Bay Area Lyme Foundation ELA Winner Uses Metabolic Modeling to Predict 77 Unique Drug Targets in Lyme Disease Bacterium

Peter Gwynne, PhD

FOR IMMEDIATE RELEASE

 

Bay Area Lyme Foundation ELA Winner Uses Metabolic Modeling to Predict 77 Unique Drug Targets in Lyme Disease Bacterium

Results will help inform future research and development of new Lyme disease therapeutics

PORTOLA VALLEY, Calif., October 19, 2023—Bay Area Lyme Foundation, a leading sponsor of Lyme disease research in the US, today announced the findings of a study identifying new essential gene and enzyme drug targets in Lyme disease bacterium, which resulted, in-part, from a grant provided to Peter Gwynne, one of Bay Area Lyme Foundation’s 2022 Emerging Leader Award (ELA) winners. Published in the peer-reviewed journal mSystems, the study uses the most comprehensive metabolic modeling to date to predict 77 unique drug targets in Borrelia burgdorferi, the bacterium that causes Lyme disease—a condition affecting nearly 500,000 new patients annually.

“Lyme disease is often treated using long courses of antibiotics, which can cause side effects for patients and risks the evolution of antimicrobial resistance. Our research supplies the blueprint and scaffolding to build better Lyme disease therapeutics that do not have off-target effects for patients,” said Peter Gwynne, PhD, lead author on the study, research assistant professor at Tufts University School of Medicine, and Emerging Leader Award winner of the Bay Area Lyme Foundation. “Many of the 77 genes and enzymes predicted as essential represent candidate targets for the development of novel antiborrelial drug development.”

Current clinical guidelines recommend treatment of Lyme borreliosis with broad-spectrum antibiotics, which can pose risks to the patient’s microbiome. The bacterium that causes Lyme disease is extremely host-dependent, with a small genome and limited metabolism—making it an excellent candidate for the development of targeted, narrow-spectrum antimicrobials.

In the study, the researchers used in silico genome-scale metabolic computer modeling to construct a map of B. burgdorferi metabolism. This map was used to predict essential genes and enzymes that can be used as drug targets. Gwynne and the Tufts University School of Medicine research team validated these targets by repurposing existing drugs that kill B. burgdorferi in culture. While these drugs are not viable treatment options themselves, they provide a blueprint for future novel drug development.

Stealth Invader: Unveiling Lyme’s Hidden Past

Kris Newby

Ticktective Podcast Transcript

 

In this interview, author/filmmaker, Kris Newby, explains the murky history behind the US government’s involvement with Lyme disease and continued efforts to hide how the military’s bioweapons programs caused the spread of tick-borne pathogens. She explains how alliances between pharmaceutical companies, insurance companies, university-based research teams, and the government led to inaccurate testing and denials of care, causing untold suffering to millions. Kris draws parallels between Long Covid and chronic Lyme and shines a light on how we are being dismissed, misinformed, and deliberately misled by the very institutions that should be protecting us.

Under Our SkinDana Parish: I’m so excited to welcome Kris Newby. Kris is an award-winning medical science writer and a senior producer of the Lyme documentary Under Our Skin, which premiered at the Tribeca Film Festival and was a 2010 Oscar Semifinalist. Her book Bitten: The Secret History of Lyme Disease and Biological Weapons has won three international book awards. I loved your book so much for journalism and narrative nonfiction. Kris has two engineering degrees and has worked as a science technology writer for Stanford Medical School, Apple Computer, and other Silicon Valley companies. Welcome Kris! 

Kris Newby: Thanks Dana, and thanks for having me on the podcast. 

Dana Parish: I’m so excited because you are one of the greatest historians of Lyme and you were so helpful to Steve Phillips and me when we wrote our book, Chronic. We loved your book. And Under Our Skin is the film that informed my view of what was really happening with Lyme disease. You’ve been working on Lyme education for 20 years. You’ve done a film, you’ve written a great book, you’ve published articles, you’ve worked in nonprofits, and you recovered from your own tick-borne diseases. How big is the Lyme problem? 

