The FDA says your adipose cells are a drug, subject to pharmaceutical regulation. Two alumni say that’s a big fat blunder.
Nearly 1.7 million women around the world developed breast cancer in 2012. Journalist and producer Shelly Ross was one of them. In 2013, after undergoing chemotherapy, she was one of 100,000 Americans to receive breast reconstruction surgery.
It was all very straightforward. The surgeon used cadaver tissue as slings to support the implants that she slid under the skin of Ross’s chest. All should have been well. But post-op, Ross was, in her own words, “feeling toxic and weak,” and the feeling didn’t abate. Four weeks after her initial surgery, she was back under the surgeon’s scalpel. Her body had rejected the cadaver tissue, which fragmented and decomposed.
Doctors removed the reconstruction and trained shower heads on the area to wash away the mess. They let the water run for more than an hour. The aggressive cleansing swept away all of the tissue between Ross’s skin and her ribcage, and scarring formed in its place. This was just the latest debilitating side effect of her cancer experience. Chemo treatments had already caused her rotator cuffs to tear. So, when she stared in the mirror, she told an FDA panel during public testimony in 2016, “I saw the devastating reflection of something that resembled a plucked chicken with two broken wings.”
For Rodriguez, who has spent his career trying to repair cell damage, whether inflicted by age or accident, it was a miracle.
But Ross had resources. Through the Cure Alliance, where she serves as president and patient advocate, Ross met a surgeon from Milan, Italy, who was repurposing his patients’ own adipose (a.k.a. fat) tissue for facial and wound reconstruction. After hearing that he had expanded his scope and successfully treated a patient like her, Ross boarded a plane.
On Dec. 30, 2013, Ross underwent another reconstructive surgery — something that her American surgeons had assured her would be impossible. The doctor removed a little more than 12 ounces of fat from her back and abdomen, processed it, and used it, along with new implants, to rebuild her chest. He took some of the leftover fat and injected it into both of her shoulders. A week later, she was home and pain free. Nine months after her surgery, full range of motion had returned to her arms.
The cure is astounding. As is the fact that Ross had to use a passport to access it.
Dr. Ricardo Rodriguez ’76, plastic surgeon and researcher, was in the audience as Ross told the FDA her story. He was there on the same crucial mission: to urge the FDA to rescind draft guidances that, in the opinion of many practitioners and patients, inhibit the ability of U.S. citizens to take part in a worldwide medical revolution. Recent research has shown that your body potentially carries the tools it needs to repair surprising levels of damage. But the FDA, citing patient safety and referencing instances in which unqualified professionals have done more harm than good, has set up regulatory hurdles that the average health care consumer cannot leap. In some cases, those hurdles stand in the face of both basic science and common sense.
Rodriguez has spent a decade studying the safe and effective healing powers of adipose tissue, and he was prepared to point all of this out to the government’s legal and medical experts. When he stepped to the mic to lay out his impassioned, air-tight argument, he was drawing on an education that began at Colgate more than four decades ago — and a friendship that started with a little a cappella in West Hall.
The beginning of a beautiful friendship
Growing up in Puerto Rico, Ricardo Rodriguez always planned to be a doctor. In high school, he sat through an admission pitch for Colgate, where a couple of his friends — the O’Shea twins, George and Robert ’73 — had enrolled. He took his first trip off his home island for an exchange program to McQuaid High School in Rochester, N.Y., during the winter of his senior year. When his hosts found out about his interest in Colgate, they drove him to campus for a tour, and he was hooked.
“I remember seeing the golden dome of the chapel, and it was like a fairy tale,” he recalled.
His love deepened in the fall of 1972, when he met his new Colgate classmates, particularly some of the first females to be admitted to the university. Colgate women were proud to engage in deep conversations, and Rodriguez “thought that this was the greatest thing in the world.”
One of those girls, biology major Mary Ann Chirba, lived one flight down from him in West Hall. While Rodriguez chose Colgate for its scenic beauty, Chirba saw it as a new frontier for her gender. “It bothered me that there was a whole group of really fine universities that had been absolutely closed to women,” she said. “So I thought, well, that’s where I should go.”
