Why Dr. Denise Faustman Isn’t Deterred by Skeptics of Her Type 1 Diabetes Cure Research

Dr. Denise Faustman is known in many circles as one of the most controversial figures in type 1 diabetes (T1D) cure research. She's raised millions of dollars and waves of hope with her work but has also been effectively shunned by the research community. Yet she barrels forward with her innovative vaccine-based approach to a cure, never letting naysayers deter her.

This is her story.

Motivated as a child

Born in Royal Oak, Michigan, Dr. Faustman now leads the Immunobiology Laboratory at Massachusetts General Hospital (MGH) and Harvard Medical School in Boston. 

As a child, Faustman recalls how much she disliked her pediatrician’s general tone and approach.

“He was really severe and didn’t talk much,” says Faustman. “I thought I could do a better job than this guy.”

And so she set out to become a doctor, doing a great deal of research throughout high school and college. Over the course of a decade after college, Faustman earned her MD, PhD, and postdoctoral degrees, always fueled by a passion for research. 

She worked as a hands-on physician in a diabetes clinic for a number of years but tells DiabetesMine that she found the work to be filled with giving patients bad news, followed by “Debbie Downer” lectures on blood sugar, cholesterol, complications, etc. Eventually, she found her way back to research.

“I liked asking questions, so I figured maybe academia was a good way to go,” explains Faustman, who began working at the Washington University School of Medicine in St. Louis with the legendary Dr. Paul Eston Lacy, known for pioneering islet cell transplantation as a potential treatment for diabetes. 

Lacy was also one of the first in diabetes research to identify and isolate the insulin-secreting cells from the pancreas of rats.

Early transplant work

“My work with Lacy was focused on making the islet cell ‘invisible,' moving the work forward to humans so we wouldn’t need to give patients immunosuppressive drugs after a transplant,” explains Faustman. 

By the time Faustman was leaving Washington University, they had performed the first islet cell transplant in 1989 with hopes that a cure for T1D was just around the corner. This research was also a significant contributor to the creation of the T1D-focused organization JDRF.

“It was the only place in the world that had isolated an islet cell,” Faustman says. “MGH and Harvard recruited me — they set me up in a lab to begin islet cell isolation and transplantation.”

Faustman’s early islet cell transplantation work focused on putting islets in patients with T1D who were also undergoing kidney transplants.

“We figured if they were already on the yucky stuff — the immunosuppressive drugs — for the kidney transplant, it was a good opportunity for an islet cell transplant.”

Within a few weeks to a couple of months, Faustman and her team at Harvard would find that the islet cells were dead while the kidney was still performing well.

“We probably did 8 to 12 transplants before we had a crystal clear bad answer,” recalls Faustman.

Today, given what we know about the immune system’s ongoing attack on pancreatic cells, this result isn’t surprising. However, at the time — the late '80s and early '90s — diabetes researchers operated under the assumption that the immune system attacked only once, at the time of diagnosis.

Bucking the community

“After seeing so many failed transplants, I said, ‘Hey, wait a minute. There’s clearly an autoimmune issue still occurring here,'” recalls Faustman. “That was my first experience in bucking the community. They just assumed the autoimmunity was gone, but there were a few us raising our hands and pointing out that the autoimmunity was still a big issue and we were not very popular.”

Sure enough, over the course of the next decade, the idea that autoimmunity continues in people with T1D became widely accepted. 

“When we started saying that islet cells weren’t the cure for diabetes, that’s when I should have learned the whole ‘keep your mouth shut’ if you’re going to go against where the money is going.”

Faustman began her unconventional approach of focusing on the generic Bacillus Calmette Guerin (BCG) vaccine, due to its known induction of Tumor Necrosis Factor (TNF) and T-regulatory cells, which have the ability to kill the bad T-cells causing T1D.

Her early results in lab mice created a lot of excitement, but since other researchers were unable to reproduce her results, skepticism among the scientific community began to spread. JDRF, a major funder of cure research, refused to back her.

Nevertheless, she started the first immune interventional clinical trials in people with long-term diabetes, instead of just people with new-onset diabetes.

