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Mon, Feb 25 5:10pm · Rare Disease Day February 28th, 2019 in Primary Sclerosing Cholangitis (PSC)

2018-02-24 Rare Disease Day

This Thursday, February 28th, we celebrate: “Rare Disease Day”. Therefore, we dedicate this week’s post to the anniversary of Rare Disease Day in an effort to raise awareness about rare diseases.

Rare diseases are individually rare but collectively common. In the United States, a “rare disease” is defined as one that affects fewer than 200,000 people. Today, there are as many as 7,000 rare diseases and new ones are discovered every year. About 1 out of 11 Americans are living with a rare disease. In fact, the total number of Americans living with a rare disease is estimated between 25-30 million. Approximately 80% of rare diseases are not acquired, they are inherited and are caused by mutations or defects in genes. In addition, over 50% of the rare diseases remain sub-clinical in childhood and become clinically apparent and/or diagnosed during adulthood.

Rare diseases are often referred to as “orphan disease”. Rare or orphan diseases are frequently not pursued by the pharmaceutical industry because they provide little financial incentive for the private sector to make and market new medications. Of interest, some of the most important drug discoveries ever made were founded on the basis of elucidating the genetic cause of a rare disease. For example, statins were developed as the result of the molecular discoveries causing homozygous hypercholesterolemia, which affects about 1 person in a million individuals. Given the lack of financial incentives to treat rare diseases the US Orphan Drug Act in 1983 has been a successful story of health-related legislation in the United States. Through a system of tax credits, government grants, and assistance for clinical research, the Orphan Drug Act has resulted in hundreds of approved orphan medicines treating over millions of patients.

Patients affected by a rare disease have frequently a diagnosis but many rare diseases have no treatment. Extremely rare diseases that lack a diagnosis are termed undiagnosed diseases or diagnostic odysseys. Thus, although virtually all undiagnosed diseases are rare diseases many rare diseases are not undiagnosed diseases.

Primary Sclerosing Cholangitis (PSC) is a rare disease. In the United States, large epidemiological studies on the incidence (i.e., the rate of occurrence of new cases of a disease per year) and prevalence (i.e., the proportion of all cases of a disease in a population) of PSC are limited. It is estimated that there are about 30,000 to 50,000 patients diagnosed with PSC in this country. However, the actual number of patients living with PSC in the United States is likely higher since individuals that remain undiagnosed or mis-diagnosed are not included in the estimation above.

For all of us who study patients with PSC this is an exciting time for research. We are making progress to discover the cause(s) of the disease and plan to use this knowledge to slow its progression or find a cure. And in this effort, we are not alone. There is a dedicated patient support group: the “PSC Partners Seeking a Cure”, which provides education and support to patients with PSC, family members and caregivers as well as promotes more research for the disease. Moreover, there is an unwavering support from benefactors and the NIH to further study PSC with the aim to discover a cure for this elusive disease. These powers are coming together offering hope and optimism for patients with PSC. There is a robust momentum in place and this is needed for a major breakthrough that will transform in a positive way the care of patients with PSC.

Mon, Feb 11 9:00am · PSC Investigator Profile: Tom Hemming Karlsen, M.D., Ph.D. in Primary Sclerosing Cholangitis (PSC)

2019-02-08 Dr. Karlsen

A decade ago, Tom Hemming Karlsen, M.D., Ph.D., who leads the Norwegian PSC Research Center (NoPSC), joined forces with Konstantinos Lazaridis, M.D., of Mayo Clinic to uncover the culprits driving PSC. At the time, neither could have foreseen the transformative power of their collaborative genetic study on the global PSC research landscape. The transformation was possible, Dr. Karlsen says, thanks to a unique spirit of community.

“We realized that to have robust and significantly valuable findings, we had to come together,” says Dr. Karlsen. In so doing, they ushered in a new era of research between the largest PSC referral centers in the U.S. and Norway that did away with the old customs of secrecy and competing laboratories not sharing research findings.

