A Whirlwind Tour: TEDxDelMar on a Type 1 Diabetes Cure, Part 1

I admit I’m not impartial, but I am a tough critic, especially of things I like and feel invested in. Let that serve as a background as I state: TEDxDelMar was an incredible set of talks, and a phenomenal overview of decades of fascinating research in type 1 diabetes. I emphatically encourage you to watch the videos when they are available — all of them.

Knowing, though, that few people have that many minutes to spare, I urge you to watch at least some of the videos, ideally at least one from each topical section. Each talk was an individual’s life work, summarized in eighteen minutes. What you’ll find below, then, are summaries of summaries, details from the twenty-eight pages of notes I took—so find the ones you’re interested in, watch the video, and, if you’re feeling really adventurous, track down the speaker and ask for more.

The Immune Pathology of Diabetes

Jeff Bluestone: The Immunologist’s View

Dr. Jeff Bluestone  is an immunologist and molecular biologist at the University of California, San Francisco, and does some of the leading research in T-cell activation and development.

Dr. Bluestone’s talk was everything we know about what goes wrong in the immune system during the development of type 1 diabetes, compressed into eighteen minutes. Some highlights:

The primary lesson: “The immune system is effectively a body at war.” In other words, the immune system is made up of T-cells, B-cells, white blood cells, and so on that are responsible for defending against pathogens, surveying for cancerous cells, and repairing damaged tissue.

The problem with this system? There is a set of related diseases—autoimmune diseases—that have a common cause: the immune system gets “so keyed up” that it starts attacking the body’s own cells.

In type 1 diabetes, this attack happens when the immune system begins to recognize proteins that beta cells are presenting.

But why does this happen? There are three components:

• An immunological component: the thymus is an organ responsible for sorting immune cells, and “negatively selecting,” or destroying, those that are self-reactive. In autoimmunity, this process is defective in some way, and self-reactive T-cells escape into circulation.
• A genetic component: the underlying cause of the immunological defect is still unclear, but it can be tied to the genetic component of type 1 diabetes. Genetics only account for a fraction of the chance of any individual developing diabetes, but still there are a few mutations that have been tied to type 1 diabetes. The most prominent of these are genetic variations in the HLA locus, which codes for the set of proteins responsible for recognizing foreign antigens in our bodies. If something in the coding of the HLA is wrong, this might lead to cells that are able to recognize and attack not just pathogens, but self-peptides as well.
• An environmental component: even among identical twins, if one twin has diabetes, the chance of the other developing diabetes is only about 30%, This implies that genetics do not tell the whole story, and that environmental conditions have a role to play. This environmental component is key, too, to the growing prevalence of type 1 diabetes worldwide, and has scientists looking to all sorts of things—hygiene, viruses, diet, vitamin D—for clues as to what predisposes a person towards diabetes.

The good news is, even with all these open questions, there are clues and pathways that we can begin to modify to try to develop treatments and to restore what is crucially lacking in autoimmunity: “It’s all about balance, Immune balance.”

Matthias Von Herrath: Attack of the Beta Cells—the Movie

Dr. Matthias Von Herrath is an immunologist at the La Jolla Institute for Allergy and Immunology. He focuses on finding ways to treat type 1 diabetes by restoring the regulation of T-cells to its natural state.

Following Dr. Bluestone’s talk on what leads to diabetes, Dr. Von Herrath gave an overview of what actually happens in the pancreas as the disease develops:

