Can Apple's ResearchKit change the face of medical research?

Every day, Medical News Today reports on a large number of studies. Many of these involve the recruitment of participants so researchers can obtain new and relevant data. The best of these studies will involve the participation of thousands of people, but getting hold of large numbers of willing volunteers can be difficult.

With access to a smartphone, anyone anywhere in the world can now potentially participate in a medical study.

"We have sent out over 60,000 letters," says Kathryn Schmitz, PhD, of Penn Medicine, explaining the recruitment process for a recent study. "Those 60,000 letters have netted 305 women."

Some researchers will acquire a large number of subjects for their studies by using data obtained by previous investigations. This method is much quicker than signing up thousands of volunteers, but it does not give the researcher the control and flexibility that comes with recruiting new volunteers.

In developed countries, smartphones are ubiquitous. Walk down a street in any city and you will likely encounter at least one person with one of these gadgets glued to their hand or head. More than just a way of communicating with other people, for many, smartphones have become an integral part of navigating life due to the wide variety of apps available to users.

iPhones, for example, do not just contain the necessary bits and bobs needed for people to initiate conversations or access the Internet. They contain a myriad of sensors and processors that can track and measure a host of different things. The combination of widespread usage and the capacity to collect data makes smartphones an ideal tool for researchers to utilize.

Here, then, could be a solution to one of the most pressing problems experienced by medical researchers. In this Spotlight, we take a brief look at ResearchKit, the latest initiative launched by Apple, attempting to harness the power of the smartphone to transform how scientists carry out research studies.

Getting started

Smartphone apps are being increasingly used for personal health purposes, both in tracking health and fitness and for detecting illness.

But while these apps can provide users with a perspective on their health, many experts have been critical about the worth of these perspectives, questioning whether they are actually beneficial to users' health.

Last year, Apple launched their Health app and a tool for developers called HealthKit, allowing them to develop software able to pool together health data collected by other apps. The aim of this was to create a range of more empowered health tracking programs, supposedly giving users greater insight into their health than before.

In March, Apple took this work a step further with the launch of ResearchKit, an open source framework that allows developers to create apps specifically for conducting medical research studies. In addition to using data obtained by the Health app, ResearchKit also allows researchers to obtain informed consent from participants remotely.

The Asthma Health app helps people with asthma treat their condition while helping researchers investigate new ways to personalize treatment.
Image credit: Icahn School of Medicine at Mount Sinai

Dr. Eric Schadt, from Icahn School of Medicine at Mount Sinai, NY, explained to MNT that electronic consenting would eliminate many of the limitations that the traditional consenting process brought to medical research.

"Traditional research has been constrained to informing potential participants about a study, the risks, the benefits and so on, by sitting directly with the participant (or on the phone) to step them through the paperwork and other material to complete the informed consent," he said.

For each participant enrolled into a study, it takes around 30 minutes for a researcher to go through the consenting process. The fact that the process is so time-consuming limits the number of people that can be signed up for a research project due to the amount of time available to researchers.

"With electronic consenting these limitations are all addressed," said Dr. Schadt. "Potential study participants can be stepped through the informed consent using their iPhone, advanced multimedia can be used to more efficiently inform the participant as to the details of the studies as well as the risks and potential benefits."

In order to prevent users from just skipping through the informing stages of the consent process, the apps feature questions to ensure that users can only consent to take part if they fully understand what they are signing up for.

Apple and the researchers behind the first five apps developed using ResearchKit that were launched in March have been very vocal about how the consenting process is a marked improvement on how studies have traditionally been set up.

Dr. Schadt has been involved with one of these first five apps, Asthma Health - an app that combines geolocating data from the phone with air quality information to help users avoid areas where asthma symptoms could be triggered, in turn, collecting data that the developers hope will allow them to discover new ways to personalize treatment of the condition.

On the first day the app was launched, Asthma Health was downloaded by 2,500 people. It would typically take researchers around 1-2 years to recruit this many subjects for a study. In the first month, 7,500 people with asthma had signed up.

This number pales in comparison, however, with the 11,000 people who downloaded the MyHeart Counts app within 24 hours of it becoming available. An element of this may well be the novelty value of being able to sign up to research studies with newfound ease, but initial signs are certainly promising.

Lots and lots of data

The other aspect of ResearchKit that Apple and the app developers are keen to promote is how much data will be obtained by studies built using the framework.

"For the researcher, especially disease research, it is all about the phenotypes," explained Dr. Schadt. "Today, cohorts assembled for disease collect very minimal numbers of phenotypes generally relating directly to the disease, and those phenotypes are collected infrequently - at most, once a year."

Studies conducted via iPhone app will differ in this respect. "With the health apps being built we can collect phenotypes that relate across the disease and wellness spectra and we can do it at high frequency, every day, or 10 or 100 times a day," said Dr. Schadt.

There are a number of inbuilt devices in iPhones that can prove useful to researchers. Data obtained by the microphone, gyroscope, accelerometer, touch screen and the global positioning system of the smartphone can all provide data relevant to research projects.

"All of these variables can be collected numerous times a day over any number of days or years, thus providing a far more detailed profile of the user than could ever be reasonably generated in a medical setting," stated Dr. Schadt.

