Investigators Add New Insights to Lyme Disease Diagnosis and Treatment

tick.jpgWith the number of reported Lyme disease infections expected to reach record highs in 2017, Massachusetts General Hospital researchers are helping to meet the need for new diagnostic tools and treatments.

The work of John Branda, MD, and Allen Steele, MD, was recently featured on the Mass General Giving Website. Here is a brief summary of the article, which you can find in full here.

A New Test for Lyme Disease

Lyme disease is caused by the bacterium Borrelia burgdorferi (B. burgdorferi), which is transmitted to humans through the bite of an infected blacklegged tick, commonly known as a deer tick. The tick must be attached for 36 to 48 hours or more before the Lyme disease bacterium can be transmitted.

As with many infectious diseases, early detection plays a key role in treatment. John Branda, MD, associate director of the Clinical Microbiology Laboratory at Mass General, and his colleagues are developing a new way to diagnose Lyme disease, as current blood tests frequently yield false negative results in the weeks after infection.

The team’s new testing technique starts with a blood sample that is first amplified by polymerase chain reaction technology, a method that can make the genetic material of a pathogen such as B. burgdorferi more easily identifiable.

Then the blood is then scanned with magnetic resonance imaging, which can quickly pick up the Borrelia DNA. The test, known as T2MR, was able to detect B. burgdorferi in blood samples from patients who were suspected of having Lyme disease but had tested negative using traditional techniques.

Genetic Factors

In a separate research study, Allen Steere, MD, a Mass General rheumatologist and the researcher who led the team that first identified Lyme disease in the 1970s, is exploring why some patients do not recover from the disease even after receiving a course of antibiotics.

While the antibiotics are able to clear the infection, some patients still experience pain, fatigue and neurocognitive symptoms. A few patients can go on to suffer from antibiotic-refractory Lyme arthritis — a painful inflammation of the joints that long outlasts the infection.

In these patients, there is mounting evidence that Lyme disease triggers an abnormal immune response, which in turn attacks the tissues of the joints, even after B. burgdorferi has been cleared by antibiotics.

Dr. Steere believes that many more severe cases may result when people with a specific genetic profile encounter a particularly virulent strain of the bacterium.

When genetic susceptibility and virulent B. burgdorferi strains combine, as they do in as many as 20% of people of Caucasian ancestry who are infected with Lyme disease, ideal conditions are created for an amplified and maladaptive inflammatory response that can attack joint tissues.

To learn more about the symptoms and causes of Lyme disease, and for tips on protecting yourself from tick bites, please visit the Centers for Disease Control’s Lyme disease website.

A Snapshot of Science: A New Approach to Targeted Cancer Treatments, Identifying Genes that Help Protect the Gut and Much More!

We wanted to share some recent Massachusetts General Hospital research that has been published in high impact, top-tier journals. This is just a small snapshot of the incredible research that takes place at Mass General each day — there’s lots more to find on the Mass General website!


Cognitive Decline, Tau and β-Amyloid in Healthy Older Adults
(Summary submitted by Rachel Buckley, PhD, and Rebecca Amariglio, PhD, both of the Martinos Center for Biomedical Imaging)

We published findings from the Harvard Aging Brain Study (Department of Neurology, Massachusetts General Hospital) investigating the link between subjective memory complaints (when a patient reports a worsening of their thinking abilities, including memory) and Alzheimer’s disease pathology in individuals who are otherwise cognitively normal. We found that increasing memory complaints were linked with greater amounts of tau in the brain, a naturally occurring protein that is associated with neuron loss in Alzheimer’s disease. We posit that memory complaints are a very early marker of disease, as they relate to tau build up before clinical tests can detect memory impairment.

