Biotechnology

Researchers Are Using Viruses to Make Superbugs Commit Suicide

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The gene-editing technology called CRISPR has its origins as a bacterial immune system against viruses, a feature which could be turned against them in the future.

By arming bacteriophage viruses with the tools to force bacteria into falling on their own swords, scientists hope we will be able to develop powerful new ways to defeat antibiotic resistant pathogens and perhaps even shape our body’s microflora.

Research presented at the CRISPR 2017 conference in the US described the progress that has been made in modifying viruses that target specific bacteria with genes that make the host’s enzymes cut into its own DNA.

Clustered regularly interspaced short palindromic repeats – CRISPR for short – are sequences of DNA made of a repeating codes that form a long palindrome.

Bacteria produce them as a kind of immune system against viruses called bacteriophages, slipping bits of the virus’s genes scavenged out of the environment into the repeating codes.

With the viral DNA stored away in CRISPR sequences, any future infections can be detected quickly and a CRISPR-associated system (or cas) enzyme can then use the sequence as a beacon, latching onto the infecting virus genes and either snipping them selectively or tearing them to shreds.

About 25 years ago, researchers realised this cut-and-paste system of CRISPR sequences and cas enzymes could be used in the lab to edit sequences artificially, and a new engineering toolkit was born.

The technology has been in the news quite a bit in recent years as advances have been made in applying it to cancer treatments and even eliminating HIV infections.

While it might not be without certain risks, CRISPR gene editing has sparked a something of a minor revolution.

Bringing it back to its roots and turning it into a weapon against its creators has a sense of serendipity about it.

“I see some irony now in using phages to kill bacteria,” said the chief scientific officer of Locus Biosciences, Rodolphe Barrangou, at the CRISPR 2017 conference.

Using bacteriophages as a form of therapy to treat infection isn’t all that new, with trials dating as far back as the 1920s.

The use of phages is appealing because they are far more specific than antibiotics, targeting only specific types of bacteria and therefore posing no risk to our own health. The viruses can also penetrate the coatings of sticky film bacteria produce for protection and adherence.

Russia experienced a fair degree of success with phage therapy behind its Iron Curtain during the Cold War, but unable to patent the naturally occurring viruses and with the bacteria quickly adapting, red tape and limitations in technology have made it far easier to focus on antibiotics in the west.

With looming epidemics of superbugs on the horizon, attention is returning to bacteriophages as ways to kill bacteria, and CRISPR has put a new spin on the old idea.

A spin-off company from North Carolina State University, Locus Biosciences is testing the limits of CRISPR technology, including giving bacteriophages CRISPR sequences containing codes for antibiotic resistance genes.

Targeting bacteria with the genes, the CRISPR sequence would form a target for the bacteria’s own cas enzymes, effectively blocking resistance or even prompting the bacteria into chewing up its own DNA and self-destructing.

In recent years our eyes have been opened to how complex our relationship is with bacteria in our environment, and how dull our tools are for dealing with them.

Variations in our gut microflora has been linked with everything from Parkinson’s disease to autism to obesity, suggesting the species of bacteria we harbour could have major ramifications on many aspects of our health.

With its razor-honed surgical precision, it’s possible the technology could one day be used to select specific strains of bacteria in our gut, deleting them from the ecosystem and allowing us to edit our microbiomes.

Given we’re practically at the dawn of both CRISPR technology and our grasp on the complexity behind our body’s bacterial ecosystems, we can only speculate for the time being.

As antibiotics slowly lose their shine it’s probably worth paying close attention to radical new solutions such as these.

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This Simple Blood Test Can Predict Cancer Years Before Symptoms Appear

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A new type of non-invasive cancer test has just delivered promising results in an early-stage feasibility study, paving the way for a future when we’ll be able to get highly accurate cancer screening with a simple blood test.

The technology, which involves scanning the blood for bits of DNA shed by tumours, is also referred to as a ‘liquid biopsy’, and these new results are getting us one step closer to a major upgrade in cancer diagnostics.

Right now, our best method for detecting cancer is a biopsy – cutting out a small piece of the tumour tissue for lab analysis. But biopsies are often painful and invasive, and you need to already have a tumour or at least a suspect tumour to cut something out of it.