Not only is the variety of forms of available data beneficial but the frequency by which it is collected is great for researchers too. Many studies are limited by only taking measurements at the baseline - the starting point of the study - and then one or two further times after that.

Infrequent measuring can make results unreliable. Let's say a study wants to examine the effects of a particular diet on body mass index (BMI), and then measures the participants' BMI at the beginning of the study, 6 months later and then after 1 year.

The results of such a study might then show minimal change in BMI after this period. But, if the two periods where BMI was measured came shortly after holidays where the participants drank a lot of alcoholic beverages and did not exercise, the results would inevitably be skewed. This skewing would be exacerbated if the study used a small number of participants.

Such a problem - the ebbing and flowing of symptoms as Apple describes it - is solved by gathering data far more regularly than many studies are able to.

In addition to this, the pool of potential volunteers is much larger with ResearchKit than it is for most studies, typically confined to a small geographic area. The ubiquity of the iPhone means that volunteers can sign up to take part no matter where they live in the world.

This also allows researchers to have access to more varied study populations, although they will be relying on participants that have access to smartphones, still a restricted demographic.

An open source framework for all

What is possibly the most interesting aspect of ResearchKit, however, is that Apple have made the whole thing open source. The core framework can be used by anyone who wishes to use the software to make their own study, and the codes for the five initial apps launched alongside the framework are also available for examination and customization.

While initial access to ResearchKit is confined to iPhones, thanks to the open sourcing of the framework, it will eventually be available to users of every kind of smartphone.

For a company that is renowned for keeping as many aspects of its products as exclusive to the brand as possible, this was a surprising move, but one that could prove incredibly beneficial.

ResearchKit was made available to developers to use from April. Although the initial apps were only available for iPhone users, the fact that the software is open source means that eventually studies will be accessible to users of Android and Windows products.

Science Practice had a go at trying out the newly available framework and commented on how quick it was to construct simple consent forms and participant surveys. Already, too, a small online community has developed in which new ideas and suggestions are being shared on how to use and improve the framework.

A major concern raised with ResearchKit is how private and secure the obtained data will be. Considering how data from the Health app could be loaded up onto the iCloud and how that platform has been hit with several high-profile hacking incidents, the concern is a valid one.

Dr. Schadt informed Yahoo! Tech that "the only people who have access to the data are the investigators of the study," stating that the data is encrypted and meets all industry standards for the transfer of sensitive data. "Apple never touches the data," he reported.

Being an open source framework may also help with privacy, according to Adrian Gropper, chief technology officer of the nonprofit group Patient Privacy Rights.

"Open source encourages people to report bugs in the software and get them fixed," he told Bloomberg Business. "The gold standard is open source because security by obscurity has been shown not to work."

Work in progress

"We believe that these studies represent an entirely new way to perform human health research, putting the participant truly at the center with frequent feedback and control of how their data are used," Dr. Andrew Trister.

"Furthermore, the power of these pervasive devices on quantifying health on an individual is tremendous, opening up real opportunities for truly personalized medicine."

Dr. Trister is a senior physician with Sage Bionetworks, a nonprofit research organization that has worked with Apple to develop ResearchKit.

There are still a number of limitations that the studies conducted by these apps will be subject to. Data provided by the instruments in a smartphone may not be as precise as those obtained using specifically-designed medical instruments. With the study being conducted remotely, it is also harder for investigators to assess the suitability of participants for their study.

Developers might argue that the sheer volume of participants now available to researchers may overshadow these limitations. At this stage, before the results of any of the studies have been processed, it feels as though the positive of having increased and easy access to large numbers of participants is the main point to take from the project.

The most reliable studies are those that are conducted over a long period of time and, as a result, it may be some time before we can effectively gauge the contribution that ResearchKit will make to the field of medical research.

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DIabetes: 'smart insulin patch' could revolutionize glucose control

Patients with diabetes have to control their blood sugar by regularly pricking their finger and giving themselves insulin shots. The procedure is painful and imprecise - injecting the wrong amount of insulin can lead to serious complications, and in some cases, coma and death.

The researchers aim to develop a smart insulin patch that would only need to be changed every few days.
Image credit: Zhen Gu

Now, the development of a "smart insulin patch" could one day make such an ordeal a thing of the past for the millions of Americans who suffer from diabetes, according to the team behind the innovation, which includes members from the University of North Carolina (UNC) in Chapel Hill and NC State in Raleigh.

The smart patch - a square sliver of tape no larger than a penny - has more than a hundred microneedles, each about the size of an eyelash, containing tiny reservoirs of insulin and glucose-sensing enzymes.

The device - which can be placed anywhere on the body - senses when blood sugar levels get too high and rapidly discharges the right amount of insulin into the bloodstream.

In the Proceedings of the National Academy of Sciences, the diabetes doctors and biomedical engineers that invented the painless patch describe how they tested it in a mouse model of type 1 diabetes and showed it lowered blood glucose for several hours.

While it shows great promise, it is too early to say if and when the patch can be used in human patients - the team says more tests and then clinical trials are needed.

