Tag Archives: multiple sclerosis

Sniffing out disease (Na-Nose)

The ‘artificial nose’ is not a newcomer to this blog. The most recent post prior to this is a March 15, 2016 piece about Disney using an artificial nose for art conservation. Today’s (Jan. 9, 2016) piece concerns itself with work from Israel and ‘sniffing out’ disease, according to a Dec. 30, 2016 news item in Sputnik News,

A team from the Israel Institute of Technology has developed a device that from a single breath can identify diseases such as multiple forms of cancer, Parkinson’s disease, and multiple sclerosis. While the machine is still in the experimental stages, it has a high degree of promise for use in non-invasive diagnoses of serious illnesses.

The international team demonstrated that a medical theory first proposed by the Greek physician Hippocrates some 2400 years ago is true, certain diseases leave a “breathprint” on the exhalations of those afflicted. The researchers created a prototype for a machine that can pick up on those diseases using the outgoing breath of a patient. The machine, called the Na-Nose, tests breath samples for the presence of trace amounts of chemicals that are indicative of 17 different illnesses.

A Dec. 22, 2016 Technion Israel Institute of Technology press release offers more detail about the work,

An international team of 56 researchers in five countries has confirmed a hypothesis first proposed by the ancient Greeks – that different diseases are characterized by different “chemical signatures” identifiable in breath samples. …

Diagnostic techniques based on breath samples have been demonstrated in the past, but until now, there has not been scientific proof of the hypothesis that different and unrelated diseases are characterized by distinct chemical breath signatures. And technologies developed to date for this type of diagnosis have been limited to detecting a small number of clinical disorders, without differentiation between unrelated diseases.

The study of more than 1,400 patients included 17 different and unrelated diseases: lung cancer, colorectal cancer, head and neck cancer, ovarian cancer, bladder cancer, prostate cancer, kidney cancer, stomach cancer, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, Parkinson’s disease (two types), multiple sclerosis, pulmonary hypertension, preeclampsia and chronic kidney disease. Samples were collected between January 2011 and June 2014 from in 14 departments at 9 medical centers in 5 countries: Israel, France, the USA, Latvia and China.

The researchers tested the chemical composition of the breath samples using an accepted analytical method (mass spectrometry), which enabled accurate quantitative detection of the chemical compounds they contained. 13 chemical components were identified, in different compositions, in all 17 of the diseases.

According to Prof. Haick, “each of these diseases is characterized by a unique fingerprint, meaning a different composition of these 13 chemical components.  Just as each of us has a unique fingerprint that distinguishes us from others, each disease has a chemical signature that distinguishes it from other diseases and from a normal state of health. These odor signatures are what enables us to identify the diseases using the technology that we developed.”

With a new technology called “artificially intelligent nanoarray,” developed by Prof. Haick, the researchers were able to corroborate the clinical efficacy of the diagnostic technology. The array enables fast and inexpensive diagnosis and classification of diseases, based on “smelling” the patient’s breath, and using artificial intelligence to analyze the data obtained from the sensors. Some of the sensors are based on layers of gold nanoscale particles and others contain a random network of carbon nanotubes coated with an organic layer for sensing and identification purposes.

The study also assessed the efficiency of the artificially intelligent nanoarray in detecting and classifying various diseases using breath signatures. To verify the reliability of the system, the team also examined the effect of various factors (such as gender, age, smoking habits and geographic location) on the sample composition, and found their effect to be negligible, and without impairment on the array’s sensitivity.

“Each of the sensors responds to a wide range of exhalation components,” explain Prof. Haick and his previous Ph.D student, Dr. Morad Nakhleh, “and integration of the information provides detailed data about the unique breath signatures characteristic of the various diseases. Our system has detected and classified various diseases with an average accuracy of 86%.

This is a new and promising direction for diagnosis and classification of diseases, which is characterized not only by considerable accuracy but also by low cost, low electricity consumption, miniaturization, comfort and the possibility of repeating the test easily.”

“Breath is an excellent raw material for diagnosis,” said Prof. Haick. “It is available without the need for invasive and unpleasant procedures, it’s not dangerous, and you can sample it again and again if necessary.”

Here’s a schematic of the study, which the researchers have made available,

Diagram: A schematic view of the study. Two breath samples were taken from each subject, one was sent for chemical mapping using mass spectrometry, and the other was analyzed in the new system, which produced a clinical diagnosis based on the chemical fingerprint of the breath sample. Courtesy: Tech;nion

There is also a video, which covers much of the same ground as the press release but also includes information about the possible use of the Na-Nose technology in the European Union’s SniffPhone project,

