Category Archives: Gene Medicine

By Chanapa Tantibanchachai

Scientists at Johns Hopkins, Rutgers, the University of Trento in Italy, and Harvard Medical School report they have developed a new molecular technique that can be used to isolate thousands of long DNA sequences at the same time, more than ever before possible.

According to the researchers, the new technologyknown as LASSO cloningspeeds up the creation of proteins, the final products of genes, and is likely to lead to far more rapid discovery of new medicines and biomarkers for scores of diseases.

Historically, figuring out what a gene does by cloning its DNA and expressing its protein was done one gene at a time. The new technology simultaneously clones and expresses thousands of protein-coding DNA sequences in a single reaction.

In a report on the technique's development, published online June 26 in Nature Biomedical Engineering, the researchers describe their novel molecular approach to simultaneously clone and express thousands of protein-coding DNA sequences in a single reaction. Historically, figuring out what a gene does by cloning its DNA and expressing its protein was done one gene at a time.

"Our goal is to make it cheap and easy for any researcher in any field to clone and express the entire set of proteins from any organism," says Ben Larman, an assistant professor of pathology at the Johns Hopkins University School of Medicine and the study's co-senior author. "Until now, such a prospect was only realistic for high-powered research consortia studying model organisms like fruit flies or mice."

The new paper describes a new type of captured DNA strand, a tool the authors refer to as a LASSO probe; LASSO stands for long adapter single-stranded oligonucleotide. Collections of these LASSO probes can be used to grab desired DNA sequencesmuch like a rope lasso is used to capture cattlebut in this case thousands at a time in a single effort.

Each target gene sequence can be up to a few thousand DNA base pairs long, which is the typical size of a gene's protein-coding sequence. The new technique is an improvement on an older method called molecular inversion probes, which is able to capture only about 200 bases of DNA, Larman says.

In a proof-of-concept study, LASSO probes were used to simultaneously capture more than 3,000 DNA fragments from the E. coli bacterial genome. The team successfully captured at least 75 percent of the gene targets. Importantly, the researchers say, these sequences are captured in a way that permits scientists to analyze what the genes' proteins do, as demonstrated by conferring antibiotic resistance to an otherwise susceptible cell.

"We're very excited about all the potential applications for LASSO cloning," Larman says. "Our hope is that by greatly expanding the number of proteins that can be expressed and screened in parallel, the road to interesting biology and new therapeutic biomolecules will be dramatically shortened for many researchers."

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With powerful new technique, scientists can clone thousands of genes at once - The Hub at Johns Hopkins

Many people think of osteoarthritis as a kind of wear-and-tear disease, but theres clearly a genetic component at work here as well.

The researchers were studying a gene called GDF5 that Kingsleys laboratory first linked to skeletal growth in the early 1990s. GDF5 is involved in bone growth and joint formation, and mutations in the coding portion of the gene have been shown to cause malformations in leg-bone structure in mice. In humans, GDF5 mutations are associated with shorter stature and joint problems; in particular, two nucleotide changes immediately upstream of the gene have been strongly associated with a 1.2- to 1.8-fold increase in the risk of osteoarthritis.

In the new study, the researchers were interested in learning more about how the DNA sequences surrounding GDF5 might affect the genes expression. Often, these noncoding sequences contain key regulatory regions known as promoters and enhancers. Capellini, Chen and Cao were able to identify a previously unknown enhancer region they termed GROW1, which is several thousand nucleotides downstream of GDF5.

When the researchers analyzed the sequence of GROW1 in the 1,000 Genomes Project database, which collects and compares sequences from many human populations around the globe, they identified a single nucleotide change that is highly prevalent in Europeans and Asians but that rarely occurs in Africans. When they introduced this nucleotide change into laboratory mice, they found that it decreased the activity of GDF5 in the growth plates of the long bones of fetal mice.

Further research showed that this nucleotide change has been repeatedly favored during human evolution. Modern humans migrated from Africa between 50,000 and 100,000 years ago. But they werent the first to leave the continent. Neanderthals and Denisovans moved north into Europe and Asia about 600,000 years ago. Interestingly, the researchers found that the same GROW1 variant was found in the DNA of both ancient and modern humans in Europe and Asia.

