For over a quarter of a century, islet replacement therapy has held the promise of insulin independence for people with type 1 diabetes. Historically, the barriers to expanding this treatment have been organ scarcity and the need for lifelong immunosuppression. But the promise of manufactured islets, along with innovations in immune evasion, is transforming what’s possible.
What’s needed for these innovations to make islet replacement therapy the standard of care for T1D?
Contributing writer Abby Scholer explores this question through the ISLET Framework, addressing the most critical challenges keeping islet replacement therapy out of the clinic and how we might overcome them.
The human experience is filled with tales of such strong hope and desire, such fierce yearning, that a person risks their life to get what they want. It is the oldest story, the plot of every dark fairy tale.
There is not much about type 1 diabetes that is a fairy tale. But even a quick scroll through the comments section of any post about insulin independence reveals that, given the chance to risk their current life for something better, many people with the disease would take it.
In type 1 diabetes, the immune system kills off cells that are essential for survival. To make up for the loss of those cells, people must take insulin injections and monitor their blood sugar using the human brain — which is assuredly not made for a state of constant alertness and NASA-level math — and all of their time and energy.
Many people with type 1 diabetes (T1D) would do nearly anything to have their brain, and all of their time and energy, back. Historically, this has not really been an option.
The only way to get these cells back and live a semi-normal life has been through islet replacement therapy: cell transplantation from a deceased donor. No insulin-producing cells? Sounds like it could be solved by just … getting some insulin-producing cells and transplanting them into people who need them. Unfortunately, it is not so simple. The reason why is twofold: scarcity and safety.
Scarcity
As with all resources relying on organ donation, cell supply is stretched thin. There would not be anywhere near enough cells to treat everyone who could benefit from islet replacement therapy.
The nature of the disease itself contributes to that scarcity. Type 1 diabetes is an autoimmune disease, a condition in which the body attacks its own cells. This is how they got killed off in the first place. And sadly, the body is no less inclined to go easy on any new insulin-producing cells it receives. Even if new ones are transplanted, the immune system will waste no time in killing them off all over again. For old times’ sake!
This is in addition to the immune system’s attack on any transplanted organs or cells. So replacement cells in any form will face the same immune environment that destroyed the originals, twofold: the autoimmune reaction specific to T1D, on top of the foreign-body rejection response triggered by any transplanted tissue.
Safety
There are many risks involved with islet replacement therapy, starting from the procedure itself. We’ll discuss all of these risks in more detail later on. But what’s important to understand up front is the most pervasive of these dangers: immunosuppressive drugs.
Remember that in islet transplantation for T1D, the immune system LIVES to kill off these replacement cells. Currently, the only way to protect them is with immunosuppressive medications. The side effects of these drugs are as harrowing and numerous as they are under-discussed. Kidney failure. Bone damage. Neurotoxicity that shows up as tremors, migraines, and brain fog. Immunosuppressants can cause high blood pressure and damage fragile vessels and organs; they increase your risk of developing cancer. Not to mention potential psychosocial side effects such as weight gain, hair loss, extreme hair overgrowth in areas such as the face, insomnia, and depression. Even more, immunosuppressants are toxic to islets, the very thing you’re trying to protect.
Why Now?
Islet replacement therapy has existed as a treatment option for type 1 diabetes for over a quarter of a century. Yet fewer than 1,500 people in the United States have received the treatment (for context, there are almost 2 million people in the US with type 1 diabetes). Even if people with T1D were willing to enter the realm of the dark fairy tale and risk their lives for the possibility of a better one, scarcity and safety issues prevented us from even having that option.
But the innovations of the past eighteen months have created a paradigm shift that has led to the field growing up, and fast. Even the federal government has caught on: over the past few weeks, for the first time, the FDA released guidelines for cell therapy manufacturers on what’s needed to get their products to approval and, eventually, to people who need them. They followed the release of these guidelines with a livestream that was attended by thousands in the middle of the day, even while being recorded and posted later.