That’s why scientists have been working on devising blood tests that can do the same thing without any surgery, and with the promise of delivering a diagnosis much earlier.

Finding cancer in the blood is possible when scientists focus on DNA fragments shed into the bloodstream by tumours. This is called circulating tumour DNA (ctDNA).

In recent years, scientists have been working on finding the best method for detecting ctDNA, using samples from patients who already have diagnosed cancer.

The latest study, which was just presented at the 2017 meeting of the American Society of Clinical Oncology (ASCO), has turned up the dial on what scientists can find when they scan for ctDNA.

“Our findings show that high-intensity circulating tumour DNA sequencing is possible and may provide invaluable information for clinical decision-making, potentially without any need for tumour tissue samples,” says lead researcher Pedram Razavi from Memorial Sloan Kettering centre.

The team used blood and tissue samples from 124 metastatic breast cancer, lung cancer, and advanced prostate cancer patients.

They scanned the samples for 508 different gene mutations, going over the specific regions of the genome up to 60,000 times. According to the scientists, this method generates 100 times more data than other sequencing approaches.

To see whether the method could catch any tumour DNA floating around in the blood, the team compared the results with those from tissue samples and genetic material from the patients’ own white blood cells.

“Our combined analysis of cell-free DNA and white blood cell DNA allows for identification of tumour DNA with much higher sensitivity, and deep sequencing also helps us find those rare tumour DNA fragments,” says Razavi.

The researchers detected 864 genetic changes across all three types of cancers in the tissue samples, and found 73 percent of those in the blood tests as well.

In 89 percent of the patients, they found at least one mutation in both tumour tissue and in blood. For breast cancer, for which liquid biopsies are more established, the success rate was 97 percent.

A huge benefit of having sensitive ctDNA tests is the chance of finding cancer years earlier than is possible with a biopsy, catching it before it has time to spread through the body.

The new method was developed with researchers from Grail, a genomics company dedicated to early cancer detection, backed by philanthropic funding from people like Jeff Bezos and Bill Gates.

Grail’s Mark Lee, who was one of the study co-authors, told Reuters that the company is now planning to use this new test to gather large-scale data from hundreds of thousands of people, both with and without cancer.

While the results are promising so far, the team will be needing a lot more research before this technology becomes an early detection tool that we all can benefit from in a routine check-up.

“It’s an important first step. We show that what we call a high-intensity approach works,” Razavi told Reuters.

The results were presented at the ASCO Annual Meeting, and have been accepted for publication in the Journal of Clinical Oncology.

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Stem cell researcher in line to become Australian of the Year 2017

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Alan is acknowledged as having laid the foundation for the next generation of researchers in his field. Photo David Kelly

ALAN Mackay-Sim’s fascination with the human body stretches back to his childhood in Sydney.

“I remember being about 12 and wandering down an uneven bush track and thinking, ‘How the hell can I walk along here and compensate for the ground, the uneven ground, and it’s all automatic?’” He says. “It was a feeling of wonder at how we work and I remember even then thinking I’d one day like to figure it out.”

Today the celebrated biomedical scientist and professor at Queensland’s Griffith University is a world authority on the human sense of smell and his groundbreaking work with stem cells has given hope to thousands of Australians with spinal cord injuries.

As director of the National Centre for Adult Stem Cell Research, Alan championed has the use of stem cells to understand brain disorders and diseases including schizophrenia, Parkinson’s disease and hereditary spastic paraplegia.

Though he is now retired, Prof Alan Mackay-Sim’s goal is to progress clinical trials in a drug that he and his team have found for a disease called hereditary spastic paraplegia.

He also led the world’s first clinical trial using stem cells to treat spinal cord injury.

In 2014 Alan’s research played a key role in the first ever successful restoration of mobility in a paraplegic person. “The patient was a man in Poland who had a stab wound to his spinal cord in the thoracic chest region,” says Alan.

“Since the treatment he’s standing, he’s walking on a walker and this year I’ve seen a video of him walking better and riding a tricycle around a gym. His feet are strapped in but he can deliver power to his legs to ride and to steer and … it’s bloody amazing!”

