Zebrafish Provide New Hope for Cancer Treatment

The imaging of tumour growth in zebrafish has revealed for the first time how newly formed cancer cells have the capacity to co-opt the immune system into spreading the disease, leading the way for investigations into potential therapies for eliminating early-stage cancer in humans. Using different coloured fluorescent tags, scientists at the University of Bristol labelled immune cells and tumour-forming cells in the translucent zebrafish in order to track their behaviour and interactions by live cell imaging.

These dramatic findings, which are the result of a collaboration between academic colleagues in the UK (University of Bristol and University of Manchester) and Italy (Institute of Molecular Oncology, Milan) are published in the online, open access journal PLoS Biology.

Tests showed that cancer cells are less likely to proliferate if white blood cells can be prevented from contacting the precursor cancer cells, suggesting that white blood cells -- the immune cells -- have the ability to promote disease by providing some kind of growth signal. Interestingly, the chemical compound that acts as a draw between the two sets of cells was shown here to be hydrogen peroxide -- commonly used as a disinfectant or antiseptic, but also a natural by-product produced by the body's metabolic process.

Describing the work, Paul Martin, Professor of Cell Biology at the University of Bristol's Schools of Biochemistry and Physiology & Pharmacology, who supervised post-doctoral fellow Yi Feng in the research project, said: "By visualizing the earliest interactions between cancer cells and their host environment, we have shown that even from their earliest stages tumours don't just avoid being destroyed by the immune system. Rather, they appear to court an immune response, co-opting the body's innate immune system to aid and abet their growth."

The team used a method to switch on the human oncogene, HRAS, in specific pigment cells (melanocytes) in the skin of early stage zebrafish embryos. Studies were carried out using zebrafish because they conserve many of the molecular and cellular components of tumour formation seen in mammals and are almost translucent, making it easy to see the cells as they move around and grow. Researchers monitored the first hours and days of development and as the embryo grew, some of the cells were transformed, ie, made cancerous by HRAS. Those transformed cells were found to actively attract the innate immune cells. The researchers got the same results, after inserting HRAS into different, mucous-secreting cells, and again when experimenting with a different oncogene, SRC. They discovered that the tumour cells produced hydrogen peroxide and that immune cells were drawn up the hydrogen peroxide gradient towards the cancer.

The researchers' movies show that the immune cells appear to engulf cancerous cells in a bid to destroy them. However, other cells formed cytoplasmic tethers linking them to cancerous cells and in some cases the cancerous cells appeared to drag the immune cells back when they started to leave the region. In order to see whether the tumour was avoiding destruction or actually co-opting the immune cells, the researchers blocked the immune response in three different ways: they prevented the development of immune cells for the first three days of the zebrafish embryos' life, and separately, they used two different strategies to limit hydrogen peroxide production. In each case, immune cells failed to migrate to the cancer site. And each time, when the immune response was blocked, fewer cancer cells formed.

Professor Martin added: "Yi's movies in Zebrafish larvae give us the first insight into how immune cells sense and then attempt to deal with the earliest stages of cancer. Now we can look closer to discover why it is that immune cells seem to aid growth of these young cancer cells and figure out ways for guiding immune cells how better to search and destroy."

Journal Reference:

1. Feng Y, Santoriello C, Mione M, Hurlstone A, Martin P. Live Imaging of Innate Immune Cell Sensing of Transformed Cells in Zebrafish Larvae: Parallels between Tumor Initiation and Wound Inflammation. PLoS Biology, 2010; 8 (12): e1000562 DOI: 10.1371/journal.pbio.1000562

Courtesy: ScienceDaily

Genetic Sequencing Used to Identify and Treat Unknown Disease

A collaborative team of scientists and physicians at the Medical College of Wisconsin and Children's Hospital of Wisconsin uses genetic sequencing to identify and treat an unknown disease.

For the one of the first times in medical history, researchers and physicians at The Medical College of Wisconsin and Children's Hospital of Wisconsin sequenced all the genes in a boy's DNA to identify a previously-unknown mutation. The team was able not only to identify the mutation, but to develop a treatment plan using a cord blood transplant, and stop the course of the disease.