Patch mimics body's own system for generating insulin

The smart insulin patch works by mimicking the body's own system for generating insulin - the beta cells of the pancreas - which produce and store insulin in tiny sacs or vesicles. They also sense changes in blood sugar and signal insulin to be released from the vesicles as needed.

The team constructed artificial vesicles that perform in a similar way out of two natural materials - hyaluronic acid (HA) used in cosmetics and 2-nitroimidazole (NI), an organic compound used in diagnostics.

Together, the two compounds form a molecule that is water-loving at one end (the HA part) and water-repellent at the other (the NI part). Groups of the molecule self-assemble into vesicles - rather like oil droplets do in water - with the water repellent ends on the inside and the water-loving ends on the outside.

The researchers found they could insert a core of solid insulin and enzymes designed to detect glucose into the artificial vesicles, which in large numbers formed millions of bubble-like nanostructures, each 100 times smaller than the thickness of human hair.

When they tested the intelligent insulin nanoparticles in the lab, the team found they responded to raised blood sugar. The excess glucose molecules entered the artificial vesicles, using up oxygen as the enzymes on board converted them into gluconic acid. This reduction in oxygen or "hypoxia" makes the water-repellent NI end of the molecules that make up the vesicles become water-loving, and the vesicles dissolve and release insulin into the bloodstream.

Patch kept blood sugar normal in diabetic mice for hours

The next step for the researchers was to find a way to administer the artificial vesicles to diabetes patients. This is when they turned to the idea of tiny microneedles incorporated into a patch, rather than rely on the large needles or catheters of the "closed-loop systems" of other approaches to glucose-sensitive insulin delivery.

They eventually produced a silicon strip with over a hundred microneedles that pierce the skin and tap into the blood flowing in the underlying capillaries. Each microneedle contains a reservoir of the artificial vesicles.

The team tested the invention in a mouse model of type 1 diabetes. They gave one group of mice a standard insulin injection - the levels dropped to normal but then quickly rose to hyperglycemic levels.

But when they treated another group of diabetic mice with the patch, their blood sugar levels normalized within half an hour and stayed that way for several hours.

The researchers also found that by varying the dose of enzyme, they could fine-tune the patch to alter glucose levels within certain ranges.

A 'game changer' for diabetes patients

Mice are less sensitive to insulin than humans, so the researchers believe that the patches could last even longer in human patients. The researchers aim to develop a smart insulin patch that would only need to be changed every few days.

Such a prospect would be a "game changer" for diabetes patients, explains co-senior author John Buse, a professor of medicine and past president of the American Diabetes Association:

"The hard part of diabetes care is not the insulin shots, or the blood sugar checks, or the diet but the fact that you have to do them all several times a day every day for the rest of your life."

Co-senior author Zhen Gu, a professor in biomedical engineering, says:

"We have designed a patch for diabetes that works fast, is easy to use, and is made from nontoxic, biocompatible materials. The whole system can be personalized to account for a diabetic's weight and sensitivity to insulin, so we could make the smart patch even smarter."

There are more than 387 million people with diabetes worldwide, and the number is predicted to rise to 592 million by 2035.

Funds from the NC TraCS Institute and the American Diabetes Association helped finance the research.

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Crows count on 'number neurons'

Neurobiologists have discovered cells in the crow brain that respond to a specific number of items. The study provides valuable insights into the biological roots of counting capabilities. What makes this finding even more interesting is that a long evolutionary history separates us from birds; as a consequence, the brains of crows and humans are designed very differently.

Crows recognized the number of dots shown in computer displays. Tübingen researchers discovered ‘number neurons’ in the crow’s end-brain that responded to a specific number of items.

Credit: Andreas Nieder

An old story says that crows have the ability to count. Three hunters go into a blind situated near a field where watchful crows roam. They wait, but the crows refuse to move into shooting range. One hunter leaves the blind, but the crows won't appear. The second hunter leaves the blind, but the crows still won't budge. Only when the third hunter leaves, the crows realize that the coast is clear and resume their normal feeding activity.

Helen Ditz and Professor Andreas Nieder of the University of Tübingen found the neuronal basis of this numerical ability in crows. They trained crows to discriminate groups of dots. During performance, the team recorded the responses of individual neurons in an integrative area of the crow endbrain. This area also receives inputs from the visual system. The neurons ignore the dots' size, shape and arrangement and only extract their number. Each cell's response peaks at its respective preferred number.

The study published in PNAS provides valuable insights into the biological roots of counting capabilities. "When a crow looks at three dots, grains or hunters, single neurons recognize the groups' 'threeness' ," says Helen Ditz. "This discovery shows that the ability to deal with abstract numerical concepts can be traced back to individual nerve cells in corvids."

What makes this finding even more interesting is that a long evolutionary history separates us from birds. As a consequence, the brains of crows and humans are designed very differently.

"Surprisingly, we find the very same representation for numbers as we have previously discovered in the primate cortex," Prof. Andreas Nieder says. "It seems as if corvids and primates with independently und distinctively developed endbrains have found the same solution to process numbers." Even abstract behavior which we think of as sophisticated mental feats ultimately has biological roots.

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The above story is based on materials provided by Universitaet Tübingen.Note: Materials may be edited for content and length.