• The first key point to understand is that diabetes is “a complicated disease—more complicated than any of us anticipated.” This is due to a number of factors, not the least of which is the awkward position of the human pancreas: “It is an angry organ,” Von Herrath joked, located in the retroperitoneal—that is way deep in the abdomen, behind everything else.
• As diabetes develops, CD8 T-cells “become misdirected—now they recognize beta cells.”
• Von Herrath proceeded to show live microscopy imaging of this recognition and attack. In this “movie” of the attack on beta cells, Von Herrath pointed out how the T-cells behave similarly to ants—they first send out a few scouts, then establish streets, then send swarms of T-cells that stick to the same routes, enveloping the beta cells.
• “But the pancreas is big, and there are many islets,” Von Herrath noted. And in fact he had calculated that at the rate the T-cells were moving in the images, it would take the effect of 250 attacking cells for about one half hour to kill one beta cell. At that rate, it would take about 4.5 years to kill off all the beta cells in the pancreas, which is approximately what is seen in the clinic.
• This time delay, notably, gives us hope for treatment—that’s 4.5 years we have to stop the attack on the beta cells, even after it has begun.
• How can we do so? The trick is that we need to suppress these attacking cells without damaging the rest of the immune system, which is doing important defensive work. In other words, we need to find effective treatments with minimal side effects.
• For this, Von Herrath turns to combination therapies—different drugs, working together to reeducate the immune system locally. Von Herrath describes the required cocktail: something to reduce the number of attacking cells, something to suppress inflammation, something to normalize the auto-antigens, and something to regenerate the beta cells.
• Developing these combination therapies, though, is no easy task, and will require the cooperation of academics, funding agencies, and industry—but it can be done!

Richard Insel: Is There a Vaccine for Diabetes?

Dr. Richard Insel is the Chief Scientific Officer of JDRF, and that impressive title only scratches the surface of an incredible career in the field of immunology and vaccination. Seriously, read his bio, and consider that he’s also a really nice guy.

Dr. Von Herrath spoke about combination therapies, and one component—normalizing auto-antigens—is what many are now looking to as a vaccine for type 1 diabetes. Dr. Insel spoke about how these vaccines would work, and what the JDRF is doing to develop them:

Insel began by highlighting the role vaccines have played in our history; some of the greatest medical advances have been in vaccines, as we are close to eradicating smallpox, polio, whooping cough, measles, and a number of other formerly devastating diseases.
The success of vaccines, Insel feels, is not over yet: “I predict in the 21st century we will see vaccines that prevent autoimmune diseases in general and type 1 diabetes specifically.”
The first questions to address, though—why do we need a vaccine?

• A recurring theme in many of the talks: type 1 diabetes is becoming more and more prevalent every year, especially in children under the age of five.
• Further, the onset of the disease, from the development of autoimmunity to insulin dependence, is getting shorter and shorter.
• Rather than let this continue, we have the chance to develop a vaccine that could stop the progression of the disease if caught early, and potentially stop the destruction of the beta cells even after onset.
• Further, as part of a combination therapy, vaccines could be an essential component of a cure for those already with type 1 diabetes.

The goal, then, is to prevent the development of the disease, vaccinating definitely those with familial risk, but also eventually every child, so that we can eradicate this disease.

But how would a vaccine work?

• During the development of autoimmunity, there is a dysregulation of the immune system, in which we see an imbalance of regulatory T-cell activity and effector T-cell activity.
• In order to address this, Insel proposes we have rationally designed vaccines for the auto-antigens that we know play a role in the development of the disease. These auto-antigens, or proteins from our own bodies that the immune cells begin to recognize, could be inoculated against, such that the body no longer views them as foreign invaders.
• These vaccines are being administered to induce tolerance through pathways we know typically induce tolerance to foods and other environmental agents: the mouth, the nose, and the blood stream.
• These vaccines, further, fit the profile Von Herrath mentioned—by focusing on the auto-antigens specific to the attack on beta cells, we don’t risk suppressing too much of the immune system.
• Notably, such vaccines would be “platform technologies”—that is, once we find a strategy that works, the same principles could be applied for other autoimmune disorders that have specific auto-antigens to address.

So where do we stand with the development of these vaccines? Insel had quite a few examples of promising technologies in various stages of tests and trials:

• Some are soluble: DNA plasmids that are introduced into the body to force the expression of auto-antigens that would then induce the body to get used to the antigen in question; beta cell auto-antigens that have been found in lettuce leaves; and peptide-based vaccines, similar to those being developed for allergies.
• Some are particles: a combination of beta cell auto-antigens and immune-modifying agents to give a double-whammy; and nanoparticle-based approaches.
• And my favorite: Steve Miller at Northwestern University is working on isolating proteins from cells that are made to die in vitro, on a cell plate in the lab, and combining those with the known auto-antigens in type 1 diabetes, to create a vaccine that looks very similar to what the T-cells would actually be encountering in the pancreas—the refuse of dying beta cells.

