Epigenetic Changes in Cancer

Lung cancer close-up MOREDUN ANIMAL HEALTH LTD/SPL / Gettyimages

The study of how covalent marks on DNA and histones are involved in the origin and spread of cancer cells
is also leading to new therapeutic strategies.

Much of the current hype in epigenetics stems from the recognition of its role in human cancer. Yet, intriguingly, the first epigenetic change in human tumors—global genomic DNA hypomethylation—was reported way back in the early 1980s, at about the same time the first genetic mutation in an oncogene was discovered.1 So why the delay in recognizing the importance of epigenetics in cancer?

In the 1980s epigenetics was a fledgling discipline, hampered by methodological limitations, while genetic knowledge of Continue reading

The Skin Gun

Scientists have invented a ballistic new way to treat burns and skin abrasions – shoot them with a stem cell gun. The gun – a sterile syringe that loads into a spraying nozzle – releases a patient’s own stem cells, generated from a piece of healthy skin, which can immediately begin repairing the skin.

 

Largest animal genome discovered

Wikimedia commons, Paul Hebert

Scientists have sequenced the entire genome of Daphnia pulex, a small crustacean commonly used as a model organism for basic biological function studies, and revealed the largest number of genes of any animal genome. The paper, published last week in Science, reports that Daphnia has a total of 30,907 genes, significantly more than the 23,000 estimated human genes.

Pfizer cuts R&D

Pfizer announce last week that it will cut some 20 percent of its R&D expenditure, from $8.5 million to $7 million, sometime next year. The pharmaceutical company also plans to shut down a UK research facility that currently employs 2,400 people and to drastically reduce staff in its Connecticut research center, according to ScienceInsider, although it may increase its Massachusetts workforce by several hundred.

While the news has come as a surprise to many, GlaxoSmithKlein’s chief executive Andrew Witty indicated that Pfizer’s loss may be GSK’s gain. “We absolutely will look at… high calibre people, talented people there,” Witty told The Telegraph. “There may be some people who want to come here…and of course we’ll look at that.”

90 retractions coming?

Nearly 100 papers might be pulled from the literature because they didn’t receive proper institutional approval, according to Retraction Watch. Joachim Boldt, former head of anesthesia at the Klinikum Ludwigshafen in Germany, was fired last year after suspicions were raised about one 2009 Anesthesia & Analgesia paper that appeared to be based on research that hadn’t taken place. But last week an ongoing investigation by Klinikum Ludwigshafen and the German state medical association of Rheinland Pfalz announced that as many as 90 studies failed to get proper institutional approval — grounds for the immediate retraction of an article, according to a letter from the editors of 11 journals. (Hat tip to ScienceInsider)

News in a nutshell

Vaccines prevent cancer?

Some vaccinations routinely given to children, such as those for hepatitis B and polio, may lower the risk of certain cancers, like leukemia. Comparing 2,800 cases of childhood cancer in Texas to more than 10,000 healthy individuals, researchers found that children born in counties where the hep B vaccine was common were 20 percent less likely to develop cancer. Similarly, kids born in areas where children are typically vaccinated for both the polio and hep B were 30 to 40 percent less likely to contract the disease, according to a new study published last week in the Journal of Pediatrics. Though some parents choose against vaccinating their children because they believe the shots can cause autism, “people can take a step back and really look at the benefit that vaccines provide — not just for the infectious diseases they were intended to prevent,” study author Michael Scheurer of Baylor College of Medicine in Texas, told Reuters. (Hat tip to FierceVaccines)

Flickr, Blake Patterson

Q&A: Alzheimer’s trial disconnect

While preclinical studies identify ways to prevent Alzheimer’s disease in animals, human trials test these same therapies in symptomatic patients — long after they are most likely to be effective

Alzheimer’s disease (AD) is a growing threat that currently afflicts some 35 million people worldwide. Without the advent of preventive therapies, the neurodegenerative disease will strike as many as 100 million people by 2050. And while laboratory studies in animal models of AD continue to uncover promising avenues for disease prevention, clinical trials in humans target patients who are already showing signs of neural degeneration.

Image: Wikimedia commons, Alzheimer Forschung Initiative e.V.

