Tony and Kelly Mantoan, with their boys Teddy and Fulton, who both suffer from SMA, a genetic disorder that makes walking, swallowing, and breathing progressively difficult.
Kelly Mantoan was nursing her newborn son, Teddy, in the NICU in a Philadelphia hospital when her doctor came in and silently laid a hand on her shoulder. Immediately, Kelly knew what the gesture meant and started to sob: Teddy, like his one-year-old brother, Fulton, had just tested positive for a neuromuscular condition called spinal muscular atrophy (SMA).
The boys were 8 and 10 when Kelly heard about an experimental new treatment, still being tested in clinical trials, called Spinraza.
"We knew that [SMA] was a genetic disorder, and we knew that we had a 1 in 4 chance of Teddy having SMA," Mantoan recalls. But the idea of having two children with the same severe disability seemed too unfair for Kelly and her husband, Tony, to imagine. "We had lots of well-meaning friends tell us, well, God won't do this to you twice," she says. Except that He, or a cruel trick of nature, had.
In part, the boys' diagnoses were so devastating because there was little that could be done at the time, back in 2009 and 2010, when the boys were diagnosed. Affecting an estimated 1 in 11,000 babies, SMA is a degenerative disease in which the body is deficient in survival motor neuron (SMN) protein, thanks to a genetic mutation or absence of the body's SNM1 gene. So muscles that control voluntary movement – such as walking, breathing, and swallowing – weaken and eventually cease to function altogether.
Babies diagnosed with SMA Type 1 rarely live past toddlerhood, while people diagnosed with SMA Types 2, 3, and 4 can live into adulthood, usually with assistance like ventilators and feeding tubes. Shortly after birth, both Teddy Mantoan and his brother, Fulton, were diagnosed with SMA Type 2.
The boys were 8 and 10 when Kelly heard about an experimental new treatment, still being tested in clinical trials, called Spinraza. Up until then, physical therapy was the only sanctioned treatment for SMA, and Kelly enrolled both her boys in weekly sessions to preserve some of their muscle strength as the disease marched forward. But Spinraza – a grueling regimen of lumbar punctures and injections designed to stimulate a backup survival motor neuron gene to produce more SMN protein – offered new hope.
In clinical trials, after just a few doses of Spinraza, babies with SMA Type 1 began meeting normal developmental milestones – holding up their heads, rolling over, and sitting up. In other trials, Spinraza treatment delayed the need for permanent ventilation, while patients on the placebo arm continued to lose function, and several died. Spinraza was such a success, and so well tolerated among patients, that clinical trials ended early and the drug was fast-tracked for FDA approval in 2016. In January 2017, when Kelly got the call that Fulton and Teddy had been approved by the hospital to start Spinraza infusions, Kelly dropped to her knees in the middle of the kitchen and screamed.
Spinraza, manufactured by Biogen, has been hailed as revolutionary, but it's also not without drawbacks: Priced per injection, just one dose of Spinraza costs $125,000, making it one of the most expensive drugs on the global market. What's worse, treatment requires a "loading dose" of four injections over a four-week period, and then periodic injections every four months, indefinitely. For the first year of treatment, Spinraza treatment costs $750,000 – and then $375,000 for every year thereafter.
Last week, a competitive treatment for SMA Type 1 manufactured by Novartis burst onto the market. The new treatment, called Zolgensma, is a one-time gene therapy intended to be given to infants and is currently priced at $2.125 million, or $425,000 annually for five years, making it the most expensive drug in the world. Like Spinraza, Zolgensma is currently raising challenging questions about how insurers and government payers like Medicaid will be able to afford these treatments without bankrupting an already-strained health care system.
To Biogen's credit, the company provides financial aid for Spinraza patients with private insurance who pay co-pays for treatment, as well as for those who have been denied by Medicaid and Medicare. But getting insurance companies to agree to pay for Spinraza can often be an ordeal in itself. Although Fulton and Teddy Mantoan were approved for treatment over two years ago, a lengthy insurance battle delayed treatment for another eight months – time that, for some SMA patients, can mean a significant loss of muscular function.
Kelly didn't notice anything in either boy – positive or negative – for the first few months of Spinraza injections. But one day in November 2017, as Teddy was lowered off his school bus in his wheelchair, he turned to say goodbye to his friends and "dab," – a dance move where one's arms are extended briefly across the chest and in the air. Normally, Teddy would dab by throwing his arms up in the air with momentum, striking a pose quickly before they fell down limp at his sides. But that day, Teddy held his arms rigid in the air. His classmates, along with Kelly, were stunned. "Teddy, look at your arms!" Kelly remembers shrieking. "You're holding them up – you're dabbing!"
Teddy and Fulton Mantoan, who both suffer from spinal muscular atrophy, have seen life-changing results from Spinraza.
(Courtesy of Kelly Mantoan)
Not long after Teddy's dab, the Mantoans started seeing changes in Fulton as well. "With Fulton, we realized suddenly that he was no longer choking on his food during meals," Kelly said. "Almost every meal we'd have to stop and have him take a sip of water and make him slow down and take small bites so he wouldn't choke. But then we realized we hadn't had to do that in a long time. The nurses at school were like, 'it's not an issue anymore.'"