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New drug triggers tissue regeneration: Faster regrowth and healing of damaged tissues

Research focuses on select tissues injured through disease, surgery and transplants, but early findings indicate potential for broad applications

The concept sounds like the stuff of science fiction: take a pill, and new tissues grow to replace damaged ones. Researchers have now announced steps toward turning this idea into reality. They have detailed how a new drug repaired damage to the colon, liver and bone marrow in animal models -- even saving mice who would have died in a bone marrow transplantation model.

Scientist holding white laboratory mouse. (stock image)

Credit: © efmukel / Fotolia

The concept sounds like the stuff of science fiction: take a pill, and suddenly new tissues grow to replace damaged ones.

Researchers at Case Western Reserve and UT Southwestern Medical Center this week announced that they have taken significant steps toward turning this once-improbable idea into a vivid reality. In a study published in the June 12 edition of Science, they detail how a new drug repaired damage to the colon, liver and bone marrow in animal models -- even going so far as to save the lives of mice who otherwise would have died in a bone marrow transplantation model.

"We are very excited," said Sanford Markowitz, MD, PhD, the Ingalls Professor of Cancer Genetics at the university's School of Medicine and a medical oncologist at University Hospitals Case Medical Center's Seidman Cancer Center. "We have developed a drug that acts like a vitamin for tissue stem cells, stimulating their ability to repair tissues more quickly. The drug heals damage in multiple tissues, which suggests to us that it may have applications in treating many diseases."

The institutions collaborating on this work next hope to develop the drug -- now known as "SW033291" -- for use in human patients. Because of the areas of initial success, they first would focus on individuals who are receiving bone marrow transplants, individuals with ulcerative colitis, and individuals having liver surgery. The goal for each is the same: to increase dramatically the chances of a more rapid and successful recovery.

The key to the drug's potential involves a molecule the body produces that is known as prostaglandin E2, or PGE2. It is well established that PGE2 supports proliferation of many types of tissue stem cells. Markowitz and University of Kentucky Professor Hsin-Hsiung Tai earlier had demonstrated that a gene product found in all humans, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), degrades and reduces the amount of PGE2 in the body.

Markowitz, also a Harrington Discovery Institute Scholar-Innovator, and James K.V. Willson, MD, a former Case Western Reserve colleague now at UT-Southwestern, hypothesized that inhibiting 15-PGDH would increase PGE2 in tissues. In so doing, it would promote and speed tissue healing. When experiments on mice genetically engineered to lack 15-PGDH proved them correct, the pair began searching for a way to inactivate 15-PGDH on a short-term basis.

The preliminary work began in test tubes. Yongyou Zhang, PhD, a Case Western Reserve research associate in Markowitz's lab and a lead author on the study, developed a test where cells glowed when 15-PGDH levels changed. Zhang then traveled to UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, where Willson serves as director. Zhang and UT Southwestern researchers Bruce Posner, PhD, and Joseph Ready, PhD, collaborated to comb through the center's library of 230,000 different chemicals. Ultimately they identified one chemical that they found inactivated 15-PGDH.

"The chemical, SW033291, acts in an incredibly potent way," Markowitz said. "It can inactivate 15-PGDH when added at one part in 10 billion into a reaction mixture, which means it has promise to work as a drug."

A series of experiments showed that SW033291 could inactivate 15-PGDH in a test tube and inside a cell, and, most importantly, when injected into animal models. The third finding came through collaboration between Markowitz and Stanton L. Gerson, MD, director of the Case Comprehensive Cancer Center, UH Seidman Cancer Center, and the National Center for Regenerative Medicine, as well as the Asa and Patricia Shiverick-Jane Shiverick (Tripp) Professor of Hematological Oncology.

Case Western Reserve research associate Amar Desai, PhD, worked between the Markowitz and Gerson laboratories to determine the effect of SW033291 on mice that had received lethal doses of radiation and then received a partial bone marrow transplant. Without SW033291, the animals died. With it, they recovered.

From there, more detailed studies showed that mice given SW033291 recovered normal blood counts six days faster than mice that were transplanted without receiving SW033291. In addition, SW033291-treated mice showed faster recovery of neutrophils, platelets and red blood cells. Neutrophils battle infection, platelets prevent bleeding, and red blood cells deliver oxygen throughout the body.

In addition, Desai's work showed that when SW033291 increases PGE2 in bone marrow, the body also begins to produce other materials that bone marrow stem cells need to survive. Finally, these benefits emerged without any adverse side effects, even at SW033291 doses much higher than would be required for 15-PGDH inhibition.

When investigators treated mice with other diseases, the SW033291 drug again accelerated tissue recovery. For example, the investigators teamed with Fabio Cominelli, MD, PhD, a Case Western Reserve Professor and Chief of the Division of Gastroenterology and Liver Disease, to study a mouse model of ulcerative colitis. SW033291 healed virtually all the ulcers in the animals' colons and prevented colitis symptoms. In mice where two-thirds of their livers had been removed surgically, SW033291 accelerated regrowth of new liver nearly twice as fast as normally happens without medication.

Because bone marrow, colon, and liver are significantly different tissues, the investigators believe the pathway by which SW033291 speeds tissue regeneration is likely to work as well for treating diseases of many other tissues of the body. However, the next stages of the research will concentrate on three diseases where SW033291 already shows promise to provide dramatic improvement.