Here’s a link to and a citation for the paper,

Diagnosis and Classification of 17 Diseases from 1404 Subjects via Pattern Analysis of Exhaled Molecules by Morad K. Nakhleh, Haitham Amal, Raneen Jeries, Yoav Y. Broza, Manal Aboud, Alaa Gharra, Hodaya Ivgi, Salam Khatib, Shifaa Badarneh, Lior Har-Shai, Lea Glass-Marmor, Izabella Lejbkowicz, Ariel Miller, Samih Badarny, Raz Winer, John Finberg, Sylvia Cohen-Kaminsky, Frédéric Perros, David Montani, Barbara Girerd, Gilles Garcia, Gérald Simonneau, Farid Nakhoul, Shira Baram, Raed Salim, Marwan Hakim, Maayan Gruber, Ohad Ronen, Tal Marshak, Ilana Doweck, Ofer Nativ, Zaher Bahouth, Da-you Shi, Wei Zhang, Qing-ling Hua, Yue-yin Pan, Li Tao, Hu Liu, Amir Karban, Eduard Koifman, Tova Rainis, Roberts Skapars, Armands Sivins, Guntis Ancans, Inta Liepniece-Karele, Ilze Kikuste, Ieva Lasina, Ivars Tolmanis, Douglas Johnson, Stuart Z. Millstone, Jennifer Fulton, John W. Wells, Larry H. Wilf, Marc Humbert, Marcis Leja, Nir Peled, and Hossam Haick. ACS Nano, Article ASAP DOI: 10.1021/acsnano.6b04930 Publication Date (Web): December 21, 2016

Copyright © 2017 American Chemical Society

This paper appears to be open access.

As for SniffPhone, they’re hoping that Na-Nose or something like it will allow them to modify smartphones in a way that will allow diseases to be detected.

I can’t help wondering who will own the data if your smartphone detects a disease. If you think that’s an idle question, here’s an excerpt from Sue Halpern’s Dec. 22, 2016 review of two books (“Weapons of Math Destruction: How Big Data Increases Inequality and Threatens Democracy” by Cathy O’Neil and “Virtual Competition: The Promise and Perils of the Algorithm-Driven Economy” by Ariel Ezrachi and Maurice E. Stucke) for the New York Times Review of Books,

We give our data away. We give it away in drips and drops, not thinking that data brokers will collect it and sell it, let alone that it will be used against us. There are now private, unregulated DNA databases culled, in part, from DNA samples people supply to genealogical websites in pursuit of their ancestry. These samples are available online to be compared with crime scene DNA without a warrant or court order. (Police are also amassing their own DNA databases by swabbing cheeks during routine stops.) In the estimation of the Electronic Frontier Foundation, this will make it more likely that people will be implicated in crimes they did not commit.

Or consider the data from fitness trackers, like Fitbit. As reported in The Intercept:

During a 2013 FTC panel on “Connected Health and Fitness,” University of Colorado law professor Scott Peppet said, “I can paint an incredibly detailed and rich picture of who you are based on your Fitbit data,” adding, “That data is so high quality that I can do things like price insurance premiums or I could probably evaluate your credit score incredibly accurately.”

Halpern’s piece is well worth reading in its entirety.

Tattoo therapy for chronic disease?

It’s good to wake up to something truly new. In this case, it’s using tattoos and nanoparticles for medical applications. From a Sept. 22, 2016 news item on ScienceDaily,

A temporary tattoo to help control a chronic disease might someday be possible, according to scientists at Baylor College of Medicine [Texas, US] who tested antioxidant nanoparticles created at Rice University [Texas, US].

A Sept. 22, 2016 Rice University news release, which originated the news item, provides more information and some good explanations of the terms used (Note: Links have been removed),

A proof-of-principle study led by Baylor scientist Christine Beeton published today by Nature’s online, open-access journal Scientific Reports shows that nanoparticles modified with polyethylene glycol are conveniently choosy as they are taken up by cells in the immune system.

That could be a plus for patients with autoimmune diseases like multiple sclerosis, one focus of study at the Beeton lab. “Placed just under the skin, the carbon-based particles form a dark spot that fades over about one week as they are slowly released into the circulation,” Beeton said.

T and B lymphocyte cells and macrophages are key components of the immune system. However, in many autoimmune diseases such as multiple sclerosis, T cells are the key players. One suspected cause is that T cells lose their ability to distinguish between invaders and healthy tissue and attack both.

In tests at Baylor, nanoparticles were internalized by T cells, which inhibited their function, but ignored by macrophages. “The ability to selectively inhibit one type of cell over others in the same environment may help doctors gain more control over autoimmune diseases,” Beeton said.

“The majority of current treatments are general, broad-spectrum immunosuppressants,” said Redwan Huq, lead author of the study and a graduate student in the Beeton lab. “They’re going to affect all of these cells, but patients are exposed to side effects (ranging) from infections to increased chances of developing cancer. So we get excited when we see something new that could potentially enable selectivity.” Since the macrophages and other splenic immune cells are unaffected, most of a patient’s existing immune system remains intact, he said.

The soluble nanoparticles synthesized by the Rice lab of chemist James Tour have shown no signs of acute toxicity in prior rodent studies, Huq said. They combine polyethylene glycol with hydrophilic carbon clusters, hence their name, PEG-HCCs. The carbon clusters are 35 nanometers long, 3 nanometers wide and an atom thick, and bulk up to about 100 nanometers in globular form with the addition of PEG. They have proven to be efficient scavengers of reactive oxygen species called superoxide molecules, which are expressed by cells the immune system uses to kill invading microorganisms.