In 2018, in an unprecedented move, JDRF and the American Diabetes Association (ADA) issued a joint statement warning the community not to get too excited about her research. They noted her studies were very small sample sizes and “the findings prompt thought-provoking questions but not definitive answers” that are needed before her work can be broadly touted as a success.

Breakthrough or not?

But Faustman says if you look at many discoveries she and her colleagues have made over the years, they were often refuted at the time and then accepted 10 years later when other researchers caught up to speed.

She provides a list of examples of early scientific dogmas that Faustman and her colleagues challenged — which later turned out to be true:

• Identifying the immune system is still attacking insulin-producing beta cells long after the initial diagnosis
• Identifying T1D results largely from changes to "miseducated" CD8 cells, in addition to the well-accepted role for CD4 cells
• Confirming the hormone TNF can kill the “bad” CD8 cells and induce helpful regulatory T-cells
• Identifying most people with T1D continue to secrete varying amounts of insulin and C-peptides for decades after initial diagnosis
• Identifying islet cells have HLA class-1 markers that track to poor T-cell development and discovery of a "downstream intracellular defect in a TNF-sensitive pathway."
• Showing BCG induced TNF, which reverses end-stage T1D in mice

“We’ve always tried to do innovative things,” says Faustman, who continues to forge ahead despite a lack of broader support from the T1D research community. 

“Almost every major breakthrough in the history of medicine started as a controversy. I don’t care what people say as long as it’s honest,” adds Faustman. “As Daniel Moynihan said, ‘Everyone is entitled to their own opinion, but not their own facts.’”   

Diabetes advocate and author James Hirsch summed up the Faustman controversy this way: "In the staid science world, she’s an unconventional thinker, she’s doing experiments that no one else is doing, and she’s devoted her life to the cause. She also ruffles feathers because she promotes her work and attracts publicity. Flamboyance is not admired in science, and some of the attacks against her have been personal and unfair. But her larger problem, and the reason the JDRF has rejected her requests over the years, centers around the reproducibility of her research and the overall soundness of her work."

Funding her work: An unexpected relationship

After billionaire Lee Iacocca lost his wife, Mary McCleary, to complications of T1D, he was determined to invest some of his wealth into finding a cure for the disease and started the Iacocca Family Foundation.

Known largely for the development of the Ford Mustang, Iacocca was a successful automobile executive at Ford Motors and was also credited for reviving the Chrysler Corporation in the ‘80s.

“One day, I’m in my office and this guy shows up,” recalls Faustman. It was George Cahill, a well-known diabetes researcher, senior leadership at Joslin Diabetes Center in Boston, and a past president of the Howard Hughes Medical Institute.

“He said, ‘I’m really interested in your work and I like the fact that you’re interested in human immunology,” recalls Faustman. “He said he’d been selected [by Iacocca] to find young people doing innovative things.”

The result was a small grant program focused on diabetic lymphocytes — and the Iacocca Family Foundation has been contributing financially to her research ever since, including a lump sum of $10 million towards her Phase I clinical trials.

Between that and other private donors, the Faustman Lab has raised over $22 million over the years and continues to actively fundraise.

Getting started with the BCG vaccine

The BCG vaccine that is the focus of Faustman's diabetes research has existed for over 100 years, primarily known for its ability to protect humans from tuberculosis. 

Initially, using BCG to treat T1D was done with the hope that it would stop the immune system from destroying precious insulin-producing beta-cells.

But back in the early 2000s, Faustman set her sights on utilizing BCG to boost levels of the hormone known as TNF. It’s well established that people with autoimmune disease are deficient in TNF. By increasing TNF, Faustman aimed to eliminate the T-cells killing off beta cells and increase the amount of T-regulatory cells, which would then help the pancreas produce new beta cells.

At first, Faustman tried to find a pharmaceutical manufacturer to discuss producing a new source of TNF, but they found it to be too costly, lasting only minutes once administered in the human body, and potentially deadly if you received too much.

“The BCG vaccine, on the other hand, is a simple drug used for vaccines around the world, so why are we trying to recreate this?” Faustman asks.

Faustman’s Phase I trial

In mice trials, the BCG vaccine was effective in near-death diabetic mice, so Faustman broke from a norm in diabetes research and chose people with long-term diabetes to participate in her Phase I trial that began in 2007.