With stem cell manufacturing and novel methods of outsmarting the immune system being tested, scarcity and safety are becoming less and less of a concern — just enough to create the possibility of islet replacement therapy becoming mainstream. So what’s really keeping it from doing so?
The State of Islet Replacement Therapy: In the Valley of the Shadow of Death?
The Chasm
In 1991, Geoffrey Moore observed that every transformative technology must move through the same maturity curve. When a technology first becomes available, its use is confined to a small group of innovators and early adopters. Before it can become more widely used or even mainstream, it must cross the chasm. The chasm represents a technology’s core usability and safety issues: things that make it too complicated, inefficient, or dangerous to actually be an improvement over the old way of doing things.
Consider the example of buying things online. E-commerce and the early consumer-facing internet, more generally, had a gaping chasm: information security. Up until the early 2000s, putting your credit card into a website was, in fact, a terrible idea. Credit card numbers, passwords, ID numbers, and potentially radioactive personal data crossed the open internet free as a bird, scoopable by any midgrade hacker. Sensitive data sat around unencrypted and indefinitely on unsecured servers, ripe for pillaging at bad actors’ convenience.
Like islet replacement therapy, e-commerce’s chasm was a safety-related one. Fortunately for you and the rest of us online today, this chasm was eventually crossed. What did it was the invention of the Secure Sockets Layer, or the “S” in HTTPS. The TL;DR of this technology: it was a protocol that encrypts the connection between your browser and a website, guaranteeing privacy (info you send is scrambled into uselessness so it can’t be intercepted) and authenticity (you can be sure you’re actually on your bank’s website, not a convincing copy of your bank’s website).
Crucial to the chasm thesis is that this innovation didn’t just make individual websites better. It improved every consumer-facing commercial interaction online. The S factor was horizontal, a foundational layer upon which all further innovations could be built: advancements in payments, user experience, and even shipping infrastructure that have transformed how we live today.
The chasm is where innovations either die or spend several years improving before taking off. Islet replacement therapy is not unique; every life-altering innovation has to reckon with its own valley of death. Crossing the chasm does not only unlock access to the new technology — it kicks off a domino effect for other innovations waiting to be built around it, an ecosystem that nourishes the new way of doing things that is better than anyone could have initially imagined.
Crossing the Chasm for Islet Replacement Therapy
Islet replacement therapy is an idea whose time has come; and now, too, the time must come for it to move beyond an idea. This requires addressing the major challenges at the depths of its chasm. Specifically, those of immune evasion, scalability, location of the islet graft, efficacy, and time’s impact on transplanted islets. Think of these five as the ISLET framework: the dimensions that have to come together for islet replacement therapy to reach the mainstream.
The Islet Framework
I — Immune Evasion
How do you protect islets from the immune system without endangering the islet recipient?
Like any fairy tale villain, the immune system drives a hard bargain. Currently, islet replacement requires dangerous immunosuppressive drugs. This is essential to prevent recurrent autoimmunity as well as the foreign-body immune rejection response accompanying any transplanted tissue. Remember that these medications suppress the immune system at the risk of death from infection, cancer, severe kidney damage, bone damage, neurotoxicity, and more. On top of these side effects, people taking immunosuppressants must live cautiously to avoid infections. Even a common cold could prove deadly.
There are multiple approaches in the works to solve this issue, from developing less toxic immunosuppressive drugs to gene-editing cells to make them invisible to potential immune attacks. It remains to be seen which, if any, will be effective, let alone their long-term effects. But there is more reason to hope for a safe solution than ever before.
S — Scalability
How can we source enough cells to meet demand for the therapy?
Beyond the core issue of immune evasion, the first barrier that islet replacement therapy faces is cell source at scale, or scalability.
Broadly speaking, there are two sources of islets: deceased donors and lab-grown cells. The deceased-donor supply will never meet population-level demand; there will always be fewer deceased-donor cells available than people who need them.