For the Mantoans, this was an enormous relief: Less choking meant less chance of aspiration pneumonia, a leading cause of death for people with SMA Types 1 and 2.
While Spinraza has been life-changing for the Mantoans, it remains painfully out of reach for many others. Thanks to Spinraza's enormous price tag, the threshold for who gets to use it is incredibly high: Adult and pediatric patients, particularly those with state-sponsored insurance, have reported multiple insurance denials, lengthy appeals processes, and endless bureaucracy from insurance and hospitals alike that stand in the way of treatment.
Kate Saldana, a 21-year-old woman with Type 2 SMA, is one of the many adult patients who have been lobbying for the drug. Saldana, who uses a ventilator 20 hours each day, says that Medicaid denied her Spinraza treatments because they mistakenly believed that she used a ventilator full-time. Saldana is currently in the process of appealing their decision, but knows she is fighting an uphill battle.
Kate Saldana, who suffers from Type 2 SMA, has been fighting unsuccessfully for Medicaid to cover Spinraza.
(Courtesy of Saldana)
"Originally, the treatments were studied and created for infants and children," Saldana said in an e-mail. "There is a plethora of data to support the effectiveness of Spinraza in those groups, but in adults it has not been studied as much. That makes it more difficult for insurance to approve it, because they are not sure if it will be as beneficial."
Saldana has been pursuing treatment unsuccessfully since last August – but others, like Kimberly Hill, a 32-year-old with SMA Type 2, have been waiting even longer. Hill, who lives in Oklahoma, has been fighting for treatment since Spinraza went on the U.S. market in December 2016. Because her mobility is limited to the use of her left thumb, Hill is eager to try anything that will enable her to keep working and finish a Master's degree in Fire and Emergency Management.
"Obviously, my family and I were elated with the approval of Spinraza," Hill said in an e-mail. "We thought I would finally have the chance to get a little stronger and healthier." But with Medicare and Medicaid, coverage and eligibility varies wildly by state. Earlier this year, Medicaid approved Spinraza for adult patients only if a clawback clause was attached to the approval, meaning that under certain conditions the Medicaid funds would need to be paid back. Because of the clawback clause, hospitals have been reluctant to take on Spinraza treatments, effectively barring adult Medicaid patients from accessing the drug altogether.
Hill's hospital is currently in negotiations with Medicaid to move forward with Spinraza treatment, but in the meantime, Hill is in limbo. "We keep being told there is nothing we can do, and we are devastated," Hill said.
"I felt extremely sad and honestly a bit forgotten, like adults [with SMA] don't matter."
Between Spinraza and its new competitor, Zolgensma, some are speculating that insurers will start to favor Zolgensma coverage instead, since the treatment is shorter and ultimately cheaper than Spinraza in the long term. But for some adults with SMA who can't access Spinraza and who don't qualify for Zolgensma treatment, the issue of what insurers will cover is moot.
"I was so excited when I heard that Zolgensma was approved by the FDA," said Annie Wilson, an adult SMA patient from Alameda, Calif. who has been fighting for Spinraza since 2017. "When I became aware that it was only being offered to children, I felt extremely sad and honestly a bit forgotten, like adults [with SMA] don't matter."
According to information from a Biogen representative, more than 7500 people worldwide have been treated with Spinraza to date, one third of whom are adults.
While Spinraza has been revolutionary for thousands of patients, it's unclear how many more lives state agencies and insurance companies will allow it to save.
A new book by Pulitzer-winning physician-scientist Siddhartha Mukherjee will be released from Simon & Schuster on October 25, 2022.
The Song of the Cell begins with the discovery of cells and of germ theory, featuring characters such as Louis Pasteur and Robert Koch, who brought the cell “into intimate contact with pathology and medicine.” This intercourse would transform biomedicine, leading to the insight that we can treat disease by thinking at the cellular level. The slightest rearrangement of sick cells might be the path toward alleviating suffering for the organism: eroding the cell walls of a bacterium while sparing our human cells; inventing a medium that coaxes sperm and egg to dance into cellular union for in vitro fertilization (IVF); designing molecular missiles that home to the receptors decorating the exterior of cancer cells; teaching adult skin cells to remember their embryonic state for regenerative medicines.
Mukherjee uses the bulk of the book to elucidate key cell types in the human body, along with their “connective relationships” that enable key organs and organ systems to function. This includes the immune system, the heart, the brain, and so on. Mukherjee’s distinctive style features compelling anecdotes and human stories that animate the scientific (and unscientific) processes that have led to our current state of understanding. In his chapter on neurons and the brain, for example, he integrates Santiago Ramon y Cajal’s meticulous black ink sketches of neurons into Mukherjee’s own personal encounter with clinical depression. In one lucid section, he interviews Dr. Helen Mayberg, a pioneering neurologist who takes seriously the descriptive power of her patients’ metaphors, as they suffer from “caves,” “holes,” “voids,” and “force fields” that render their lives gray. Dr. Mayberg aims to stimulate patients’ neuronal cells in a manner that brings back the color.