However, theres a dark side to this stocky, hardy body type: The GDF5 variant that reduces bone length comes hand-in-hand with the two upstream nucleotide changes known to confer an increased risk for osteoarthritis.

Its clear that the genetic machinery around a gene can have a dramatic impact on how it works, said Capellini. The variant that decreases height is lowering the activity ofGDF5in the growth plates of the bone. Interestingly, the region that harbors this variant is closely linked to other mutations that affect GDF5 activity in the joints, increasing the risk of osteoarthritis in the knee and hip.

The potential medical impact of the finding is very interesting because so many people are affected, said Kingsley. This is an incredibly prevalent, and ancient, variant. Many people think of osteoarthritis as a kind of wear-and-tear disease, but theres clearly a genetic component at work here as well. Now weve shown that positive evolutionary selection has given rise to one of the most common height variants and arthritis risk factors known in human populations.

Researchers from the University of Waterloo in Ontario, Canada, also contributed to the study.

The research was supported by the National Sciences and Engineering Research Council of Canada, the Arthritis Foundation, the National Institutes of Health (grant AR42236), the Howard Hughes Medical Institute, the Milton Fund of Harvard, the China Scholarship Council and the Jason S. Bailey Fund of Harvard.

Stanfords Department of Developmental Biology also supported the work.

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Decreasing height, increasing arthritis risk evolutionarily advantageous for humans - Stanford Medical Center Report

Findings of a large, multi-institutional breast cancer study could lead to more personalized risk assessment for women of African heritage and hasten approaches to diagnosing aggressive breast cancers early and treat them effectively. While the odds of developing breast cancer are nearly the same in white and black women, black women are 42% more likely to die from the disease.

The study, published online May 4, 2017, in JAMA Oncology, was designed to understand the racial disparity in survival rates by beginning to unravel the germline genetic variations and tumor biological differences between black and white women with breast cancer.

People have long associated breast cancer mortality in black women with poverty, or stress, or lack of access to care, but our results show that much of the increased risk for black women can be attributed to tumor biological differences, which are probably genetically determined, says study author Olufunmilayo Olopade, MD, professor of medicine and human genetics at the University of Chicago.

The good news, she says, is that as we learn more about these genetic variations, we can combine that information with clinical data to stratify risk and better predict recurrences especially for highly treatable cancers and develop interventions to improve treatment outcomes.

This is a great example of how team science and investments in science can accelerate progress in identifying the best therapies for the most aggressive breast cancers, says co-author Charles Perou, PhD, a member of the University of North Carolina Lineberger Comprehensive Cancer Center and professor of genetics, and pathology & laboratory medicine at the UNC School of Medicine.

In the largest dataset to date that has good representation of tumors from black women, we did not find much difference between the somatic mutations driving tumors in black and white women, he says. Yet, black women were more likely to develop aggressive molecular subtypes of breast cancer. Now we provide data showing that differences in germline genetics may be responsible for up to 40% of the likelihood of developing one tumor subtype versus another.

The study used DNA data collected from 930 women154 of predominantly African ancestry and 776 of European ancestryavailable through The Cancer Genome Atlas (TCGA), established by the National Cancer Institute and the National Human Genome Research Institute. Researchers combed through the data methodically, looking for racial differences in germline variations (normal DNA), somatic mutations (tumor acquired), subtypes of breast cancers, survival time, as well as gene expression, protein expression and DNA methylation patterns.

The crucial long-term benefit of this study, according to Olopade, is that it is a step toward the development of polygenic biomarkers, tools that can help us better understand each patients prognosis and, as we learn more, play a role in choosing the best treatment.

Genes matter, she says. This is a foot in the door for precision medicine, for scientifically targeted treatment.

Managed care executives need to learn how to do population risk stratification so they can get better outcomes for ALL patientsblack and white, Olopade adds. It is no longer acceptable to see the widening disparities in survival among black and white and not develop interventions to reduce it.