Region-Specific Association of Subjective Cognitive Decline With Tauopathy Independent of Global β-Amyloid Burden
Buckley RF, Hanseeuw B, Schultz AP, Vannini P, Aghjayan SL, Properzi MJ, [et al.] Amariglio RE
Published in JAMA Neurology on October 2, 2017


New Approach to Targeted Cancer Treatment 
(Summary submitted by Conor L. Evans, PhD, of the Wellman Center for Photomedicine)

We have created a promising new light-activated, cancer-targeting therapeutic. Cancer drugs often cannot reach every cell in a tumor, leaving behind cells that can become resistant to treatment. At the same time, these drugs can cause unwanted systemic problems, such as weight and hair loss, elsewhere in the patient’s body. Our therapeutic was built to diffuse throughout tumors, target cancer cells, and kill these cells only when activated by light to avoid unwanted and burdensome side effects. We hope that this approach could one day find use in the fight against treatment-resistant cancers, like breast and lung.

An Integrin-Targeted, Highly Diffusive Construct for Photodynamic Therapy
Klein OJ, Yuan H, Nowell NH, Kaittanis C, Josephson L, Evans CL
Published in Scientific Reports on October 17, 2017


Identifying Genes that Help Protect the Gut 
(Summary submitted by Javier Elbio Irazoqui, PhD, formerly of the Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease)

The intestinal epithelium is a single layer of cells that protects the gut from environmental insult. Defects in this layer are linked to many diseases, including inflammatory bowel disease. Despite its critical importance, very little is known about the genes in the epithelium involved in this function. We found that transcription factor TFEB, a master regulator of lysosomal gene expression, provides a protective effect, and this function is mediated by expression of apolipoprotein A1, the major constituent of HDL, aka “good” cholesterol. Our findings suggest that enhancement of TFEB activity in the intestinal epithelium could be a therapeutic approach to enhance Apolipoprotein A1 expression for the treatment of inflammatory bowel disease.

Transcription Factor TFEB Cell-Autonomously Modulates Susceptibility to Intestinal Epithelial Cell Injury In Vivo
Murano T, Najibi M, Paulus GLC, Adiliaghdam F, Valencia-Guerrero A, Selig M, [et al.] Xavier RJ, Lassen KG, Irazoqui JE
Published in Scientific Reports on October 24, 2017


Patient Resistance to Immune Checkpoint Blockade Therapies
(Summary submitted by Nir Hacohen, PhD, of the Cancer Center)

Cancer therapy has been transformed in the last few years by immune-based therapies, called ‘checkpoint blockade’ therapies. An important question is why some people respond and others do not respond to this therapy. By analyzing the DNA of tumors from patients who developed resistance to checkpoint therapy, we found changes in the DNA of a key gene that is critical for tumors to be detected by the immune system. In this way, the tumor has learned how to hide from the immunotherapy. Knowing this will help us decide which patients would benefit from immune therapy. Finding ways to make these resistant tumors visible to the immune system is an important goal for the coming years.

Resistance to Checkpoint Blockade Therapy Through Inactivation of Antigen Presentation
Sade-Feldman M, Jiao YJ, Chen JH, Rooney MS, Barzily-Rokni M, Eliane JP, [et al.] Flaherty KT, Sullivan RJ, Hacohen N
Published in Nature Communications on October 26, 2017

Pocket-Sized Device Provides Food Allergy Sufferers with Life-Saving Tableside Lab Results

If you’re among the 50 million Americans with a severe allergy to foods like gluten or nuts, every meal at a restaurant can feel like a potential land mine. Even if the restaurant has made an effort to provide dishes that are allergen-free, worries of cross-contamination and a subsequent severe or potentially life threatening reaction can still put a damper on your dinner plans.

To help ease concerns and keep food allergy sufferers safe, a team at Massachusetts General Hospital has developed a new device small enough to fit on a keyring that costs only $40 and can quickly and accurately test for food allergens.

While advances have been made in the packaged food industry, where new federal regulations require the manufacturer to disclose whether the product is made in a facility that also processes common allergens, these disclosures are not always accurate and there are no similar regulations for the restaurant industry.

Rather than force diners to completely avoid foods that have the chance of containing an allergen, or eat something only to regret it later, Mass General researchers created integrated exogenous antigen testing (iEAT), a pocket-sized device that can accurately analyze food for the presences of allergens in less than 10 minutes. Specifically, the device can screen for peanuts, hazelnuts, wheat, milk and eggs.