Ever the scientist, however, Alan cautions that much work lies ahead if progress is to be made in benefiting other people with spinal cord injuries. “While the patient in Poland is a very good achievement, it’s scientifically the conservative to say, ‘Well that’s one example. Give me some more examples,’” says Alan.

“It’s three years since he had the injury and the odds are that this is because he had these cells put in his spinal cord rather than some other effect but, you know, yes — you really need to repeat it to show that it’s pretty impressive.”

Mackay-Sim led the world’s first clinical trial using stem cells to treat spinal cord injury.

Although retired, Alan remains emeritus professor at Griffith University and lists repeating the success that was had in Poland as one of his major goals. “We have a team whose intentions are to move the clinical trials forward,” he says. “I’m chair of a scientific advisory board for that so that’s one goal — to see the next phase of clinical trials.

“My other goal is to progress our clinical trials in a drug that we’ve found for a disease called hereditary spastic paraplegia. We’ve got a drug that we’re going to take to clinics to phase one clinical trials, for safety trials. My goal would be to take that through to phase two, which is the efficacy trial, and to get that drug into the population.”

Today, Alan is acknowledged as having laid the foundation for the next generation of researchers in his field and says the future of medical science is immensely exciting.

“I started my university degree in 1970,” he says. “In that time our understanding of neuroscience has multiplied 1000 times over. And with the technologies that are available, and with our application of all sorts of chemistries; all sorts of computing techniques, all sorts of machinery and instruments, technologies like the genome, the stem-cell technologies — these are all huge developments.”

“It’s an exciting time to be around and if we can afford the science I can definitely say can there’s a rosy future for humanity ahead.”

CommBank have been proud partners of Australian of the Year Awards for over 37 years, celebrating and championing those who make our country a better place. The awards honour an extraordinary group of respected Australians, whose actions inspire conversation on issues of national importance.

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This implantable micro-machine can deliver medications from inside the body

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Scientists have developed a bio-compatible micro-machine capable of being implanted inside the body, where it could act as a wireless medical device to deliver drugs directly under the skin.

The device, which measures only 15 millimetres long, is actually a squishy version of a mechanism called a Geneva drive, which has been used in wristwatches going as far back as the 17th century. Only this time, it would be worn inside and not outside the body.

Most of today’s implanted medical aids are made from static components that don’t allow freely moving parts. And because they often include batteries or other kinds of electronics that are toxic to the body, they can create complications with the human tissue that surrounds them.

Of course, devices such as pacemakers have been successfully implanted in patients for decades, but compared to inflexible, metallic devices, researchers think soft, supple implants could make a range of new medical treatments possible in the future.

“Traditional implantable devices are made of silicon or metal, and there are certain manufacturing processes that you would use to make devices out of those materials,” researcher Samuel Sia from Columbia University told Abby Olena at The Scientist.

“But they don’t work on biological materials, which are much softer, and so we had to develop our own methods.”

To develop an implant with moving parts that could be safely implanted inside the body, the team turned to hydrogels – a material composed of polymer chains with high water content (over 90 percent), which makes it soft, flexible, and highly compatible with biological tissue.

Using a method to stack layered sheets of this hydrogel, the researchers can fabricate their squishy Geneva drive in about 30 minutes – but developing the technique and discovering the right materials to use took some eight years of research.

The team ultimately decided on polyethylene glycol (PEG)–based hydrogels, which are biodegradable and approved by the FDA for use in medical devices.

“Of course, you have other devices that are also made out of bio-compatible materials, but those are mostly passive devices,” researcher Albert van den Berg from the University of Twente in the Netherlands, who was not involved in the study, told The Scientist.

“[T]hese are active, command-able devices. It’s really a breakthrough.”

Each full revolution of the small gear rotates a larger gear by 60 degrees, exposing one of six potential drug reservoirs to an aperture, through which medication can be released to the body.

While the device isn’t a fully independent micro-robot, capable of acting on its own, it is a machine that can perform its function inside the body without any direct physical contact with the outside world – save the nearby presence of a single magnet.