Breast cancer is not one disease, and it impacts women differentially, she says. We now have very effective treatment for the most aggressive breast cancers, and we should make sure all patients benefit from genomic testing. We also need to make sure that women get the right treatment at the right time based on their level of risk. We can no longer practice as if one size fits all.

Managed care should cover genetic testing and comprehensive risk assessment at diagnosis and promote accurate diagnosis to get the best therapies for (their) enrollees. (They) should promote access to clinical trials. It pays high dividend to get it right and not have to treat advanced cancers.

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Racial genes disparity in breast cancer mortality linked to genes - ModernMedicine

A single gene mutation that helped early humans survive in Europe and Asia during the Ice Age may alsoincrease the risk of arthritis in modern-day humans.

Researchers from the Stanford University School of Medicine and Harvard University have found a gene mutation thathelped our ancestors survive colder temperatures by coding for shorter limbs, according to new research published in the journal Nature Genetics.

As modern humans migrated out of Africa between 50,000 and 100,000 years ago during the last Ice age, they were faced with colder temperatures.Agenetic variant for shorter limbs may have helped thembetterwithstandfrostbite, the researchers argue. Shorter bones also meant there was less chance of breaking a bone if they slipped on ice.

Theres a downside, however.The gene in question, known as GDF5, which isinvolved in bone growth and joint formation,also increases one'srisk of osteoarthritisa condition that causes joints to become painful and stiff. In humans, mutations in the GDF5 gene have been shown to belinked to a 1.2 to 1.8 times increase in the risk of osteoarthritis.

Of course, the prospect of painful joints is not a pretty one, nor particularly useful if youre hunting mammoths inIce AgeEurope. However, the risk from cold temperatures may have outweighed the risk ofosteoarthritis,which usually occurs after prime reproductive years. The gene was repeatedly favored as early humans migrated out of Africa and moved into colder corners of the world. Its thought that at least half of Europeans and Asians have the gene variant, yet it remains relatively rare in African populations.

Because its been positively selected, this gene variant is present in billions of people, David Kingsley, professor of developmental biology at Stanford, said in astatement. So even though it only increases each persons risk by less than twofold, its likely responsible for millions of cases of arthritis around the globe."

Armed with thisfresh insight, Professor Kingsley believes their study could havepractical implications in the world of medicine.

"This is an incredibly prevalent, and ancient, variant. Many people think of osteoarthritis as a kind of wear-and-tear disease, but theres clearly a genetic component at work here as well," he added. "Now weve shown that positive evolutionary selection has given rise to one of the most common height variants and arthritis risk factors known in human populations.

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Gene That Helped Humans Survive Migration Out Of Africa Increases Arthritis Risk - IFLScience

BBC News

Chief medical officer calls for gene testing revolution BBC News "I want the NHS across the whole breadth to be offering genomic medicine - that means diagnosis of our genes - to patients where they can possibly benefit," her report says. People with rare diseases could benefit from having greater access to the ... Gene testing could revolutionise cancer treatmentITV News All cancer patients should have their DNA tested to save lives, Chief Medical Officer saysTelegraph.co.uk Call for revolutionary DNA cancer care on NHSSky News The Sun -The Times (subscription) all 29 news articles »

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Chief medical officer calls for gene testing revolution - BBC News

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Chief medical officer calls for gene testing revolution - BBC News BBC News Cancer patients should be routinely offered DNA tests to help select the best treatments for them, according to England's chief medical officer. Prof Dame Sally ... Gene testing could revolutionise cancer treatment - ITV NewsITV News All cancer patients should have their DNA tested to save lives, Chief ...Telegraph.co.uk Gene testing could save THOUSANDS of lives and should be offered to all NHS cancer patients, says top docThe Sun Sky News -The Times (subscription) all 18 news articles »

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Chief medical officer calls for gene testing revolution - BBC News - BBC News

BUSINESS heavyweights Brian Kennedy and Sir Brian Souter have thrown their support behind a Borders-based drug firm that aims to make chemotherapy four times more effective than current treatments.

The tycoons have participated in a 1.8 million funding round at Ryboquin ahead of a planned acquisition of current partner Nanogenic Solutions, which has developed a method for revolutionising the treatment of diseases at a genetic level.