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The iEAT system

Developed by co-senior team leaders Ralph Weissleder, MD, PhD, Director of the Center for Systems Biology (CSB) at Mass General and Hakho Lee, PhD, Hostetter MGH Research Scholar and Director of the Biomedical Engineering Program at the CSB, the device consists of three components:

  1. A small plastic test tube that the user can put a small sample of food into. The tube contains a solution that dissolves the sample and adds magnetic beads to the solution. The beads are designed to bind to the food allergen of interest.
  2. The user can then drop the solution onto an electrode chip, which is inserted into the keychain sized reader.
  3. The reader analyzes the sample and indicates on a small display whether the allergen is present, and if so, in what concentration.

Testing performed by the research team showed that measurements of the concentration of the allergen is extremely accurate. In fact, the device could detect levels of gluten that were 200 times lower than the federal standard. Accuracy is key because everyone’s sensitivity varies — some individuals could experience a reaction after consuming a miniscule trace of an allergen.

Weissleder and Lee have also developed a smartphone app to complement iEAT. With the app, users can compile and store the data they collect as they test different foods for various allergens at different restaurants and even in packaged foods. The app is set up to share this information online so others with the app will be able to find restaurants with foods that consistently have no or low levels that are below the individual’s triggering concentration.

cell phone app

Consumers may be able to purchase the $40 iEAT device and corresponding app in the near future — the research team has granted a license to a local start-up company to make the system commercially available. Weissleder and Lee also report that they could apply this technology to detect other substances in food such as MSG or even pesticides.

This research was recently highlighted in an NIH article and published in ACS Nano.

It was also recently featured in a news story on CBS Boston.

Could the Microbiome be the Key to Ending Chemotherapy-Induced Pain?

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Most of us have experienced the odd sensation of “pins and needles” in our hands or feet. While annoying and painful, the sensation usually goes away quickly.

But for many people with peripheral neuropathy, a disorder involving increased sensitivity of nerves outside of the brain and spinal cord, this experience may linger for months to years.

“It’s a horrible condition,” said Shiqian Shen, MD, clinical investigator in the Massachusetts General Hospital Center for Translational Pain Research and director of the Mass General TelePain Program. “You literally want to shake off your leg, but you can’t.”

Unfortunately, a third of cancer patients who receive chemotherapy encounter this as a side effect, a condition known as chemotherapy-induced peripheral neuropathy (CIPN). This neuropathy is a result of nerve damage or impairment of the nervous system and often is chronic. If the pain is severe enough, chemotherapy dosages must be lowered, which causes the treatment to be less effective.

With the survival rates for many cancers increasing due to the improved understanding of genetic mutations, targeted therapies and immunotherapy, CIPN has become a major challenge and can hurt a survivor’s quality of life.

Dr. Shen and Jianren Mao, MD, PhD, chief of the Mass General Pain Management Center and vice chair for research in the Department of Anesthesia, Critical Care and Pain Medicine, are leading a research team in exploring why patients undergoing chemotherapy develop CIPN.

There is strong evidence that the gut, which carries about 10 trillion bacteria, has a major impact on the central nervous system. Previous research in the field has also shown that gut microbiota plays a critical role in the tumor-killing effect of many chemotherapeutics drugs. In a recent study published in Nature Neuroscience, the researchers questioned whether an immune response that results from interactions between chemotherapy drugs and the bacteria in the microbiome also plays a role in developing CIPN.

The researchers exposed two sets of mice, one with a normal microbiome and one that had their microbiome essentially eliminated through antibiotic treatments or genetic engineering, to oxaliplatin—a chemotherapy drug used to treat colon or rectal cancer and that is known to cause CIPN. The normal mice manifested symptoms of CIPN while those without a microbiome did not. Therefore, a microbiome is necessary for CIPN symptoms to manifest.

Next, the team dug into why the microbiome influences the onset of CIPN.

