Bristol, UK
Near the meeting of the rivers Frome and Avon in South West England lies the city of Bristol. Its burgeoning population belies its history of 11th century Iron Age hill forts and Roman villas. Today, its economy is based on creative media, electronics and aerospace industries. Yet, in the labs of one easily overlooked start-up, a new age in the treatment of diabetes is being born.
The U.S. Centers for Disease Control estimate that 13 percent of American adults have diabetes. And that number is growing. It can lead to devastating effects if not treated properly, and commonly involves rigorous and troublesome self-monitoring.
Most of the food you eat is broken down into sugar, also called glucose, and released in your bloodstream. It supplies the body as its main source of energy.
When your blood sugar goes up, that signals the pancreas to release insulin, which, in turn, lets the blood sugar into your body’s cells.
Diabetes occurs when the body either doesn’t make enough insulin or can’t properly use the insulin it makes. As a result, glucose remains in your bloodstream, leading to high blood sugar levels. Extended sugar levels can lead to serious long-term problems, including neuropathy, vision loss, and heart and kidney disease.
There are two types of diabetes: type 1 and type 2. People with type 1 diabetes, an autoimmune disease that destroys the insulin-producing cells in the pancreas, must take insulin either by injection multiple times a day or by an insulin pump, all day, every day for the rest of their lives. There is no cure for type 1 diabetes. Type 2 diabetes, which can sometimes be managed by healthy diet and exercise, can also require insulin injections along with some other oral medications to help with proper insulin absorption and sensitivity.
Diabetes is usually managed by supplementing the body’s insulin level after vigorously monitoring blood glucose levels with multiple needle finger pricks, glucometer readings and injections each day. Not an ideal arrangement.
Today, some people with diabetes have adopted new technology. Compact mechanical continuous glucose monitoring systems check blood sugar levels through sensor patches. Adhesive patches hold the sensor in place, allowing it to take glucose readings in the fluid that surrounds cells in the body, day and night. It’s a significant step forward in the management of diabetes, but it’s not without its shortfalls. The sensors generally must be replaced every 10 to 14 days and are somewhat invasive.
Many of these setbacks can be traced back to the efficiency of the glucose binders used. The management and control of blood sugars and the everyday events that affect blood sugar levels (i.e. food intake, exercise, stress, illness, other medications, etc.) is a constant balancing act for those that have diabetes. And for those with type 1 diabetes especially, taking a break from diabetes management is never an option. If sensors are not accurate or if they fail to work properly, a person with diabetes can be in real trouble.
Scientists from Bristol University, as part of the Russell Group, a collection of 24 world-class research-intensive UK universities, discovered a glucose binding molecule that can sense the presence of glucose in the bloodstream. The molecule is a cage-like structure that only a glucose molecule fits into. It can be used as a receptor or sensor for blood glucose.
“The core structure is simple and symmetrical, yet provides a cavity which almost perfectly complements the all-equatorial β-pyranoside (glucose) substrate. The receptor’s affinity for glucose, at Ka ~ 18,000 M−1, compares well with natural receptor systems. Selectivities also reach biological levels.[i]
This is a breakthrough level of selectivity for glucose from a synthetic sensor.
Glucose binding receptor
Robert Tromans in his lab with a HORIBA Duetta
The Bristol start-up, Carbometrics is a collection of organic chemists working to perfect sensors for continuous blood glucose level monitoring. Robert Tromans, Ph.D., is a co-author of the breakthrough research and Head of Research for the company.
The discovery goes beyond monitoring blood glucose levels. Glucose binding molecules are also required for initiatives in creating glucose-responsive insulin.
Because of this potential, the company initially formed by the research group at the University of Bristol was acquired by Novo Nordisk. Tromans and the team started Carbometrics, which now collaborates with Novo Nordisk who are using their sensor to develop the latest glucose responsive insulin.
Tromans said Carbometrics is trying to take advantage of the glucose receptor in two ways:
Glucose has a specific shape, and the glucose binding molecule acts like a glove that will only accommodate and sense that molecule.
“So that way you can effectively have a signal or an output from the molecule when the glucose goes in, you can then process this signal into a useful output that could be read by an external device,” he said. “We've basically designed a molecule that has the perfect shape for glucose, but no other molecules.”
Carbometrics is forming partnerships with companies that specialize in the transmission of that information to external devices. As well as with the current collaboration with Novo Nordisk to use it to signal insulin to activate in the presence of glucose.
