DR. KELLY MCNAGNY’S LAB: Researchers target protein to stop spread of aggressive tumours
A side-by-side comparison of lung metastases showing the control antibody on the left and the podocalyxin antibody on the right. Researchers developed the podocalyxin antibody and found that it slowed tumour growth and spread. UBC Media Release | April 9, 2015
Inhibiting a specific protein associated with aggressive, hard-to-treat tumours slows down their ability to spread to other sites in the body, a team of UBC researchers has discovered.
In a study recently published in Breast Cancer Research, researchers describe how inhibiting podocalyxin, a protein marker found in many highly aggressive tumours, dramatically slowed the growth and metastasis of these tumours in mice. In collaboration with the Centre for Drug Research and Development, they also developed an antibody that targets podocalyxin, and found that it slows tumour growth and spread.
“It really, really knocks down the invasiveness of the cells and their ability to migrate and spread to other sites in the body, which is the hard thing to treat in metastatic cancer,” explains Dr. Kelly McNagny of UBC’s Biomedical Research Centre.
Podocalyxin is associated with about five percent of breast cancers, the majority of ovarian cancers, and subsets of colon, renal and bladder cancers. Earlier studies by the same group of researchers and others have shown that its presence in tumours correlates with disease progression and poor survival.
“In most cases, if you have this particular marker on your primary tumour, you’re much more likely to have a poor disease outcome later,” says McNagny. “Our data suggest that expression of this protein enhances the ability of a subset of tumour cells to spread to other sites in the body, and this new antibody inhibits that process.”
This latest discovery offers additional hope for those suffering from metastatic disease. McNagny’s team plans to do further testing of their results, including toxicology studies on the antibody they developed.
This research was supported by an operating grant from the Canadian Institutes of Health Research and an Impact grant from the Stem Cell Network Centre of Excellence. It was the result of a strong collaboration between the UBC laboratories led by Kelly McNagny and Calvin Roskelley, and the Centre for Drug Research and Development led by John Babcook.
This research was honoured with a Distinguished Master’s Thesis STEM Award for the Biological Sciences from the Western Association of Graduate Studies (WAGS/UMI), awarded to UBC MSc graduate Kimberly Snyder, one of the lead authors of the study. Her thesis was selected from nominees representing 89 graduate schools in 13 U.S. states and three Canadian provinces in western North America.
DR. JOHN SCHRADER’S LAB: The research team led by Dr. Schrader and based at the Biomedical Research Centre showed that small variations in the standard seasonal flu vaccine can give lifetime immunity to all strains of influenza virus. See Full Article Frontiers in Immunology, 2012 May; doi: 10.3389/fimmu.2012.00087
Vaccines contain substances from a particular bacteria or virus and induce your immune system to make more antibodies that protect against that particular bacteria or virus. Antibodies are made by the immune system and come in millions of shapes. Each antibody binds specifically to substances from particular bacteria or viruses. When you recover from an infection with a particular bacteria or virus, you are immune to that bacteria or virus, because you make more antibodies against the critical substance in that germ.
Have you ever wondered why you have to get a flu vaccination every year, whereas childhood vaccination for measles can last a lifetime? That is because the flu virus constantly mutates and changes to avoid our antibodies. Thus the specific antibodies that protected you against last year’s flu don’t protect you from the next year’s flu variant.
Imagine enormously enlarging the flu virus. It would look like a beach ball, covered with hundreds of tulips sticking out of it. The tulip is the viral protein called hemagglutinin, or HA for short. The HA, like the tulip has a head and a stem. The HA head is very variable, like different varieties of tulip flowers. But the HA stem is quite constant, like the tulip stem, and is the same in most flu viruses. For fifty years scientists thought that the human immune system could only makes antibodies against the variable HA head and not against the constant HA stem. That is why flu vaccination has to be done every year because the virus constantly changes the HA head. The head of HA attaches the flu virus to the human cells in the nose or lungs. Protective antibodies against influenza stick to the HA head and block the flu virus’ attachment to the human cells.