Disease biologist Todd Golde of University of Florida College of Medicine talked to The Scientist about this disconnect, its consequences, and possible solutions to the problem — the topic of an opinion piece he co-authored, published online today (January 26) in Neuron.
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Mom’s blood carries fetus genome

A complete copy of the fetal genome exists in the mother’s blood, suggesting many prenatal diagnoses could be performed noninvasively

[Published 8th December 2010 07:00 PM GMT]

Circulating in the blood of pregnant women is the full genome of their unborn child, according to a study published online today (December 8) in Science Translational Medicine.

Image: Wikimedia commons, Swangerschaft

The results suggest that whole genome sequencing of fetuses may be possible without invasive procedures, and hold implications for the prenatal diagnoses of every genetic disease.

This study provides “a window into the fetal genome,” said reproductive geneticist Diana W. Bianchi of the Mother Infant Research Institute at the Tufts University School of Medicine, who was not involved in the research. “In principle, that means that you could noninvasively prenatally diagnose anything because the sequence is going to be there.”

In 1997, chemical pathologist Dennis Lo of The Chinese University of Hong Kong and his colleagues discovered the presence of fetal DNA in maternal blood. Scientists have since developed noninvasive procedures to prenatally diagnose certain diseases. Down syndrome, for example, results from an abnormal number of chromosomes, and can be detected by searching mother’s blood for disproportionate amounts of DNA from different chromosomes. And genetic diseases inherited from the father may also be detected by searching the mother’s blood for the paternal mutation.

It was unclear, however, if the entire fetal genome was present in the maternal plasma, which would give clinicians more confidence in the tests currently available by limiting the rate of false-negative results. Additionally, it might make it possible to screen for genetic diseases that are caused by genetic mutations inherited from the mother, as well as sequence the entire genome of the unborn child, without subjecting the mother to invasive procedures that carry a small risk of miscarriage.

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Evolving the Scientific Method

Technology is changing the way we conduct science.

The Undruggables

Can young biotechs chasing elusive drug targets succeed where so many have failed? They think so.

G-protein coupled receptors in the cell membrane
Courtesy of Anchor Therapeutics and Arkitek Studios

John Andrews finished his presentation and turned to the roomful of pharmaceutical employees. Chief scientific officer for NeurAxon, a small Canadian biotech developing pain therapeutics, Andrews braced himself for the onslaught. The comments came rapid-fire: Can it be produced efficiently? Yes, in just a few steps. It is really soluble? It has been from day one. Is it truly selective? Yes.

In the back of the room, a senior chemist stood up. He, like many of the scientists present, had been working unsuccessfully for years to develop a similar drug. “Well,” he said, “You’re either geniuses, extremely lucky, or frauds.” Andrews smiled.

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Jawless evolution explained

A new genetic analysis tips the scales to one side of a long-term debate on the evolution of jawless vertebrates

[Published 18th October 2010 08:00 PM GMT]

Genetic evidence is laying to rest a long-standing argument over the evolution of jawless vertebrates — hagfish and lampreys — and providing insights regarding the common ancestor of all vertebrates.

Sea lamprey
Image: Wikimedia commons

For years, biologists have debated the origins of jawless vertebrates — molecular biologists have argued that molecular evidence shows they are each other’s closest relatives, while morphologists maintained that detailed anatomical features suggest lampreys were more closely related to jawed vertebrates.

In the most recent study, published Monday (18 October) in Proceedings of the National Academy of Sciences (PNAS), scientists on opposite sides of the argument looked at microRNA data, and found jawless vertebrates are indeed monophyletic, meaning they evolved from a common ancestor not shared by jawed vertebrates.

“I was staggered by this paper,” said Philippe Janvier, a paleontologist at the Muséum National d’Histoire Naturelle in Paris, France, and a long time supporter of the idea that lampreys were more closely related to jawed vertebrates. “It’s very hard for me to recognize that I’ve been wrong in my assumption,” said Janvier, who did not participate in the research, but this paper provides “very, very strong support for the monophyly — the common origin of lampreys and hagfishes apart from the origin of the jawed vertebrates.”
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The Gates of Immortality

Did biology evolve a way to protect offspring from the ravages of aging by creating a physical barrier that separates the parent from its young?

he idea that every organism must age was a concept that surprised many biologists. For a long time, aging was thought to be a process occurring only in multicellular organisms. The reason for this arguably odd presumption was that we knew somatic cells—such as those that comprise the kidney, brain, and liver—lost their functionality over time: they aged. Furthermore, those cells divided only a limited number of times, around 50, after which they reached the so-called Hayflick limit, stopped proliferating, and died.