In testing with mice bred to develop bone cancer (osteosarcoma), the researchers magnetically triggered the release of the chemotherapy medication doxorubicin over the course of 10 days.

The results showed that using the device with just 10 percent of a regular doxorubicin dosage was more effective in stopping tumour growth and killing cancer cells than conventional chemotherapy – with a 56 percent reduction in cancer cells for iMEMS, compared with 39 and 19 percent reductions for high- and low-dosage systemic treatments respectively.

The device was also less toxic to the subject overall than a conventional treatment, since such a reduced amount of chemotherapy medication was released.

While it’s early days for the technology as a whole, and these promising results have only been seen in mice so far, the researchers hope that one day their micro-machines could be used to deliver cancer-fighting medications in humans – or other kinds of drugs we need, like insulin.

“People are already making replacement tissues and now we can make small implantable devices, sensors, or robots that we can talk to wirelessly,” Sia said in a press release.

“Our iMEMS system could bring the field a step closer to developing soft miniaturised robots that can safely interact with humans and other living systems.”

The findings are reported in Science Robotics.

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Scientists are genetically engineering Salmonella to destroy brain tumours

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Salmonella is commonly linked to fevers and food poisoning, and generally speaking, it isn’t good news at all for your body. But scientists have come up with an exception: a genetically engineered form of Salmonella bacteria that can eat away at cancer tumours.

The modified bacteria target tumours in the brain rather than seeking out the human gut where Salmonella usually causes damage – and the technique could lead to  a highly targeted technique of fighting one of the worst types of cancer there is.

Researchers from Duke University gave the treatment to rats with the aggressive brain cancer glioblastoma, and saw significant increases in lifespans, with 20 percent of the rodents surviving an extra 100 days compared to control animals – the equivalent of 10 years in human terms.

“Since glioblastoma is so aggressive and difficult to treat, any change in the median survival rate is a big deal,” says one of the team, Johnathan Lyon.

“And since few survive a glioblastoma diagnosis indefinitely, a 20 percent effective cure rate is phenomenal and very encouraging.”

salmonella-close-lookBacteria (pink) take hold of cancer cells (blue). Credit: Duke University

It’s a promising direction of study, since survival rates of humans with this cancer are pretty bleak. Only about 30 percent of patients with glioblastoma live for more than two years after diagnosis.

Part of what makes it so hard to treat is that the tumours hide behind the blood-brain barrier, which separates the circulating blood from the brain’s own fluid.

Conventional drugs can’t easily reach through this membrane, so a more targeted approach is needed to stop glioblastoma from thriving.

To achieve this, the researchers used a genetically adjusted and detoxified form of Salmonella typhimurium, modified to be deficient in a crucial organic compound called purine.

Glioblastoma tumours are an abundant source of this enzyme, which induces the bacteria to seek out the cancer cells to get the purine that they need.

And when the bacteria get to the tumours, two more genetic tweaks kick into action.

Because cancerous cells multiply so quickly, oxygen is scarce inside and around tumours. Knowing this, the scientists coded their Salmonella to produce two proteins called Azurin and p53 in the presence of low levels of oxygen.

These compounds instruct the cancer cells to effectively self-destruct, so the end result is like a genetically-coded guided missile, seeking out the tumour and blitzing cancerous cells when it arrives.

The researchers say the technique is much more accurate than surgery, and because the bacteria are otherwise detoxified, there should be no damaging side effects for the patient.

Of course, having success with a group of rats is no guarantee that the treatment will translate to the human body, but the researchers are hopeful that the technique can be developed to treat cancer patients in the future.

The first step is to get that 20 percent success rate up. Based on initial tests, the 80 percent of cases where the treatment had no effect could be down to the tumour cells outpacing the bacteria, or inconsistencies in the Salmonella‘s penetration in the body.

“It might just be a case of needing to monitor the treatment’s progression and provide more doses at crucial points in the cancer’s development,” says Lyon.

“However, this was our first attempt at designing such a therapy, and there is some nuance to the specific model we used, thus more experiments are needed to know for sure.”

The research has been published in Molecular Therapy Oncolytics.

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