Ludwig has a long history of pioneering cancer discoveries. Today, Ludwig scientists around the world are collaborating on new projects, and on ways to move breakthroughs toward the ultimate goal of patient benefit. These are some of the novel ways Ludwig researchers have teamed up to advance our understanding and control of cancer.
Our leader in Oxford: Q&A with Xin Lu, director of Ludwig Oxford
Why did you choose to pursue a career in science?
I don’t think I chose it so much as it was thrust upon me. I grew up during China’s Cultural Revolution and in the late sixties, Chairman Mao issued a call for the “Down to the Countryside Movement,” in which young students from the city were sent to live in the countryside. Having been brought up in an urban area, I didn’t have the skills or stamina for intensive agricultural labor, and knew I’d never survive. So at the age of 13, I decided to study the violin and practiced every day for at least three hours. I hoped it would give me a skill that could be exchanged for food. But I was one of the lucky ones and right after I graduated from high school, the colleges and universities reopened and I was able to sit for the exams. You’ll remember that schools and universities had been closed as the Cultural Revolution began heating up in the mid-sixties, and it wasn’t until 1977 that the ﬁrst nationwide university entrance examination was held. I chose science with no particular interest in the subject but, after the ﬁrst biology course, I realized that I really loved it.
What do you consider your most important discovery so far?
Identiﬁcation of the ASPP family of proteins and its importance in regulating p53, which is a primary target for mutation in a diverse range of cancers. There are three family members—ASPP1, ASPP2 and iASPP, and all bind to p53. ASPP1 and ASPP2 activate p53 and iASPP inhibits it. Since all three play important roles in tumor development and response to therapy, we’re investigating the ASPPs as potential biomarkers and targets for anti-cancer therapies. Through the identiﬁcation and characterization of the evolutionarily conserved ASPP family of proteins, our lab was one of the ﬁrst to show how to selectively activate p53 to kill cancer cells. We now know that the ASPPs have other important functions, including in the heart and brain.
Does this research have real-world applications?
Yes. For example, one of our discoveries provides a clue as to why some healthy people, even high-performance athletes, suffer completely unexpected heart failure. When we were looking at how iASPP might be involved in the growth of tumors, we found that mice that lack this gene died prematurely of sudden cardiac death. Our studies showed that iASPP has a previously unknown role in controlling desmosomes—one of the main structures that help to “glue” heart muscle cells together. Mice lacking iASPP were prone to arrhythmogenic right ventricular cardiomyopathy (ARVC), a genetic, progressive heart condition that in humans mainly affects young adults. We have also found that deletion of ASPP2 is implicated in a neurodevelopmental disorder.
What do you ﬁnd most exciting about your work?
Discovery. It’s what drives science and scientists. For proteins to function correctly they need to be in the correct part of the cell, but nearly half of proteins that enter the nucleus don’t have an identiﬁable nuclear localization signal. When we were looking at how the ASPP proteins get into the nucleus of the cell, it led us to the discovery of a protein code that deﬁned a new nuclear import pathway we named RaDAR, which turns out to be the second most common mechanism we know of by which proteins are imported into the nucleus. Interestingly, the most frequently mutated site in p16 in melanoma creates a RaDAR code, enabling the mutant protein to enter the nucleus. Right now, we’re also looking at ways to exploit this pathway and study its implications in human disease.
Do you still have links with China?
I have a collaborative grant from Cancer Research UK (CRUK) with the Chinese Academy of Medical Sciences. I also helped CRUK establish its China Fellowships program and am a founding member of international review committees of the Chinese Academy of Sciences and the Tsing Hua University and Peking University Schools of Life Sciences. I was also a Chair of the UK Chinese Life Science Society, which promotes collaborations between China and the UK in the life sciences. Right now my group is working with colleagues in China to identify the molecular causes of esophageal and stomach cancers—with a focus on cancer-causing pathogens—to improve treatment efficacy and develop cancer prevention strategies.
Are there any signiﬁcant differences in cancer incidence between Asia and the Western world?
Gastric cancer is more common in Asia than the Western world; it is the second most common cancer in China. The largest contributor is a type of bacteria called H. pylori. It’s a risk factor for gastric cancer and very prevalent throughout Asia. CagA is a protein produced by H. pylori and CagA-positive H. pylori induces gastric cancer by suppressing p53. It does this by hijacking the activating function of the tumor suppressor ASPP2 and triggering degradation of p53, one of our body’s main defense mechanisms against tumor cell development. Our work on the role of ASPP proteins in tumor suppression pathways could lead to novel therapeutic strategies for prevention of this cancer.
Are women gaining ground in science professions?
In China we have a saying: ‘women hold up half the sky’. So gender bias has never been a big part of my life. Both my parents were doctors and, growing up, I never saw any difference in the way men and women were treated. The director of the Cancer Institute, Chinese Academy of Medical Sciences—China’s most prestigious cancer institute, where I got my Master’s degree—was a woman, and half the principal investigators were as well. In fact, when I came to the UK, I was rather surprised that the number of female scientists was very low compared to China in the 1980s. In the UK, there are now a lot of positive steps being taken through the Athena SWAN Charter, which encourages and recognizes commitment to advancing the careers of women in higher education and research. We need the very best scientists, male and female, to drive forward discoveries, and right now there aren’t enough women making it to the highest levels.
If you could be present at one scientiﬁc discovery, which one would it be?
Penicillin. It’s truly a miracle drug and one of the greatest advances in therapeutic medicine. Prior to 1940, there was no effective treatment for infections like pneumonia, tuberculosis or rheumatic fever. People could develop blood poisoning from a cut or scratch and many would die. It’s strange to think that my career followed penicillin’s path from its discovery at St. Mary’s Hospital in London, where I started my work with Ludwig, and then on to Oxford, where its therapeutic potential was recognized.
What do you like to do when you aren’t working?
Sleep. But visiting art museums and galleries is a close second. When you think about it, art and science are very similar. They both try and answer big questions. Art is seen as creative and emotional; science, as methodical and rational. Both are a means of investigation—one in a laboratory, the other in a studio. Both involve long hours, tedious work and often it seems like nothing is working or coming out the way we hoped. But the end result—a breakthrough scientiﬁc discovery or great work of art—are both exciting, and very rare accomplishments.
You started the Ludwig Oxford Branch at the University of Oxford approximately nine years ago. What makes this a great location for the Branch’s research?
The Oxford campus has grown to be one of the largest biomedical research centers in Europe, and it is a vibrant and stimulating place to work. Recent additions include the neighboring Kennedy Institute for Rheumatology, which houses many leading immunologists, the Target Discovery Institute and the nearly-completed Big Data Institute. In terms of cancer research in particular, being in Oxford is great because it is one of the three major centers of research designated by Cancer Research UK, and the Biomedical Research Centre here facilitates fantastic clinical links. Oxford is also a perfect environment for students and postdocs to develop their careers. The whole university is within cycling distance, so there are no practical barriers to them visiting and working with other institutes. The Oxford college system also brings together people from different disciplines and offers extra support and opportunities.