To address the numerous unanswered questions about PSC, in 2009 Drs. Lazaridis and Karlsen collaborated to build the PSC Resource Of Genetic Risk, Environment and Synergy Studies, termed PROGRESS, a comprehensive collection of clinical data and research biospecimens from over 1,300 PSC US patients. And in 2010, Dr. Karlsen co-founded the International PSC study group.

“By establishing the international group in this relatively narrow research area for a rare disease, there is only a minimum of competition and as much complementarity and collaboration as possible,” says Dr. Karlsen. “We don’t have people working on redundant topics and competing, which is often the case in academia. Instead, we helped bring people together in a constructive way.”

More recently, in his role as Professor of Internal Medicine at University of Oslo and the Head of Research of the Division of Surgery, Inflammatory Diseases and Transplantation, Dr. Karlsen has worked to expand what used to be mostly clinical research into a comprehensive translational research unit aiming to cover all areas of PSC research. His goal: Understanding what causes the disease by exploring disease mechanisms through basic research focused on immunology and metabolism and then translating those more mechanistic studies for clinical utility, such as the development of biomarkers.

The NoPSC Research Center has grown from a small, Oslo-based team of three to a team of 25-30 supported by more than $2.5 million annually of competitive grants funding. As the European leader in PSC research, NoPSC maintains a substantial biorepository and data resource from over 700 Norwegian PSC patients. Moreover, researchers from NoPSC have pioneered studies of genetics and microbiome in PSC.

“If you really want to dramatically change the way we’re dealing with disease, you have to understand it,” says Dr. Karlsen. “I think there is some big secret hidden somewhere within PSC. I think that there is something very fundamental hidden currently in disease pathophysiology, which to me is exemplified by the many paradoxes in the disease – it’s like a puzzle that doesn’t come together. I tend to say that the day we fully understand PSC; biology will have changed a little bit.”

To uncover that secret, Dr. Karlsen is collaborating with Dr. Lazaridis and researchers from Emory University and the University of Illinois as part of a recently funded National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) RC2 grant. For this project, Dr. Karlsen is enthusiastic about the application of artificial intelligence and its potential to generate answers to the fundamental questions about disease development. In addition, the use of unbiased technologies may shed new light on how to improve diagnosis and prognostication for PSC patients.

“A twenty percent lifetime risk of cancer for PSC patients is a lot when you’re living with a chronic disease,” says Dr. Karlsen. “If by these multi-omics technologies, we can come up with new tools to provide an early diagnosis of cancer in the patient, which can then be removed by liver transplantation, I think it would be wonderful.”

As part of the RC2 collaboration, Dr. Karlsen and Dr. Johannes Hov in his team will lead studies to investigate the role of gut microbiota, specifically how the diversity of bacteria in the gut influences development of PSC. Such studies come on the heels of reports that 25-30% of PSC patients who undergo a liver transplant experience disease recurrence. Dr. Hov’s group will collect information about gene content in gut microbiota and also use associated technologies to assess the metabolic influences from that gene content by measuring a wide variety of physiologic compounds. Of note, therapies to manipulate the contents of the gut are currently being tested.

“The main thing that is important to be aware of as a patient is that if you go five years back we were using one drug, which we don’t really know if it works, and there was not much innovation going on. Today, five years later there are many, many drugs being tested for PSC and some of them show very promising results,” says Dr. Karlsen. “I think PSC will change from a disease which you basically are told we cannot do anything about it to a disease we can treat in some way or the other, and I think that transformation will happen in the next 5-10 years.”

Such confidence stems from what he says makes Mayo Clinic such a great partner. “I appreciate Mayo’s very stable and robust commitment to PSC, which goes decades back, like ours in Oslo,” says Dr. Karlsen. “The fact we have now worked together for so many years, actually has allowed us to get to know each other very well and I value many of the Mayo colleagues as friends as much as academic collaborators.”