Injecting insulin could be dangerous if it is too high or low a dose. If too much insulin is injected and blood glucose falls too low, this can be very dangerous (i.e. coma) and potentially fatal. Injecting too little insulin and leaving blood glucose too high causes the long-term health effects discussed earlier. The purpose of Carbometrics’ collaboration with Novo Nordisk is to develop insulin that would, through these receptors, sense the level of blood glucose and adjust its own delivery to necessary levels.
Novo Nordisk is leading the research program for these glucose responsive insulins. Carbometrics is supporting it through a research collaboration.
“Insulin itself doesn't know how much glucose is in your body,” Carbometrics Research Operations Manager Stacy Coomber said. “So we are helping to create something that when it comes into contact with glucose, will change something about the insulin, which will mean it will either work or it won't depending on how much glucose is in your body. What we're trying to do by assisting Novo Nordisk’s research program is to develop insulin that basically turns off and on in the presence of glucose in the blood.”
“You would basically be giving your body insulin that responds the way insulin in someone without diabetes responds,” Coomber said.
Although the finger prick test is good to monitor blood sugar levels, it must be done regularly, and it’s not that accurate, she said. So, the other project the company is working on are glucose sensors.
“The main idea is that you'll have a sensor in your body that you're just putting in once a year or every few years, and it’s linked to your phone or an external sensor that you can constantly check for your amount of blood glucose without ever having to prick your finger,” Tromans said. “It can interface with your biology and it will give out a signal depending on the amount of glucose that is present.”
“Similar technologies exist currently but are limited due to the imperfect selectivity to glucose, where results can be affected by other compounds in the blood (such as paracetamol or vitamin C),” Coomber said. “We hope that our sensor with its high selectivity, will be able to overcome the problems currently faced by glucose sensing technology.”
Engineers can create microscopic radio transmitters that take the signal from the molecule and send it to an external device.
Diabetes is only one avenue where this continuous glucose sensing molecule can be useful. Bioprocessing scientists must know the amount of glucose in industrial scale reactors, where enzymes and proteins are grown. Intensive care patients can have their glucose levels monitored alongside, say, their heart rate and oxygen levels.
The continuous glucose binding molecule can reduce the stress of traditional finger prick testing. It removes the social barrier traditional blood sugar self-testing carries. It also provides the patient with diabetes with peace of mind, knowing there is something that’s continuing to monitor their blood sugar levels.
Duetta Fluorescence and Absorbance spectrometer
The chief tool Carbometrics scientists use in terms of developing the sensor is fluorescence.
“We can attach our glucose binding molecule to something fluorescent and the amount of fluorescent light emitted can change depending on how much glucose is present. Then you suddenly have something that you can measure the amount of glucose with” Tromans said.
They are constantly tweaking and changing the glucose binding molecule to give a better response when glucose is made or is nearby. That means changing its chemical structure and tweaking it slightly and then seeing how it responds to glucose.
The team uses fluorescence to determine how good an interaction there is between the glucose and receptor, because some molecules they make detect glucose better than others. Fluorescing properties engineered into the receptor indicates how tight a fit there is between the glucose and receptor, and therefore, how good the receptor is working. It’s a benchmark for effectiveness.
The scientists at Carbometrics use a HORIBA Duetta benchtop spectrometer to make their fluorescence measurements. The Duetta is a spectrofluorometer that combines, simultaneously, the functions of fluorescence and absorbance spectrometers. With its high-speed built-in CCD detector, the Duetta can acquire a full spectrum from 250 nm to 1,100 nm in less than one second, making it the fastest fluorescence spectrometer on the market.
“We use that every day to benchmark how good our receptors are in terms of how well they bind glucose, how much fluorescence we get out,” Tromans said. “The main thing we really like about the Duetta is that it's really fast. So you can get a lot of data very quickly.”
The Duetta also can simultaneously acquire absorbance, transmittance and a fluorescence Excitation Emission Matrix (A-TEEM) of a particular sample, producing faster, more accurate excitation emission matrixes (EEMs).
“We use it quite a bit as well, because fluorescence and absorption are closely linked and it’s very important to know both parameters,” he said.
“That’s something that we really use because basically you get a new molecule and that’s the first experiment you do. It tells you everything you need to know about its fluorescence, and you can do that in a couple of minutes, maybe even seconds on the Duetta. On our old spectrometer it took about 10 hours to do.”
The time to commercialization of the glucose binding molecule is both difficult to say and confidential. But Tromans was willing to go this far:
“We are currently collaborating with several partners to achieve this goal. I think that’s fair to say.”
[1] Robert A. Tromans, Tom S. Carter, Laurent Chabanne, Matthew P. Crump, Hongyu Li, Johnathan V. Matlock, Michael G. Orchard & Anthony P. Davis A biomimetic receptor for glucose Nature Chemistry volume 11, pages 52–56 (2019)
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