T cells use superoxide in a signaling step to become activated. PEG-HCCs remove this superoxide from the T cells, preventing their activation without killing the cells.

Beeton became aware of PEG-HCCs during a presentation by former Baylor graduate student Taeko Inoue, a co-author of the new study. “As she talked, I was thinking, ‘That has to work in models of multiple sclerosis,’” Beeton said. “I didn’t have a good scientific rationale, but I asked for a small sample of PEG-HCCs to see if they affected immune cells.

“We found they affected the T lymphocytes and not the other splenic immune cells, like the macrophages. It was completely unexpected,” she said.

The Baylor lab’s tests on animal models showed that small amounts of PEG-HCCs injected under the skin are slowly taken up by T lymphocytes, where they collect and inhibit the cell’s function. They also found the nanoparticles did not remain in T cells and dispersed within days after uptake by the cells.

“That’s an issue because you want a drug that’s in the system long enough to be effective, but not so long that, if you have a problem, you can’t remove it,” Beeton said. “PEG-HCCs can be administered for slow release and don’t stay in the system for long. This gives us much better control over the circulating half-life.”

“The more we study the abilities of these nanoparticles, the more surprised we are at how useful they could be for medical applications,” Tour said. The Rice lab has published papers with collaborators at Baylor and elsewhere on using functionalized nanoparticles to deliver cancer drugs to tumors and to quench the overproduction of superoxides after traumatic brain injuries.

Beeton suggested delivering carbon nanoparticles just under the skin rather than into the bloodstream would keep them in the system longer, making them more available for uptake by T cells. And the one drawback – a temporary but visible spot on the skin that looks like a tattoo – could actually be a perk to some.

“We saw it made a black mark when we injected it, and at first we thought that’s going to be a real problem if we ever take it into the clinic,” Beeton said. “But we can work around that. We can inject into an area that’s hidden, or use micropattern needles and shape it.

“I can see doing this for a child who wants a tattoo and could never get her parents to go along,” she said. “This will be a good way to convince them.”

The research was supported by Baylor College of Medicine, the National Multiple Sclerosis Society, National Institutes of Health, the Dan L. Duncan Cancer Center, John S. Dunn Gulf Coast Consortium for Chemical Genomics and the U.S. Army-funded Traumatic Brain Injury Consortium.

That’s an interesting list of funders at the end of the news release.

Here’s a link to and a citation for the paper,

Preferential uptake of antioxidant carbon nanoparticles by T lymphocytes for immunomodulation by Redwan Huq, Errol L. G. Samuel, William K. A. Sikkema, Lizanne G. Nilewski, Thomas Lee, Mark R. Tanner, Fatima S. Khan, Paul C. Porter, Rajeev B. Tajhya, Rutvik S. Patel, Taeko Inoue, Robia G. Pautler, David B. Corry, James M. Tour, & Christine Beeton. Scientific Reports 6, Article number: 33808 (2016) doi:10.1038/srep33808 Published online: 22 September 2016

This paper is open access.

Here’s an image provided by the researchers,

Polyethylene glycol-hydrophilic carbon clusters developed at Rice University were shown to be selectively taken up by T cells, which inhibits their function, in tests at Baylor College of Medicine. The researchers said the nanoparticles could lead to new strategies for controlling autoimmune diseases like multiple sclerosis. (Credit: Errol Samuel/Rice University) - See more at: http://news.rice.edu/2016/09/22/tattoo-therapy-could-ease-chronic-disease/#sthash.sIfs3b0S.dpuf

Polyethylene glycol-hydrophilic carbon clusters developed at Rice University were shown to be selectively taken up by T cells, which inhibits their function, in tests at Baylor College of Medicine. The researchers said the nanoparticles could lead to new strategies for controlling autoimmune diseases like multiple sclerosis. (Credit: Errol Samuel/Rice University)

Trojan horse nanoparticle for asthma

A brand new technique for dealing with asthma is being proposed by researchers at Northwestern University (US), according to an April 18, 2016 news item on ScienceDaily,

In an entirely new approach to treating asthma and allergies, a biodegradable nanoparticle acts like a Trojan horse, hiding an allergen in a friendly shell, to convince the immune system not to attack it, according to new Northwestern Medicine research. As a result, the allergic reaction in the airways is shut down long- term and an asthma attack prevented.

The technology can be applied to food allergies as well. The nanoparticle is currently being tested in a mouse model of peanut allergy, similar to food allergy in humans.

“The findings represent a novel, safe and effective long-term way to treat and potentially ‘cure’ patients with life-threatening respiratory and food allergies,” said senior author Stephen Miller, the Judy Gugenheim Research Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine. “This may eliminate the need for life-long use of medications to treat lung allergy.”

An April 18, 2016 Northwestern University news release (also on EurekAlert) by Marla Paul, which originated the news item, expands on the theme,

It’s the first time this method for creating tolerance in the immune system has been used in allergic diseases. The approach has been used in autoimmune diseases including multiple sclerosis and celiac disease in previous preclinical Northwestern research.