The researchers determined that the mice who experienced CIPN had higher levels of two proteins involved in inflammation (IL-6 and TNFalpha) in the dorsal root ganglia (DRG). This inflammatory response in the DRG leads to an increase in neuron sensitivity, which is what causes the neuropathy pain and tingling in a person’s extremities.

The team found further evidence that suggests a reaction between the chemotherapy agent and bacteria in the microbiome, releases lipopolysaccharides (LPS), a molecule found in bacteria on the gut lining, into the bloodstream. LPS then appears to cause a chain reaction that increases the levels of the two inflammatory proteins in the DRG.

“We found there’s a concurrent response—one initiated by the chemotherapy agent, and one by the inflammatory response,” said Shen. “They work hand in hand to promote the pain.”

However, there is a dilemma to sort out. Previous research has found that chemotherapy treatments such as oxaliplatin and cyclophosphamide are dependent on the gut microbiome. Meaning chemotherapy does not work well without help from a normal microbiome, but having it runs the risk of developing CIPN.

“Our research has revealed that you cannot get rid of the gut microbiome entirely to prevent side-effects because your therapeutic effect is also linked to the same presence,” says Shen.

The researchers are conducting follow-up studies to see if the same results are found in humans, and to see whether the same phenomenon exists in other type of neuropathic pain.

Potential in the Clinic

Since eliminating a cancer patient’s microbiome will essentially render chemotherapy treatment ineffective, more research will need to be done to see if investigators can determine if and how an individual’s microbiome composition affects their likelihood of developing CIPN. If they can identify favorable bacteria profiles, clinicians may be able to reduce the risk of developing CIPN by prescribing probiotics or fecal transplants in advance of starting chemotherapy. On the flipside, knowing the optimal microbiome profile that reduces risk of CIPN for every chemotherapy agent may help oncologists select the ideal chemotherapy drug for each patient.

Kamryn Eddy Finds Hope for Patients with Eating Disorders

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The people we encounter early in life can often have a profound impact on our future. For Massachusetts General Hospital psychologist Dr. Kamryn Eddy, a childhood friend influenced her career trajectory.

“I had a close friend in high school who had anorexia,” says Dr. Eddy. “As a result, she had a number of health concerns, including osteoporosis, and was told at age 16 that she would never be able to have children.”

She recalls being shocked that a doctor would give such a definitive and dire prognosis to someone so young. Eddy has kept in touch with her friend, who found help for her eating disorder and was eventually able to recover. Her friend now has a healthy young daughter.

“That early experience was one of my introductions to the world of eating disorders,” says Eddy. “Seeing my friend’s battle and eventual recovery from her illness also showed me that there can be hope for people suffering from eating disorders.” Continue reading “Kamryn Eddy Finds Hope for Patients with Eating Disorders”

Research Awards and Honors: October 2017

Massachusetts General Hospital’s talented and dedicated researchers are working to push the boundaries of science and medicine every day. In this series we highlight a few individuals who have recently received awards or honors for their achievements:

Deepak Balani.jpg

Deepak Balani, DMD, PhD, research fellow in the Endocrine Unit, has received the 2017 American Society for Bone and Mineral Research (ASBMR) Young Investigator Award. The award recognizes young investigators who submit top-ranking abstracts to an ASBMR Meeting. Balani received the award and a plaque at the ASBMR annual meeting in September.

“ASBMR is one of the top scientific societies primarily established to bring together clinical and experimental scientists involved in the study of bone and mineral metabolism. ASBMR organizes an annual meeting that invites top scientists from all over the globe. Getting chosen as one of the top abstracts and presenting my work in front of such a talented audience is very gratifying. For years Endocrine Unit of the Massachusetts General Hospital has been at the forefront of bone biology research. I am extremely happy that I have taken part in continuing this tradition.”

 

Alex Soukas.jpg

Alex Soukas, MD, PhD, of the Diabetes Unit and the Center for Genomic Medicine, has received the Glenn Award for Research in Biological Mechanisms of Aging. The award provides unsolicited funds to researchers investigating the biology of aging. The mission of the Glenn Foundation for Medical Research is to extend the healthy years of life through research on mechanisms of biology that govern normal human aging and its related physiological decline, with the objective of translating research into interventions that will extend healthspan with lifespan. Soukas will use this award to continue his work in understanding the genetic mechanisms of aging and aging-related diseases.

