By Julie Mettenburg
In 1990, Dr. Ann Marie Schmidt had just finished her residency in internal medicine – having held the prestigious post of chief resident – as well as fellowships in hematology and medical oncology at New York University School of Medicine. She seemed bound for a brilliant career in medicine, but then a different kind of opportunity came knocking. Dr. Schmidt was offered the chance to work on a diabetes research study at Columbia University Medical Center on a topic of particular interest to her: abnormalities of endothelial cells, the thin layer of cells lining vascular walls.
She then applied to JDRF for a postdoctoral fellowship – a type of funding award that JDRF reserves for young, highly promising researchers whom it hopes to steer toward a career in diabetes research.
Dr. Schmidt got the fellowship, and so began her career as a full-time researcher – and her long and highly productive partnership with JDRF. Since then, she has had stellar success as a scientist. She is an internationally recognized expert in vascular biology and a thought leader in the field of diabetes complications. Her life’s work has centered around a molecule she helped identify that holds huge implications for understanding, treating, and preventing the complications of diabetes.
Dr. Schmidt’s story underlines how important it is for JDRF to attract talent to the field of diabetes science. Moreover, it’s a classic example of how JDRF nurtures promising research, advancing it from basic science studies to clinical research – and eventually to the point where it can benefit people with type 1 diabetes. The path can be long, but the payoff can be profound.
RAGE and its Role in Complications
The molecule that Dr. Schmidt and her team at Columbia discovered is known as RAGE, or Receptor for Advanced Glycation Endproducts. It is a cell receptor – in effect, a small notch on cells that interacts with other molecules called ligands. These ligands accumulate in type 1 diabetes because of high levels of blood sugar, thereby leading to activation of the RAGE molecule.
Thanks to the research of Dr. Schmidt’s team, it is now clear that this interaction is central to the development of multiple kinds of complications in diabetes. To understand why, think of RAGE as a lock, and the ligand as a key. Once they interact, the cell changes – Dr. Schmidt has shown that the interaction disrupts critical cell functions and causes damage, especially in the walls of the blood vessels – and complications are set in motion.
In diabetes, Dr. Schmidt discovered, there are two important types of ligands that interact with RAGE, one of which is known as Advanced Glycation Endproducts, or AGEs. These are harmful molecules that form as a result of high blood glucose. It has been shown that in people with diabetes, higher levels of AGEs means a higher risk for complications. The second important type of ligand is a class of inflammatory mediators called S100/calgranulins.
By 2000, Dr. Schmidt’s team had determined that RAGE, by binding to these two ligands, plays a central role in the development of atherosclerosis, kidney disease, and other complications of diabetes – as well as non-diabetic conditions such as Alzheimer’s disease and cancer. With JDRF’s help, the team turned their focus to determining whether blocking the RAGE-ligand interaction could be a new way to treat – and prevent – complications.
Six years later, Dr. Schmidt’s work had moved from the laboratory to the clinic. Based on Dr. Schmidt’s discoveries, two pharmaceutical companies – Pfizer and TransTech Pharma – reached a licensing agreement to develop and commercialize drugs aimed at blocking RAGE. Pfizer is now testing compounds in clinical studies, one of which seeks to treat diabetic kidney disease and another to stop Alzheimer’s disease.
But the story doesn’t end there. Dr. Schmidt had come to the conclusion that RAGE may also play a role in repairing vascular damage – and that blocking it might thus block its beneficial effects. She set out to better understand this repair/impair dichotomy and to determine whether there might be a better treatment target than RAGE itself – one that would not also block RAGE’s possible benefits. JDRF agreed that this was a research path worth following. So in 2007 – 17 years after she received her postdoctoral fellowship – Dr. Schmidt was again named a recipient of one of JDRF’s most prestigious funding awards: the Scholar Award. But this time, it recognized her achievements instead of her potential.
The Scholar Award goes to some of the top scientists in diabetes research – those who have a track record of conducting pioneering, transformative research that has the potential to be paradigm-shifting. From JDRF’s perspective, Dr. Schmidt’s work perfectly fit the bill.
As her Scholar Award study continues, Dr. Schmidt is about to launch another JDRF-funded study. She recently received a three-year, $2.3 million grant to pursue three projects, whose goals include developing a new class of RAGE therapies to ultimately deliver RAGE-blocking compounds to patients while gathering more information on molecules key to the RAGE system and trying to identify treatment targets beyond RAGE itself.
She calls this an exciting time for her research, with the potential to discover entirely new forms of anti-RAGE therapies. “I’m very grateful to JDRF for giving us the chance to do this,” she says.
For its part, JDRF is excited by the possible implications of Dr. Schmidt’s research.
“What’s particularly exciting is that Dr. Schmidt’s work holds the promise of being effective against multiple complications,” says Barbara Araneo, Ph.D., who directs JDRF’s Complications Therapies program. “In theory, RAGE-related treatments could be used for all complications. They also have the potential to be used earlier in the process of complications development, giving us the opportunity to stop the progression of complications before they can do serious damage.”
Over the past two decades, Dr. Schmidt has been far more than just a recipient of JDRF funding. She has consistently and generously volunteered her time to JDRF. She is a former co-chair of JDRF’s Medical Science Review Committee, a group of scientists who play an essential role in guiding the process via which JDRF determines which research grant applications to fund. She has also chaired JDRF’s “study sections” and other committees overseeing the complications research portfolio. All in all, Dr. Schmidt has helped to provide the scientific guidance essential to ensuring JDRF is funding the most promising research – and moving as quickly as possible toward better treatments and ultimately a cure for type 1 diabetes.
“She has been a brilliant volunteer to JDRF,” says Dr. Araneo.
In recognition of her outstanding achievement in diabetes research and service, JDRF awarded Dr. Schmidt its David Rumbough Award for Scientific Excellence earlier this year.
After two decades at Columbia, where her research career began, Dr. Schmidt recently returned to NYU along where she was trained, along with her team of 20 diabetes researchers. She is NYU’s Dr. Iven Young Professor of Endocrinology and her post includes a joint appointment in the Department of Pharmacology, where she serves as director of the Diabetes Research Program.
Dr. Schmidt believes JDRF fills a niche that is critical to research, acknowledging that some of her work is “higher-risk” than National Institutes of Health (NIH) grants allow. The type of “high-risk/high-reward” research she is pursuing with her Scholar Award, for example, “could not be funded by anyone else other than JDRF,” she says.
JDRF plays a critical role in the research community – identifying where gaps in investment exist and where funding them can make big difference, says Dr. Schmidt. “JDRF has always had that sense, that they don’t want to fund the same things as NIH,” she says.
She adds that JDRF pioneered multidisciplinary research funding – bringing together scientists from many different specialties to work on a problem together – an approach she has used in her research to speed progress toward providing real results for people with diabetes complications. “JDRF recognized sooner than anybody that you could put people together, even if they are not the types who were typically put together,” she says.
JDRF was also among the first organizations in the diabetes science world to recognize something else: namely, the great potential Dr. Schmidt had to make significant contributions to progress. Twenty years later, JDRF is glad they saw that promise in Dr. Schmidt, and tremendously grateful for all her meaningful work.