The asthma allergy study was in mice, but the technology is progressing to clinical trials in autoimmune disease. The nanoparticle technology is being developed commercially by Cour Pharmaceuticals Development Co., which is working with Miller to bring this new approach to patients. A clinical trial using the nanoparticles to treat celiac disease is in development.

“It’s a universal treatment,” Miller said. “Depending on what allergy you want to eliminate, you can load up the nanoparticle with ragweed pollen or a peanut protein.”

The nanoparticles are composed of an FDA-approved biopolymer called PLGA that includes lactic acid and glycolic acid.

Also a senior author is Lonnie Shea, adjunct professor of chemical and biological engineering at Northwestern’s McCormick School of Engineering and of obstetrics and gynecology at Feinberg, and chair of biomedical engineering at the University of Michigan.

When the allergen-loaded nanoparticle is injected into the bloodstream of mice, the immune system isn’t concerned with it because it sees the particle as innocuous debris. Then the nanoparticle and its hidden cargo are consumed by a macrophage, essentially a vacuum-cleaner cell.

“The vacuum-cleaner cell presents the allergen or antigen to the immune system in a way that says, ‘No worries, this belongs here,’” Miller said. The immune system then shuts down its attack on the allergen, and the immune system is reset to normal.

The allergen, in this case egg protein, was administered into the lungs of mice who have been pretreated to be allergic to the protein and already had antibodies in their blood against it. So when they were re-exposed to it, they responded with an allergic response like asthma. After being treated with the nanoparticle, they no longer had an allergic response to the allergen.

The approach also has a second benefit. It creates a more normal, balanced immune system by increasing the number of regulatory T cells, immune cells important for recognizing the airway allergens as normal. This method turns off the dangerous Th2 T cell that causes the allergy and expands the good, calming regulatory T cells.

If I understand this rightly, they’re rebalancing the immune system so it doesn’t treat innocuous material (dust, mould, etc.) as an allergen.

Here’s a link to and a citation for the paper,

Biodegradable antigen-associated PLG nanoparticles tolerize Th2-mediated allergic airway inflammation pre- and postsensitization by Charles B. Smarr, Woon Teck Yap, Tobias P. Neef, Ryan M. Pearson, Zoe N. Hunter, Igal Ifergan, Daniel R. Getts, Paul J. Bryce, Lonnie D. Shea, and Stephen D. Miller. PNAS 2016 doi: 10.1073/pnas.1505782113 Published ahead of print April 18, 2016,

This paper is behind a paywall.

Nanotechnology delivery system for skin disease therapies

A Feb. 29, 2016 news item on ScienceDaily announces a new development concerning free radicals that may be helpful with skin diseases and pathologies,

Researchers at The Hebrew University of Jerusalem have developed a nanotechnology-based delivery system containing a protective cellular pathway inducer that activates the body’s natural defense against free radicals efficiently, a development that could control a variety of skin pathologies and disorders.

A Feb. 29, 2016 Hebrew University of Jerusalem press release on EurekAlert, which originated the news item, expands on the theme,

The human skin is constantly exposed to various pollutants, UV rays, radiation and other stressors that exist in our day-to-day environment. When they filter into the body they can create Reactive Oxygen Species (ROS) – oxygen molecules known as Free Radicals, which are able to damage and destroy cells, including lipids, proteins and DNA.

In the skin – the largest organ of the body – an excess of ROS can lead to various skin conditions, including inflammatory diseases, pigmenting disorders, wrinkles and some types of skin cancer, and can also affect internal organs. This damage is known as Oxidative Stress.

The body is naturally equipped with defense mechanisms to counter oxidative stress. It has anti-oxidants and, more importantly, anti-oxidant enzymes that attack the ROS before they cause damage.

In a review article published in the journal Cosmetics, a PhD student from The Hebrew University of Jerusalem, working in collaboration with researchers at the Technion – Israel Institute of Technology, suggested an innovative way to invigorate the body to produce antioxidant enzymes, while maintaining skin cell redox balance – a gentle equilibrium between Reactive Oxygen Species and their detoxification.

“The approach of using the body’s own defense system is very effective. We showed that activation of the body’s defense system with the aid of a unique delivery system is feasible, and may leverage dermal cure,” said Hebrew University researcher Maya Ben-Yehuda Greenwald.

Ben-Yehuda Greenwald showed that applying nano-size droplets of microemulsion liquids containing a cellular protective pathway inducer into the skin activates the natural skin defense systems.

“Currently, there are many scientific studies supporting the activation of the body’s defense mechanisms. However, none of these studies has demonstrated the use of a nanotechnology-based delivery system to do so,” Ben-Yehuda Greenwald said.

Production of antioxidant enzymes in the body is signaled in the DNA by activation of Nrf2 – a powerful protein that exists in every cell in our body. This Nrf2 cellular-protective signaling pathway is a major intersection of many other signaling pathways affecting each other and determining cell functionality and fate. Nrf2 is capable of coordinating the cellular response to internal as well as external stressors by tight regulation of phase-II protective enzymes, such as the antioxidant enzymes.