Our influenza research started in the spring of 2009, when reports came out of Mexico about a new influenza virus that could make some young adults seriously ill. Our intention was to generate human monoclonal antibodies from people that had recovered from swine flu or pandemic H1N1 of 2009. These monoclonal antibodies could be produced in a factory and could be used to potentially treat people seriously ill with the swine flu. In August of 2009, we noticed that many of the antibodies from people recovering from swine flu had genetic characteristics of artificial antibodies against the HA stem of bird flu. (Bird flu, or avian H5N1 influenza, has a death rate in humans of greater than 60 %.) These artificial antibodies targeted the constant HA stem and, thus, protected against many varieties of influenza viruses. We tried our antibodies against swine flu against the HA of bird flu and it bound to the HA stem. So then we knew that broadly cross-protective antibodies against many types of flu could be made by humans. But we also noticed that the antibodies we had generated against swine flu that bound to the swine flu HA stem also bound well to different batches of the seasonal flu vaccine. That meant the standard flu vaccine contained the constant part of the flu virus – the HA stem. We predicted that the swine flu vaccine would induce antibodies against the HA stem and protect against many different flu viruses, as the pandemic H1N1 flu vaccine was produced by the same methods as the seasonal flu vaccine.
When the pandemic vaccine become available in November 2009, we analysed the antibodies from vaccinated humans. We found that vaccinated humans produced many antibodies against the HA stem of swine flu and that these antibodies could protect mice against infections with bird flu. We proved that these antibodies block the function of the HA stem and prevented the entry of the virus into the cell. The influenza virus cannot afford to vary the HA stem because, mutations in the stem weakens the virus and it cannot penetrate and enter the cell.
Then we asked ourselves, what was the difference between pandemic flu and seasonal flu? Why, when we were vaccinated with the seasonal flu vaccine, did we not make broadly cross-protective antibodies against many varieties of flu viruses? Why doesn’t long-lasting immunity normally develop to flu? We suspected that the different thing about swine flu was that humans had no contact with the swine flu or a related virus. When the human immune system is repeatedly stimulated with variants of the head of HA by seasonal flu every year – either by infection or vaccination, the antibody-producing cells of the human immune system focus on the rapidly changing head of the HA. Thus the antibody-producing cells that make antibodies to the constant part of the flu virus, the HA stem, get out-competed. But if we vaccinate with a flu virus that was circulating not in humans but in animals – like the 2009 pandemic H1N1 flu that was circulating in swine and a had a very different head on the HA – the antibody-producing cells that make antibodies against the HA head of seasonal flu virus would not get stimulated, and the immune system would be free to make antibodies against the constant part of the HA , the stem. We had already proved that most humans vaccinated with the swine flu vaccine make many cross-protective antibodies that could protect mice against lethal infections with bird flu.
So our concept of a universal flu vaccine was to vaccinate with conventional vaccines based on a mixture flu viruses that were circulating not in humans, but in animals like like ducks and pigs.
Our paper also showed that therapeutic antibodies against a potentially lethal emerging virus could be generated in months after the virus is identified. Future progress in gene-therapy with antibodies may mean people can be rapidly immunized against an emerging virus in a few months.
DR. KELLY MCNAGNY’S LAB: McNagny and Colleagues Uncover Antibiotic Link to Asthama See Full Article in EMBO (2012 May 1;13(5):440-7)
Asthma is a common, increasingly frequent, chronic inflammatory disease of the airways that affects over 100 million people worldwide. It is associated with shortness of breath, coughing and wheezing, and necessitates the use of puffers by millions of children. This treatment is required to prevent considerable short- and long-term morbidity and mortality.
Lung sections from mice reveals worse evidence of asthma after vancomycin treatment
Although the cause of asthma remains a mystery, it has long been believed that improved sanitation methods and the broad use of antibiotics has adversely affected the development of the immune system. This reduced exposure to bacteria, the so-called “hygiene” hypothesis, renders children at increased risk of developing the disorder. This hypothesis has, however, not been tested.
Since the gut is a normal reservoir for bacteria, the research teams of CBR investigator, Dr. Kelly McNagny (Biomedical Research Centre) and Dr. Brett Finlay (Dept of Microbiology and Immunology; Michael Smith Laboratories) collaborated to evaluate the role of antibiotics and gut microbes on the development of asthma.
Using a mouse model of allergic asthma, they found that when the antibiotic vancomycin is used at low dose early in life, it profoundly alters the bacterial community in the gut, and markedly increases the incidence and severity of the asthma. Interestingly, when mice were treated with vancomycin as adults, the asthma rates were not affected. Moreover, not all antibiotics had the same effect, i.e. streptomycin did not alter asthma rates when given at any time, indicating that only specific bacteria influence the development of allergic asthma.
