"It's the only thing so far that really slows this disease down without adverse side effects," Allan J. Tobin, a UCLA professor emeritus of physiological science and neurology, said about the new drug. "The amazing thing about this emerging story, however, is that it started from basic research on the brain." Tobin, whose laboratory conducted critical neuroscience research in the late 1980s and 1990s, is a member and former director of UCLA's Brain Research Institute.
Type 1 diabetes -- also known as insulin-dependent diabetes or juvenile diabetes (because it usually begins in childhood or adolescence) -- afflicts more than 1 million Americans. It is characterized by a failure of the body to produce insulin because the immune system attacks and destroys the body's insulin-producing cells of the pancreas.
On Sunday, Sept. 17, at a meeting in Copenhagen of the European Association for the Study of Diabetes, Johnny Ludvigsson -- pediatrics professor at Sweden's University Hospital, Linköping University -- will present results from the phase II study conducted in eight hospitals in Sweden in collaboration with Diamyd Medical (www.diamyd.com), a life science company located in Stockholm, Sweden.
This fundamental discovery that influenced thinking about diabetes was made in the Life Sciences Division of UCLA's College of Letters and Science, said Arthur P. Arnold, UCLA professor and chair of physiological science.
"The broad insight of a basic neuroscience team eventually bore fruit in the fight against this disease," Arnold said. In the 1980s, using newly developed recombinant DNA techniques, Tobin's laboratory was studying genes involved in brain development and function. Tobin's team included graduate student Daniel Kaufman, now a UCLA professor in the department of molecular and medical pharmacology, and graduate student Mark Erlander, now executive vice president and chief scientific officer of AviaraDx, a biotechnology company in Carlsbad, Calif.
Together, Kaufman and Erlander were the first to isolate the genes encoding GAD (glutamic acid decarboxylase) which is an important enzyme because it synthesizes one of the main neurotransmitters for communication between neurons. Tobin's laboratory used these tools to study neuronal development in the brain. What no one knew at that time was that GAD was also made in the cells that made insulin in the pancreas -- cells that use the chemical transmitter made by GAD to communicate with other pancreas cells to help control glucose levels in the blood.
A year later, Kaufman's car fortuitously broke down while he was a postdoctoral scholar at the Salk Institute in San Diego, Calif. Forced to wait, he went to the library and stumbled on a report in a medical journal showing a connection between autoimmunity to an unknown protein in insulin-producing cells and diabetes. Kaufman surmised that this unknown protein was in fact GAD, the protein he had studied in Tobin's lab.
To study the possible connection between GAD and diabetes, Kaufman again worked with Tobin and Erlander, using the research tools they had developed to test whether autoantibodies against GAD could be found in frozen blood samples taken from individuals before they developed type 1 diabetes. They found that they could detect autoantibodies against GAD years before the symptoms of diabetes appeared.
In type 1 diabetes, the immune system destroys the insulin-producing cells slowly, over as many as seven years before any symptoms appear, Tobin said. "These tools allowed us to detect the early appearance of an autoimmune reaction more than five years before the onset of diabetes," Tobin said.
Many laboratories throughout the world are now using recombinant GAD to determine whether individuals have autoantibodies to GAD and are likely to develop diabetes. This pre-diagnostic test will be invaluable for preventing diabetes -- but first, there must be a therapeutic to slow the progression of the disease.
In his own laboratory at UCLA, Kaufman, along with UCLA's Jide Tian, Michael Clare-Salzler, Eli Sercarz, Paul Lehmann and Tobin, searched for ways to "tolerize" the immune system of diabetes-prone mice to the GAD protein before the autoimmune attack began. The team reported in the journal Nature in 1993 that when young, diabetes-prone mice were treated with a small amount of the GAD protein, their immune systems learned to tolerate the protein. The autoimmune response that leads to type 1 diabetes never developed in these mice as they grew older.
Next, Kaufman and Tian developed the GAD vaccine that was able to inhibit the autoimmune response after it had already begun to attack the insulin producing cells. Kaufman and Tian showed in a study they published in Nature-Medicine in 1996 that, even after the type 1 diabetes disease process had started in diabetes-prone mice, its progression could be inhibited by the GAD vaccine.