On her birthday in mid-September of 1972, she was sitting in her room when she heard a booming voice in her doorway, singing “Happy Birthday” in Spanish. “I thought, what a character!” Chirba remembered. That character was Rodriguez, a French literature major who was still holding on to those medical aspirations.
“We dated for a while, and then we didn’t,” Chirba said. “But we stayed really good friends.”
After graduation, Rodriguez went off to medical school in Wisconsin, and Chirba took a job at Harvard Medical School. Rodriguez proceeded to Tulane, then did his residency in plastic surgery at Yale, where he subsequently joined the medical school faculty. Today, he’s in private practice in Baltimore, Md., and holds a teaching appointment at Johns Hopkins University.
Chirba, after being bitten by a lab rat, decided that medicine wasn’t for her. Instead, she went to Boston College Law School for her JD, then earned a master’s and a doctorate in public health from Harvard. She’s done her share of teaching as well — at Boston College Law, Harvard Law, and New York University.
Rodriguez and Chirba have stayed in touch through the years, helping each other through rough patches. “I valued her for all of her qualities,” Rodriguez said. “She was an artist. She was better at science than I was. I always knew she’d do great things.”
In 2007, Rodriguez took his wife, Leeza, on an unconventional date to hear more about the use of stem cells in regenerative medicine. A picture of a rat’s heart matrix was projected on the screen in a Baltimore convention space. Devoid of blood cells, muscle cells, and nerve fibers, the heart looked like a pearly white grocery bag.
Someone hit a button, starting a time-lapse video. Pipelines of red blood mixed with concentrated stem cells started to shoot into the heart matrix. The bag morphed into a quivering, translucent strawberry. More time. More blood. More stem cells. After a lapse of three weeks from the first injection of biological material, a fully functioning, pink and pounding heart filled the frame.
For Rodriguez, who has spent his career trying to repair cell damage, whether inflicted by age or accident, it was a miracle. “That’s like a resurrection,” he said. “There’s no other way to explain it.” Somehow, stem cells went into the heart, looked around, and started to differentiate into the component parts of the organ, the muscles, and complex webs of nerves.
The video helped to upend a principle that Rodriguez had held as true throughout his decades-long career. Therapies are usually honed as much as possible to target a specific condition in the body and address it, in spite of the vast number of variables that exist from person to person. “You’re trying to find the most precise tool for the most precise effect,” Rodriguez said. “That’s how you prove it works, and that’s how the FDA approves it.” But stem cells represented the mirror opposite of that approach: take an element from the human body and send it into a complex scenario in which it will address a broad number of issues without any intervention from the physician. Then, study the reaction and try to replicate it. “You make your application, and then you try to understand how it happened to see if you can make it better,” Rodriguez said.
“You’re trying to find the most precise tool for the most precise effect. That’s how you prove it works, and that’s how the FDA approves it.”
— Dr. Ricardo Rodriguez
Conversations Rodriguez was having with fellow plastic surgeon and educator Dr. Adam Katz at this time upended another principle. Conventional wisdom had previously held that fat couldn’t be used to repair a cancer patient’s breast tissue after radiation treatment. Radiation reduced the flow of blood in breast tissue, and because fat doesn’t bring its own blood supply along when it’s transferred from, say, a thigh, it wouldn’t be able to support itself in the new location. “Even now, if you get the latest edition of a radiation therapy book,” said Rodriguez, “it will say that there is no cure for radiation damage.” Fat was therefore a terrible grafting material and a medical biohazard with a high disposal cost. But, because he had a surplus in his lab, Katz had started centrifuging this liposuction biproduct and had found concentrated stem cells at the bottom of the test tube. Consequently, he started experimenting with the use of fat stem cells (a.k.a. adipose stem cells) to reconstruct and heal breasts after cancer-related radiation therapy. It worked.