Kris Newby: Ginormous and growing. The CDC’s latest estimate is half a million new cases of Lyme disease a year, and I’m sure everyone remembers when Covid hit a half a million. It was like, “Oh no, we have a problem here.” But for some reason, Lyme disease hasn’t bubbled up as a problem. 500,000 cases a year is an average of 1,300 a day. And, obviously, that mostly happened in the summer, so it’s huge. I am often frustrated because I’ve been working in this field for 20 years and not much has gotten better. The disease—this tick-borne disease—if it’s caught early, it can be cured. But we have a test that isn’t reliable in the first month, and later on it’s no better than a coin flip. About 10-30% of the people who are treated with a recommended treatment—according to what study you read—go on to become chronically ill. And the establishment has invested very little in new treatment protocols. I did an analysis with another Bay Area Lyme person of the NIH grants for the last five years, and less than 1% of the Lyme disease NIH budget is spent on treatments

Dr. Liz Horn Explains How Lyme Disease Biobank Samples are Foundational to the LymeX Diagnostics Prize 

Lyme Disease Biobank

BAL Spotlight Series

 

In this interview, the LymeX Diagnostic Prize talked with Liz Horn, PhD/MDI, Principal Investigator for Bay Area Lyme Foundation’s Lyme Disease Biobank (LDB), about her work in Lyme disease, the challenges researchers face, how the LymeX Diagnostics Prize could help further our understanding of the disease and how Lyme patient samples from our biobank are critical to the competition’s success.

This interview has been edited from the original

“What’s exciting about the LymeX Diagnostics Prize is that you have a lot of different people with good ideas and different teams with a lot of different technologies trying to solve this problem.”

– Liz Horn, PhD/MDI

Lyme Disease BiobankThe LymeX Diagnostics Prize is a multiphase competition funded by the US Department of Health and Human Services (HHS) and the Steven & Alexandra Cohen Foundation to accelerate the development of Lyme disease diagnostics. Through October 2023, the 10 teams selected to be part of Phase 2 of the LymeX Diagnostics Prize are participating in a virtual accelerator designed to help them refine their concepts for detecting active Lyme disease infections in people. As the Phase 2 accelerator cohort continues to develop their diagnostics, the teams have access to scientific advisors who provide valuable insight and feedback from their extensive experience in Lyme disease diagnostics, one of whom is Dr. Horn. The Phase 2 cohort also has access to the blood and urine samples donated to LDB by Lyme patients.

A cancer biologist by training, Dr. Horn has spent her career working with nonprofit research organizations to help build research programs, registries, and biorepositories. She joined Bay Area Lyme Foundation in 2013 to lead the creation of a Lyme disease biorepository. As a scientific advisor for the LymeX Diagnostics Prize, Dr. Horn is mentoring participating teams through office hours and webinars.

LymeX: As the principal investigator for the Bay Area Lyme Foundation’s Lyme Disease Biobank, you have extensive experience in Lyme disease research. How did you first start working in the field, and what are you focusing on now with the biorepository?

Ticktective with Dana Parish: Stealth Invader: Unveiling Lyme’s Hidden Past

Ticktective™ with Dana Parish

Kris Newby

Kris Newby is an award-winning medical science writer and the senior producer of the Lyme disease documentary UNDER OUR SKIN, which was a 2010 Oscar semifinalist. Her book BITTEN: The Secret History of Biological Weapons and Lyme Disease has won three international book awards for journalism and narrative nonfiction. She has two engineering degrees and has worked as a science/technology writer for Stanford Medical School, Apple, and other Silicon Valley companies.

To read the podcast transcript, click here.

A Broader Definition of Health Through Ancestral Learning, Diet and Better Understanding of the Human Body

Chris Kresser

Ticktective Podcast Transcript

 

In this podcast episode, host Lia Gaertner interviews Chris Kresser, a renowned expert in functional medicine and ancestral health. Kresser shares his personal health journey, which involved struggling with chronic illness and eventually finding his way to functional medicine. He discusses the importance of zooming in and zooming out in managing chronic illness, as well as the broader definition of health as human flourishing. Kresser also talks about his approach to diet, which involves giving himself permission to eat a variety of foods while prioritizing those that make him feel good. He emphasizes the importance of the ecosystem in managing chronic illness, focusing on factors such as gut health, lifestyle, stress management, and finding joy and fulfillment in life. Kresser concludes by offering advice to individuals with Lyme disease and chronic illness, highlighting the significance of addressing the entire ecosystem rather than solely focusing on the pathogen.