 

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Mon, Jan 28 12:00pm · Q & A: Ricky Safer, CEO of PSC Partners Seeking a Cure in Primary Sclerosing Cholangitis (PSC)

 

2018-01-29 PSCers2

For the past 15 years, PSC Partners Seeking a Cure has sought to be a safe haven, providing information and support, for those diagnosed with PSC and their caregivers. The non-profit organization got its start thanks to the determination of one Denver-area woman, Ricky Safer, and her family. When the lifelong health and exercise enthusiast received her shocking diagnosis, she decided to stop working as a French instructor and start the organization. Fast forward to 2019, and PSC Partners Seeking a Cure now reaches patients across the globe and has supported over $3 million in PSC research grants.

Mayo Clinic Connect recently talked with Safer, who shared the organization’s mission, the only one of its kind in the United States, the progress made, and her hopes for the upcoming 15th annual conference for PSC patients and caregivers in Rochester, Minn.

 

What is the mission and vision of PSC Partners Seeking a Cure?

To provide education and support to patients, families, and caregivers, and to raise funds to research causes, treatments and cures for primary sclerosing cholangitis.

 

How does PSC Partners Seeking a Cure promote awareness and research?

Through our website, social media presence, brochures, and annual conferences, people learn about our organization and become involved. It’s an amazing community that has arisen and is now international. Receiving a diagnosis of PSC is a very scary event; my desire was for our organization to be a place where PSC patents know we have accurate information and resources about the disease on our website and can connect with others who know what they’re going through.

We have supported over $3 million of PSC research internationally. Our Scientific Medical Advisory Committee helps us decide which grants would be the most promising for us to support. One of our first grants went to Dr. Lazaridis to study the genetics of PSC. After we gave him our seed grant, he received a multi-million dollar grant from the National Institutes of Health to follow through on his genetics research. We’ve had a wonderful relationship with Mayo throughout the years.

 

What should patients and caregivers know about the 2019 annual conference in Rochester, Minnesota from June 21-23?

We started the annual conferences to give people updated information on every aspect of the disease and how to cope with it for both patients and caregivers. We go to a different medical center each year and choose medical centers that specialize in PSC. The Mayo PSC clinicians and researchers are all very well-known and highly respected, and we’re very excited to be coming back. We’re expecting between 325 and 350 patients and caregiver attendees, which is a big group for a rare disease.

When people come the first time to the conference, they’re very apprehensive because they want to learn and meet other people with the disease but don’t want it to be a depressing experience. It seems counterintuitive, but we laugh, we cry, we laugh, we cry, and at the end of the weekend, there’s a wonderful feeling of hope and friendship.

We try to appeal to patients of all different ages and all different stages of the disease, plus to caregivers. The majority of attendees come with family members, so there’s a real family feeling.

We’ll have more than two dozen speakers who will talk about every medical topic that has to do with PSC and related diseases – from why clinical trials are important and how people can participate to  navigating medical insurance, how to cope with PSC, how to find accurate medical information, nutrition, and a lot on research. The medical and coping sessions are on Friday and Saturday, and Sunday is reserved for our peer groups. We now have 17 different peer groups. Everyone helps each other with personal experience, we form bonds and remain really close. Once people find us it’s like home.

New this year, attendees will have the opportunity to participate in research at Mayo by providing blood and stool samples. On both Friday and Saturday of the conference, there is also plenty of time for attendees to talk one-on-one with Mayo speakers and ask them some of the questions they have. Also, if patients want to come early or stay late, they can make appointments to see Mayo specialists.

 

Could you tell us about your organization’s recent major accomplishments?

One of the things that has helped us expand is the relationships we’ve been able to build with these top medical centers. We have a patient registry, so we can help researchers recruit patients for clinical trials. We also have launched a podcast series to discuss various aspects of PSC with clinicians and patients.

One of our big successes in 2018 was obtaining a specific diagnosis code, called an ICD-10 code, for PSC. We spent a year working with the government agency that sets up codes and we testified in Washington, and in October of last year, a specific ICD-10 code for PSC was launched. One of our big projects for this year is an educational campaign to make sure providers throughout the country know we now have this code and code their patients accordingly. This specific PSC code (K83.01) will remove many of the current obstacles to PSC research.

