Welcome to our second issue of the CIRCULAR VISION newsletter

CIRCULAR VISION and the past year

Despite vast investments in cancer research over the last decades, we still do not detect some of the most deadly cancers of our time, and we struggle to treat them. This also applies to one of the major chronic illnesses, Inflammatory Bowel Disease, (IBD), where we often detect relapses in disease late. That means that there is a large unmet need of individual procedures that can measure, monitor and detect these diseases. We in the CIRCULAR VISION consortium seek to meet this need by developing a new biomarker, circular DNA, for detection and treatment of cancer and IBD.

In the past year, we have screened hundreds of tumor and plasma samples for cancer, and collected over 900 samples from IBD patients to meet our goals. Our results have been published in a number of high impact journals, including Molecular Cell.

One of our successes is the development of technologies to analyze circular DNA from blood plasma, and we can now distinguish between lung cancer patients and healthy individuals, based on the circular DNA found in their plasma.

Additionally, we have identified the first unique patterns of circular DNA for early detection of active IBD.

With our short term goals and milestones completed, we went through an EU audit in January with great compliments and recognition of our scientific work. We can thereby continue our successful scientific and technological advances in the next year with publication, patents and identification of new markers from our patient screens.

In this newsletter, we have interviewed one of the world’s leading scientists on the subject of circular DNA and cancer, Professor Paul Mischel from Stanford University, who explains why studying circular DNA is the next step in developing personalized medicine for cancer. We also talked to Cristiano Consorte, an IBD patient that tells his story of how it is to be diagnosed and living with IBD, and he shares his advice on managing the disease in the daily life.

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Cristiano Consorte shares his story about living with inflammatory bowel disease, IBD

Cristiano experienced his first medical emergency in August 2010, while on holiday from his studies in Italy. The disease presented itself as an abnormal cardiac episode, and was considered an isolated incident. The second episode, happened in November, where Cristiano went to the emergency room, due to blood in his stool, and he ended up being hospitalized for almost two weeks. The medical doctors gave him a colonoscopy and did other examinations, which eventually led his diagnosis, ulcerative colitis, a type of IBD.

In the beginning, Cristiano could not even leave the bed. He had to figure out what he could eat and drink, and what kind of medication would work for him. His world had been turned upside down.

Cristiano had his parents to lean on, when the first episode presented itself, as he was living at home, as many university students do in Italy. After he was diagnosed with IBD, he shared his experience with his university friends, who were very supportive of him. He got his degree in engineering, and from there went on to work in Switzerland, while still living in Italy. Onwards, the real turning point was the support he received from the Italian patient organization for IBD, which not only provided him with a list of hospitals specialized in treating IBD patients, but have a number of resources to draw on. When asked how it helped him, he said,

“It really makes a difference that you can share your experience with others, with other patients”

Cristiano moved to a hospital better suited to treat him, and eventually made his way to Milan, which has a dedicated environment for IBD patients. It made a big difference, from useful information on how to improve his quality of life, to taking him and his life as a whole, into consideration in their treatment, and not just the illness.

When asked about what he would like to be different in the future, he expressed his dislike for the preparation for a colonoscopy.

“It takes three days, where I cannot go out.”

There are side effects as well. Remembering once in July, having to get one, Cristiano ended up with a fever, shivering and feeling cold, despite it being July and the weather quite hot. He is not very fond of the blood tests either, but with it being infrequent, it is manageable.

Knowing the impact having IBD has had on his own life, he volunteered for a summer camp, for elementary school children with IBD. He explains that with IBD being an invisible disease, it can be difficult to explain how it affects you, as the symptoms are not well known. The patient organization can help clarify the aspects of the disease. However, people who are outside the “bubble” of the patient association and the medical community, they tend to not understand. As Cristiano expressed,

“They act as if you are over exaggerating your symptoms, and you are using the diagnosis, as an excuse, to avoid doing things you do not feel like doing.”

Now imagine being a child in elementary school with IBD, trying to explain yourself to other children or your teacher. Cristiano expressed that, he can understand that not everyone wants to spend the time explaining it under some circumstances, like for a job. Cristiano’s opinion?

“The best way is to talk about it and make it as clear as possible. At least with your parents, relatives, and friends. We are all different and sometimes we are not able to perform the same [tasks], because we are different people.”

what is IBD?

Inflammatory bowel disease, known as IBD, can be separated into two main types of illnesses, Crohn’s disease and ulcerative colitis. Both involve chronic inflammation of the gastrointestinal (GI) tract, and the long term inflammation can cause permanent damage.
     Crohn’s disease distinguishes itself by affecting any part of the GI tract. Damage appears in patches next to healthy tissue and inflammation can reach through several layers of the GI tract walls. Ulcerative colitis on the other hand, occurs in the large intestine and rectum. The damaged areas are continuous, which can spread further into the colon, and inflammation is only present on the inner lining of the colon.
     Common symptoms of IBD include persistent diarrhea, abdominal pain, rectal bleeding/bloody stools, fever, weight loss and fatigue. The exact cause is unknown, however it results from a weakened immune system. For some it is an environmental component that triggers the onset of the disease, and for others there appears to be a genetic component. The disease can occur at any age, but is more common at age 15-35. The intensity of the symptoms can vary a lot over time, and patients can experience long periods of remission and flare-up of symptoms. If the illness does not respond to medication, surgery can be necessary.
     IBD affect more than 3.4 million people in Europe, 3 million adults in US, with an estimate of at least 10 million people worldwide.