 

Lia Gaertner: Welcome to the Ticktective podcast and video series, a program of the Bay Area Lyme Foundation, where our mission is to make Lyme disease easy to diagnose and simple to cure. I’m your host, Lia Gaertner, director of Education and outreach. Lyme disease is the most common vector-borne disease in the USA and is a global issue. This show includes interviews with the researchers we fund, as well as other interesting people in the Lyme scientific community. We are a nonprofit foundation based in Silicon Valley. Thanks to a generous grant that covers all of our overhead, 100% of all donations go directly to support, research and prevention programs. You can find out more or donate@bayarealyme.org.

Lia Gaertner: Thank you, Chris Kresser, for joining me on the Ticktective™ video and podcast series.

Chris Kresser: Thanks for having me, Lia. It’s a pleasure.

The Paleo Cure by Chris KresserLia Gaertner: Chris Kresser is a renowned expert leading clinician and top educator in the fields of functional medicine and ancestral health. He is the author of the New York Times bestselling book, The Paleo Cure, as well as the book Unconventional Medicine. Chris is the co-founder and educational director of the California Center for Functional Medicine and the founder of the Kresser Institute. Chris regularly shares his evidence-based insights from trusted sources and world-renowned health practitioners and coaches through his blogs, webcast interviews, and his own podcast, Revolution Health Radio. So, Chris, during your decade-long struggle with chronic illness, you learned firsthand where healthcare mattered most and where it came up short. After seeking the help of more than 30 healthcare practitioners and ultimately having to learn and implement behavior changes on your own with limited support, you emerged with your health and a vision and drive for changing and improving the practice and education of functional medicine. Can you please tell us about your health journey?

Chris Kresser: I’ll be brief because it was long and arduous, but I took off to travel around the world for a couple of years in my early twenties, and I was doing a lot of surfing. I was in a little village on Sumbawa, which is an island in Indonesia, and a bunch of the people there who were surfing at that break got exposed to a waterborne pathogen, actually several pathogens. There was a stagnant pool of water near the river mouth there, and locals dug a trench to drain that pool into the river mouth. And all of that water where cows had been defecating went out into the surf break, which are often located right at the river mouth. And unbeknownst to a lot of us who were there surfing, we were exposed to it and I would say 70-80% of the people there got quite sick.

I took some antibiotics that I had in my medical kit and the acute phase of it passed relatively quickly. But as I continued to travel after that, I went to the Maldives and was there for a few months and I was in South Africa and Reunion Island, Mauritius, and Madagascar. After about six, seven months, I started feeling really sick and it became clear to me that it wasn’t something that was just temporary that was going to go away. So, I made my way back to Australia and that was where I started to seek medical care. And then when I didn’t make much progress, I decided to go back home to the US and although most of the doctors and other practitioners I saw meant very well and did their best to help me, it was pretty clear that the medical system was not set up to deal with those kinds of problems.

Infectious Minds: Unraveling the Link Between Infections & Psychiatric Disorders

Robert Bransfield, MD

Ticktective Podcast Transcript

 

In this interview, psychiatrist Dr. Robert Bransfield explains the links between neuropsychiatric disorders and infections. He recounts his successes treating patients who repeatedly fail to respond to conventional interventions. Dr. Bransfield describes how clinical diagnoses of infection, along with correct administration and interpretation of testing, plus treating patients with antibiotics can, in many cases, lead to an abatement of a variety of psychiatric disorders, from psychosis to depression and anxiety. He also explores the connection between tick-borne diseases in maternal-fetal transfer of infections and the rise in autism in children.

Note: This interview has been edited for clarity. Bibliography and references are posted below.

 

“What are people in the future going to say about the Lyme crisis? I’m sure this will be judged by history as a great failure of our healthcare system, that we didn’t move quickly enough with this, and that people were holding back progress.”

—Dr. Robert Bransfield

Dana Parish: Hi, I am Dana Parish, and I am hosting the Ticktective podcast on behalf of Bay Area Lyme Foundation. I am here today with a wonderful psychiatrist, Dr. Robert C. Bransfield, MD, DLF APA. He is a graduate of Rutgers College and George Washington University School of Medicine. He completed his psychiatric residency training at Sheppard and Enoch Pratt Hospital. He’s board certified by the American Board of Psychiatry and Neurology in psychiatry and is a distinguished life fellow of the American Psychiatric Association. He’s a clinical associate professor of Psychiatry at Rutgers Robert Wood Johnson Medical School and the Hackensack Meridian School of Medicine, and he is well published in the peer reviewed literature. Welcome Dr. Bransfield. Thank you so much for talking to me today. How are you?