We’re also in the process of expanding our mentor program for patients and caregivers, so if you would like to talk to someone else with the disease we can connect you. Throughout the years many hundreds of people have participated and those friendships last forever.

 

What are your organization’s plans for the future?

We are always interested in raising as much money as we can to support more research, and we are trying to expand our educational efforts throughout the country to reach more people. We’re still very much a majority volunteer organization with volunteers from all over the country and Canada, who really help keep our programs going. It’s probably the most rewarding thing I’ve ever done professionally. If you ever came to one of our conferences, you would see we are a very tenacious group and our whole attitude is, “We may have PSC, but PSC doesn’t have us.”

 

Mon, Jan 14 8:05am · PSC Investigator Profile: Dr. Gary Miller in Primary Sclerosing Cholangitis (PSC)

2019-01-11 metabolomics

Mayo Clinic is at the forefront of research designed to uncover the environment’s role in PSC, thanks to a unique collaboration with Gary Miller, PhD, a toxicologist and Professor of Environmental Health Sciences and Vice Dean, Research Strategy and Innovation, at Columbia University.

Dr. Miller’s interest in figuring out how environmental chemicals affect neurodegeneration in Parkinson’s disease spurred him, and former colleagues at Emory University, to devise novel methods for measuring the exposome, a concept introduced in 2005. He’s since served as the founding director of the first exposome-based research center in the U.S., and penned the first book on the topic (The Exposome: A Primer). Since 2017, Dr. Miller has worked with Mayo Clinic’s Dr. Konstantinos Lazaridis to become the worldwide leader in understanding the environmental culprits contributing to PSC pathogenesis and outcomes.

For Mayo Clinic Connect, Dr. Miller explains what the exposome is and reveals the promise an improved understanding of it offers patients with PSC.

The exposome is a measure of all the external forces acting upon us

In biology, we think about the forces acting upon organisms and the nature vs. nurture paradigm. The nature part is primarily represented by genetics and understanding our genetic programming. We think about nurture as a combination of all the external forces acting upon us – dietary effects, the air we breathe, the water we drink, emotional or work-related stresses we have, radiation, sunlight – and the environment in this very large way is what the exposome is.

The role of genetics and environment in PSC

There’s so little information about how environmental factors affect PSC. The study that was recently funded by the National Institute of Diabetes and Digestive and Kidney Diseases is really going to give the first picture of how our complex environment plays a key part in PSC. Based on the genetic data that I’ve seen, the environmental part has to play a significant role. Is it dietary? Is it exposure to chemicals at work? I don’t know what it is yet, but we’re doing this study to learn.

Developing a comprehensive and unbiased way of measuring environmental exposures or non-genetic factors in disease

We have a very comprehensive way of doing genetic studies, but we’ve historically had a very biased way of looking at the environment. We tend to study chemicals that are in the news. We’re worried most about bisphenol A (BPA) plasticizers when there are many other things in our lives that have a much bigger influence. When you think about all the concern around plasticizers, I can tell you that cigarette smoke is causing more health problems than all of those plasticizers combined. If you only think about one compound at a time, we tend to make very cursory analyses and don’t get the whole picture.

The exposome is really about doing studies in an unbiased way. We don’t concern what the external forces are, we just want to see which ones are most associated with a disease outcome. When you use this unbiased approach, you also have the ability to find things that may promote a healthy outcome. The exposome is much more about looking at multiple exposures at the same time, looking at how nutrients and toxicants are adding in together so you have to look at them at the same time. That’s something that’s been very difficult to do and had remained totally conceptual until we developed the HERULES Exposome Research Center at Emory University. At that time, about five years ago, we weren’t ready to do exposome studies. We were building the infrastructure, building up the technology, putting a lot of effort into the informatics, really developing the tools that we would need to do the studies. 

Understanding the exposome offers promise for PSC patients

When Dr. Lazaridis contacted me, we were just at the point where we thought we had an approach to measure the exposome. We hadn’t published it yet, but we thought it was the way to go. The PSC project was the first test case that really had this highly integrated, comprehensive analysis of chemicals and responses in the body, it was and remains very exciting.