Mr Kennedy, who teamed up with Graeme Souness in an ultimately failed attempt to acquire Rangers in 2012, has also joined the board of the Ryboquin.

The Selkirk-based companys executive chairman Paul Murray said the backing of Mr Kennedy and Sir Brian was testimony to the potential of Ryboquin.

The groups chief executive officer Alan Walker added: Mr Kennedy rose from fairly modest circumstances to a personal wealth of many hundreds of millions through his business acumen. Hes successful, hes shrewd and he is a nice guy who is easy to work with. Hes already brought a new dimension of big business to what is still quite a small company.

Mr Kennedy said: I am delighted to be part of Ryboquin and to be working with the team that could make great progress in the treatment of cancer and other diseases.

Spun out of Edinburgh-based medicine developer Ectopharma in 2013, Ryboquin is focused on commercialising patented intellectual property in the area of delivering gene therapy, primarily to cancer patients.

Going forward, he said the business would continue to develop its own products, but had also agreed in principle to acquire Nanogenics.

Ryboquin currently licenses Nanogenics gene therapy delivery system LipTide, which was initially developed by University College London.

He said there was no timetable for the acquisition but that a seven-figure investment would likely be required in the future.

The acquisition is agreed but not yet actioned so at some point we will require further funding. The implication is that it is good to have shareholders who have a history of wealth, he said.

Mr Walker added that LipTide gave the business a potential revenue stream.

To be quite frank, its been tough trying to raise money through traditional sources, he said. We dont have venture capital money, which is why we place the emphasis on high net worth individuals. But if we can make LipTide a commercial success we can become cash flow positive and the need for equity funding goes down, if not goes away.

The current 1.8m round, led by existing backers, business angel group TRI Capital and Scottish Investment Bank, will be used to accelerate product development and finance corporate expansion.

Mr Walker said clinical trials of its Ryboquin ECP-102 product, currently being developed with the University of Strathclyde, will take place in 2019, with Manchesters Christie hospital the likely venue.

Ryboquin ECP-102 aims to radically improve the effectiveness of chemotherapy, by utilising LipTide, a microscopic particle which delivers RNA (Ribonucleic acid) to affected cells. RNA is one of four major macromolecules, along with DNA, which are essential for all known forms of life.

When the human genome was cracked, we thought we had the solution to all these genetic diseases, but you couldnt deliver the genetic material to the right place and only the right place, so this great promise was not realised, said Mr Thomson. Nanogenics product solves that problem and actually delivers the genetic material.

Currently, there are believed to be some 8,000 diseases caused by mutations in genes, from cystic fibrosis to cancers. And developing a drug delivery system that can treat such diseases on a targeted cellular level has become one of the biggest pursuits in global biotechnology.

This is what genetic medicine has been waiting for all these years; if you can affect specific genes and change [a patients] genetic make-up, youre looking at a revolutionary treatment.

Mr Walker said the company was in discussions with global pharmaceutical companies to promote LipTide. He has recently returned from a trade show in California where he held meetings with 36 potential partners.

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Tycoons fund biotech firm with ambitions to 'revolutionise' cancer treatment - Herald Scotland

Earlier this year, theNorth American Association of Central Cancer Registriesestimated that 1.69 million people in the U.S. alone will be diagnosed with some form of cancer in 2017. With such a huge number of people being diagnosed with complex diseases, such as cancer, the industry must continue to step up efforts to improve the outcomes. One option showing considerable potential is taking a precision medicine approach to determine the patients optimal treatment based on their personal molecular makeup and genomic profile.

Precision medicine gained significant attention following the launch of thePrecision Medicine Initiative, which saw the White House under President Obama invest $215 million, to broadly support research, development, innovation into the area.Similar projects, such as the Precision Medicine Catapult in the UK, added to the buzz. This interest, combined with technological developments and advances in data mining, has started to show promising results.

The life sciences industry, however, is facing a roadblock when it comes to turning promising research into a practical treatment option. Clinicians and researchers alike are finding it difficult to understand the data available to them and then translate the findings into treatments that will significantly improve clinical outcomes for patients. So, what can the life science industry do to turn precision medicine into reality?