Robert Bransfield: Thank you for inviting me.

Dana Parish: It’s my pleasure. I’ve learned so much from you over the years about microbes and mental illness. You’ve blown my mind a million times and I cannot wait to share your knowledge today with everybody who’s going to watch and listen to this podcast. So, my first question is, does psychiatry pay enough attention and does medicine pay enough attention to microbes in infections and pathogens in mental illness? And if not, what is going on with the brain when we get neurologic infections?

Brain InfectionRobert Bransfield: Well, not enough. If you look at the old views of what caused psychiatric issues, it was thought to be demonic possession. Then we blamed our mothers, and then we blamed serotonin. It doesn’t quite make sense (to people) that there’s something that causes psychiatric illness. But these illnesses don’t just come out of nowhere. 

The problem is that nothing in the known universe for its size is more complex than the human brain. So, understanding the pathophysiology of the human brain is very challenging, especially the part involving psychiatric illness. That is much more complicated than general neurological illness where the circuits are not as complex as the circuits that impact psychiatric functioning. So, this causes a problem. When we look at all the possibilities, there are many things that contribute to mental illness—microbes are just one of them. But I think they are a very significant one and when you look long and hard enough, this does explain many psychiatric illnesses. 

Ticktective with Dana Parish: From Harvard MD to MS Patient: Wisdom from Both Sides

Ticktective Podcast: a Bay Area Lyme Foundation Program

Annie Brewster, MD

Annie Brewster is an Assistant Professor of medicine at Harvard Medical School, a practicing physician at Massachusetts General Hospital, in Boston, a writer and a storyteller. She is also a patient, diagnosed with Multiple Sclerosis in 2001. In response to the disconnection she experienced in healthcare, both as a patient and a provider, and motivated by her belief in the power of stories, she started recording patient narratives in 2010. Integrating her personal experiences with the research supporting the health benefits of narrative, she founded Health Story Collaborative (HSC) in 2013. HSC is dedicated to helping individuals navigating health challenges find meaning, and ultimately heal, through storytelling. She is excited by interdisciplinary, cross-institutional collaborations that break through resistance to change. She is widely published in the press and is author of The Healing Power of Storytelling: Using Personal Narrative to Navigate Illness, Trauma, and Loss (2022).

Foundational Work Scores Results

John Aucott, MD

BAL 10-year Anniversary Series

 

10 Years of Collaboration Bringing Hope: How Dr. John Aucott’s Relationship with Bay Area Lyme Helped Get Groundbreaking Biobanks Launched to Fuel the Research Engine of Lyme Disease Investigations

 

John Aucott, MDIn this blog, part of our 10-year anniversary blog series, we talk with John Aucott, MD, Associate Professor of Medicine at Johns Hopkins University, Director of the Lyme Disease Research Center, about his work and how his investigations are helping us understand persistent/chronic Lyme infections. A long-term collaborator and grant recipient of Bay Area Lyme Foundation, Dr. Aucott reflects on his history with our organization, the ongoing plight of Lyme disease patients, and the slow growth in government funding for investigations into the disease. He talks about the early days of identifying the need for well-characterized samples from Lyme patients and his role in helping launch biobank programs, including his own SLICE Study Biorepository and BAL’s Lyme Disease Biobank. 

Bay Area Lyme: I want to take you right back to the very beginning of your relationship with Bay Area Lyme (BAL), the founding of your SLICE study and our Lyme Disease Biobank (LDB) and talk about everything that was happening 10 years ago. People talk about the “norming, storming and forming” stages of organizations, and there was an awful lot of activity going on 10 years ago in the world of Lyme disease. And so, please share your thoughts on what was happening around that time, your part in it, and how you came into the picture with BAL and our biobank.