“I received notification of the award by email during a meeting with a Harvard PhD student in my laboratory. Normally I wouldn’t open email during a meeting, but saw the title “Glenn Award” and could not resist. There are few moments in science when one feels like cheering out loud in science, and this was certainly one of them. I was surprised, amazed, and humbled to have been given such a great honor as the Glenn Award. The funding from this award will jump start our research aimed at promoting healthy aging in humans.”

 

Marc Wein.jpgMarc Wein, MD, PhD, of the Endocrine Unit, has received the 2017 American Society for Bone and Mineral Research Rising Star Award for his research, “Dissecting the roles of class IIa HDACs in osteocyte biology.” This award provides funding to promising young scientists and physician-scientists in the bone field who have already been recognized by individual National Institutes of Health “K awards” and other similar international professional development programs.

“I was thrilled to receive the 2017 Rising Star Award from the American Society for Bone and Mineral Research. I’m an endocrinologist interested in bone biology and new therapeutics for osteoporosis. The ASBMR has recognized the immense value of additional grant support for junior faculty starting independent research programs. This generous award will allow us to pursue ambitious studies on bone cell function that will identify new genes and pathways relevant to osteoporosis drug development. I’m deeply grateful for this award and the recognition by the ASBMR.” 

Meet our Fall Communications Intern!

Please join us in welcoming Nishtha Yadav, a graduate student at Emerson College and our communications intern this semester. Be sure to check back here for updates on what she’s working on!

Nishtha.jpg

Name

Nishtha Yadav

Where do you attend school and what’s your major, and year?

I’m a second year Communication Management graduate student at Emerson College.

Where are you from?

I currently live in Brookline, but I’m originally from New Delhi, India.

Why are you interning at the Mass General Research Institute?

I wanted to get a glimpse of how a leading research institute pushes out information to their stakeholders about clinical trials and research conducted at the hospital and its affiliates. As someone who enjoys writing long-form, research-oriented articles and has an avid interest in learning more about the healthcare industry, this internship was a perfect fit for me.

What do you hope to gain or learn while interning here?

Previously, I worked as a reporter with a leading English daily in India and did not get an opportunity to write research based articles due to the 24/7 news cycle. So, I hope I’m able to strengthen my research and writing skills.

Also, by the end of my internship, I hope I’ve a better sense of scientific/health industry terminology, which would help me in understanding complex research being conducted by scientists and clinicians.

Why are you interested in health communications?

This summer, I interned at Dana-Farber Cancer Institute and had an opportunity to be a part of their radio-telethon, where all the patients, researchers and doctors were present to raise funds for cancer research. I saw patients, right from babies to octogenarians, and their families who couldn’t stop thanking their doctors for saving their lives. That’s when I realized that communicating with the public about medical breakthroughs and treatments is of utmost importance – it can save lives!

What are your future/career goals?

I would like to work either in the nonprofit sector or work as a crisis management professional. Years from now, I also see myself running for public office in India.

Secretly, I’m hoping that I’ll be discovered by Ryan Murphy and become the next Sarah Paulson! (Murphy is the creator of the American Horror Story, Glee, People vs. O.J. Simpson, etc., and Paulson is an award-winning actress, famous for her work in the American Horror Story and People vs. O.J. Simpson)

What do you like to do when you’re not being an intern?

Apart from planning my Oscar acceptance speech and binge-watching Netflix, I try to listen to as many podcasts as I can and read as much as I can, while trying different varieties of herbal tea.

Favorite dinosaur?

Dino from The Flintstones. Just kidding! Argentinosaurus is my favorite dinosaur. I always get the sense that they were free-willed and walked around their natural habitat like a king/queen.

Favorite food?

My mother has an elaborate recipe for cottage cheese (called Paneer in South Asia) – it’ll always be my favorite food.