Unicellular organisms were thought to be capable of dividing forever, as long as conditions allowed: one generation begetting the next down through time—a sort of immortality. If unicellular organisms were like somatic cells, then they would age as they divide, reach the Hayflick limit, and die.

It wasn’t until the 1950s that researchers who thought about aging began to change their minds. It became clear that the daughter cells of some unicellular organisms seemed to rejuvenate, to start from scratch, while the mother cells accumulated the cellular aberrations that signaled aging. This pattern of aging was seen in such evolutionarily distant organisms like Saccharomyces cerevisiae, known as budding or baker’s yeast, and bacteria such as Caulobacter crescentus and Escherichia coli.1–3 Aging, it seems, is a universal property of all living beings.

For me, that realization begged a more fundamental question, one that as biologists, we are scarcely allowed to ponder: Why do cells allow some mistakes to accumulate? If evolution is such a powerful process—one that finds solutions to all manner of problems—how could there be processes or problems that can’t be fixed?

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Green-thumbed biotechs say they can use plants to make drugs faster, cheaper, and better than top pharmaceutical companies

Botanical Biopharming

In 2001, ProdiGene was a poster child for the plant biotechnology industry. A privately owned biotech in College Station, Texas, ProdiGene was the first to successfully commercialize a product made from a transgenic plant—a protein called trypsin produced in corn kernels and sold to the pharmaceutical industry for mammalian cell culturing. They also had more than 18 other plant-made products in development, including vaccines for traveler’s diarrhea, hepatitis B, and AIDS. That spring, the MIT Technology Review voted ProdiGene’s oral vaccine patent one of the “five patents that will transform business and technology.”

But a year later, things began to spiral downhill. In September 2002, the US Department of Agriculture ordered ProdiGene to destroy 155 acres (63 hectares) of corn in Iowa that may have cross-pollinated with a nearby test site of ProdiGene’s transgenic corn. Then in October, the USDA seized 500,000 bushels of soybeans contaminated by ProdiGene’s corn in Nebraska. In the end, ProdiGene was slapped with over $2 million in fines and clean-up fees by the government. “That was the end of ProdiGene,” says Zivko Nikolov, former vice president of bioprocessing at the company.

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Cell+phone

Ozcan’s lensfree cell phone microscope

The seeds for electrical engineer Aydogan Ozcan’s latest invention—a lensless microscope that can spot pathogens in blood and water samples in remote areas with no access to other imaging technology—were planted in the shadows.

Ozcan first had the idea for lensfree imaging as he sat alone in his lab experimenting with a sensor array from a “hacked security camera” that he’d purchased on eBay. As the sensor array collected the shadows cast by microscopic polystyrene particles when overhead fluorescent light was bent by their irregular surfaces, it dawned on Ozcan that a lot of information lurked in the inky silhouettes of tiny bodies, given that cells of different species or different cell types within one organism often contain distinctive shapes. “I realized that the shadows of cells are really interestingly textured and useful,” recalls Ozcan, based at the University of California, Los Angeles.

Because Ozcan was capturing those images with microchips that come as standard parts of most modern cell phones, he thought he could make a cheap device that could work with the mobile phones most of us carry to identify and differentiate waterborne parasites and human cells and bring much needed medical technology to the poorest places on Earth.

“It was evident for me that in Africa or other resource-poor countries you might not have access to resources, but you do have access to cell phones,” Ozcan says.

This microscope could bring imaging tech to far flung places.

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Surprise breast cancer source

Some breast cancer tumors may not originate from stem cells as previously believed, according to a study published in the September 3rd issue of Cell Stem Cell. The discovery is an important step in the development of treatments for these cancers.

BRCA1 structure
Image: Wikimedia commons,
Lijealso

“Understanding the origins of these types of breast cancer is not only critical for developing preventative strategies against the disease but also for developing new targeted therapies,” said Matthew Smalley, a mammary cell biologist at the Breakthrough Breast Cancer Centre in London and lead author on the study.