“At the time, we were concerned that we would not have the budget to recruit new onset patients,” says Faustman.

In the end they were able to use the BCG vaccine to treat T1D in 9 participants — all of whom had lived with the disease for 15 to 20 years. The early results were underwhelming. 

At 22 weeks, there were no changes in A1C results or insulin production. Faustman did find small changes in biomarkers, like T-regulatory cells and C-peptide cells. Regardless, she says these findings wouldn’t feel like much of a victory to those living with the day-to-day burdens of T1D.

Around the same time, research using the BCG vaccine in new onset multiple sclerosis patients was published, and it was impressive.

“That data showed that BCG was preventing relapses, showing in MRI scans that lesions [on the brain] were not progressing, and some were even reversing,” recalls Faustman. “And these findings were occurring after year two and year three of starting treatment with BCG. BCG is halting the disease and producing brain recovery.” 

This research led Faustman to re-open her own BCG study, which closed after the planned 22-week trial was complete. 

“We looked at our data and thought, ‘Why would we think we’d see clinically meaningful data at 22 weeks?’ We realized we needed to reopen that study and look at the longer-term results.”

Sure enough, when they brought every participant back three to four years after BCG vaccinations, they found notable changes.

“We started by looking at their A1Cs,” explains Faustman, “and it was not a subtle finding.”

Three years after receiving BCG, every participant experienced anywhere from a 10 to 18 percent reduction in A1C, and their insulin needs had decreased by at least a third.

She says many people questioned her choice to include long-term patients instead of newly diagnosed. Her response: “There’s a belief that once you get the disease, and have had it for years, it’s too late. But isn’t that what the public wants: A treatment for the people who’ve had diabetes for years and years?”

The other point of criticism was the sample size of just nine patients. "When you see a small study with huge statistical significance, it means that everybody responded to the treatment," she says.

Also, Faustman and her team waited a year to publish results of their Phase I trial, and later did a more comprehensive five-year followup, published in 2018. She says they "resisted publishing the findings until we could better understand what led to the stable and long-term corrections in blood sugar levels and a one-third drop in insulin needs."

Exploring her own results

“We’ve looked closely at what the pancreas is doing by administering glucagon and drawing blood. There was only a little blip in insulin secretion. No way that this little amount could explain a drop in A1C from 8.5 to 7.0 percent,” explains Faustman. 

“Was it a change in insulin resistance?” recalls Faustman of their next speculative guess.

An expensive thing to test, they sent patient serums to Metabolon, a unique lab that analyzes biochemistry, genetics, and more. 

The results: no significant changes in insulin resistance when evaluated for metabolites consistent with this metabolic change.

What they did find, however, was a huge increase in “purine metabolism.” Purines are uric acid that accumulates in the blood — but why would BCG affect this?

“When we looked deeper into understanding this, we became acutely aware that at baseline, [people with diabetes] had a metabolic effect that hadn’t been described before,” explains Faustman. “People with type 1 diabetes using more oxidative phosphorylation than glycolysis for energy.”

Oxidative phosphorylation uses no sugar for fuel compared to glycolysis, which uses tons.

“This is a defect in white blood cells,” explains Faustman. “We looked at the lymphoid system in the participants before they started BCG and they were not using much sugar for energy. Then we looked after BCG and glucose was now their primary source of energy. The BCG treatment was flipping lymphoid metabolism to become a regulator of blood sugar levels.”

Recalling that BCG is actually a live but weakened strain of tuberculosis, it is known that when you develop tuberculosis, it switches energy metabolism in the same exact way. 

“Our best result was an outlier,” says Faustman of the participants. “His A1C is at 5.5 percent, he can go off his insulin entirely sometimes for a few months. Then he might see his blood sugars start to rise again and he goes back on a small amount of insulin.”

Faustman adds that, strangely, when his blood sugar levels do start rising he does not produce ketones. 

“We monitor ketones in all our participants. We think the reason he isn’t going into ketoacidosis is because the pathway that leads to the use of oxidative phosphorylation starts right after the production of ketones.”