This accomplishment is published in the December 19, 2010 online edition of Genetics in Medicine Making a Definitive Diagnosis: Successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Lead authors are Elizabeth Worthey, Ph. D., and Alan N. Mayer, M.D. Ph.D. Collaborators at Children's Hospital and the Medical College are David A. Margolis, M.D., James Verbsky, M.D., Ph.D., Howard J. Jacob, Ph. D., and David Dimmock, M.D.

At the age of 3, Nicholas Volker of Monona, Wisconsin, had already endured more than 100 surgeries, but was progressively getting sicker. His intestines continued to swell and more abscesses formed, and doctors concluded they were dealing with an unknown cause of disease.

Dr. Alan D. Mayer, assistant professor of Pediatrics at the Medical College, and pediatric gastroenterologist with Children's Hospital, decided to look for the genetic source of the disease.

"Exhaustive efforts to reach a diagnosis revealed numerous abnormalities in Nick's immune system, but none pointed to a specific disease," Dr. Mayer explained. "So we decided the next logical step was to sequence his entire exome."

Researchers examined all 20,000 of his genes looking for the cause of this rare disease. After three months poring over data, the researchers identified a unique mutation in one gene. They confirmed that mutation to be responsible for Nick's previously-undocumented form of bowel disease, which is part of a broader XIAP deficiency.

The team then performed a blood cord transplant in June using stem cells from a matched, healthy donor. Five months later, Nick is home and eating a healthy diet for the first time.

"There has been no return of the bowel disease," said Dr. David A. Margolis, the program director for the Blood and Marrow Transplant Program at Children's Hospital, and associate professor of pediatrics at the Medical College. "At this point, he is a transplant recipient and his current treatment focuses on maintaining his health with the challenges posed by the transplant."

The Medical College of Wisconsin and Children's Hospital of Wisconsin are developing a new strategy as well as formal policies and procedures to guide the approach to future cases in which genetic sequencing will be used as a diagnostic tool.

"We are confident that genomic sequencing will have a growing role in establishing the correct diagnosis for patients and, most importantly, improving outcomes," said Dr. Jacob, the Warren P. Knowles Professor of Molecular Genetics, director of the Medical College's Human and Molecular Genetics Center and professor of physiology

Journal Reference:

1. Alan N. Mayer, David P. Dimmock, Marjorie J. Arca, David P. Bick, James W. Verbsky, Elizabeth A. Worthey, Howard J. Jacob, David A. Margolis. A timely arrival for genomic medicine. Genetics in Medicine, 2010; : 1 DOI: 10.1097/GIM.0b013e3182095089

Courtesy: ScienceDaily

Rise in Oxygen Drove Evolution of Animal Life 550 Million Years Ago

Researchers funded by the Biotechnology and Biological Sciences Research Council (BBSRC) at the University of Oxford have uncovered a clue that may help to explain why the earliest evidence of complex multicellular animal life appears around 550 million years ago, when atmospheric oxygen levels on the planet rose sharply from 3% to their modern day level of 21%.

The team, led by Professor Chris Schofield, has found that humans share a method of sensing oxygen with the world's simplest known living animal -- Trichoplax adhaerens -- suggesting the method has been around since the first animals emerged around 550 million years ago.

This discovery, published in the January 2011 edition of EMBO Reports, throws light on how humans sense oxygen and how oxygen levels drove the very earliest stages of animal evolution.

Professor Schofield said "It's absolutely necessary for any multicellular organism to have a sufficient supply of oxygen to almost every cell and so the atmospheric rise in oxygen made it possible for multicellular organisms to exist.

"But there was still a very different physiological challenge for these organisms than for the more evolutionarily ancient single-celled organisms such as bacteria. Being multicelluar means oxygen has to get to cells not on the surface of the organism. We think this is what drove the ancesters of Trichoplax adhaerens to develop a system to sense a lack of oxygen in any cell and then do something about it."

The oxygen sensing process enables animals to survive better at low oxygen levels, or 'hypoxia'. In humans this system responds to hypoxia, such as is caused by high altitudes or physical exertion, and is very important for the prevention of stroke and heart attacks as well as some types of cancer.