In bone marrow transplants, for example, effects of SW033291 in accelerating tissue growth would provide the body the cells required to fight off the two most common and sometimes fatal complications, infection and bleeding. For those suffering the debilitating impact of colitis, accelerating tissue growth could heal colon ulcers more quickly, which in turn could allow patients to take lower dosages of other medications that treat colitis -- some of which have serious side effects. Finally, the promise of tissue growth could increase survival rates for patients with liver cancer; in some cases today, physicians are unable to perform surgery because the amount of the liver to be removed would be so great as to pose severe risk to the patient. But having a drug to accelerate the liver's regrowth could make surgery a viable option.

The team's next step will be to complete studies showing safety of SW033291-related compounds in larger animals, a required part of the pathway to secure approval from the U.S. Food and Drug Administration for trials in humans. If the drugs prove safe and effective in those clinical trials, they could then become available for general use by physicians. Investigators hope to partner with pharmaceutical companies to be able to start human trials within three years.

"These are thrilling times for us as researchers, and it is also an exciting time for Case Western Reserve," Markowitz said. "In Cleveland, there has been a major effort in the last two to three years to figure out how all our institutions can together work to develop drugs. This discovery is really something we should celebrate. It helps put us on the map as a place where new drugs get invented."

Markowitz added that this research received crucial financial assistance from Case Western Reserve University School of Medicine's Council to Advance Human Health (CAHH), from the Harrington Discovery Institute at University Hospitals, and from multiple National Institutes of Health grants that included the Case GI SPORE, led by Markowitz, and the National Center for Accelerating Innovation at the Cleveland Clinic. Additional support was received from the Marguerite Wilson Foundation; the Welch Foundation; the Cancer Prevention & Research Institute of Texas; Inje University; and the Korean National Research Foundation. Generous major gifts also came from the Leonard and Joan Horvitz Foundation and the Richard Horvitz and Erica Hartman-Horvitz Foundation.

Markowitz said the authors' contributions to this research are truly a tribute to the powers of collaboration. Senior authors Hsin-Hsiung Tai, Stanton L. Gerson, Joseph M. Ready, Bruce Posner, James K.V. Willson and Markowitz provided substantial leadership. Markowitz and Willson, former director of the Case Comprehensive Cancer Center and now director of the Simmons Cancer Center at UT Southwestern, initiated the project to study the potential of inhibiting 15-PGDH as a tissue-healing treatment strategy. Tai, at the University of Kentucky, Lexington, originally discovered 15-PGDH and tested SW033291 as a 15-PGDH inhibitor. Gerson and Markowitz partnered to show the SW033291 drug is effective for regenerating bone marrow in mice. Ready, a UT Southwestern chemist, synthesized SW033291 for the studies and has made multiple other highly promising derivatives of the compound. Posner, also a chemist from UT Southwestern, oversaw the search through the 230,000 compounds in the UT Southwestern chemical library.

Lead authors Yongyou Zhang, Amar Desai, Sung Yeun Yang, Ki Beom Bae, Monika I. Antczak, Stephen P. Fink and Shruiti Tiwari contributed equally to the scientific investigation. Zhang, Case Western Reserve, led the experiments that identified the drug. Desai, Case Western Reserve, performed experiments that showed that SW033291 works in bone marrow transplantation in mice. Yang and Bae, now at Inje University in Korea, worked in the Markowitz laboratory on studies of colitis (Yang) and on liver regrowth after surgery (Bae). Antczak worked in the Ready lab at UT Southwestern on the chemical synthesis of SW033291. Fink and Tiwari, both of Case Western Reserve, completed the work on the colitis mouse model.

Markowitz also cited important collaboration of two Case Western Reserve participating authors -- gastroenterologist Fabio Cominelli, who played a role in the success of the colitis experiments in mice, and Mark Chance, who contributed proteomics expertise for studies that showed how SW033291 works. Other participating investigators also contributed substantially: Joseph E. Willis, Dawn M. Dawson, David Wald, Wei-Dong Chen, Zhenghe Wang, Lakshmi Kasturi, Gretchen A. Larusch, Lucy He, Luca Di Martino, Juan Sanabria, Chris Dealwis, and Debra Mikkola, all of Case Western Reserve; Zora Djuric, University of Michigan, Ann Arbor; Ginger L. Milne, Vanderbilt University, Nashville; and Noelle S. Williams, Jacinth Naidoo, and Shuguang Wei, all at UT-Southwestern, Dallas.

"An impressive number of individuals contributed to the discovery of this 15-PGDH inhibitor drug," Markowitz said. "Each one of them has done something absolutely remarkable and indispensable to the success of the study."

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The above story is based on materials provided by Case Western Reserve University. Note: Materials may be edited for content and length.

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Body's response to spicy foods guides design of new pain relief drugs

The molecular interactions that allow capsaicin to activate the body's primary receptor for sensing heat and pain have been identified by scientists, paving the way for the design of more selective and effective drugs to relieve pain.

People sense ambient temperature changes.