What is holding back advances?

The emergence of new technology, combined with the use of huge knowledge databases, has been largely credited for recent advances in precision medicine. By using Next Generation Sequencing tools alongside gene expression profiling, physicians and researchers can better understand the makeup of the disease and how it is affecting the patient, within minutes.

By using data and research from previous laboratory experiments, researchers can identify the drug on the market with the highest chances of being effective against the particular proliferation mechanism driving the disease. This type of approach will revolutionize the treatment of complex diseases such as cancer, and in theory could saves countless lives around the globe. However, this requires a blend of deep technical and scientific skills, technical know-how to crunch the data, and scientific understanding to draw accurate clinical inferences. Without this blended approach, precision therapy for cancer will remain promising yet impractical.

Case study: Wake Forest Hospital and Elseviers R&D Solutions

Elsevier completed a precision medicine pilot with Dr. Francisco Castillos from Wake Forest, a small oncology practice in Winston-Salem, North Carolina (NC). The pilot aimed to treat three late-stage cancer patients, who had exhausted all standard-of-care treatment options, using a two-pronged precision medicine approach.

Castillos was able to understand in detail the pathways activated in the individuals cancer using Elseviers Pathway Studio tools. Then, he could point to what FDA-approved drugs that would be effective for the particular molecular mechanism driving the disease, or point to the relevant clinical trials. These analyses were reached through a combination of aggregating and harmonizing data, and Castillos scientific understanding and insight. While this study proves the viability of precision medicine in cancer, it is not an approach that can be replicated at scale.

A better use of data is key to precision medicine success

To achieve successful precision medicine at scale and to be able to offer it as an everyday treatment option, researchers in drug R&D need to better understand and manage the reams of unstructured data available to them. The data generated from understanding disease mechanisms is vital to successful drug development. Researchers need to find actionable insights relating to a particular gene, disease or biomarker, which requires searching the relevant published scientific literature, abstracts and clinical trial data and connecting the disparate pieces of information.

The type of approach conducted by Castillos, combining the use of molecular profiling and data mining tools, will help researchers tap into the existing repository of therapeutic drugs already on the market. In the last 25 years, hundreds of FDA-approved drugs have become available, with well-known mechanisms of action. With this approach, it would be possible to identify which approved therapies may be the best choice for a given patient or patient group/sub-group, based on what is driving their disease at a molecular level.

Not limited to the treatment of cancer

Precision medicine is the face of 21st-century medicine and can be used to treat many complex diseases, even at the earliest of stages, when a tissue biopsy is available and a genomics profile can be evaluated. The one treatment fits all approach is no longer the only viable option. Those suffering from complex diseases such as multiple sclerosis, schizophrenia, and depression are prescribed medication every day that proves ineffective due to their genetic makeup and individual factors which determine patient response. According toNNT,the 10 top-selling drugs in the U.S. help at best one in four of the patients using them, or in the worst case just one in 24 patients benefit from the drug theyre taking.

There is no denying that challenges involved with precision medicine are complex and there is lots of work to be done by the life science industry. Despite this, precision medicine will inevitably become the expected method of treatment for many diseases. Back in 2006, there were only13 examplesof precision medicine drugs, treatments and diagnostics products available. By 2014, this number had increased to 113, and is only set to grow following a better understanding of what the data generated by technology actually means, and how it can be used.

To do this, physicians and clinical researchers need to better understand the data available to them using digital solutions that accelerate patient analysis and accurately mine the data. Only then can they can match patients to an FDA-approved drug, and improve outcomes for patients all over the world.

Photo: Getty Images

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Up close and personal: How the life science industry can improve outcomes through precision medicine - MedCity News

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Selkirk-based Ryboquin secures 1.8m equity funding BBC News ... Brian Kennedy and Sir Brian Souter. Executive chairman Paul Murray said their support was "testimony to the potential" of the firm. Founded in 2013, Ryboquin's business is focussed on gene therapy, primarily in the field of human cancer medicine. and more »

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Selkirk-based Ryboquin secures 1.8m equity funding - BBC News

At Jacobs Island Dog Park on Wednesday afternoon, Laura Tonnessen threw a stick into the river for her dog Thor. He barked enthusiastically, retrieving and dropping the stick at her feet. But in a few days, on the Fourth of July, Tonnessen knows Thors demeanor will change. The loud fireworks frighten him.

