Sherman Prize winner discusses integration, cooperation in IBD

Stephen R. Targan

In his long career as a gastroenterologist, Stephen R. Targan, MD, has seen many innovations and treatments emerge in his field.  But, throughout these changes over 30 years, one guiding principle has remained the same.

“The basis, really, of all I’ve done – whether it’s basic science, translational science, clinical science and research – has been based on the concept I had over 30 years ago: that this disease set is very complex and very heterogeneous,” Targan, who is the director of the Inflammatory Bowel and Immunobiology Research Center at Cedars-Sinai Medical Center, said in an interview. “In order to understand the underpinnings of these diseases, we’re going to need to have integrated scientific interactions to approach it.”

Targan was one of four recipients of the 2017 Sherman Prize, which honors excellence in Crohn’s disease and ulcerative colitis. In a press release announcing the winners, Targan was described as a “luminary in the field of IBD, known as a collegial integrator who has assembled world-class teams to hasten discoveries that have led to treatment breakthroughs.”

Targan spoke with Healio Gastroenterology and Liver Disease about his career achievements, important advances in IBD treatment, and the need for integrated care among various specialists.

Q: Why is it important to you to mentor new physicians?

Even from very early on in my career, I’ve had the opportunity to train all levels of individuals, inspire them, and focus careers, certainly on science and discovery, but specifically in IBD. Whether they turn out to be clinical people or bench researchers I really have been lucky that I’ve interacted with hundreds of people who have gone on to become superstars internationally.  That’s one of the major things I’ve always wanted to do.  At this point in my career, I’ve been thinking about a legacy of what my passion’s about. It’s been really rewarding.

Q. Why is integration so important in terms of understanding and treating IBD?

A lot of my work has been focused around unraveling the difficulty and being able to codify the complexity and heterogeneity of these diseases.
We did a document 30 years ago, where we laid this out as important, and every time a new technology comes along, every new discovery has confirmed that this disease is very heterogenous. We began to learn about the different subtypes of the illness, and this was very important to moving the field forward, particularly in terms of treating the right patients with the right kind of medicine.

Integrated research involves coming to a particular question from many different angles. We call it “360.” What that means is that on a daily basis, basic scientists, translational scientists, geneticists, clinicians, and clinical trialists are all interacting and discussing things on a daily basis, which then synergizes. Everyone is coming from a different point of view. So, there are clinicians who observe patients that have a certain expression of a disease. A scientist might not know that, but has some data that may explain different findings, and different materials they have collected. Geneticists can then say, “Oh, and here are the pathways that underpin what you guys are observing.” It just accelerates things, as opposed to waiting for someone to publish something and reading it, and months later, going and doing something related to that. It’s been quite successful for us to do this integrated science. It started out here in Cedars, where there were eight people I brought over, and now we have 130 who are involved in this integrated approach.

Q: How did you come to identify biomarkers for IBD subgroups and potential treatment targets?

The biomarkers came from our finding peripheral antibody responses to certain components of bacteria and fungi, and things that were in the mucosa. They measured not only the hosts’ response to these. As it turns out, these patients who express certain patterns of these have different kinds of disease, and thus have different kinds of biology.

We’ve already shown that some of these markers will mark for people who, say, will not respond at all to a particular medication. So, it’s helped to devise this.
In terms of the potential targets, we‘ve been working for years and have done a lot of biology related to a protein called TL1A. As it turns out, this is a unique cytokine; we’ve shown that it’s a cytokine that drives a fibrosis of scarring. So, we found genetically that with this protein, there was a variant in this gene, and that variant in the gene cause those who had it to overexpress this protein to develop Crohn’s disease.

We created an animal that overexpressed this protein, and lo and behold, this animal recreated Crohn’s disease where there was scarring and structuring. We were able to reverse the fibrosis by creating an antibody and treating these mice, and the fibrosis went back and totally reversed. We were able to then create a drug that is going to go into patients.

For this drug, we had a drug discovery and development unit – very talented scientists – who became part of the integrated science here, in daily talking to the geneticists and the biologists.  This integrated team was able to generate the science that would move that drug ahead, and identify seven more potential targets in the same way. Then we created composition matter, and now we’re moving it ahead. We’re hoping to put this into patients within the next year to 18 months.

What accomplishments are you most proud of in your career?

I never really thought about that. There are probably two things: the concept that turned out to be true regarding the heterogeneity of IBD is one. Also, being involved in the science and leading the trial that I think was the start of the whole biologic therapy era in autoimmune disease.  My colleagues and I discovered some of the science and led the trial for the first biologic, which was infliximab, or Remicade [Janssen]. That was in 1996. So those are two things I would say I’m proud of.  by Jennifer Byrne

Disclosure: Targan reports working on a drug discovery and development unit that was involved in drug development.