Living With Diabetes

Steve Edelman: Xtreme Diabetes Makeover

Dr. Steve Edelman is an endocrinologist extraordinaire, and the founder of Taking Control of Your Diabetes, an organization devoted to helping diabetics manage and thrive with diabetes.  He presented a history of his life with diabetes, and how he came to feel that patient education and ownership were key to happy and healthful living with diabetes:

Dr. Edelman was diagnosed with type 1 diabetes as a teenager, and recalled being reprimanded by teachers for taking too many trips to the bathroom, and yelled at by classmates in line behind him at the drinking fountain.

When he was diagnosed, the only available patient education was a class in which he was one skinny kid with type 1 diabetes, surrounded by 49 adults with type 2 diabetes. All he remembered from the class? Ketchup has lots of sugar in it. Not exactly the most useful piece of diabetic advice.

At the time, the only available home testing was urine strips, which were woefully inadequate. Whenever he went in to see the doctor, he took a urine test and a blood test, but regardless of the results, his doctor always gave him the same useless feedback: “Steve, you’re doing fine; I’ll see you next time.” To test his doctor, Edelman once ate five donuts on the way to the clinic. His urine strip turned dark, indicating a high blood sugar, and the blood test confirmed it. Still, his doctor said exactly the same thing—“Steve, you’re doing fine; I’ll see you next time.”

Since then, Edelman has been working to fight this common paradigm of the unknowing patient and the unconcerned doctor: “There has to be a better way to promote education. One size does not fit all.”

In 1995, Edelman started TCOYD in the hopes of changing the status quo. The first conference brought together diabetics from all walks of life, and many saw for the first time that they were not alone, and further that diabetes crosses all socioeconomic boundaries.

With modern technology, “we really have the tools now to keep people healthy until the cure comes.” Yet, statistics show, this isn’t happening. Why not? “You can have the best researchers in the world, the best therapies, but if you don’t have diabetes on your priority list, it’s not going to matter.”

Edelman sees a number of big barriers that keep us all from optimal diabetes management:

• The way we administer hormones (insulin, amylin, and the like) is not physiological, and so we are fighting a time delay and absorption variability, which makes dosing much more difficult.
• Fear of hypoglycemia prevents many people from even getting near normoglycemia.
• There is not enough individualized, culturally sensitive care available.
• Healthcare providers are often uninformed about the requirements of the disease.

Edelman started the Xtreme Diabetes Makeover project to see what it would take to really change the care and practices for a set of people who were not succeeding at managing their diabetes. What Edelman found was that diabetes management is not about being smart, or wealthy, or of a certain age—“It’s about becoming activated.”

Athena Tsimikas: Surviving Your Hospital Stay

Dr. Athena Tsimikas, in addition to being a respected clinical endocrinologist for many years, is the Corporate Vice President of the Scripps Whittier Diabetes Institute in La Jolla, California. She focuses on ways to improve long-term care and outcomes for diabetics.

Dr. Tsimikas spoke about the great gaps in current standards and practices for diabetics entering hospitals like those she helps to run through the Scripps Whittier Diabetes Institute:

The increasing prevalence of diabetes does not stay at home; an increasing number of patients in hospitals have diabetes, and yet most hospitals are ill-equipped to handle this growing portion of their population

Studies show that maintaining normoglycemia during illness and during hospital stays improves the expected outcomes for patients, but the frequent standard is to let patients run extremely high. Stress, lack of exercise, new carb-rich foods, and steroids all contribute to the prevalence of hyperglycemia in diabetics during their hospital stays.

Tsimikas has tried showing the data and the studies, and has requested change—but the real connection, she learned, came with stories she has collected. She told of three patients—David, Julie, and Chris—all diabetics, all in the hospital for different reasons, and all having to fight to get even borderline care.

Rather than working with patients to figure out insulin needs and optimize care, nurses defaulted to a reactive, sliding scale of insulin dosing, failing to understand the differences between insulin types or the effect hospital food would have on glucose values.