Ben-Yehuda Greenwald has also discovered a new family of compounds capable of activating the Nrf2 pathway. Moreover, by incorporating them into the unique delivery system she has developed, she managed to efficiently stimulate the activation of the Nrf2 pathway and mimic the activity of the body’s’ natural way of coping with a variety of stress conditions.

“The formula we have created could be used in topical medication for treating skin conditions. Our formula could be used both as preventive means and for treatment of various skin conditions, such as infections, over-exposure to UV irradiation, inflammatory conditions, and also internal disease,” she said.

While the researchers focused on the skin, the formulation could prove to be effective in enhancing the body’s natural protection against the damaging effects of ROS in other parts of the body, such as inflammation in cardiovascular diseases, heart attack, cancer, multiple sclerosis and Alzheimer’s.

Here’s an image provided by Ben-Yehuda Greenwald illustrating the team’s work,

Caption: These are the consequences of skin exposure to stressors. Credit: Maya Ben-Yehuda Greenwald

Caption: These are the consequences of skin exposure to stressors. Credit: Maya Ben-Yehuda Greenwald

Here’s a link to and a citation for the paper,

Skin Redox Balance Maintenance: The Need for an Nrf2-Activator Delivery System by Maya Ben-Yehuda Greenwald, Shmuel Ben-Sasson, Havazelet Bianco-Peled, and Ron Kohen. Cosmetics 2016, 3(1), 1; doi:10.3390/cosmetics3010001 Published: 15 January 2016

This paper appears to be open access.

Parvus Therapeutics (Calgary, Canada) and reprogramming immune cells

An international collaboration of Canadian, Spanish, and US scientists has announced a new therapeutic approach which could reverse autoimmune diseases in a Feb. 17, 2016 news item on Nanotechnology Now,

• Nanotechnology Approach Restores Glucose Regulation and Motor Function in In Vivo Preclinical Models of Diabetes and Multiple Sclerosis, Respectively; Joint Swelling and Destruction Resolved in In Vivo Model of Rheumatoid Arthritis
• Parvus’ Approach Can Be Tailored to Treat Diverse Diseases

A Feb. 17, 2016 Parvus Therapeutics news release (also on EurekAlert), which originated the news item, provides more detail and a strong orientation to marketing communication,

Parvus Therapeutics today announced the publication in Nature of a seminal paper describing the discovery and applications of a novel therapeutic approach employing nanomedicines, referred to as “Navacims”TM, to reprogram white blood cells to become regulatory cells capable of blunting autoimmune responses and restoring the equilibrium of the immune system. Navacims are nanoparticles (NPs) coated with disease-relevant peptide-major histocompatibility complexes (pMHCs) that alter the behavior of pathogenic T lymphocytes by binding directly to their antigen receptors. The peer-reviewed article, titled “Expanding antigen-specific regulatory networks to treat autoimmunity” reports on a body of work, including results in multiple in vivo disease models, built on more than eight years of research by Parvus Founder and Chief Scientific Officer, Pere Santamaria, M.D., Ph.D.

Dr. Santamaria commented, “Autoimmune diseases, including type 1 diabetes, multiple sclerosis, and rheumatoid arthritis, are extraordinarily complex responses of our immune system against some of our own tissues (e.g. pancreas, brain and joints, respectively), leading to chronic organ inflammation, organ dysfunction, and, in some cases, premature death. Blunting these incompletely understood immune responses without suppressing the normal components of our immune system that protect us against infection and cancer is not currently possible.”

“However, our work offers a pharmaceutical solution to this fundamental problem,” Dr. Santamaria continued. “Navacims essentially re-program disease-causing white blood cells to become disease-suppressing cells, known as regulatory cells, leading to sustained therapeutic effects in various spontaneous and experimental autoimmune diseases, as reported in our article in Nature. Essentially, we have found that Navacims can be tailored to treat a wide range of autoimmune diseases, while sharing a common structure. Importantly, they have been shown to affect human white blood cells in the same manner as they do murine cells. Furthermore, Navacims have shown promising safety findings in preclinical in vivo models. Based on our results to date, we believe Navacims represent a therapeutic platform with broad-ranging health care implications.”

Findings being reported in Nature include:

pMHC class II Navacims expanded cognate CD4+ T-cells that consistently have a TR1-like, regulatory T cell surface phenotype, transcriptional pattern and cytokine profile (mouse=human TR1 cells) systemically.

pMHC class II-Navacims designed to target T cells in newly diabetic nonobese (NOD) mice restored normoglycemia (normal blood sugar regulation) in the majority of the mice tested.

Tailored pMHC class II Navacims restored motor function to paralyzed C57BL/6 mice at the peak of Experimental Autoimmune Encephalomyelitis (a model of Multiple Sclerosis).

pMHC class II Navacims, targeting disease-causing T cells in joints, resolved joint swelling and destruction in arthritic mice.