The alternative is lab-grown cells: stem cell-derived islets (SC-islets). This is the only path to a widely accessible solution. The science to create these cells has been in place in some cases for decades. But manufacturing them safely and dependably, especially in large enough quantities, is a critical challenge.
Islet manufacturing is also quite resource-intensive. My sugarscience colleagues reported that manufacturing cost was a recurring specter haunting conversations at this year’s ADA. This goes for clinical trials of cell therapies, doubly so. This cost is due in large part to the raw materials required to manufacture these products: reagents, which are quite expensive and have limited shelf lives. This is in addition to high-priced specialized facilities and expert labor.
L — Location (graft site)
Where should the cells be implanted in the body for the best outcomes?
This dimension is the location where the islet graft will be transplanted. Where in the body should islets be implanted for maximum potency, safety, and survival? Infusing islets into the liver has been the default approach for decades, but the portal-vein infusion procedure can create a hostile environment for islets due to an immediate blood-mediated inflammatory reaction (IBMIR), lack of oxygen, and mechanical stress. The liver also carries surgical risk, as the infusion itself can cause extreme bleeding or hepatic hematoma, which is highly life-threatening. The risks of this site extend beyond the initial procedure. As a graft site, the liver offers no way out: once islets are seeded into the liver, they cannot be retrieved if something goes wrong. Research is being conducted on alternative sites, such as the anterior rectus sheath, the omentum, or even the anterior chamber of the eye. This is such an active area of investigation because the field is starting to acknowledge that the liver may not be these islets’ idea of prime real estate, after all.
E — Efficacy
How can we make cell clusters that work as well as standard human islets?
While scalability is about quantity, efficacy is about cell quality: the cells’ potency and purity. As in, do the cells actually work to replace those destroyed by the immune system in type 1 diabetes? Do they secrete insulin in response to glucose? What about other vital hormones beyond insulin, such as glucagon and somatostatin (and others)? Do they do so in sufficient quantities on an acceptable timeline, reliably? And are they able to do it under the conditions of everyday life, such as if the person in whom the islets are engrafted exercises or eats dessert, in a way that mimics natural function?
The closest things we have to standards for cell potency come from a handful of recent publications. A protocol from Wu, Berggren, et al. reliably produces functional islets from eight different stem cell lines while removing off-target cells. In 2022, the Balboa group was the first to describe testing methods for characterizing how a stem cell-derived islet product compares with the benchmark of primary human islets. Critically, there is still no defined FDA guidance on this issue, making it possibly the most underserved pre-competitive space in the field.
T — Time’s Impact on the Islet Transplant
A fascinating yet troubling feature of manufactured islet replacement therapy is that there are currently no long-term outcomes to study because the field is so young. Two of its defining concerns, though, are time-based: durability and genomic stability.
Durability
How can we maximize the length of time that islets will survive and function in the body?
Durability refers to the durability of the islet transplant, or how long the graft survives. The historical record on deceased donor islet transplantation does not inspire confidence in this metric: across the roughly 1,500 transplants documented in the Edmonton and US/EU registries, only a handful of patients have maintained insulin independence beyond a decade without additional procedure(s). At the time of this writing, no modern trials yet have a five-year follow-up to determine whether stem cell-derived islets behave differently. If the long-term answer is that any graft slowly fails, whether through chronic rejection, hypoxia (lack of oxygen), or other forms of attrition we don’t understand, then durability is a substantial gap in the chasm, and the field may have to plan for retransplantation.
Genomic Stability
How can we ensure the cells’ DNA stays intact and safe at scale?