Tsimikas identified this grave problem in standards of care, and put together a plan to address it in the network of five hospitals she worked with. She and her team recognized that for the system to work, they would need three things:

• Technology: data collection and review was insufficient. “If you don’t have data, what can you do?” Tsimikas asked. And data written once, and never read, would not cut it—the hospitals needed a system for collecting, aggregating, and analyzing data about blood glucose values and other key metrics. So, Tsimikas developed a system that created and distributed patient reports for all the necessary care personnel.
• Manpower: lots of tools with no one who knows how to use them gets us nowhere. Tsimikas saw that they needed available, local experts at each hospital—nurses who specialized in care for diabetics, who knew insulin curves backward and forward, who could estimate the carbs in an unlabeled soup.
• Education and training: in addition to the specialized nurses, the general staff needed to be brought up to speed on different types of insulin, how to dose to maintain blood glucose levels, and not just in reaction to hyperglycemia. Tsimikas and her team created guides about dosing, diabetes, and food choice. They standardized the carbohydrate counts for meals, and made sure to provide patients and nurses with the necessary nutritional information.

There are still many gaps in care, and Tsimikas is working to find ways to address them.

• There is a large need for systems for rapid, real-time data transfer and decision making on the hospital floor.
• The home-use blood glucose monitoring systems should not be the standard at hospitals, as they are not accurate enough. To this end, the hospital system has just made a million dollar investment to get clinical-grade blood glucose monitoring systems.

Nigel Calcutt: Preventing and Treating Complications

Dr. Nigel Calcutt is a professor of molecular pathology at the University of California, San Diego. His research focuses on the mechanisms and treatment of neuropathy, and he has a fabulous English accent that leads me to assume everything he says must be very learned and is certainly true.

Dr. Calcutt spoke about complications resulting from diabetes, and what he and others like him see as the path forward to better care:

Dr. Calcutt began with an analogy about humor in America—we like, he noted, stories that start out with a seemingly insurmountable problem, and end with a solution. And this talk followed that format; he began with the terrifying problems faced by many diabetics, but by the end had reached a point of hope and treatment.

Calcutt quoted from the recent Diabetes Plan put together by the National Institute of Digestive, Diabetes, and Kidney Diseases (NIDDK) for members of Congress: “Diabetes kills with neither speed nor precision, but with stealth and the slow accumulation of insults.”

These accumulated insults and complications attack four main points: blood vessels, eyes, kidneys, and nerves.

The problem, though, is that we don’t really understand how these complications come about; we know from the Diabetes Control and Complications Trial, a large study from the early nineties, that blood glucose management seems correlated with the development of complications. But what happens between blood glucose management and the development of complications on a biological level? How might the former lead to the latter?

Calcutt studies nerve disease, and notes that the “classic case is of the diabetic patient who loses sensation in his feet.” The loss of sensation or continuous pain, however, is not really an issue in the feet or in the place of pain; rather, it is a disease of the nerves.

We have identified many of the pathways that lead from glucose management to things like nerve disease, and many of these pathways seem to converge on certain biochemical elements. This is promising, as we can then approach these points of convergence looking for therapies and treatments.

There are a number of areas of potential improvement in this research that Calcutt and others are moving towards:

• Better models: diabetic rats and mice have been good starting points, but they are not the best models. A better animal model might be cats—there is an epidemic of type 2 diabetes in cats right now, and we see that some of them develop complications very similar to human neuropathy.
• Better therapies: therapy is not just limited to proteins and drugs anymore; there is a lot of progress on the cell therapy front, and we are getting better at regenerating lost tissues and cells.
• Better measurements: what we measure now in complications requires that we wait for disease development.  Are there better biomarkers, better things to measure, so that we can see disease sooner and react? One advance here is the finding that scientists can observe nerves in living humans, noninvasively, by using a microscope trained at the cornea. This allows doctors to watch nerves in patients over time, and react much sooner.
• Better patients: here Calcutt is not referring to better behaved patients, but rather to the fact that we spend a lot of time trying to figure out what went wrong in patients with neuropathy, but the other side of that coin has lots to teach as us well: what protects patients who don’t develop complications?