SLICE Studies
The Study of Lyme disease Immunology and Clinical Events (SLICE), Johns Hopkins University Lyme Disease Research Center

John Aucott: My first memory is that I flew out to California and my agenda at that time was getting people interested in research. There was very little funding for Lyme disease research, and to some extent there still isn’t a great amount of funding for Lyme disease, especially the kind of research I do, which is clinical translational research. I’m an MD, so my research involves bridging basic science to human beings to patients. So, to be very candid about it, I was interested in getting BAL interested in my work. I pitched what we were doing. We had already set up the Johns Hopkins SLICE study, the Study of Lyme disease Immunology and Clinical Events. And at that point it was one of only two large scale biobanks collecting for Lyme disease. The other one is Dr. Gary Wormser’s, who still has a biobank in Valhalla, New York.

So, I was pitching the idea of a Lyme disease biobank to BAL, and this was a whole new concept. A biobank is a hard concept to sell initially because people don’t understand that setting up a biobank is like being Levi Strauss: It’s selling the Levis and the picks, and the shovels—not selling them the actual gold in your pocket. And it’s a hard pitch because people don’t understand that somebody has to supply the foundational work so that other people can mine for the gold. But BAL caught on to the idea that the biobank that we had at Hopkins was a crucial resource that would enable collaboration with other researchers to advance the scientific understanding of disease mechanisms and potentially identify and validate biomarkers for improving diagnostics and treatments.

LymeAid 2013
LymeAid 2014 Scientific Panel (from left): Wendy Adams, John Aucott, MD, Carin Rollins, and Bill Robinson, MD, PhD

Bay Area Lyme bought into the importance of this idea. The first thing that happened was you asked me to be on the BAL Scientific Advisory Board soon thereafter. BAL expressed support for the SLICE study’s biobank at Hopkins and you actually gave us one of our first grants to help support our biobank work. So, that was the first thing that happened. We applied for a grant, and we got a grant from BAL to help us because we had not yet gotten federal funding for it. So, that was one of the first grants to support it, and now in 2023 we are finally receiving our first NIH funding.

How to Diagnose if Lyme Disease is Affecting the Heart and How to Best Treat It

Adrian Baranchuk, MD

Ticktective Podcast Transcript

 

Dr. Adrian Baranchuk, Professor of Medicine at Queen’s University in the Division of Cardiology in Ontario, Canada discusses his screening process for identifying Lyme infections in the heart and how to treat these patients without unnecessary pacemakers. He has published research and spoken on the topic of Lyme carditis at numerous conferences. He is passionate in his efforts to educate doctors on diagnosing Lyme-related AV heart block. Dr. Baranchuk joined Bay Area Lyme Advisor Lia Gaertner to discuss the cardiological manifestations of Lyme disease, Lyme Carditis and specific cases that illustrate his approach.

Lia Gaertner: Welcome to the Ticktective podcast and video series, a program of the Bay Area Lyme Foundation, where our mission is to make Lyme disease easy to diagnose and simple to cure. I’m your host, Lia Gaertner. Lyme disease is the most common vector-borne disease in the USA and is a global issue. This podcast includes interviews with the researchers we fund, as well as other interesting people in the Lyme scientific community. We are a nonprofit foundation based in Silicon Valley. Thanks to a generous grant that covers all of our overhead, 100% of all donations go directly to support research and prevention programs. You can find out more or donate@bayarealyme.org. Thank you for joining the Ticktective video and podcast series, Dr. Baranchuk

Adrian Baranchuk: Thank you very much for having me.

Lia Gaertner: Dr. Baranchuk, a native of Buenos Aires, Argentina, completed his training in internal medicine in cardiology, along with clinical fellowship in cardiac electrophysiology. Dr. Baranchuk is a tenured professor of medicine at Queen’s University in the division of cardiology in Ontario, Canada. He is the editor-in-chief of the Journal of Electrocardiology, as well as a member of numerous editorial boards and a reviewer for several medical journals. Dr. Baranchuk has authored eight books and published more than 700 articles in prestigious international journals, as well as 54 book chapters, and he’s presented more than 270 abstracts around the world. He is the vice president of the International Society of Halter and Non-Invasive Electrocardiology, and the Secretary of the Inter-American Society of Cardiology. He’s also the past president of the International Society of Electrocardiology. He’s been elected as a member of the Electrophysiology Leadership section of the American College of Cardiology, and is the recipient of several teaching awards as well as being voted one of the 10 most influential Hispanics in Canada.

Adrian Baranchuk: Thank you very much for the invitation. I am so pleased to be here with you today.