The second is genomic stability: whether a cell’s DNA stays intact as that cell is grown, edited, and divided billions of times over. Every cell division is a chance to miscopy three billion letters of DNA, and manufacturing islets at scale demands an enormous number of divisions. Worse, if one cell stumbles onto a mutation that helps it grow faster, its descendants outcompete the healthy ones, so a batch that looks pristine at the master cell bank can be dangerously abnormal by the dose that goes into a person. With more editing, more expansion, and more fine-tuning come more opportunities for a cancer-causing clone to emerge. And a hypoimmune one at that.
Many Routes Across: It Will Not Be One Cure
For years, the public conversation about a T1D cure has been organized around the question: What is the cure? Now, the paradigm shift seems to be recognizing that this complex multi-part problem will require a complex multi-part solution.
It’s becoming clear that to answer this question, as with HTTPS, we need to add an S — cureS.
As Ginger Viera put it during a recent Diabetech episode,
“There might actually be a few [‘cures’] on the menu.”
By this, she means different cell types and sources, implant sites, methods of immunosuppression, or even immune tolerance, and more.
Meaning, the key will be “figuring out which combination [of therapies] works best for this person’s body, which works best for that person’s body — based on complex details in our individual DNA, our [immunology profiles], things you and I don’t even understand. One cure is not going to be the ‘cure’ for all. There are going to be multiple ways at it.”
One example of this combination approach is cell source. Cells from different sources come with distinct advantages and faults. Broadly speaking, there are three potential sources of insulin-producing cells:
1 | Deceased donor islets: Islets derived from the pancreatic cells of deceased organ donors.
2 | Stem cell-derived islets (SC-islets): Islets grown and differentiated in a lab environment, sourced from a master cell bank or from the recipient’s own cells (autologous cells). Stem cells may also be gene-edited for immune evasion or other favorable qualities.
3 | Porcine islets (xenotransplantation): Islets from genetically engineered pigs grown and transplanted under highly engineered clinical experimental conditions.
Note: Each of these sources will be analyzed in-depth in the deep dive on Scalability.
Each option on the cell source menu comes with its own benefits and tradeoffs. Deceased-donor islets are clinically validated but variable in quality and limited in supply. Stem cell-derived islets can be produced at scale, but questions about safety and potency remain, not to mention the major manufacturing challenges. Beyond the human realm, encapsulated porcine islets sidestep the supply problem but open up an entirely new set of regulatory and immunological issues.
None of these is the cure on its own. But taken together, insights from each type could piece together a functional cure that could become a safe and accessible new standard of care.
This cocktail approach is the way to envision the next decade of islet replacement therapy for T1D. Rather than a silver bullet, the field is hard at work on a set of approaches that may one day be matched to patients based on disease stage, HLA type, autoantibody profile, residual C-peptide, age, and even lifestyle constraints. For example, the pediatric ICU nurse who can’t risk any additional exposure to human pathogens with a suppressed immune system may end up best suited to porcine islets, while a newly diagnosed teen with residual beta-cell mass may try in vivo gene editing instead.
The chasm-crossing, when it happens, will look like this: multiple cell source options, each paired with one or more immune-modulation approaches, each optimized for a different set of stability and durability risks, along with different methods and sites of engraftment, each personalized at scale.
These are the dimensions that will eventually unlock a functional cure. Not all are within the next decade, or even “five more years” away.
The realistic window for crossing the chasm is hard to define. I am the last person who will come here specifically to tell you that it is five more years. But I am willing to wager that someday, there will come a moment when a meaningful mass of people with T1D can access islet replacement therapy. The potential paths to this are the subject of the rest of this series.
In Conclusion
Islet replacement therapy for T1D is in its chasm-crossing era. The good news is that there is a constellation of teams weaving the web across. Some making cells, some making antibodies, some making manufacturing equipment, and many more doing some sort of obscure, unglamorous work that we don’t even know about, but that will certainly save us all.
These innovations will eventually connect a path to the other side of the chasm. And with it, the possibility of functional cureS, each a different route across the chasm to a land where every person with type 1 diabetes will have even a measure more control over what their life looks like.
Me personally, I’ll take the zipline.
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