What I think is most promising for the PSC patients is that we can take a blood sample and see what a patient’s overall exposome looks like. It’s not necessarily only about what caused PSC in a patient, it’s about what we can do to improve the care and therapy of a patient with PSC. If a scientist or clinician has a drug or some intervention that might help treat PSC, it could take years to see a change in outcomes like liver failure. But with the exposomics techniques that we’re using, we can detect perturbations in patients’ biology. We’re trying to measure all these chemicals in the body, and it’s not just exogenous chemicals coming from outside; we also want to measure the endogenous chemistry, so we’re measuring external chemicals and the body’s response to them at the metabolic level. We can see the problem, so for example, if an intervention such as a change in diet restores or improves the normal function, we could measure that in weeks to months. The idea is that we can assess and measure the restoration of what’s happening in the body – a shift to a healthier state – before waiting for a long-term outcome.

If we were to find that altering someone’s diet improves his/her blood profile for substances that we think are bad for PSC, people could make changes right away. You get to make decisions about what you bring into your body; for example, you can change your diet, and a clinician can recommend you change your diet without FDA approval. Now I’m not saying we know there is something like that, but we can look for something that can provide a very quick intervention.

Or if we found 100 chemicals that were elevated in PSC patients’ blood, we could test whether any of those chemicals affect liver function using cell culture, animal models, or other systems. Rather than guessing, we would use that data to say we know these chemicals get elevated in patients, do they have bad outcomes. Also, it may be that chemical X is only bad if you have gene Y and this is a goal of our grant that the National Institute of Diabetes and Digestive and Kidney Diseases awarded to our team.

Mayo Clinic investigative team: going to great lengths for PSC patients

We need to bring comprehensive evaluation of the environment into medicine, and I think the exposome is the way to do it. It’s not about looking at one or two chemicals, it’s about looking at the exposome level and saying it’s not just chemicals from air pollution, it’s also the chemicals in the water, the pharmaceuticals we take, all of these different things. We need to find a way to allow clinicians to incorporate the environment into how they care for patients, and it’s not really there now, there’s not a way to do it.

I was very much struck by the group at Mayo reaching out to us; it was very illustrative of the innovation they bring to treatment. They’re looking for information wherever they can find it. They’re very open to new ideas, they’re so driven to learn more about conditions, and their willingness to look at a fairly untested concept is a testament to that dedication.

The future of exposome research

At Mayo Clinic, they do extraordinary work treating patients. As a scientist in a school of public health, my interest is how we can use this information to improve the public health. Monitoring people over time to show how their lifestyle changes are improving their internal chemistry is, I think, a much better, holistic way to monitor someone’s health or improve management of a disease. We’re looking at applying the exposome broadly to studies of cancer, cardiovascular disease, Alzheimer’s disease, and kidney conditions. From a public health standpoint, we’re trying to affect the lives of millions of people and modifying the environment to me is one of the most powerful ways of doing that.

Oct 22, 2018 · Investigative team wins NIDDK grant for Primary Sclerosing Cholangitis research in Primary Sclerosing Cholangitis (PSC)

2018-09-19-RC2 Grant Graphic

A Mayo Clinic-led research consortium recently received a significant, five-year grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to study the pathogenesis and outcomes of Primary Sclerosing Cholangitis (PSC), a chronic, progressive liver disease that lacks effective medical therapy. Dr. Konstantinos Lazaridis, a hepatologist and an established clinician investigator from Mayo Clinic in Rochester, Minnesota, is the Principal Investigator of the study.

Investigative teams at four academic medical centers – Mayo Clinic, Emory University, University of Illinois Urbana-Champaign (UIUC), and University of Oslo, Norway – aim to define the gene-environment interactions driving the disease by using artificial intelligence approaches. In so doing, they will identify molecular disease signatures associated with environmental exposures, metabolism-related chemicals and gut bacteria that are unique to PSC patients. Another goal: integrate and share clinical and experimental data as well as biospecimens generated through the grant-funded research with the broader research community by creating the PSC Scientific Community Resource.