For years, scientists have believed that most breast cancers originated from basal stem cells, which have the ability to give rise to any of the breast tissues. But comparing mice expressing mutant versions of the BRCA1 gene, which is known to cause breast cancer, in different breast cell types, Smalley and his colleagues discovered that BRCA1 tumors actually come from progenitor cells, which can only differentiate into a single tissue type.

Top 7 papers in neuroscience

#1 Neurons complete hippocampus loop

There’s a new, important function for a once-obscure cell population in the brain: CA2 pyramidal neurons, a subset of cells in the hippocampus, form a link between electrical inputs and outputs in the hippocampus.

V. Chevaleye et al., “Strong CA2 pyramidal neuron synapses define a powerful disynaptic cortico-hippocampal loop,” Neuron, 66:560-72, 2010. Eval by Stephen Fitzjohn and Graham Collingridge, MRC Centre for Synaptic Plasticity, UK; Johannes Hell, University of California, Davis.

Neurons in the mouse brain
Image: Wikimedia Commons, Neurolle

#2 Non-overlapping neurons

The medial entorhinal cortex, a hub for memory and navigation in the brain, consists of two tangled but functionally separate networks that have different long-range axonal targets, and thus may be involved in different functions in the brain. The finding offers insights to how neural networks function, and — in conditions like epilepsy — dysfunction.

C. Varga et al., “Target-selective GABAergic control of entorhinal cortex output,” Nat Neurosci, 13:822-4, 2010. Eval by Edvard Moser, Norwegian University of Science and Technology, Norway; Jeff Isaacson, University of California, San Diego.

#3 “We’re going to need a bigger model”

In a detailed mathematical analysis, researchers analyze the capacity of computational models to model neuronal oscillations — the repetitive rise and fall of membrane potentials. They find that current single-cell oscillation models are not adequate, and there is a need for additional computational models to assess this mechanism.
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‘Identical’ cells? Not so much

Genetically identical cells may be far more different than previously believed. Published this week in Science, researchers find striking variation in levels of gene expression among individual, genetically identical E. coli, seemingly the result of simple chance.

“The paper is quite rich,” said Sanjay Tyagi, a molecular biologist at New Jersey Medical School who was not involved in the research. “People think that if an organism has a particular genotype, it determines its phenotype — that there’s a one-to-one relationship,” said Tyagi. “But as it turns out, [differences in gene expression] can arise just from chance.”

Microfluidic device allows multiplex
imaging of library strains.

Image courtesy of Yuichi Taniguchi,
Paul Choi, Gene-wei Li, and Huiyi Chen,
Harvard Universi

In traditional gene expression studies, researchers grind up a population of cells, then identify overall amounts of gene products from the resulting mixture. Researchers at Harvard University instead studied cells one by one, still calculating averages but also capturing variation in the population with single molecule sensitivity — and found cells expressing genes at wildly different levels. “It’s single molecules meet systems biology,” said Sunney Xie, senior author on the paper and a chemical biologist at Harvard University.

Xie’s team, along with collaborators at the University of Toronto in Canada, tagged 1018 genes — about one-fourth of the E. coli genome — with fluorescent labels, then counted protein and mRNA copies in individual cells using a high-throughput system. They found that mRNA and protein copy numbers vary greatly from cell to cell, what researchers call “noise.”
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New lab-grown lungs

Two new lab-grown versions of lungs may one day serve as a way to sidestep both animal testing and organ transplantation.

Image: Wikimedia commons,
Patrick J. Lynch

One engineered rat lung, described in Science Express today (June 24), even successfully helped rats breathe for brief periods.

“This is the first ever published paper that really demonstrates that regenerative medicine can provide an alternative to clinical transplantation of the lungs,” said translational medical researcher Paolo Macchiarini of Karolinska Institutet in Sweden, who was not involved in the research.

Currently, the only treatment for the lung diseases that cause some 400,000 deaths each year is to transplant a new, healthy organ — a procedure that is hampered by organ rejection complications and a severe shortage of donors. But now, bioengineer and vascular biologist Laura Niklason of Yale University and her colleagues may have developed a way to eventually address both of these issues.

Treating adult rat lungs with detergent solutions to remove their cellular components gave the researchers their starting point — a lung skeleton, or the extracellular matrix that gives the lungs their structure. The team then repopulated the lungs with epithelial and endothelial cells from rat lungs, which grew over the scaffolds to create brand new lungs.

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