Visit the European association for IBD, EFCCA, for more information.

CIRCULAR VISION is an EU consortium that is focused on developing technology to detect this new biomarkers for IBD and cancer, and at the same time test whether the biomarker can be used with patients in the clinic. CIRCULAR VISION is working with a new biomarker that may potentially be used to follow IBD patients, perhaps through liquid biopsies like urine and blood samples.

Circular DNA in cancer? Read about the expert Paul Mischel and his work

Cancer has been studied for a long time, and large resources have gone into curing various types of cancers. Despite this, many are still difficult to treat, and the long term prognosis for patients with these cancers are poor. What we are now seeing, is that circular DNA could be one of the reason those cancers are so difficult to treat.

Birgitte Regenberg met one of the leading figures in circular DNA research, Professor Paul Mischel from Stanford University, at a scientific meeting at Lago Maggiore in Switzerland this summer. She interviewed him in one of the breaks about the links between the mysterious circular DNA and it impact on cancer.

Paul Mischel has been interested in cancer for a long time, since he lost his father to cancer when he was just a boy. So he went into medicine to look the enemy in the eye. While doing research on cancer, Paul realized that some patient’s cancers were changing very fast to become resistant to chemotherapy, and this is what took him and his colleagues to the circular DNA.

The circular DNA are large pieces of DNA with oncogenes and other genes that no longer sit on the chromosomes, but have circularized. Paul and his team realized that the circular DNA does not follow the normal rules of chromosomal inheritance, where the genetic material is passed down equally when cells divide. Instead, one cell will end up with more oncogene circles than the other, which meant that the cancers are changing their genomes at a rate that was unanticipated. Still it made sense in light of the rapid evolution of tumors and their resistance to chemotherapy.

Back in 1965 people had already seen these little particles in the cancer cells of children, which were called ‘double minutes’. In the 1970’s and 1980’s people like Jeff Wall and Robert Schimke were doing elegant work in the field, but with the appearance of new technologies for mapping of the human tumours, the work became forgotten.

It was thought that double minutes were extremely rare and only found in about 1.4% of all cancers. What Paul and his team have discovered now, is that the most common drivers of oncogenes, are amplified on circular DNA, and that more than a third of cancers carry oncogenes on circles. Due to them being passed down unevenly to daughter cells, it allows cancers to change their genomes very quickly, evolve and develop drug resistance.

When asked about, how we can get rid of circular DNA in tumours, and if there a cure, Paul replied that the circular DNA is a vehicle that allows rapid evolution, just like bacteria.

“We have no trouble thinking about bacteria developing rapid drug resistance, however, we - as a species - have had a hard time wrapping our head around the fact that human cancer cells actually do this too.”

He goes on to explain that in precision medicine and targeted therapy, there is the idea that if you can sequence the tumour and identify the mutated gene that is actually causing the cancer, you can choose a drug designed to target that gene, and the patient would get better. There is proof of principles that this works for some cancer patients, but often cancers are not playing by the rules when they are driven by circular DNA. So people working in this field, have to rethink the whole strategy.

Birgitte and her lab have shown that our genomes are riddled with small circular pieces of DNA that create variety and are a normal part of our physiology. Paul explains that that this may teach us something about the things that can go wrong in normal cells. The circular DNA that Paul and his team are studying in cancer, is rare in normal cells. The question is now, if cancer that are driven by circular DNA have particular vulnerabilities that can be used target the cancer.

However, first we have to understand the biology of circular DNA, and then develop medicines and diagnostics for cancers that are caused by circular DNA. Paul ends his interview by looking into the future

“I think that we are all working together, to share and explore, to eventually understand how to get this to the right vehicle, so we can develop the right diagnostics and right treatments for patients.”

Birgitte Regenberg is an Associate professor at the Department of Biology, University of Copenhagen, and her laboratory has spent the last decade exploring the presence and function of circular DNA in various organisms. She is the leader of the CIRCULAR VISION project, where one of the goals is to make cell models to study circular DNA in cancer.
Regenberg Lab

Professor Paul Mischel is a physician and a scientist, whose laboratory has made new discoveries in the pathogenesis of human cancer. He is Professor and Vice Chair of Research for the Department of Pathology and Institute Scholar of ChEM-H at Stanford University.
Paul Mischel Lab

Newsletter editors:
Birgitte Regenberg
Jessica Lehd Lauesen