“This is the first translational study of PSC in which we aspire to examine how the interaction of genetic risk along with environmental exposures (i.e., the exposome) leads to development of PSC and its outcomes,” Dr. Lazaridis said. “We are thrilled about this scientific opportunity to better understand PSC and believe the discoveries we make will improve the care of our patients. We are indebted to the study participants for their trust to make this research effort possible.”

To conduct the study and generate the proposed Resource, the team will draw on large, active biorepositories, comprised of patient blood and stool samples. Despite PSC’s rarity – one in 10,000 individuals are diagnosed with the disease – approximately five percent of the entire United States PSC patient population has already consented and provided samples for the planned scientific research.

Since genetics alone could not explain why some people develop PSC and others don’t, the thinking is that casting a broader net via “multi-omics” analysis will help to uncover the complex underpinnings of the disease. Simply put, the investigators will examine and incorporate data from several “omics” layers, specifically the genome (genetics), exposome (environment), metabolome (metabolites), methylome (DNA methylation), transcriptome (gene expression), and metagenome (DNA sequencing of bacteria).

To discover changes in patient blood specific to PSC, the team will test for the presence of environmental exposures – pollutants, pesticides, medications, etc. – and the biological responses corresponding to those exposures. Cutting-edge, ultrahigh resolution mass spectroscopy platforms will be used to evaluate the exposome and metabolome in PSC patients as well as healthy- and disease-controls. Preliminary exposome and metabolome profiling has already revealed chemical exposures and corresponding changes in key liver, lipid metabolism and branched chain amino acid pathways in PSC patients not found in controls. By also identifying DNA methylation patterns, which can change the activity of a DNA segment without changing its sequence, and measuring gene expression levels, researchers will assess “the “methylome” and “transcriptome,” in the hope of uncovering other PSC markers.

Investigators also will assess gut microbial diversity, “the metagenome,” given changes in the types and numbers of helpful and harmful bacteria in the gut are associated with diseases including PSC. They will perform DNA sequencing on the microbes found in stool of patients with PSC, other disease states and healthy controls to get a global overview of processes occurring in the gut. This study will also incorporate a novel exposome-level analysis of stool to elucidate links between microbe classification and exposome-metabolome profiles contributing to PSC.

The resulting, omics-specific datasets will be individually analyzed to identify PSC-associated features, accounting for confounders such as age, sex and genetic variation. Systems biology and high-performance computing expertise will then be leveraged to integrate multiple layers of omics data into a meaningful, multi-omics whole. High-resolution clinical data collected from these patients also will be combined with omics data to shed new light on processes underlying PSC variability in regards to disease onset, features, and outcomes. The hope is to improve predictions of which patients will need liver transplantation, identify biomarkers for PSC-associated malignancy, uncover culprits driving the strong relationship between PSC and inflammatory bowel disease (IBD), as well as reveal differences in the development between childhood and adult PSC.

“Having a better understanding of these clinical priorities holds great promise for a more individualized approach to clinical surveillance and therapy of patients with PSC,” Dr. Lazaridis said.

In total, multi-omics assessments will be generated from over 3,600 individuals, including PSC patients, those with other relevant diseases and healthy-controls. Moreover, the approach – broad patient-based studies and centrally-administered resources upon which new hypothesis can be generated and tested – may serve as a model to inspire new lines of investigation and prioritize clinical trials. The datasets will be accessed by a wide range of investigators, given the fact that PSC is highly associated with IBD as well as bile duct and colon cancers.

“The discovered multi-omics signatures of PSC will provide a springboard for development of novel hypotheses regarding pathogenic mechanisms underlying the disease,” Dr. Lazaridis said. “This is a hypothesis generating grant that could lead to innovative lines of research and hopefully new therapies for this devastating disease.”

Oct 8, 2018 · PSC Physician Scientist Profile: Dr. Konstantinos Lazaridis in Primary Sclerosing Cholangitis (PSC)

2018-09-28-DrLazaridis

Having trained at the National Human Genome Research Institute (NHGRI) in the early 2000s, Konstantinos N. Lazaridis, M.D., is no stranger to sifting through sequences of human genomes to uncover genetic variants and mutations associated with diseases such as Primary Sclerosing Cholangitis (PSC).

