father?

RM: Honestly, it is difficult to separate the roles. As a scientist, I do not necessarily have to separate the roles. Since I am not directly in charge of your treatments, I am able to be objective, especially after I take some time to step away and cool down before any engagement.

KM: How did you decide what medications to use for repositioning?

RM: I based most of my recommendations on genetic evidence. My team and I were tasked with repositioning drugs based on how well they fit into our target, or had to reposition certain drugs we had in our portfolio. We usually had a list of a bunch of drugs we could reposition and chose those drugs that were found to already be safe for use in humans. Most of these drugs for some reason or another had failed their drug trial for efficacy or original indication to treat a certain disease.

If the drug failed its drug trial for the disease we originally planned, then we would look for another disease the drug could treat. A majority of these drugs were already developed and found to be safe. Rarely would we use any drugs still in the development pipeline.

We also had the possibility to use a drug developed by a different company as long as it was off-patent. Since the timeline of a patented drug is around 20 years, pharmaceutical companies may only have seven years left after trial phases to make a patented drug available to the market. In order to reposition a drug that was developed by another company and was off-patent, we would have to get a new use patent, which would state that we were the only ones that could use this patent in the U.S. in the treatment of any disease.

One of the most famous examples of a use-patented drug is thalidomide. Thalidomide was originally developed in 1957 to treat nausea, especially for pregnant women. It became over-the-counter and was distributed by pharmaceutical companies across the U.S. It was later discovered that pregnant women who had taken the drug gave birth to babies with deformed or missing limbs. Currently, thalidomide is sometimes used in the treatment of multiple myeloma and leprosy, but is contraindicated for pregnant women.

KM: How long does it take from the initial idea phase of repositioning a drug to market availability of the drug?

RM: It takes at least seven years, but probably more like ten years for repositioned drugs to be approved for use in the treatment of another disease. Sometimes, a drug that is repositioned does get to skip Phase I of the drug trial as long as it is used in the same dosage. This phase can sometimes be skipped if the drug has previously been proven to be safe in humans.

KM: In the 10 years since my diagnosis, there has been an increase in the incidence of autoimmune diseases. What do you think accounts for this?

RM: No one truly knows why this increased incidence is occurring. There are several theories out in the field. It might be better diagnosis of these diseases, but most likely there is also something else happening. One theory is that there is an unidentified pathogen spreading throughout the population potentiating new disease occurrences.

Another theory is the hygiene hypothesis for autoimmune diseases. This theory is derived from the observation from a number of studies that have indicated there is a direct link between the decreasing level of infectious burden and the increased rates of a number of autoimmune diseases. Since we are no longer fighting as many pathogens, our bodies begin to turn on themselves. This observed increase in autoimmune diseases is primarily happening in the Western world. As countries westernize, they begin to show increases of autoimmune diseases like their fellow developed nations.

KM: What do you struggle with most as both a scientist and a father to an IBD patient?

RM: As a scientist who has studied the disease extensively, I struggle in some ways with knowing too much about the disease and how damaging it can be for people if it is not under control. Personally, I also struggle with always trying to make sure you are getting the best treatment options available. In the beginning, it was a major struggle for me. When you first asked me if you should either go on 6-MP, which is a pill, or do Remicade infusions, I knew Remicade might work, but pills would enable you to live as normal a life as you could. Honestly, if you could go on a treatment that provided you with the same level of deep remission that 6-MP has without the long-term effect, I would want you to switch. Unfortunately, there are not many other treatment options that would work as well for you as 6-MP has. I wish there were more studies done on the effects of long-term, decade usage of 6-MP.

KM: What treatment do you see as promising to treat IBD?

RM: There might be some promise in the microbiome research occurring across the world. There is always hope for new drugs and new types of treatment regimes.

KM: What does the future of scientific study look like for autoimmune diseases?

RM: There is a lot of research being done on autoimmune diseases. These diseases seem to have some connection to each other. The treatment options developed for one disease can be used to treat another.  For instance, many of the drugs developed for rheumatoid arthritis (RA) are used to treat other autoimmune diseases. In many cases, RA and IBD are connected. A primary example of this connection is Remicade, which was originally approved for the treatment of RA and later repositioned for IBD.

KM: What gives you hope as a scientist? As a dad?

RM: Based on the new drugs coming to market, there is an increased awareness of the disease. There has also been growing support for the disease, which means more research can be done to discover better treatments and hopefully one day a cure. You have been in remission for over five years, which is a remarkably long time. That gives me great hope.