Hell hide behind furniture and act weird and whine, Tonnessen said.

Last year, Tonnessens friends pitbull, Cracker, ran away and was lost for three days because he was spooked by loud fireworks. It was traumatic to lose him for so long, Tonnessen said, and she makes sure to keep Thor inside on the holiday to prevent him from running away, too.

Michael Edwards, a student at the University of Montana, said his 130-pound great Pyrenees, Snowy, climbs into the bathtub, pulls the shower curtain closed with her mouth, and howls until the thunder storm or fireworks end.

If shes outside, she runs. They once found her about seven miles from their house, trying to escape the source of the noise. Animal shelters report that July 4-5 are their busiest days of the year.

When dogs bark, flee or cower on the Fourth of July, they are exhibiting symptoms of a panic disorder called noise phobia.

Fireworks and other loud noises terrify a fraction of all dogs, and their reactions sometimes endanger their health. Dogs may jump through windows, climb fences or run away for days to try to escape the sounds of patriotic celebration.

This phobia, which is a symptom of underlying anxiety issues, has recently been linked to a certain gene in dogs, says Dr. Leticia Fanucchi, a veterinary behaviorist at Washington State University's College of Veterinary Medicine.

Some dogs are more genetically predisposed to anxiety disorders, Fanucchi said, just like humans.

The area that is activated in our brain for fear is the amygdala, and the amygdala can be triggered long before the prefrontal cortex can process information, Fanucchi said.

Its like people who suffer from arachnophobia even if you explain that the spider won't hurt them, it activates the amygdala and makes them panic.

The amygdala is where irrational fears trigger a fight, flight or freeze response, while the prefrontal cortex controls reason and rational decision-making. Dogs panic at the sound of fireworks because they think their lives are at risk, even if they are safe at home.

Fanucchi said not all breeds of dogs carry this anxiety gene, and some are more prone to it than others. Within one breed, a dog could have the anxiety gene while another might not. This explains why some dogs dont react at all to loud noises. Those that do are typically anxious about other things, as well.

What we do know is that a good chunk of the dogs that have noise phobia do have generalized anxiety as an underlying disease, Fanucchi said. About 40 percent of the dogs that have generalized anxiety have noise phobia. So noise phobia is a big red flag that something else is going on with that dog, and it needs to be diagnosed and treated appropriately.

For this Fourth of July, its too late to start a long-term medication regimen to treat anxiety because medications typically take a few weeks to become effective, Fanucchi said. But there are other, short-term practices that can minimize dogs anxiety and keep them safe.

Creating a quiet and distracting setting for dogs can help them stay calm, said Emily Adamson, director of Organizational Advancement at the Humane Society of Western Montana. Scent therapy, like lavender spray, is popular for calming dogs, Adamson said.

Food toys and soft music (they play classical at the shelter) help distract the dogs from the source of their fear. For people who do take their dogs outside, Adamson recommends double-checking their ID tags to make sure the information is current, in case the dogs run away.

And then, theres the Thundershirt.

Dr. Lindsey Rewinkel at Pruyn Veterinary Hospital in Missoula said Thundershirts are available at pet stores and some veterinary hospitals, and serve as a dog anxiety vest.

Its a heavy fabric fashioned into a shirt that you wrap them in, Rewinkel said. Its not quite as severe as a swaddle, but the goal is to make them feel comforted. That has helped an incredible amount of dogs cope with noise phobias if they're not as severe.

Finally, there are medications vets can prescribe that sedate dogs and minimize their anxiety symptoms on the Fourth of July if none of these other practices work. Rewinkel said she always urges people to also treat the underlying anxiety issue with long-term behavioral therapy, and not just resort to medication, which can serve as a Band-Aid solution to a larger problem.

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Why does your dog hate Fourth of July fireworks? It's genetic - The Missoulian