“The findings being reported in Nature represent a scientific advance for Parvus and also a major achievement in the field of Immunology,” said Janice M. LeCocq, CEO of Parvus. “We believe that Dr. Santamaria’s work has the potential to transform the treatment of many of the more than 80 major autoimmune diseases affecting humankind, alleviating the suffering of millions of patients and their families. Over the coming year, we will be dedicating much of our in-house efforts to the advancement of our two lead programs for type 1 diabetes and multiple sclerosis.”

“Dr. Santamaria’s work to target the immune system dysfunction that causes type 1 diabetes represents the kind of innovative work that JDRF believes will eventually get us to a cure for this disease,” said Juvenile Diabetes Research Foundation Vice President of Discovery Research Julia Greenstein, Ph.D. “He and his colleagues have made exciting progress towards possibly developing a new class of drugs that could rebalance certain T-cells and ultimately provide a cure for type 1 diabetes and other autoimmune diseases as well.” The JDRF has funded the work of Dr. Santamaria and his colleagues at Parvus to explore Navacim-based treatments for diabetes.

Parvus’ strategy is to establish partnerships with major pharmaceutical companies to undertake the clinical and commercial development of many of its product pipeline candidates while also reserving rights to others suitable for its own development and commercialization. Parvus currently is engaged in late stage discussions with multiple pharmaceutical companies with regard to the type 1 diabetes (T1D) program. Manufacturing scale-up is now underway to supply upcoming preclinical and clinical studies.

The work being reported in Nature was led by Dr. Pere Santamaria and largely executed at the University of Calgary, Cumming School of Medicine (animal models of disease) and the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (humanized mouse work), with significant contributions from investigators at Institutions in Europe and the US. Further, Innovate Calgary, the technology-transfer and business-incubation center for the University of Calgary, provided early support for the transfer of the Navacims technology to and incubation of Parvus Therapeutics, which was organized as a separate entity in 2012.

It should be noted that this intervention has been tested on ‘humanized’ mice and, at this point, there don’t seem to have been any human clinical trials. At a guess I’d say we’re still several years away from this therapeutic intervention reaching the market, should it prove to be successful in humans.

Here’s a link to and a citation for the paper,

Expanding antigen-specific regulatory networks to treat autoimmunity by Xavier Clemente Casares, Jesus Blanco, Poornima Ambalavanan, Jun Yamanouchi, Santiswarup Singha, Cesar Fandos, Sue Tsai, Jinguo Wang, Nahir Garabatos, Cristina Izquierdo, Smriti Agrawal, Michael B. Keough, V. Wee Yong, Eddie James, Anna Moore, Yang Yang, Thomas Stratmann, Pau Serra, & Pere Santamaria. Nature (2016) doi:10.1038/nature16962 Published online 17 February 2016

This paper is behind a paywall.

Herbicide nanometric sensor could help diagnose multiple sclerosis

This research into nanometric sensors and multiple sclerosis comes from Brazil. According to a June 23, 2015 news item on Nanowerk (Note: A link has been removed),

The early diagnosis of certain types of cancer, as well as nervous system diseases such as multiple sclerosis and neuromyelitis optica, may soon be facilitated by the use of a nanosensor capable of identifying biomarkers of these pathological conditions (“A Nanobiosensor Based on 4-Hydroxyphenylpyruvate Dioxygenase Enzyme for Mesotrione Detection”).

The nanobiosensor was developed at the Federal University of São Carlos (UFSCar), Sorocaba, in partnership with the São Paulo Federal Institute of Education, Science & Technology (IFSP), Itapetininga, São Paulo State, Brazil. It was originally designed to detect herbicides, heavy metals and other pollutants.

A June 23, 2015 Fundação de Amparo à Pesquisa do Estado de São Paulo news release on EurekAlert, which originated the news item, describes the sensor as it was originally used and explains its new function as a diagnostic tool for multiple sclerosis and other diseases,

“It’s a highly sensitive device, which we developed in collaboration with Alberto Luís Dario Moreau, a professor at IFSP. “We were able to increase sensitivity dramatically by going down to the nanometric scale,” said physicist Fábio de Lima Leite, a professor at UFSCar and the coordinator of the research group.

The nanobiosensor consists of a silicon nitride (Si3N4) or silicon (Si) nanoprobe with a molecular-scale elastic constant and a nanotip coupled to an enzyme, protein or other molecule.

When this molecule touches a target of interest, such as an antibody or antigen, the probe bends as the two molecules adhere. The deflection is detected and measured by the device, enabling scientists to identify the target.

“We started by detecting herbicides and heavy metals. Now we’re testing the device for use in detecting target molecules typical of nervous system diseases, in partnership with colleagues at leading centers of research on demyelinating diseases of the central nervous system”

The migration from herbicide detection to antibody detection was motivated mainly by the difficulty of diagnosing demyelinating diseases, cancer and other chronic diseases before they have advanced beyond an initial stage.