Ever the scholar-practitioner, Rodriguez channeled his excitement into research on the promising developments he saw at his conference and in Katz’s explorations. Beginning in 2007, he started using Katz’s techniques, injecting concentrated fat cells into patients’ breasts after lumpectomy and radiation treatments. The cells not only provided structure for the breast, but they also healed the tissue damage caused by the radiation.
The secret is in the stem cells. These cells have yet to become a specific kind of cell within the body — whether fat, muscle, nerves, or something else. Most people have heard about embryonic stem cells, because of the controversy that comes from harvesting them. But scientists have learned, through years of investigation, that stem cells also cluster around material like bone marrow and fat, lurking on the edges and conducting small-scale repair duties as needed.
Rodriguez and other reconstructive surgeons can use liposuction to remove a trove of fat, place it in a centrifuge to separate out the parts with the highest concentration of stem cells in tow, and inject that enriched concentration back into the patient. It all takes place in the same facility and during the same surgical procedure. Rodriguez calls it “supercharging the healing process.” If the liposuctioned fat left the room, required elaborate processing, or needed to be transported elsewhere, it would be in danger of contamination, and the FDA would wrap Rodriguez in red tape.
Government red tape comes in many forms, including guidances released by the FDA to clarify how they will enforce laws. At the end of 2014, the FDA released a new series of draft guidance documents related to the use of adipose cells. With every word he read, Rodriguez fumed. He knew he had to call his old friend.
The guidance in question had the tantalizing title Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) from Adipose Tissue: Regulatory Considerations. Until its release, Rodriguez had believed that, if he liposuctioned fat in his operating room, enriched it on the centrifuge, and put it back into his patient immediately, the resulting adipose cells would fall under section 361 of the Public Health Service Act. He was removing structural fat from a thigh and using it to restore the structure of an irradiated breast and heal the tissue damage. Under section 361, that’s called minimally manipulated homologous use of a cell or tissue. Rodriguez could do those procedures all day, every day and never need to ask the government for approval.
Among the reasons he was thundering on the phone to Chirba was line 182 of the guidance. It read:
- Example B-3: The basic function of breast tissue is to produce milk (lactation) after childbirth. Because this is not a basic function of adipose tissue, using HTC/Ps from adipose tissues for breast augmentation would generally be considered a non-homologous use.
- Translation: Since the breast is only for producing milk and adding fat to the breast will only change its shape, not facilitate lactation, then this is not a similar — or homologous — use of the cells. Therefore, those cells will be regulated under section 351 of the Public Health Service Act. Your cells, under that section, are a drug, and they must be subjected to clinical trials and applications for approval, which can cost millions of dollars and take years to complete.
Rodriguez knew that the majority of women never use their breasts to feed children. But for all women, breasts serve as a secondary sex organ. Eight years after embracing the efficacy of adipose stem cells in the treatment of breast cancer patients who have had these organs removed, Rodriguez realized that a vital tool might be yanked from his surgical tray. “[We were] mutually appalled,” Chirba said. “As we have so often done over the years, we forged a game plan to solve a big problem.”
Sept. 13, 2016: day two of public testimony on the draft guidances that so enraged Rodriguez and Chirba. Eight FDA representatives sat onstage in an auditorium at the National Institutes of Health in Bethesda, Md., and Rodriguez rose to speak his piece.
First, he told the panel, the FDA says that adipose tissue is a connective tissue that serves only a structural purpose. But the government’s own cited source also says that adipose tissue can serve several other functions. It can store and regulate energy, cushion and occupy space, or respond to stimuli from the nervous and hormonal systems. All of this is crucial because, to gauge whether or not you’re complying with an FDA requirement for homologous use, you have to know what the function of the product is in the first place. The multifunctional nature of adipose tissue, beyond its structural capacity, makes it possible to heal a breast damaged by radiation, he argued.
Then there’s a second problem. Due to the government’s language, doctors aren’t allowed to take adipose stem cells and inject them into a mastectomy wound for the purpose of healing the damage, because adipose cells cannot restore lactation — which, according to the government’s guidance, is the single purpose of the breast.