“But to sift for the needle in the hay stack, which is required for making impactful discoveries about disease, you need hundreds, thousands of samples; gathering them is no easy task with a disease as rare as PSC,” Dr. Lazaridis said. Despite the fact that PSC affects only 1 in 10,000 people in the United States, Dr. Lazaridis and his team have collected samples from about 1,500 PSC patients during the past 10 years. The result: about 30,000 tubes of biospecimens with more than a half a million clinical data points collected into a single database representing to our knowledge the largest and most comprehensive PSC biorepository anywhere in the world. And as this effort continues and grows the challenges are changing, including how to maintain and enhance this important resource.

“It has been a humbling experience and a privilege,” Dr. Lazaridis said. “I still remember my emotions when holding in my hands a box containing invaluable individual DNA specimens from the first 100 PSC patients who enrolled in our study from all over the United States, entrusting their genetic blueprint to us. I felt I had in my hands the cause of PSC, and I was wondering how long it would take us and others to crack the mysteries of this disease.”

By examining those blueprints, Dr. Lazaridis and several collaborating groups have now discovered 20 genetic variations associated with development of PSC. Recently in collaboration with industry, the team was able to generate exome sequences of nearly all 20,000 genes comprising each PSC genome in the biorepository. “Each patient and data point have something to tell us about the big picture of this disease,” Dr. Lazaridis said. “So, we have many pieces of a really enormous puzzle to put together.”

Destiny it seems brought Dr. Lazaridis from Greece to Mayo Clinic to figure out that puzzle.

“As a medical student in Greece, I was exposed to many patients with autoimmune hepatitis, and autoimmunity as a disease process was a very intriguing to me,” Dr. Lazaridis explained. “Also, the liver is a resilient organ in charge of several body functions including metabolism and detoxification of substances as well as bile production for digestion.”

Thus, after medical school, his transition to studying the molecular biology of systemic lupus erythematous, an autoimmune disorder that affects many organs including the liver, seemed a natural fit. He secured a two year post-doc position at the University of Texas and the Veterans Administration (VA) Hospital in San Antonio. During that time, Dr. Lazaridis realized he needed specialty training in gastroenterology and hepatology, which the immunologists he was working with couldn’t provide.

In the pre-internet era, to learn which medical center offered the best gastroenterology and hepatology training program, he headed to the VA hospital library. He located a copy of Gastroenterology, the top peer-reviewed journal of the specialty, to find out which institutions the Editor and editorial board hailed from. “At that time, the Editor (Dr. Nicholas LaRusso) and the entire editorial team of Gastroenterology were from Mayo Clinic,” Dr. Lazaridis said. “In the spark of a moment, Mayo Clinic became the goal for my training in gastroenterology and hepatology.”

He applied for a spot in the Internal Medicine training program, but received no word as to whether he was invited for an interview. During the last week of the interviews, he decided to call the office of the program director, three times actually.

“I was busy with experiments that day at the VA and almost forgot to call the program; it was late in the afternoon when I got a free moment,” Dr. Lazaridis said. “After getting no answer the first two calls, I could have stopped, but I persisted and the third time I got Dr. Schultz, the program director himself, on the phone. I explained the situation, and was surprised that he reviewed my application as we were talking and told me that I was an excellent candidate for the program. He offered me an interview a week after the official period.”

The first week of February 1993, Dr. Lazaridis visited Rochester for an interview, and shortly thereafter became an Internal Medicine resident with the good fortune of having Dr. Greg Gores as his advisor. Dr. Gores encouraged him to pursue the Clinician Investigator Training Program and to work with Dr. LaRusso in his laboratory on the molecular mechanisms of cholestasis.

Three years later, Dr. Lazaridis sought to bring his research experience to the patient level, pursuing translational research using human biospecimens. At the suggestion of Drs. Gores and LaRusso, Dr. Lazaridis was given an opportunity for additional research training as a Mayo Clinic Scholar. His mentors suggested he make a choice between studying human genomics or virology of hepatitis C with the goal of establishing an innovative, research program on liver disease in the Division of Gastroenterology and Hepatology.