The criteria for establishing a diagnosis of multiple sclerosis or neuromyelitis optica are clinical (supplemented by MRI scans), and patients do not always present with a characteristic clinical picture. More precise diagnosis entails ruling out several other diseases.

The development of nanodevices will be of assistance in identifying these diseases and reducing the chances of false diagnosis.

The procedure can be as simple as placing a drop of the patient’s cerebrospinal fluid on a glass slide and observing its interaction with the nanobiosensor.

“If the interaction is low, we’ll be able to rule out multiple sclerosis with great confidence,” Leite said. “High interaction will indicate that the person is very likely to have the disease.” In this case, further testing would be required to exclude the possibility of a false positive.

“Different nervous system diseases have highly similar symptoms. Multiple sclerosis and neuromyelitis optica are just two examples. Even specialists experience difficulties or take a long time to diagnose them. Our technique would provide a differential diagnostic tool,” Leite said.

The next step for the group is to research biomarkers for these diseases that have not been completely mapped, including antibodies and antigens, among others. The group has begun tests for the detection of head and neck cancer.

Here’s a link to and a citation for the paper,

A Nanobiosensor Based on 4-Hydroxyphenylpyruvate Dioxygenase Enzyme for Mesotrione Detection by P. Soto Garcia, A.L.D Moreau, J.C. Magalhaes Ierich,  A.C Araujo Vig, A.M. Higa, G.S. Oliveira, F. Camargo Abdalla, M. Hausen, & F.L. Leite. Sensors Journal, IEEE  (Volume:15 ,  Issue: 4) pp. 2106 – 2113 Date of Publication: 20 November 2014 Date of Current Version: 27 January 2015 Issue Date: April 2015  DOI 10.1109/JSEN.2014.2371773

This paper is behind a paywall.

Multiple sclerosis stopped by a biodegradable nanoparticle?

Researchers at Northwestern University (Chicago, Illinois) have halted the progress of multiple sclerosis in mice. The Nov. 18, 2012 Northwestern University news release on EurekAlert provides more details,

In a breakthrough for nanotechnology and multiple sclerosis, a biodegradable nanoparticle turns out to be the perfect vehicle to stealthily deliver an antigen that tricks the immune system into stopping its attack on myelin and halt a model of relapsing remitting multiple sclerosis (MS) in mice, according to new Northwestern Medicine research.

In MS, the immune system attacks the myelin membrane that insulates nerves cells in the brain, spinal cord and optic nerve. When the insulation is destroyed, electrical signals can’t be effectively conducted, resulting in symptoms that range from mild limb numbness to paralysis or blindness. About 80 percent of MS patients are diagnosed with the relapsing remitting form of the disease.

The Northwestern nanotechnology does not suppress the entire immune system as do current therapies for MS, which make patients more susceptible to everyday infections and higher rates of cancer. Rather, when the nanoparticles are attached to myelin antigens and injected into the mice, the immune system is reset to normal. The immune system stops recognizing myelin as an alien invader and halts its attack on it.

“This is a highly significant breakthrough in translational immunotherapy,” said Stephen Miller, a corresponding author of the study and the Judy Gugenheim Research Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine. “The beauty of this new technology is it can be used in many immune-related diseases. We simply change the antigen that’s delivered.”

“The holy grail is to develop a therapy that is specific to the pathological immune response, in this case the body attacking myelin,” Miller added. “Our approach resets the immune system so it no longer attacks myelin but leaves the function of the normal immune system intact.”

The nanoparticle, made from an easily produced and already FDA-approved substance, was developed by Lonnie Shea, professor of chemical and biological engineering at Northwestern’s McCormick School of Engineering and Applied Science.

There are human clinical trials taking place now (from the news release),

The study’s method is the same approach now being tested in multiple sclerosis patients in a phase I/II clinical trial — with one key difference. The trial uses a patient’s own white blood cells — a costly and labor intensive procedure — to deliver the antigen. The purpose of the new study was to see if nanoparticles could be as effective as the white blood cells as delivery vehicles. They were.

For interested parties, here’s the full citation for the article and a link,

Microparticles bearing encephalitogenic peptides induce T-cell tolerance and ameliorate experimental autoimmune encephalomyelitis” by Daniel R Getts, Aaron J Martin, Derrick P McCarthy, Rachael . Terry, Zoe N Hunter, Woon Teck Yap, Meghann Teague Getts, Michael Pleiss, Zunrong Luo, Nicholas JC King, Lonnie D Shea and Stephen D Miller in Nature Biotechnology (2012) doi:10.1038/nbt.2434

The article is behind a paywall.  I found these details  in the news release about how the antigen and nanoparticles work with the immune system particularly interesting,

In the study, researchers attached myelin antigens to the nanoparticles and injected them intravenously into the mice. The particles entered the spleen, which filters the blood and helps the body dispose of aging and dying blood cells. There, the particles were engulfed by macrophages, a type of immune cell, which then displayed the antigens on their cell surface. The immune system viewed the nanoparticles as ordinary dying blood cells and nothing to be concerned about. This created immune tolerance to the antigen by directly inhibiting the activity of myelin responsive T cells and by increasing the numbers of regulatory T cells which further calmed the autoimmune response.