If BCG is preventing the process of oxidative phosphorylation as the primary source of energy, ketones aren’t occurring either.

“We realized on a systemic level that we were able to change sugar metabolism. Participants also experience fewer low blood sugars because their insulin doses have decreased so much.”

Faustman adds that while they know BCG can reduce a person’s A1C level by 10 to 18 percent, they haven’t tried the treatment on the more extreme cases with A1Cs above 10 percent. 

“This is such an individual disease. Could the results of this treatment mean some people end up just taking some basal insulin while others might choose to just do insulin for meals? We don’t know yet," she says.

Phase II: Faustman’s research today

Today, Faustman and her team continue to follow patients who have been involved in multiple BCG trials at the lab, including the 150 patients in the double-blinded Phase II clinical trial that kicked off in 2015. The estimated completion date for that study at the ClinicTrials.gov site is July 2023, a surprisingly long timeline.

“We are building a large and well-controlled data set,” explains Faustman. “Pending approval by the FDA, we hope this year to start a multi-institution pediatric trial.”

To date, she says more than 236 patients have been involved in the BCG trials either completed or enrolled and 143 have been treated with BCG. 

Skeptics believe that Faustman may be dragging her feet on completion of next-round trials. And given the JDRF and ADA's joint statement urging caution on interpreting her Phase I results, some believe that standing up and supporting Faustman could pose a conflict-of-interest for other experts in the community whose research is funded and supported by the JDRF.

But who knows? This pushback may eventually help her gain more support from the research community, not unlike what happened with Dr. Bernard Fisher’s revolutionary work that challenged norms in the treatment of breast cancer.

BCG’s growing popularity in other research

Meanwhile, using the BCG vaccine to treat other conditions has been growing in popularity remarkably.

“One of our biggest challenges was not just that we had a lot to learn about type 1 diabetes, we had a lot to learn about BCG,” explains Faustman. 

“As part of a global coalition of BCG researchers, we have fundamentally changed our understanding of how BCG interacts with the immune system, how long it takes to work, and how long it lasts,” she says. 

“I get a call at least once a month from someone working on fibromyalgia, allergies, autoimmunity, Alzheimer’s, and other conditions that might benefit from BCG. There’s a global interest, especially in Europe and Australia. There are even some very interesting data sets showing that the right strain of BCG, at the right time and sequence, can delay the onset and possibly prevent type 1 diabetes.”

There are also 22 global trials using the BCG to prevent or lessen the impact of COVID-19. Faustman details BCG and COVID-19 research in her own work, noting that multiple studies have shown there are fewer COVID cases in areas where the BCG vaccine is universally applied. Dr. Faustman is a co-principal investigator on a multi-center BCG/COVID-19 trial.

Of course, as BCG’s popularity rises and the data continues to expand, Faustman has found new and interesting allies, such as health insurance companies and large employers, who understand the value of an inexpensive intervention with limited dosing. 

“I’m a lot more popular now. I have a lot of new friends!” she notes with amusement considering the flack she’s taken over the years.

“There has been interest from big pharma, too, just not so much in BCG,” says Faustman. “They know we have identified a novel pathway and are starting to think about new ways to attack it. It will be interesting to see what they come up with.”

As for her trial participants, they never miss an appointment.

“I have participants who rent an RV in Montana and drive to Boston just so they don’t have to worry about COVID-19 interfering with their appointments,” says Faustman with gratitude. “Our participants are all very educated in their disease and grateful to be involved. It’s a real privilege for our nursing staff.”

The interest from others with T1D continues to grow, too.

Faustman has a lengthy waiting list of patients who would love to enroll in the next study — if only it were that simple.

“Everybody should register. You’ll get the newsletter once a year with updates, and notified of upcoming trial opportunities. But our trials are very narrow with specific details about how long you’ve lived with type 1 and other factors that mean not just anyone can participate," she explains.

People with T1D can e-mail DiabetesTrial@partners.org to register and stay up-to-date on Faustman’s work.

As for the critics, Faustman intends to continue ignoring them. 

“Discovery is always a disruptive process,” says Faustman. “I am not here to confirm what people want to see.”

- - - - - - - - - -

Written by Ginger Vieria and originally published on DiabetesMine