When the Nazis invaded Austria in 1938, a Jewish teenager named Theodore Mischel fled with his family to the United States just in time to avoid getting killed. The young man returned to Europe as an American soldier and miraculously survived World War II. He was spared combat in the Battle of the Bulge, one of the deadliest battles of the war, because he contracted mumps. He had dodged death twice, but years later, a lethal and excruciatingly painful stomach tumor crossed his path. His son Paul, then 14, decided he would study medicine and dedicate his life to fighting cancer. He wanted to “look the enemy in the eye.” Five months ago, his team discovered that mysterious, tiny DNA circles appear in the cells of more than half of patients with highly aggressive tumors. Mischel, born 62 years ago in upstate New York, is leading a $25 million international consortium to solve the mystery of these DNA loops. He believes his work “could revolutionize the treatment of up to a third of all cancer patients.”
Mischel, from Stanford University, visited Madrid to participate in a symposium organized on Thursday by the CRIS Cancer Foundation, a non-profit organization that announced an investment of €11 million to fund cancer research projects. The American doctor, who is a member of the Spanish foundation’s international scientific committee, made a momentous discovery in 2014. The human cell’s instruction manual, DNA, is mostly stored in packages called chromosomes. In 1965, researchers in the United States and the United Kingdom detected an enigmatic extrachromosomal circular DNA, hundreds of times smaller, in the cells of people with tumors. For half a century, this genetic material was considered rare and insignificant. Until Mischel’s team revealed, just over a decade ago, that this tiny bit of DNA outside the chromosomes was linked to highly aggressive cancers. Five months ago, he announced that these elusive molecules — which contain mutated genes that cause cancer or genes linked to the ability to evade the body’s defenses — are omnipresent in people with the most lethal tumors. It’s a new paradigm. Mischel compares it to the discovery that the Earth was not the center of the universe.
Question. You wanted to “look the enemy in the eye.” What have you seen in that gaze over the decades?
Answer. I saw something that doesn’t care. It’s our own cells that stop listening to us, looking out for themselves and not us. And I’ve seen the horror. It’s frightening: our own cells are going rogue, which is why it’s such a problem. Those cells are us, but not entirely us anymore. We’re going to have to be very thoughtful and wise to prevent it from happening, to catch it early if it does happen, and to treat it far more effectively. And I think it will be possible to cure it in many people; we’re already seeing it.
Q. Is this extrachromosomal circular DNA a trigger for cancer or a consequence of an existing tumor?
A. It’s not just a consequence, it’s a trigger. We’ve studied people with Barrett’s esophagus [a disorder caused by acid reflux from the stomach, which increases the risk of developing a malignant esophageal tumor], and if they had higher levels of extrachromosomal DNA, cancer developed later. We also have evidence in mice of its biological mechanism, which shows that it’s a transformative event that causes cancer. It’s a trigger.
Q. This circular DNA was identified in 1965, but until 2014 it was thought to be rare and of no importance.
A. We had a high-resolution map of the human genome, but it was from normal cells in healthy people. The inference was that what you detected in a cancer cell was in the same place as in a normal cell, but it turns out not to be. Often, those genes that were driving cancer weren’t where we thought they were according to the map [within the chromosomes], but were in extrachromosomal DNA elements.
Q. You compare the old chromosome-centered cancer paradigm to astronomer Ptolemy’s old map of the solar system, with planet Earth at the center. In that example, you are Nicolaus Copernicus, who placed the Sun at the center.
A. That would be saying something. Let’s just say I’m someone who was inspired by Copernicus and asked this question: Where are things actually in the cancer genome? The map was wrong.
Q. Five months ago your team published a study that revealed that this circular DNA is found in 17% of the cancer patients whose samples were analyzed, but the percentage exceeds 50% in people with some very aggressive tumors, such as HER2+ breast cancer and glioblastoma in the brain.
A. And in many other types. We finally had a clear idea of how frequent this was. And the answer is: very frequent.
Q. And is extrachromosomal DNA the trigger for all these tumors?
A. I don’t think we can necessarily say that. What we can say is that it’s there in all of these cancers. If you also consider our other data, which show that extrachromosomal DNA can be a factor that causes cancer, then I think we can assume, with relative certainty, that in some of these patients it was the causative event. We’re also seeing that extrachromosomal DNA can become a problem by causing resistance to cancer treatment. These circles are one of nature’s ways of rapidly changing genomes. And that’s exactly what’s happening, both in causing cancer and in creating resistance to treatments.
Q. You have $25 million to research this circular DNA. What questions do you want to answer with that money?
A. We set out to answer several questions: How does it form? How does it function? What goes wrong for this to happen in the first place? How does it evolve and how does it cause cancer to evolve? What is its role in the development of resistance to treatments? How does it affect the immune system? Could we find a way to activate the immune system against this extrachromosomal DNA? And finally, can we develop new treatments? There is still a lot of work to do, but we have already begun to transform our fundamental understanding of some of the most aggressive cancers.
Q. One of your friends had glioblastoma and told you, “Whatever you do, do it quickly, because people like me don’t have much time.” When will we see treatments targeting extrachromosomal DNA?
A. The first one is already in clinical trials in patients. It’s a drug targeting a protein called CHK1, and it’s being tested by a company we founded, called Boundless Bio. And there are more in the pipeline. We need to develop more effective treatments, because these are the patients who are being left behind. Patients like my father, who likely had this extrachromosomal DNA. He had stomach cancer, a type of tumor where about 38% of patients have these circles. And, in really aggressive cases, even more. My father’s was very aggressive.