“The key here is that this antigen/particle-based approach to induction of tolerance is selective and targeted. Unlike generalized immunosuppression, which is the current therapy used for autoimmune diseases, this new process does not shut down the whole immune system,” said Christine Kelley, National Institute of Biomedical Imaging and Bioengineering director of the division of Discovery Science and Technology at the National Institutes of Health, which supported the research.

All in all, this seems a gentler approach to the disease.

More than the “Emperor’s New Clothes” insight

Happy 2010 to all! I’ve taken some time out as I have moved locations and it’s taken longer to settle down that I hoped. (sigh) I still have loads to do but can get back to posting regularly (I hope).

New Year’s Eve I came across a very interesting article about how scientists think thanks to a reference on the Foresight Institute website. The article, Accept Defeat: The Neuroscience of Screwing Up, by Jonah Lehrer for Wired Magazine uses a story about a couple of astronomers and their investigative frustrations to illustrate research on how scientists (and the rest of us, as it turns out) think.

Before going on about the article I’m going to arbitrarily divide beliefs about scientific thinking/processes into two schools. In the first there’s the scientific method with its belief in objectivity and incontrovertible truths waiting to be discovered and validated. Later in university I was introduced to the 2nd belief about scientific thinking with the notion that scientific facts are social creations and that objectivity does not exist. From the outside it appears that scientists tend to belong to the first school and social scientists to the second but, as the Wired article points out, things are a little more amorphous than that when you dig down into the neuroscience of it all.

From the article,

The reason we’re so resistant to anomalous information — the real reason researchers automatically assume that every unexpected result is a stupid mistake — is rooted in the way the human brain works. Over the past few decades, psychologists [and other social scientists] have dismantled the myth of objectivity. The fact is, we carefully edit our reality, searching for evidence that confirms what we already believe. Although we pretend we’re empiricists — our views dictated by nothing but the facts — we’re actually blinkered, especially when it comes to information that contradicts our theories. The problem with science, then, isn’t that most experiments fail — it’s that most failures are ignored.

The DLPFC [dorsolateral prefrontal cortex] is constantly censoring the world, erasing facts from our experience. If the ACC  [anterior cingulate cortex, typically associated with errors and contradictions]] is the “Oh shit!” circuit, the DLPFC is the Delete key. When the ACC and DLPFC “turn on together, people aren’t just noticing that something doesn’t look right,” [Kevin] Dunbar says. “They’re also inhibiting that information.”

Disregarding evidence is something I’ve noticed (in others more easily than in myself) and have wondered about the implications. As noted in the article, ignoring scientific failure stymies research and ultimately more effective applications for the research. For example, there’s been a lot of interest in a new surgical procedure (still being tested) for patients with multiple sclerosis (MS). The procedure was developed by an Italian surgeon who (after his wife was stricken with the disease) reviewed literature on the disease going back 100 years and found a line of research that wasn’t being pursued actively and was a radical departure from current accepted beliefs about the nature of MS. (You can read more about the MS work here in the Globe and Mail story or here in the CBC story.) Btw, there are a couple of happy endings. The surgeon’s wife is much better and a promising new procedure is being examined.

Innovation and new research can be so difficult to pursue it’s amazing that anyone ever succeeds. Kevin Dunbar, the researcher mentioned previously, arrived at a rather interesting conclusion in his investigation on how scientists think and how they get around the ACC/DLFPC action: other people.  He tells a story about two lab groups who each had a meeting,

Dunbar watched how each of these labs dealt with their protein problem. The E. coli group took a brute-force approach, spending several weeks methodically testing various fixes. “It was extremely inefficient,” Dunbar says. “They eventually solved it, but they wasted a lot of valuable time.”The diverse lab, in contrast, mulled the problem at a group meeting. None of the scientists were protein experts, so they began a wide-ranging discussion of possible solutions. At first, the conversation seemed rather useless. But then, as the chemists traded ideas with the biologists and the biologists bounced ideas off the med students, potential answers began to emerge. “After another 10 minutes of talking, the protein problem was solved,” Dunbar says. “They made it look easy.”

When Dunbar reviewed the transcripts of the meeting, he found that the intellectual mix generated a distinct type of interaction in which the scientists were forced to rely on metaphors and analogies [my emphasis] to express themselves. (That’s because, unlike the E. coli group, the second lab lacked a specialized language that everyone could understand.) These abstractions proved essential for problem-solving, as they encouraged the scientists to reconsider their assumptions. Having to explain the problem to someone else forced them to think, if only for a moment, like an intellectual on the margins, filled with self-skepticism.

As Dunbar notes, we usually need more than an outsider to experience a Eureka moment (the story about Italian surgeon notwithstanding and it should be noted that he was an MS outsider); we need metaphors and analogies. (I’ve taken it a bit further than Dunbar likely would but I am a writer, after all.)

If you are interested in Dunbar’s work, he’s at the University of Toronto with more information here.