The GAD vaccine activated T-cells that recognized GAD, Kaufman and Tian reported. "The T-cells traveled to the pancreas and, recognizing the GAD protein in the insulin-producing cells there, released calming substances called 'anti-inflammatory' cytokines, which suppressed the immune cells that were killing the insulin-producing cells," Tian explained.
UCLA licensed the technology to Diamyd Medical for clinical development. Tobin and Kaufman both serve on the scientific advisory board of Diamyd.
Based on the success of the GAD vaccine to prevent diabetes in mice, Diamyd Medical conducted a phase II clinical trial by treating adults who recently had been diagnosed with diabetes. The results showed that treatment with the GAD vaccine could preserve some insulin production for at least two years after the onset of the disease in adults.
Given these promising results, Diamyd next conducted a larger double-blind clinical trial of the GAD vaccine in 70 children and adolescents who were newly diagnosed with diabetes. After treating new diabetics with the GAD vaccine, or a placebo, the patients were followed for 15 months, without the clinicians knowing which treatment the patients had received. This month Diamyd Medical broke the code and announced that the GAD vaccine demonstrated statistically significant efficacy in preserving insulin production and that no serious adverse events associated with the therapy were observed.
Tobin and Kaufman are optimistic about the drug, which is called Diamyd, but both said it is likely to be at least a few years before a drug for type 1 diabetes is available.
"If the result holds up in a phase III trial, it's going to make a big difference," Tobin said. "It feels terrific."
"It's tremendously gratifying to see our work go from the lab to a clinical application, with the potential to help so many people," Kaufman said. "The data are very strong, and are convincing even to scientists who were initially skeptical. The vaccine is highly targeted; it activates only the immune cells that recognize GAD, which then suppresses the immune cells that are attacking the insulin-producing cells. Most of us who go into science hope our research will advance medical treatment and improve human lives; it's great news."
He added, "Such long-term preservation of insulin production after the onset of diabetes is quite remarkable. Preserving insulin-production is crucial for delaying the complications associated with long-term diabetes, such as kidney and heart disease, and neuropathy. Now that the vaccine has shown efficacy in preserving insulin production after disease onset, we are anxious to see whether the vaccine can also prevent the development of type 1 diabetes."
The children who are likely to develop type 1 diabetes can be identified by screening for autoantibodies to GAD in their blood, Kaufman said. Tobin, 64, is currently managing director of MRSSI, which advises two nonprofit organizations, the High Q Foundation and CHDI, both dedicated to finding therapies for Huntington's disease. From 1975 to 2003, he was on the faculty of UCLA, where he taught introductory biology and neuroscience. He is the coauthor of "Asking About Life," a prize-winning biology textbook whose premise is that questions are more important than answers.
Tobin's research was funded by the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health. Kaufman's research is funded by the National Institute of Diabetes & Digestive & Kidney Diseases, also part of part of the National Institutes of Health.
Tobin recalls bringing the excitement of his research into the UCLA classes he taught.
"When I taught the introductory biology course, I said here's the standard stuff about the immune system, but let me tell you about something that just happened in my lab," Tobin recalled. "There's a thrill of discovery, and also a sense that there remain challenges ahead; science isn't just learning a set of facts but learning how to approach and formulate scientific problems. That engagement really serves undergraduates at UCLA very differently from undergraduates at non-research colleges."
As is often true in science, solutions to important problems come from unexpected places, and basic research provides the foundation for future applications.
"Type 1 diabetes never occurred to me," Tobin said. "I was interested in how cells in the brain signal one another. We were trying to understand how some cells in the brain told other cells to slow down or stop.
"One of the great things about UCLA's College of Letters and Science is that scientists working on basic questions talk with one another and with medical school scientists. At first it wasn't obvious that inhibitory signaling in the brain and in the pancreas uses the same molecules, but they do. The diabetes diagnostic and therapeutic came out of basic research in an unpredictable way."
Stuart Wolpert | EurekAlert!
Investigators may unlock mystery of how staph cells dodge the body's immune system
22.09.2017 | Cedars-Sinai Medical Center
Monitoring the heart's mitochondria to predict cardiac arrest?
21.09.2017 | Boston Children's Hospital
Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.
A warming planet
Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.
The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...
Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...
Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!
When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...
For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.
Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...
19.09.2017 | Event News
12.09.2017 | Event News
06.09.2017 | Event News
22.09.2017 | Medical Engineering
22.09.2017 | Physics and Astronomy
22.09.2017 | Physics and Astronomy