For More Information:

Stephen R. Targan, MD, can be reached at Thalians Health Center
8730 Alden Drive, Los Angeles, CA 90048; email:
daniel.gonzalez2@cshs.org

Stephen R. Targan

In his long career as a gastroenterologist, Stephen R. Targan, MD, has seen many innovations and treatments emerge in his field.  But, throughout these changes over 30 years, one guiding principle has remained the same.

“The basis, really, of all I’ve done – whether it’s basic science, translational science, clinical science and research – has been based on the concept I had over 30 years ago: that this disease set is very complex and very heterogeneous,” Targan, who is the director of the Inflammatory Bowel and Immunobiology Research Center at Cedars-Sinai Medical Center, said in an interview. “In order to understand the underpinnings of these diseases, we’re going to need to have integrated scientific interactions to approach it.”

Targan was one of four recipients of the 2017 Sherman Prize, which honors excellence in Crohn’s disease and ulcerative colitis. In a press release announcing the winners, Targan was described as a “luminary in the field of IBD, known as a collegial integrator who has assembled world-class teams to hasten discoveries that have led to treatment breakthroughs.”

Targan spoke with Healio Gastroenterology and Liver Disease about his career achievements, important advances in IBD treatment, and the need for integrated care among various specialists.

Q: Why is it important to you to mentor new physicians?

Even from very early on in my career, I’ve had the opportunity to train all levels of individuals, inspire them, and focus careers, certainly on science and discovery, but specifically in IBD. Whether they turn out to be clinical people or bench researchers I really have been lucky that I’ve interacted with hundreds of people who have gone on to become superstars internationally.  That’s one of the major things I’ve always wanted to do.  At this point in my career, I’ve been thinking about a legacy of what my passion’s about. It’s been really rewarding.

Q. Why is integration so important in terms of understanding and treating IBD?

A lot of my work has been focused around unraveling the difficulty and being able to codify the complexity and heterogeneity of these diseases.
We did a document 30 years ago, where we laid this out as important, and every time a new technology comes along, every new discovery has confirmed that this disease is very heterogenous. We began to learn about the different subtypes of the illness, and this was very important to moving the field forward, particularly in terms of treating the right patients with the right kind of medicine.

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Integrated research involves coming to a particular question from many different angles. We call it “360.” What that means is that on a daily basis, basic scientists, translational scientists, geneticists, clinicians, and clinical trialists are all interacting and discussing things on a daily basis, which then synergizes. Everyone is coming from a different point of view. So, there are clinicians who observe patients that have a certain expression of a disease. A scientist might not know that, but has some data that may explain different findings, and different materials they have collected. Geneticists can then say, “Oh, and here are the pathways that underpin what you guys are observing.” It just accelerates things, as opposed to waiting for someone to publish something and reading it, and months later, going and doing something related to that. It’s been quite successful for us to do this integrated science. It started out here in Cedars, where there were eight people I brought over, and now we have 130 who are involved in this integrated approach.

Q: How did you come to identify biomarkers for IBD subgroups and potential treatment targets?

The biomarkers came from our finding peripheral antibody responses to certain components of bacteria and fungi, and things that were in the mucosa. They measured not only the hosts’ response to these. As it turns out, these patients who express certain patterns of these have different kinds of disease, and thus have different kinds of biology.

We’ve already shown that some of these markers will mark for people who, say, will not respond at all to a particular medication. So, it’s helped to devise this.
In terms of the potential targets, we‘ve been working for years and have done a lot of biology related to a protein called TL1A. As it turns out, this is a unique cytokine; we’ve shown that it’s a cytokine that drives a fibrosis of scarring. So, we found genetically that with this protein, there was a variant in this gene, and that variant in the gene cause those who had it to overexpress this protein to develop Crohn’s disease.

We created an animal that overexpressed this protein, and lo and behold, this animal recreated Crohn’s disease where there was scarring and structuring. We were able to reverse the fibrosis by creating an antibody and treating these mice, and the fibrosis went back and totally reversed. We were able to then create a drug that is going to go into patients.

For this drug, we had a drug discovery and development unit – very talented scientists – who became part of the integrated science here, in daily talking to the geneticists and the biologists.  This integrated team was able to generate the science that would move that drug ahead, and identify seven more potential targets in the same way. Then we created composition matter, and now we’re moving it ahead. We’re hoping to put this into patients within the next year to 18 months.

What accomplishments are you most proud of in your career?

I never really thought about that. There are probably two things: the concept that turned out to be true regarding the heterogeneity of IBD is one. Also, being involved in the science and leading the trial that I think was the start of the whole biologic therapy era in autoimmune disease.  My colleagues and I discovered some of the science and led the trial for the first biologic, which was infliximab, or Remicade [Janssen]. That was in 1996. So those are two things I would say I’m proud of.  by Jennifer Byrne

Disclosure: Targan reports working on a drug discovery and development unit that was involved in drug development.

For More Information:

Stephen R. Targan, MD, can be reached at Thalians Health Center
8730 Alden Drive, Los Angeles, CA 90048; email:
daniel.gonzalez2@cshs.org

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