Beyond exposing the insight and inventiveness that has arisen out of cell-based thinking, it seems that Mukherjee’s bigger project is an epistemological one. The early chapters of The Song of the Cell continually hint at the potential for redefining the basic unit of biology as the cell rather than the gene. The choice to center biomedicine around cells is, above all, a conspicuous choice not to center it around genes (the subject of Mukherjee’s previous book, The Gene), because genes dominate popular science communication.
This choice of cells over genes is most welcome. Cells are alive. Genes are not. Letters—such as the As, Cs, Gs, and Ts that represent the nucleotides of DNA, which make up our genes—must be synthesized into a word or poem or song that offers a glimpse into deeper truths. A key idea embedded in this thinking is that of emergence. Whether in ancient myth or modern art, creation tends to be an emergent process, not a linearly coded script. The cell is our current best guess for the basic unit of life’s emergence, turning a finite set of chemical building blocks—nucleic acids, proteins, sugars, fats—into a replicative, evolving system for fighting stasis and entropy. The cell’s song is one for our times, for it is the song of biology’s emergence out of chemistry and physics, into the “frenetically active process” of homeostasis.
Re-centering our view of biology has practical consequences, too, for how we think about diagnosing and treating disease, and for inventing new medicines. Centering cells presents a challenge: which type of cell to place at the center? Rather than default to the apparent simplicity of DNA as a symbol because it represents the one master code for life, the tension in defining the diversity of cells—a mapping process still far from complete in cutting-edge biology laboratories—can help to create a more thoughtful library of cellular metaphors to shape both the practice and communication of biology.
Further, effective problem solving is often about operating at the right level, or the right scale. The cell feels like appropriate level at which to interrogate many of the diseases that ail us, because the senses that guide our own perceptions of sickness and health—the smoldering pain of inflammation, the tunnel vision of a migraine, the dizziness of a fluttering heart—are emergent.
This, unfortunately, is sort of where Mukherjee leaves the reader, under-exploring the consequences of a biology of emergence. Many practical and profound questions have to do with the ways that each scale of life feeds back on the others. In a tome on Cells and “the future human” I wished that Mukherjee had created more space for seeking the ways that cells will shape and be shaped by the future, of humanity and otherwise.
We are entering a phase of real-world bioengineering that features the modularization of cellular parts within cells, of cells within organs, of organs within bodies, and of bodies within ecosystems. In this reality, we would be unwise to assume that any whole is the mere sum of its parts.
For example, when discussing the regenerative power of pluripotent stem cells, Mukherjee raises the philosophical thought experiment of the Delphic boat, also known as the Ship of Theseus. The boat is made of many pieces of wood, each of which is replaced for repairs over the years, with the boat’s structure unchanged. Eventually none of the boat’s original wood remains: Is it the same boat?
Mukherjee raises the Delphic boat in one paragraph at the end of the chapter on stem cells, as a metaphor related to the possibility of stem cell-enabled regeneration in perpetuity. He does not follow any of the threads of potential answers. Given the current state of cellular engineering, about which Mukherjee is a world expert from his work as a physician-scientist, this book could have used an entire section dedicated to probing this question and, importantly, the ways this thought experiment falls apart.
We are entering a phase of real-world bioengineering that features the modularization of cellular parts within cells, of cells within organs, of organs within bodies, and of bodies within ecosystems. In this reality, we would be unwise to assume that any whole is the mere sum of its parts. Wholeness at any one of these scales of life—organelle, cell, organ, body, ecosystem—is what is at stake if we allow biological reductionism to assume away the relation between those scales.
In other words, Mukherjee succeeds in providing a masterful and compelling narrative of the lives of many of the cells that emerge to enliven us. Like his previous books, it is a worthwhile read for anyone curious about the role of cells in disease and in health. And yet, he fails to offer the broader context of The Song of the Cell.
As leading agronomist and essayist Wes Jackson has written, “The sequence of amino acids that is at home in the human cell, when produced inside the bacterial cell, does not fold quite right. Something about the E. coli internal environment affects the tertiary structure of the protein and makes it inactive. The whole in this case, the E. coli cell, affects the part—the newly made protein. Where is the priority of part now?” [1]
Beyond the ways that different kingdoms of life translate the same genetic code, the practical situation for humanity today relates to the ways that the different disciplines of modern life use values and culture to influence our genes, cells, bodies, and environment. It may be that humans will soon become a bit like the Delphic boat, infused with the buzz of fresh cells to repopulate different niches within our bodies, for healthier, longer lives. But in biology, as in writing, a mixed metaphor can cause something of a cacophony. For we are not boats with parts to be replaced piecemeal. And nor are whales, nor alpine forests, nor topsoil. Life isn’t a sum of parts, and neither is a song that rings true.
[1] Wes Jackson, "Visions and Assumptions," in Nature as Measure (p. 52-53).