As a pediatric heart specialist, Dr. Steven Lipshultz has taken pride in the work he's done to help kids here in metro Detroit. He's also shed plenty of tears with families of children he couldn't help.
At one point, those tears became a catalyst for action. Lipshultz, a skilled physician scientist, recognized he had the ability to keep more kids alive by taking what he saw in clinical practice into the research lab for a deeper dive.
This is a story about the power of translational, or "bedside to bench," research—when a clinical physician observes firsthand a medical issue requiring research, then personally seeks a solution in the laboratory.
What Lipshultz saw at the bedside was the advent of multi-agent chemotherapy, lifesaving drugs that helped kids survive leukemia and other childhood cancers. He also saw the deadly side effects of those drugs. In essence, children were overcoming cancer, but the drugs they needed for survival were damaging their hearts.
"The price of the cure is that these medications are not exclusively restricted to killing cancer cells," Lipshultz says. "They will kill any call that is rapidly dividing. … [Children] didn't die of cancer, but of heart failure. It's a very tragic substitution of one disease for another."
Lipshultz, who is a pediatric cardiologist at Children's Hospital of Michigan (CHM) and interim director of the Children's Research Center of Michigan (CRCM), recalls one patient with neuroblastoma, a type of cancer that affects nerve cells, whose heart failed after cancer treatment.
"She died in front of me. You never forget that," Lipshultz says. " She was 16 years old, with decades of active, productive life ahead of her."
This was a turning point in Lipshultz's career that would make a lifesaving difference to children with cancer, not just here in Michigan, but across the globe.
The value of translational research
One of a relatively small number of medical professionals trained in both clinical and research medicine, Lipshultz set himself a goal to discover a treatment that wouldn't destroy the hearts of kids treated with chemotherapy.
"I made a promise that I would do whatever I could through translational research to say we could get the best cures for cancer, and at the same time, avoid toxicity and late effects of cancer therapies," Lipshultz says.
Dr. Steven Lipschultz holding frozen DNA samples
Through intensive, years-long research into the mechanism by which the chemotherapy drugs were damaging to heart cells, Lipshultz, who is also a professor at Wayne State University School of Medicine, tested cells in culture dishes, then in treatment models in lab animals, observing 200 different drugs. When he found one that was effective, he sought funding for multicenter, randomized clinical trials from the National Cancer Institute.
Because the trial was so successful, the government urged Lipshultz to publish data
, even before the trial's conclusion. In 2014, the FDA granted "orphan" status to the drug, used as treatment for disease that affects fewer than 200,000 people per year. By 2017, the drug protocol was also approved for use in Europe for children newly diagnosed with cancer that would receive heart-damaging chemotherapy.
Today, kids have a much better chance of surviving chemo, thanks to Lipshultz's "bedside to bench" research.
A rare combination of skills
Translational pediatric physician-scientists must have an understanding of basic scientific research, their field of expertise, and the potential impact a discovery can have on disease in a pediatric patient. Some run carefully constructed clinical trials to test drugs in a lab setting based directly on the needs they see in patients they care for every day. That is a relevant connection to patients that even doctorate-level researchers don't have.
"What's fundamental about translational research is it is part of a continuum of research that gets new therapies and new understandings important in outcomes to the patient," says Dr. Valerie Paula Opipari, pediatric hematologist and oncologist, and chair of the Department of Pediatrics at C. S. Mott Children's Hospital in Ann Arbor.
Pediatric translational research has ushered in effective treatments for many childhood illnesses, to the point that seasoned pediatricians have seen dramatic changes in survival rates just during their own careers.
When Opipari started practicing, the majority of childhood cancers were not curable. Leukemia, for example, had a 15 percent survival rate. Today, five-year survival rates are between 60 and 85 percent, depending on the type of leukemia, according to the American Cancer Society.
"In virtually every discipline in pediatric medicine, that is the story," says Opipari. "With cystic fibrosis, most didn't make it past their second decade. Now we have many living into their sixth decade because of translational research."
Where there were no treatments or cures for hypoplastic left heart syndrome, a congenital defect that causes an underdeveloped left side of the heart, today there are three surgical procedures, and patients now in their fifth decade of life.
"In pediatrics, translational research has been critical," says Opipari.
More funding needed
In a medical model that requires physicians to spend time with patients and then bill for their services, health systems rarely have funding for even highly skilled physician scientists to spend time in a laboratory setting, regardless of the potential for breakthrough cures. Pediatric specialists agree that research is grossly underfunded.
"Part of it is numbers," says Dr. Jeffrey Taub, oncology division chief at CHM. He cites childhood cancer, which accounts for 2 percent of all cancers, as an example.
Dr. Jeffrey Taub
"Cancer sucks" pin on Dr. Taub's lapel
"At the funding level, as the government cuts back on research, they think they should fund proportionate to the number of cases. If a disease affects 400 kids a year, why spend millions on research, compared to a disease that affects 50 million people a year? Children don't vote, and they are not advocates for themselves."
In addition, panels that award funding aren't always staffed by pediatric specialists, or those who understand the critical importance of pediatric research.
Stagnant federal funding makes recruiting research talent challenging, despite local economic growth stimulated by funding. According to the American Society of Clinical Oncology, every dollar of federal funding stimulates $2.21 in economic growth
. Just 12 percent of new research grant proposals were funded by the National Cancer Institute in 2015, down from 27 percent in 2001.
The National Institutes of Health (NIH) funds 3 to 5 percent of pediatric cancer research, leaving a dependence on private and foundation funding, even though discoveries made in pediatrics have implications for adult disease.
"If the NIH were to take that funding to 20 or 25 percent, imagine what could be accomplished, and what an impact that could make on adult disease," says Opipari.
Michigan's future of translational research
After spending years in a translational research environment at Boston Children's Hospital and Harvard Medical School, Lipshultz arrived at CHM, where there was no such program. Through a relationship between CHM and CRCM, with funding from the Children's Hospital of Michigan Foundation
, Lipshultz has been able to establish a supportive environment to train pediatric physician scientists.
Last year, a two-center proposal between the programs at University of Michigan and Wayne State University was granted funding by the government for three physician scientists, and a fourth will be funded by U-M.
It takes about 10 years to become fluent in both clinical and laboratory research. But Lipshultz thinks the outcome is worth the time spent.
"Continued support of the Children's Research Center of Michigan might lead to new therapies we can't possibly imagine today," he says. "We don't yet have every child going home for a long, healthy life, so there is much more than needs to be done. Translational research is about as important as it gets."
This article is part of "Children of Michigan," a series on the importance of health and wellbeing for Michigan's children. It is made possible with funding from the Children's Hospital of Michigan Foundation.
All photos by Nick Hagen.