Chirba had zeroed in on this point during her testimony the day before. “I ask this agency,” she said, “to explain why a breast is mainly a lactation organ and nothing else.” She also gave them a lawyer’s perspective on their guidance. The judiciary regularly defers to executive agencies’ judgment when it comes to enforcing laws. But this guidance would certainly be ruled arbitrary, because the FDA ignored adipose tissue’s versatility and a breast’s multiple functions.
The agency’s restrictions, if enforced, would preclude women from using their own cells for reconstruction therapies. With more than 100,000 breast reconstructions taking place in the United States each year, the academic quickly becomes practical. Just ask Shelly Ross.
“High benefits, high rewards, high risks in some instances — the FDA doesn’t have a regulatory pathway that really fits this,” Chirba said. Thus, the fight over a few technical paragraphs in an obscure FDA publication.
The pathway forward
The one-two punch, legal and medical, continues. Since teaming up to address adipose stem cell issues, Chirba and Rodriguez have appeared side-by-side on numerous panels, including those sponsored by IFATS, the International Federation for Adipose Therapeutics and Science, of which Rodriguez is currently president. Together, as classmates and collaborators, they have continued to raise awareness among researchers, practitioners, and legal experts, educating them on the healing potential and legal complexity surrounding adipose cells.
All of this bickering misses the point, according to Rodriguez. The FDA was founded to make sure that drugs are pure, safe, and do the job that the manufacturer claims that they will do. The process of injecting refined fat cells into a breast to spur healing after radiation therapy is already proven to be sanitary, safe, and effective. According to Rodriguez and Chirba, the FDA should stop trying to shame fat for the wrongs that are caused by wayward practitioners. Fat cells don’t kill people. People — irresponsible doctors — do.
“Any practicing physician here in this audience,” Rodriguez told the FDA panel last year, “knows that accreditation of practitioners and health care facilities is the industry standard for maximizing patient safety before, during, and after therapy. The specter of losing one’s credentials is a powerful motivator and deterrent.”
With more than 100,000 breast reconstructions taking place in the United States each year, the academic quickly becomes practical.
If this were a movie based on a John Grisham novel, audiences across America could anticipate a dramatic conclusion. The FDA would hear two days of moving testimony. The panel would deliberate. An official would come to the podium in Bethesda and say, “The government withdraws its draft guidances and will work with IFATS, Rodriguez, Chirba, and other experts to design regulations that protect patients and their access to emerging therapies.”
There would be cheering and crying. Rodriguez and Chirba would toast with tumblers of 18-year-old Glenmorangie single-malt Scotch (product placement) from the doctor’s extensive cellar, and credits would roll.
But the FDA hasn’t. And according to Rodriguez, they probably won’t. Because these are draft guidances and not yet binding, the agency will most likely not respond in any way to the testimony they heard in September 2016. They will simply leave the documents alone, and not enforce them. “[The FDA] was undermined by the ridiculousness of their position,” Rodriguez said. “I don’t think they’re going to try to enforce it, so we’re still injecting fat into the breast.”
But what about the more creative uses of adipose tissue and the perfectly good fat that plastic surgeons throw away? What about the clear sack that was once — and then once again became — a fully functioning heart?
“The minute that I take the fat out and inject it through the veins,” Rodriguez said, “that’s really poking the tiger, so we’re not going to do that, but these are things that we could be doing today. I think it would be great if we could inject stem cells into people who have been irradiated in the abdomen or in other parts of the body that are crippled by radiation disease — but we can’t.”
So there are no credits rolling, although credit is due, and given.
“I’m so proud of Ricardo,” Chirba said. “He is so devoted to this, purely because it’s medically important. He could be performing a lot more surgery and making a lot more money. Instead, he goes all over the world to train doctors. It’s like Where’s Waldo.”
As in so many struggles where the little guy takes on the reigning power, sometimes you win by not losing. It’s not necessarily glorious, and there are no parades to welcome you back after a day of testimony in a government auditorium. But who needs a parade when you can see a cancer patient smile at the sight of her own body or know that a friendship is still thriving after 45 years?