“I chose the former in a heartbeat,” Dr. Lazaridis said. “This was an easy decision. At that time, the Human Genome Project was well underway and the promise of genomics in medicine was overwhelming.” He interviewed with luminary scientists in the field, Eric Lander, Ph.D., at the Massachusetts Institute of Technology and Francis Collins, M.D., Ph.D., at the NHGRI for the opportunity to join one of the laboratories as a Mayo Clinic Scholar. He was offered a position at both places, and made another key decision.

“I decided to join Dr. Collins’ laboratory because the project that Francis proposed to work on for my training in genomics – dissecting the genetics of type 2 diabetes – could serve as a prototype for what I envisioned developing for cholestatic liver disease,” said Dr. Lazaridis. “I saw the potential of genomics to reveal answers where there were none and opportunities to better understand disease pathogenesis tailored to an individual patient’s genetic blueprint. My two year training at NHGRI was an outstanding experience. Working with Francis changed forever the way I was perceiving mechanisms of disease and taught me the fundamental importance of human disease registries and bio-repositories.”

in 2003, Dr. Lazaridis brought that vision and training back to Mayo Clinic and started his own research program dedicated to dissecting the genetic contributions of rare, progressive, cholestatic liver diseases, such as PSC. “I have immensely benefited from the unparalleled mentoring of Drs. Gores and LaRusso over the past two decades.” Lazaridis said. “They always pointed me in the right direction, yet trusted my decisions and efforts as I was developing a novel program within our Division.”

Today, the primary goal of his research program is to find a cure for and improve the care of patients with PSC. But to find a cure, Dr. Lazaridis emphasizes that the causes of the disease need to be understood. “We believe the development of PSC results from the interaction of environmental exposures and the genetic profile of an individual,” Dr. Lazaridis said.

During the past decade, his team has made significant progress to understand the genetic underpinnings that predispose patients to develop PSC. Through such studies they have determined that genomics alone can’t explain why some people develop PSC and others do not.  Although Dr. Lazaridis began work to elucidate the role of the genome first because scientific tools were available, he’s now turning his attention to studying the role of environmental exposures (“the exposome”) in developing PSC. With the availability of new scientific tools, his team will examine how the interactions of genetic risks and environmental exposures (i.e., toxins and chemicals, etc.) lead to PSC and its complications.

“We are making great progress to unravel the causes of PSC because of patients trust and contribution to our studies, synergy between PSC-focused scientific groups, strong benefactor commitment and funding support from NIH,” Dr. Lazaridis said. “All these forces are coming together to bring an end to this disease…and we will.”

Sep 10, 2018 · Exposomics in PSC Research in Primary Sclerosing Cholangitis (PSC)

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A major goal of our current research for Primary Sclerosing Cholangitis (PSC) involves capturing “the exposome,” or the role of environmental exposures – pollutants, pesticides, medication, diet, etc. – and the associated biological responses to these exposures.

In this video, Mayo Clinic hepatologist, Dr. Konstantinos Lazaridis explains what the exposome is and discusses the significance of this work in elucidating how PSC develops.

Jul 2, 2018 · Mayo Clinic leads biobanking efforts in support of PSC Research in Primary Sclerosing Cholangitis (PSC)

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For more than four decades, the Mayo Clinic Division of Gastroenterology and Hepatology has led the field in clinical and scientific discoveries related to Primary Sclerosing Cholangitis (PSC) and has served as the main referral center for PSC in the United States. As a result, Mayo Clinic is home to the largest PSC biobank in the United States, if not the world. Given the rarity of PSC, the biobank containing biospecimens collected from about 1,500 patients represents a critical resource for translational research studies of the disease.

In the following video, Mayo Clinic hepatologist Konstantinos N. Lazaridis, M.D. explains the importance of this biobank, the effort it took to build it, his team’s immediate and future goals and the privilege of studying such a unique collection of biospecimens.