Credit: Courtesy of J. Zheng lab

UC Davis researchers have identified the molecular interactions that allow capsaicin to activate the body's primary receptor for sensing heat and pain, paving the way for the design of more selective and effective drugs to relieve pain. Their study appeared online June 8 in the journal Nature Chemical Biology.

Capsaicin is the ingredient that makes chili peppers spicy and hot. The same pathway in the body that responds to spicy food is also activated after injury or when the immune system mounts an inflammatory response to bacteria, viruses, or in the case of autoimmune disease, the body's own tissues.

'While we have known that capsaicin binds to the TRPV1 receptor with exquisite potency and selectivity, we were missing important atomic-level details about exactly how the capsaicin molecule interacts with TRPV1, one of the body's primary receptors for sensing pain and heat,' said Jie Zheng, professor of physiology and membrane biology at UC Davis and senior author on the paper.

Using computer models based on atomic force fields and existing low resolution 3-D reconstructions of the TRPV1-capsaicin complex, the researchers identified several structural areas that enable capsaicin to strongly bind to the TRPV1 receptor.

'Computational biology methods are becoming very powerful tools for predicting and ultimately validating the high-resolution structure of important biological proteins and ligands, such as capsaicin and TRPV1, when they interact,' said Vladimir Yarov-Yarovoy, assistant professor of physiology and membrane biology at UC Davis and co-author on the study.

'These tools are especially useful when the interactions are small and transient, and cannot be captured easily with high-enough resolution using traditional experimental approaches,' he said.

Fan Yang, postdoctoral fellow in the Zheng lab at UC Davis and first author on the paper, agrees.

'The electron density observed in the cryo electron microscopy structure of the TRPV1-capsaicin complex is much smaller in size compared to the chemical structure of capsaicin,' Yang said. 'With computational docking, we were able to detail the atomic interactions between capsaicin and the TRPV1 channel and later validate the molecular architecture using other experimental approaches.'

The new structural information may serve to guide the drug-design process.

'Just as we can 'get used to' a spicy dish by the end of the meal, we believe that there are ways to develop highly specific molecules that make TRPV1 less sensitive to painful stimuli,' Zheng said.

The research also explains why capsaicin does not activate the body's other channels for sensing temperature, and why the TRPV1 receptor in many other species is not activated by capsaicin. For example, birds are missing two key interaction sites, which explains why birds are insensitive to the spiciness of chili peppers.

'It is thought that the presence of capsaicin is an evolutional advantage for plants, protecting them from species that would eat the leaves while allowing birds to ingest the peppers to spread the seed,' Zheng said.

The researchers also found that sweet peppers contain a compound called capsiate, which is almost identical to capsaicin in spicy peppers but differs at one key interaction site.

'The difference is sufficient to make the sweet pepper compound bind to TRPV1 very poorly, which is probably part of the reason why it does not taste spicy,' Zheng said. 'On the Scoville pungency scale, capsaicin is 16 million, and capsiate is only 16,000.'

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The above story is based on materials provided by University of California - Davis Health System. Note: Materials may be edited for content and length

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'Taste for sugar' could be HIV's major weakness

It turns out that having a sweet tooth is not just the downfall of many of us humans. According to a new study, a taste for sugar could also be HIV's major weakness and a target for future treatment.

The study, published in PLOS Pathogens, suggests that if the virus is unable to access sugar and other nutrients after invading a cell, it is unable to replicate itself and, therefore, unable to grow and spread.

Researchers from Northwestern Medicine, IL, and Vanderbilt University, TN, were able to utilize an experimental new compound to shut down the sugar and nutrient pipeline in immune cells and starve HIV to death.

"This compound can be the precursor for something that can be used in the future as part of a cocktail to treat HIV that improves on the effective medicines we have today," says Harry Taylor, research assistant professor in medicine at Northwestern University Feinberg School of Medicine.

HIV grows in specific types of immune cells called CD4+ T cells. When these cells are active, responding to pathogens in the blood, their supplies of sugar and other nutrients necessary for growth are increased. The virus purposefully seeks out activated T cells and hijacks their glucose supplies.

The researchers discovered that turning on a cell component called phospholipase D1 (PLD1) signaled for activated T cells to increase their supplies of sugar and the vital nutrients. By blocking this component, the researchers were able to in turn block the sugar pipeline, depriving the invading HIV of the building blocks required for it to grow.

A previous attempt to prevent the virus from stealing immune cells' sugar and nutrients using drugs was carried out in the 1990s, but the drugs led to serious side effects in patients with HIV and sometimes ended up killing healthy cells.

Blocking sugar supplies could also prevent premature organ damage

The new approach appears to not only be safer but has the additional effect of slowing the spread of abnormally activated immune cells. HIV triggers the excess activation and growth of T cells which can lead to inflammation in the body, causing premature organ damage in patients with HIV even when the virus is suppressed by medicine.

"Perhaps this new approach, which slows the growth of the immune cells, could reduce the dangerous inflammation and thwart the life-long persistence of HIV," Prof. Taylor speculates.

Before joining Northwestern University, Prof. Taylor was on the faculty at Vanderbilt, where we knew that researchers had managed to identify a compound that could stop breast cancer cells from spreading by blocking PLD1.