Lia Gaertner: I’d like to start with a case study published in the Canadian Medical Association Journal (CMAJ). It reads:

“A fatal case of Lyme disease in a previously healthy 37-year-old man illustrates the challenges of diagnosing Lyme disease in the absence of classic symptoms. The patient originally presented to his family doctor with flu-like symptoms, including fever, sore throat, nasal congestion, and migratory joint pain. Several weeks earlier, he had been in contact with ticks but didn’t recall removing one. His physician suspected a viral infection and the patient’s symptoms resolved. However, weeks later, he developed heart palpitations, shortness of breath, and chest discomfort for which he was sent to the emergency department. Lyme disease was suspected as the ECG showed complete heart block. He was admitted to the hospital and started treatment for Lyme carditis. But his condition unfortunately worsened quickly. Clinicians were unable to reverse the course of his illness, and he died. Serology results confirmed Lyme disease and an autopsy showed Lyme carditis.” 

Biosafety is Key to Our Future: The Truth About Germs, Lab Leaks, and Information Warfare

Raina MacIntyre, MD, PhD

Ticktective Podcast Transcript

 

In this episode of Ticktective™, Dana Parish talks with Raina MacIntyre (MBBS Hons 1, M App Epid, PhD, FRACP, FAFPHM) about how lab safety lapses are still leading to frequent undocumented lab leaks, her concerns over Long Covid and the ongoing dangers of the pandemic, and how public health agencies use information warfare to keep everyone in the dark about what is happening at the forefront of biomedical investigations, especially in the field of experimental gain of function research. Raina MacIntyre is Head of the Biosecurity Program, Kirby Institute, University of New South Wales (UNSW), Australia, and author of Dark Winter. She has over 450 peer-reviewed publications, has received many awards including the Sir. Henry Wellcome Medal from the Association of Military Surgeons of the US and is a member of the WHO COVID-19 Vaccine Composition Technical Advisory Group and WHO Smallpox and monkeypox working group.

Dana Parish: Welcome to the Ticktective podcast, a program of the Bay Area Lyme Foundation, where our mission is to make Lyme disease easy to diagnose and simple to cure. I’m your host Dana Parish, and I’m the co-author of the book Chronic and I sit on the advisory board of Bay Area Lyme Foundation. This program offers insightful interviews with scientists, clinicians, patients, and other interesting people. We’re a nonprofit based in Silicon Valley, and thanks to a generous grant that covers a hundred percent of our overhead, all of your donations go directly to our research and prevention programs. For more information about Lyme disease, please visit us@bayarealyme.org.

Dana Parish: Hi, I’m Dana Parish and I’m thrilled today to welcome Dr. Raina McIntyre. Let me tell you a little bit about her. Raina McIntyre, MBBS is head of the Biosecurity program, Kirby Institute, UNSW. She leads research on prevention of epidemic infections, including EPI watch, an AI-driven early warning system for serious outbreaks. She has over 450 peer reviewed publications. She’s received many awards including the SIR Henry Welcome Medal from the Association of Military Surgeons of the US. She was on a US National Academies of Science Engineering Medicine Pandemic Consensus Committee, and she’s a member of W’S Covid 19 Vaccine Composition Technical Advisory Group and WHO Smallpox and Monkeypox Working Group. Has written over 450 publications and I am really pleased to have met you through this new nonprofit that we’re both a part of called BiosafetyNow.org. You know, it’s an honor to be able to learn from you and meet you, and I’d love to talk a little bit about your background and what it means to be a biosecurity expert and an MD and a PhD in your area of expertise.

Raina MacIntyre: I started my career as a medical doctor and I was going to be a cardiologist because I’d done a lot of cardiology, in my specialist physician training and wanted to do cardiology. But I was also interested in epidemiology. I saw an ad for this Master of Applied Epidemiology, which is the Australian Field Epidemiology Training Program, which is a type of hands-on training in outbreak investigation that was pioneered by the US CDC called the Epidemic Intelligence Services. And in some countries when you do it, you get a degree. So, I decided to do that degree and it was quite life-changing for me because it was a new way of learning where you do just short bursts of classroom learning, but then you go out in the field, you investigate outbreaks and you apply the learning that you had in the classroom to practical problems in the field where you’re investigating outbreaks, trying to work out: What is this? Where did it start? How can it be stopped?