Trichoplax adhaerens is a tiny seawater organism that lacks any organs and has only five types of cells, giving it the appearance of an amoeba. By analysing how Trichoplax reacts to a lack of oxygen, Oxford researcher Dr Christoph Loenarz found that it uses the same mechanism as humans -- in fact, when the key enzyme from Trichoplax was put it in a human cell, it worked just as well as the human enzyme usually would.

They also looked at the genomes of several other species and found that this mechanism is present in multi-cellular animals, but not in the single-celled organisms that were the precursors of animals, suggesting that the mechanism evolved at the same time as the earliest multicellular animals

Defects in the most important human oxygen sensing enzyme can cause polycythemia -- an increase in red blood cells. This latest work could also open up new approaches to develop therapies for this disorder.

Professor Douglas Kell, Chief Executive, BBSRC said "Understanding how animals -- and ultimately humans -- evolved is essential to our ability to pick apart the workings of our cells. Knowledge of normal biological processes underpins new developments that can improve quality of life for everyone. The more skilful we become in studying the evolution of some of our most essential cell biology, the better our chances of ensuring long term health and well being to match the increase in average lifespan in the UK and beyond."

Journal References:

1. Christoph Loenarz, Mathew L Coleman, Anna Boleininger, Bernd Schierwater, Peter W H Holland, Peter J Ratcliffe, Christopher J Schofield. The hypoxia-inducible transcription factor pathway regulates oxygen sensing in the simplest animal, Trichoplax adhaerens. EMBO reports, 2010; DOI: 10.1038/embor.2010.170
2. Kalle T Rytkönen, Jay F Storz. Evolutionary origins of oxygen sensing in animals. EMBO reports, 2010; DOI: 10.1038/embor.2010.192

Courtesy: ScienceDaily

Free Radicals Good for You? Banned Herbicide Makes Worms Live Longer

It sounds like science fiction – Dr. Siegfried Hekimi and his student Dr Wen Yang, researchers at McGill’s Department of Biology, tested the current “free radical theory of aging” by creating mutant worms that had increased production of free radicals, predicting they would be short-lived. But they lived even longer than regular worms! Moreover, their enhanced longevity was abolished when they were treated with antioxidants such as vitamin C.

The researchers then sought to mimic the apparent beneficial effect of the free radicals by treating regular, wild worms with Paraquat, an herbicide that works by increasing the production of free radicals. Paraquat is so toxic to humans and animals that it is banned in the European Union and its use restricted in many other places. Much to his delight, Hekimi discovered that the worms actually lived longer after being exposed to the chemical. “Don’t try this at home!” Dr Hekimi feels he should remind everyone. These findings were published December 6 in PLoS Biology.

Free radicals are toxic molecules produced by our bodies as it processes oxygen. As the body grows and uses its cells’ various functions, it consumes oxygen, generating free radicals as a by-product, which in turn causes damage to cells. A long-standing theory suggests that aging is caused by a vicious cycle involving increasing production of free radicals, followed by damage to the cell and a further increase in free radicals because of the damage.

“These findings challenge our understanding of how free radicals are involved in the aging process,” Hekimi said. “The current theory is very neat and logical, but these findings suggest a different framework for why oxidative stress is associated with aging.” The genetically modified worms demonstrated that the production of free radicals can help to trigger the body’s general protective and repair mechanisms. In other words, at certain stages in life, free radicals may be a key part of our well-being, despite their toxicity.

“Further experimentation is required to explore exactly how this data might change our theory of aging,” Hekimi explained. “Free radicals are clearly involved, but maybe in a very different way than in the way people used to think”. For this work, the research team headed by Dr. Hekimi received funding from the Canadian Institutes of Health Research. Dr Hekimi also holds the Robert Archibald and Catherine Louise Campbell Chair of Developmental Biology.

Journal Reference:

1. Heidi A. Tissenbaum, Wen Yang, Siegfried Hekimi. A Mitochondrial Superoxide Signal Triggers Increased Longevity in Caenorhabditis elegans. PLoS Biology, 2010; 8 (12): e1000556 DOI: 10.1371/journal.pbio.1000556

Courtesy: ScienceDaily