The researchers speculated whether blocking this same cell component in CD4+ T cells would have the same effect in slowing the spread of HIV by blocking the supply of glucose and nutrients. They tested their theory in vitro and, sure enough, HIV was unable to access enough resources to reproduce.

Dr. Richard D'Aquila, director of Northwestern's HIV Translational Research Center, believes that the study's findings could hopefully lead on to future breakthroughs.

"This discovery opens new avenues for further research to solve today's persisting problems in treating HIV infection: avoiding virus resistance to medicines, decreasing the inflammation that leads to premature aging, and maybe even one day being able to cure HIV infection," he states.

Prof. Taylor hopes to identify additional compounds with the potential for development into medicines that could starve HIV in this way without harming cells. This discovery could also have application in the treatment of other diseases such as cancer that similarly rely on access to sugar and other nutrients found in cells to grow and spread.

Last month, Medical News Today reported on a study that identified a "can opener" molecule that renders HIV vulnerable to antibodies that could kill off infected cells.

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Wired Health: how are innovative technologies disrupting health care?

Last Friday, April 24th, marked the second annual Wired Health conference in London, UK, where members of the health care industry and curious spectators came together to discuss and explore how technology is shaping medicine today.

Health care aficionados, technological innovators and curious spectators met in London for a 1-day summit investigating the latest advances in the medical sector.

While Wired Health 2014 focused on harnessing self-monitored data, this year's agenda targeted disruption in health care.

In 1997, Harvard Prof. Clayton M. Christensen created the term "disruptive innovation" to describe how new technologies can alter existing markets or sectors by injecting simplicity, accessibility and affordability into what has become the over-complicated, high-cost norm.

Though the term "disruption" typically carries a negative connotation, in these terms, it points to positive change that shakes up the system for the better.

At the summit in London last week, members of the health care industry proudly harnessed this term and demonstrated how departing from the standard way of doing things has made a significant impact on the existing landscape of medicine.

Changing behavior through perception

"Psychology is technology," said Rory Sutherland, vice chairman of UK-based marketing firm Ogilvy & Mather, as he took the main stage. "What you call things affects how people behave."

Addressing advancements in understanding human behavior, Sutherland cited the rise in unnecessary visits to the UK's emergency departments coinciding with a shift in what it was called. Though it was once widely known as "Accidents and Emergencies," it is now referred to as merely "A&E," taking away the inherently bloody connotations and making it sound more like the initials of two people in love.

Rory Sutherland, of Ogilvy & Mather, addresses a packed audience at Wired Health 2015.

Referring to the emergency department by its full name on signs and in official literature could encourage patients to direct themselves to their GPs instead, decreasing the number of patients who unnecessarily use the emergency service and saving the UK's National Health Service (NHS) precious money.

"If you create a name for something," Sutherland added, "we automatically assume it's a norm."

He also explained that the way choices are presented can affect outcomes, particularly in the health care setting.

For example, when the NHS implemented the use of delayed prescriptions for antibiotics - when a prescription goes into effect a few days after an appointment, in a "wait-and-see approach" - unnecessary use of antibiotics decreased significantly.

In effect, changing the choice structure of things can alter behavior.

Removing the 'wrong' choice

Another man who recognizes that manipulating how choices are made can have positive effects in the field of medicine is Marc Koska, founder of the LifeSaver program. He noted that around the world, 1.3 million people die every year from infected needles that are reused.

After years of researching this problem, Koska came up with a simple solution to disrupt it: a syringe that is impossible to reuse. His K1 syringe is made on the same machinery and from the same materials as existing syringes, but it has an auto-disable mechanism that prevents reuse by employing a plunger that automatically locks in place and breaks if forced.

Koska showed conference-goers heartbreaking undercover footage of small children receiving injections with needles that had previously been used on HIV-positive patients, demonstrating the problem the global health care community faces.

The issue is so great that the World Health Organization (WHO) announced their third ever global policy, aiming to reduce unnecessary injections and ensure that only auto-disable syringes are used. This mandate will come into effect in 2020.

Koska noted that for every $1 spent on proper syringe disposal, over $14 could be saved on health care costs resulting from HIV, HBV and HCV. His charity SafePoint is working to improve this basic level of health care around the world. By taking the option of making the wrong decision out of the equation, Koska and colleagues are disrupting the unsafe practices that put patients at risk.

Bringing the element of choice to alternative limbs

For those who have lost limbs, there has been relatively little choice when it comes to what kind of prosthetic will become their new arm or leg. Though there have been advancements in so-called bionic reconstructions, the ability for a patient to take ownership over the design of their new limb has not really been an option - until now, that is.

The Alternative Limb Project, led by Sophie de Oliveira Barata, brings this choice to the patient, creating bespoke prosthetics for those who have lost their limbs. Each client can plan the design, and the company then works with product designers to create beautiful works of art that are also functional arms, hands, legs or feet.

Some of the designs featured by The Alternative Limb Project included a crystal leg, a limb with a speaker and mp3 dock, and a Japanese-inspired leg with pullout compartments for storage.

Some of the beautiful creations on display at Wired Health even included secret compartments in which the wearer can store things.

Speaking to a packed crowd, de Oliveira Barata explained that one of her clients recently had the idea to add a drone to an artificial arm that can "fly off the arm like a hawk" and take aerial photos.