Overall, these intriguing findings, published in the journal EMBO Reports (2012 May 1;13(5):440-7) strongly suggest that certain bacteria are critical during childhood in promoting development of a robust immune system that can protect against allergic asthma. Extension of this work to humans will be fascinating and important. These findings will hopefully lead to novel insights into the interplay between bacteria and the immune system, the development of novel therapies for asthma, and the clinical selection and use of antibiotics that do not ultimately contribute to asthma.
TAKA MURAKAMI, MANAGER, GENOTYPING FACILITY, Biomedical Research Centre, UBC interviewed by Genetic Engineering & Biotechnology News, June 15, 2012 as part of an Expert Panel For Full Article Biotechnology News, June 15, 2012
Jun 15, 2012 (Vol. 32, No. 12)
An Exclusive Q&A with Our Expert Panel
Benjamin Bronfin, M.D. , Rohit Kumar Mahajan, Ph.D. , Chris Meda , Taka Murakami, Vyacheslav Palchevskiy, Ph.D. , Kevin Papenfuss
Once the concept of PCR popped into Kary Mullis’ head in 1983 it wasn’t long before scientists realized they had a revolutionary technology in their hands. Because now they could take the smallest slice of DNA and amplify it an infinite number of times for analysis and further research. Indeed, PCR so transformed the life science field that Mullis was awarded the Nobel Prize in Chemistry in 1993.
Many researchers regard PCR as a workhorse in molecular biology. Novel applications, new reporter chemistries, and advancing microfluidics are already leading to higher throughput and more sensitive PCR techniques.
Mikael Kubista, Ph.D., one of GEN’s editorial advisory board members, helped pioneer the development of real-time qPCR. In the May 1 issue of GEN Dr. Kubista noted that qPCR is developing rapidly, although most current efforts are on pre-analytic and data-mining processes rather than on the qPCR technique itself.
In this special GEN Tech Tips PCR feature, we asked some of the world’s other leading practitioners of PCR methods to talk about ways to improve and get more out of their work with various PCR techniques. The people interviewed for this special feature included Benjamin Bronfin, M.D., director of R&D at Cambridge Biomedical; Rohit Kumar Mahajan, Ph.D., associate director, assay development at Vical; Chris Meda, consultant and former president at Response Genetics; Taka Murakami, manager of the genotyping facility at the University of British Columbia; Vyacheslav Palchevskiy, Ph.D., postdoctoral fellow at UCLA, pulmonary and critical care division; and Kevin Papenfuss, scientific consultant specializing in PCR, formerly of Life Technologies. You will find that their insights also have applications to your research.
DR. FABIO ROSSI’S LAB: Muscle Injury Activates Resident Fibro/Adipogenic Progenitors That Facilitate Myogenesis See Full Article www.nature.com/ncb/journal/v12/n2/full/ncb2015.html
Following damage, many organs regenerate and return to their original state. When regeneration fails a fibrous scar tissue, often containing scattered adipocytes, replaces the functional tissue and interferes with both organ function and responses to therapy. The source of this fibrous tissue is still controversial: which kinds of adult stem cells are in charge of making the scar? Dr Rossi’s team has provided an answer to this question by identifying a new type of progenitors, found in essentially all tissues and located in close association with blood vessels, which can generate both fibroblasts as well as adipocytes.
So are these progenitors “bad guys”? Not always! These cells are activated by damage even when regeneration proceeds normally and scar is not formed. In this context, these fibro/adipogenic progenitors (FAPs) provide support, through the production of trophic factors, to the stem cells that are actually fixing the tissue. Any attempt to control fibrosis through drugs that block these cells will have to keep in account the fact that they can be useful too. Finally, their ability to make new fat cells makes them into attractive candidates for use in certain metabolic diseases. For example, when FAPs are transplanted into mice that lack fat and have type 2 diabetes, they generate new fat cells and reduce blood glucose, essentially curing the metabolic imbalance. In conclusion this novel cells type plays a multitude of roles, some positive and some negative depending on the environment and the specific situation. Presumably, therapeutics that modulate their functions could be beneficial in a number of diseases.