Q. Does that drug work?
A. We don’t know, it’s being tested.
Q. Does it work in mice?
A. Yes, it works very well in mice and is now being tested in people. I’m confident we’ll have effective treatments for patients with tumors driven by this extrachromosomal DNA.
Q. Your consortium’s website claims you could “revolutionize treatment for up to a third of all cancer patients.” Do you believe that? A third of all patients?
A. I believe so. In the study we published five months ago, we saw that this circular DNA was present in 17% of all cancers, but that data corresponded mainly to early-stage tumors. Now we know that, as cancer progresses and metastasizes, the frequency increases. We don’t know what the maximum percentage is.
Q. Is it theoretically possible to have a single drug for that third of cancers?
A. That’s been everyone’s dream, to have a drug that would work across these types of cancer. I think it’s within the realm of possibility that we could develop drugs that work on tumors that have extrachromosomal DNA, regardless of the type of cancer. In this field, we’ve learned that most malignant tumors, when not detected very early, generally require multiple drugs. So, of course, we’re going to have to investigate this possibility as well.
Q. In recent weeks, the Trump administration has canceled or frozen billions of dollars in science funding. Do you have a problem with Trump’s cuts? [The $25 million for his consortium comes from the U.S. National Cancer Institute and Cancer Research UK.]
A. Cancer research is incredibly important. What most people fear most is cancer. It’s a scourge. It’s a plague on humanity. There’s nothing more important, and I think it’s critical that we put all our resources into helping these patients and into research, which is the heart of that help. It’s an obligation. The people we need to listen to are the people whose children, siblings, partners, parents are suffering from cancer. People like me don’t do this work for ourselves. We’re inspired to change things because this is one of the biggest problems facing humanity. So my answer is that the right thing to do now, both in the United States and around the world, is to make a full-on effort to ease the burden of suffering from cancer, to figure out how to prevent it, how to diagnose it early, how to treat it more effectively. Nothing is more important.
Q. Are there also cuts in cancer research funding under the Trump administration?
A. We don’t know what’s going to happen, really, and that uncertainty is a very difficult situation. We need to make it very clear that funding for cancer research is critical. I think most people see it that way, because I don’t know anyone whose family hasn’t been affected by cancer.
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The consequences of the torrential rains that hit the province of Valencia last October were devastating and will be remembered for years. Their deadly impact — a court is investigating whether the regional authorities’ mismanagement of the emergency exacerbated the disaster — was enormous: in just a few tragic hours, 232 people died in Valencia due to flooding, representing 70% of all deaths linked to torrential rains in Europe throughout 2024.
This is the conclusion drawn from the 2024 European State of the Climate Report, published Tuesday by the Copernicus Climate Change Service, a subsidiary of the European Commission, and the World Meteorological Organization (WMO). The study compiles weather trends and events from last year on a continent that is warming faster than the rest due to human-caused climate change. As was the case across the Earth’s surface as a whole, 2024 was the warmest year on record in Europe since direct measurements began. And a warmer planet often means more extreme and frequent weather events, such as heat waves and episodes of waterspouts and flooding.
The chapter on torrential rains and storms highlights how these events “affected an estimated 413,000 people in Europe” and caused “at least 335 lives lost” last year. Of these, according to the document, at least 232 people died in Valencia during the October DANA (the Spanish acronym for Isolated Depression at High Levels). “Damage to infrastructure and economic losses were severe, totaling approximately €16.5 billion,” it adds, referring to the cold snap, which also hit the Spanish provinces of Albacete, Cuenca, and Málaga. This event also accounted for the majority of flood-related economic losses in Europe last year, which the study estimates at “at least €18 billion.”
According to Copernicus, in 2024, 30% of Europe’s rivers experienced flows exceeding the high flood threshold (i.e., floods that occur every five years), while 12% of the river network experienced flows exceeding the severe flood threshold (i.e., those with a 20-year frequency). “Europe experienced the most widespread flooding since 2013,” says Samantha Burgess, Climate Strategy Director at the European Centre for Medium-Range Weather Forecasts and one of the coordinators of the analysis presented on Tuesday.
The chapter on torrential rains analyzes two specific flooding events in 2024: the Valencia flood in late October and Storm Boris, which caused extreme rainfall in Central and Eastern Europe in the second half of September. Flooding occurred in parts of Germany, Poland, Austria, Hungary, the Czech Republic, Slovakia, Romania, and Italy. Scientific attribution analyses have been published for both cases, suggesting that climate change fueled these torrential rains.
The Copernicus and WMO report not only analyzes what has already happened, but also what is expected for the future. “Europe is one of the regions with the largest projected increase in flood risk,” it explains, based on what has already been established by the Intergovernmental Panel on Climate Change (IPCC), affiliated with the United Nations. In its latest review of scientific knowledge on climate change, this panel of experts noted that “an increase in extreme precipitation and surface water flooding is expected in all regions of Europe.”
As previously observed, “between 1960 and 2010, river flood risks increased in Western and Central Europe and the United Kingdom by 11% per decade and decreased in Eastern and Southern Europe by 23% per decade.” “The three most recent decades saw the highest number of floods in the past 500 years,” the authors summarize. As global warming progresses, problems will worsen. “Every additional fraction of a degree of temperature rise matters because it accentuates the risks to our lives, to economies and to the planet,” Secretary-General of the WMO Celeste Saulo warned in the Copernicus-WMO report. “Adaptation is a must,” she added.
Behind tragedies like the one experienced in Valencia last fall is the intensification of extreme events due to climate change, but also the lack of oversight in urban planning and construction in flood zones. The report emphasizes the importance of preparing for climate change: “51% of European cities have adopted dedicated climate adaptation plans, representing encouraging progress from 26% in 2018,” the authors state.
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