Her unique approach empowers her clients to take ownership of their limbs, making them stand out as works of art, rather than as something to be hidden away.

Work from the company was recently thrust into the spotlight when the UK's Channel 4 introduced singer and performance artist Viktoria Modesta as "the world's first amputee pop artist."

In the video below, Modesta wears several creations from The Alternative Limb Project, including the "Spike," the "Crystal" and the "Light."

Writing on the company's website, Modesta explains how, after a voluntary operation to remove her leg - which was damaged from birth - she did not want to hide her altered body:

"Initially, after my voluntary operation, I mostly wanted to get a leg that provided balance to my body in its shape. Three years after the amputation, I then saw it as an opportunity to regard the leg as a fashion item and an art project which seemed rather fun and exciting."

Disrupting the aging process

Another speaker who took the stage at Wired Health was Brad Perkins, of Human Longevity, Inc. (HLI) - a company that focuses on genomics and cell therapy. They are tackling diseases caused by age-related decline by building a comprehensive database on human genotypes and phenotypes.

Perkins began his career at the Centers for Disease Control and Prevention (CDC), eventually spearheading investigations into the anthrax attacks in the US in 2001.

He explained that over the past 30 years, there has been a genomic revolution in bacteriology, in terms of how we study it, adding that "we humans are next" to go under the microscope.

HLI are currently working on building their database on human genotypes and phenotypes, and Perkins noted that "health care systems will be disrupted by this technology."

Interestingly, the integrated health records, along with clinical data that they are using to build their database, will become cloud-based and subjected to machine learning. HLI's 5-year goal is to achieve 1 million integrated health records so that they can fully interpret the meaning of the human genome.

"There is a potential to generate as many insights into health and disease as there has been in the last 100 years in the next 10 years," Perkins said, thus contributing to extended life spans.

Notable technological innovations

Between the Bupa Startup Stage - a platform for new companies to present their products and innovations - and the Wired Health Clinic - an exhibition where conference-goers were able to interact with new technologies - there was no shortage of interesting gadgets and gizmos.

Starstim cap

Ana Maiques models the Starstim cap from Neuroelectrics for MNT at Wired Health.

One of the most striking gadgets was a noninvasive wireless cap, which acts as a neurostimulator. Named Starstim, the cap was created by Neuroelectrics, a company led by Ana Maiques.

The cap works by delivering a low current directly to the brain through small electrodes, and it acts as an electroencephalography (EEG) and accelerometry recording system.

Because the cap is portable, it can be used both in a clinical setting and at home, where patients can employ neurofeedback to balance their EEG.

Potential applications include treatment for ADHD, chronic pain, stroke rehabilitation, cognitive enhancement, addiction and depression.

Lumo graphic reader

When dealing with innovation, there are naturally challenges to overcome, and one of the biggest is funding. Anna Wojdecka, creator of the Lumo, spoke to Medical News Today about her search to find adequate funding to take her design from prototype to finished product. She described her product as such:

"Lumo is a low-cost graphic reader for the blind and visually impaired. It translates colors into sound and black lines into tactile feedback, enabling the user to read shapes, graphs and diagrams directly from a page and draw in color."

She added that the aim of her product is to "make learning environments more inclusive and enrich interaction between blind and sighted people." When the finished product is available, Wojdecka told it will sell for between $150-200. She can be contacted via Twitter @helloLUMO.

Tao WellShell

The Tao WellShell fits in the palm of the hand, acting as a gym on the go.
Image credit: Tao Wellness

Another notable gadget was the Tao WellShell, which is a handheld device that fits in the palm of the hand and works in tandem with an app to give the user a resistance workout anywhere. It can be used at home, sitting at a desk or even on a bus, train or plane.

Insulin Angel

In the realm of tiny handheld devices sits the Insulin Angel, which tracks a medication's temperature to help the user monitor and maintain effectiveness. In addition to warning the user in the event the medication has been forgotten, the Insulin Angel also tracks medication usage and waste, and displays results through a smartphone app.

Cupris Health smartphone otoscope

Given that smartphones have become our constant companions these days, innovations that incorporate these devices make other technologies easily accessible. Cupris Health is a company that is doing just that; they have turned smartphones into medical devices by employing clip-on attachments.

They displayed their smartphone-connected otoscope at the conference, explaining that parents can now take pictures of their children's ears and send the images and symptoms directly to the doctor, who can remotely advise on treatment.

How can these disruptions work together?

If conference-goers were hoping to be spoiled for choice, Wired Health 2015 certainly did not disappoint. The vast amount of startups, gadgets and solutions on display was staggering. Though the main theme of disruption was reinforced throughout the speakers' presentations and in the innovations shown in the main hall, there was a sense of disjointedness this year.

Whereas last year's conference was overwhelmingly focused on how to harness data, this year's focus felt a bit forced, as if there was no clear way to sew everything together. But perhaps this is indicative of just how quickly and in how many different directions the health care industry is moving.

Indeed, how data, research and innovation can be unified and harnessed to result in positive health outcomes is the challenge the medical community faces today. Perhaps Wired Health 2016 will focus on this issue.

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