All these things lead to a better understanding of the pathogenesis of the disease, earlier diagnosis, and ultimately more effective therapies. And in that, there is hope. Here Calcutt quotes Nelson Mandela: “It always seems impossible until it’s done.”

Bill Polonsky: Psyching Out Diabetes

Dr. Bill Polonsky stands out from the other speakers in that he is a psychologist, and as such is focused on the emotional and psychological impact of diabetes. Through his work at the Behavioral Diabetes Institute, he has been foundational in establishing an awareness of the mental burden of diabetes, and how it can be treated.

Dr. Polonsky approached the question of the psychological cost of diabetes from the starting point Dr. Edelman set up—why are so few patients reaching metabolic goals? What is holding us back?

Statistics from studies conducted in Wisconsin and Sweden show that only around 20% of diabetics are meeting a stated HbA1c goal of less than 7%.

What’s the problem here? For one, diabetes is “a disease that takes a tremendous amount of people’s own efforts, in their own homes.”

The problem, then, is not one of motivation—“Almost nobody is unmotivated to live a long and healthy life”—the problem is that diabetes care is, simply put, tough. “The day you develop type 1 diabetes, the universe has handed you a new job.”

Polonsky set out to address these issues many years ago, and to help diabetics handle the emotional weight of the disease, but, Polonsky lamented, “Our success has been middling.”

More recently, Polonsky and his team have taken a new approach—rather than trying to find out what people are doing wrong, he, like Dr. Calcutt, has started observing what successful patients are doing right.

• A subset of patients maintains their HbA1cs without too many hypoglycemic events, and stays engaged without getting overwhelmed.
• What are they doing, Polonsky asked, and how can we bottle this?

Polonsky found three main areas where successful patients were different:

• Biology: the “difficulty” of diabetes varies from person to person. This may be an issue of genetics, surviving beta cells, or other unknown components.
• Personality: diabetics who manage well tend to be very conscientious, and to set up systems for themselves. Many have the mindset of an engineer, Polonsky found.
• Psychology: for many people, there is a point where something just “clicks” in their diabetes management, and things begin to fit into life and to make sense. This clicking is different for different people, but seems to be a common feeling.

Since biology and personality are hard to change, Polonsky focused on the psychological component—what makes diabetes click for people? He found three common ingredients that lead to a fruitful psychological relationships with diabetes:

• “Evidence-based hope”: People who live well with diabetes recognize that it doesn’t have to be a death sentence or a life filled with complications; it can be managed, and life as a diabetic can be full and happy. Polonsky points to the statistics here—for example, in the DCCT study from the nineties, only 1% of diabetics followed ended up with severe vision loss.
• Checkered thinking: “Our ability to imitate the pancreas is limited,” Polonsky notes, and those who recognize this and adjust accordingly manage better. Diabetes, in other words, isn’t all good—numbers perfect with no excursions—or all bad—full of failure—but is sometimes good and sometimes bad. Checkered.
• Community: successful diabetics don’t do diabetes alone. They find one or more people—a spouse, a friend, a counselor—who helps carry some of the burden and stress of disease management.

Polonsky’s lesson, in the end? This disease is manageable, not just physically, but emotionally, which is equally, if not more, important.

And here, friends, we break for lunch—or, in this recap, we break until tomorrow, when we will cover the talks on beta cell replacement and diabetes technology. (click here to continue)

Karmel Allison is ASweetLife’s science editor and a regular contributor.  She writes the blog Where is My Robot Pancreas?

Karmel Allison

Karmel was born in Southern California, diagnosed with Type 1 Diabetes at the age of nine, and educated at UC Berkeley. Karmel now lives in San Diego with her husband, where she is loving the sunshine, working in computational biology at the University of California, San Diego, and learning to use the active voice when talking about her diabetes.

Karmel Allison

Karmel was born in Southern California, diagnosed with Type 1 Diabetes at the age of nine, and educated at UC Berkeley. Karmel now lives in San Diego with her husband, where she is loving the sunshine, working in computational biology at the University of California, San Diego, and learning to use the active voice when talking about her diabetes.