Category Archives: Genetic Medicine

Professor Sir John Bell, Regius Professor of Medicine at the University of Oxford, delivered a speech at the MHRAs 14th Annual Lecture in London, outlining his vision for the UK life sciences industry. Here, Nikki Withers summarises the key take-home messages from the talk, including how UK researchers and investors should grab the bull by the horns and adopt a less risk-averse approach to research ideas, particularly in the genomics arena.

FROM THE discovery of antibiotics to the 100,000 Genomes Project, the UK has for many years played a leading role in health innovation and medical science. However, to ensure the country continues to be a key R&D player, focus needs to shift towards the next generation of therapeutics.

Looking forward, Professor Bell predicts that scientific research will focus on viral vectors and nucleic acid-based therapies over the coming years. Addressing an audience of about 200 healthcare leaders from the Life Sciences community, he stressed how important it was for the UK to jump on these opportunities. Despite being discovered in Cambridge, the UK was slow to exploit antibody technology to scale, he explained. It is crucially important we dont miss the next platform.

Appointed UK Life Sciences Champion by the Prime Minister in 2011 and author of the Life Sciences Industrial Strategy, Professor Bell has been at the forefront of the life sciences sector for many years. His vision is for the UK to focus on three key areas: genomics, digital health and early diagnosis.

The UK has a long history of genetics research, arguably originating from Darwin and his theory of evolution, according to Professor Bell. We are, without a shadow of a doubt, the leading country in the world in the genomic domain. He highlights two major projects: UK Biobank and Genomics Englands 100,000 Genomes Project, both of which push the UK up the ranks as leaders in genomics research.

UK Biobank is a global health resource that provides health information of 500,000 participants to researchers. Genotyping has been undertaken on all participants, providing a wealth of genomics information. Likewise, the ground-breaking 100,000 Genomes Project, launched by then-Prime Minister David Cameron in 2012 and led by Genomics England, is another example of a UK genetics programme that delivers large-scale data and is accessible for research scientists around the world.

The UK has a spectacular science base. Weve got three of the top 20 medical research programmes and two of the top universities in the world.

However, Professor Bell pointed out that the main challenge associated with this fast-moving research area relates to regulations. Gene editing, nucleic acid-based therapies, these are going to be the next big thing, he said. In genomics we need to regulate an expanding set of genetic tests where the indications and tools change daily, so the big question is how to get them regulated.

His suggestion was for regulators to concentrate on areas where innovation is at the cutting edge. They need to concentrate on speed and efficiency. The industry is frustrated by the lack of pace, particularly by European regulators.

Professor Bell also stressed his desire for researchers and investors to support high-risk science. Generally, investors dont want to invest and there is the dampening effect of peer review. The really interesting and high-risk stuff tends to get killed, he professed.

Concluding the talk, Professor Bell said: The UK has a spectacular science base. Weve got three of the top 20 medical research programmes and two of the top universities in the world. Weve got the largest biotech cluster outside of the US and the largest and most innovative drug regulator in Europe. For a pretty dinky island in the North Sea, were doing pretty well.

We need to get academia, the NHS and industry pharma, biotech, diagnostics and digital aligned to think hard about what the future of the UK might be and to identify the next opportunities to grow our research and economic base in the life sciences.

The future of Life Sciences: Keeping the UK at the forefront of medical and scientific excellence, was hosted by the MHRA on 9 October 2019 at The Kings Fund in London.

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Championing genomics in the UK: the next generation - Drug Target Review

Every minute of every day our bodies are bombarded with millions of different molecules that we breathe, eat and touch including bacteria, viruses, chemicals and seemingly harmless compounds like food and pollen.

For every one of these encounters, our immune system has to decide if the substance is a threat or not, if it is foreign or self and how the body should respond to stay healthy. To do this, we rely on two immune systems working in tandem.

Scientists have discovered a new human autoinflammatory disease that results from a mutation in an important gene in one of these systems.

The syndrome, now known as CRIA (cleavage-resistant RIPK1-induced autoinflammatory) syndrome causes recurring episodes of debilitating and distressing fever and inflammation.

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Our bodys first line of defence is the innate immune system that is effectively a hard wired and fast response, explains Dr Najoua Lalaoui from the Walter and Eliza Hall Institute of Medical Research (WEHI) and the Department of Medical Biology at the University of Melbourne.

This system works in the skin and mucous membranes like the mouth, making sure that any invaders like bacteria are detected and destroyed quickly, she says.

If pathogens do enter the body, the innate immune cells move to the site of infection and physically devour invaders and activate chemical messengers to alert the body.

This can lead to an inflammatory reaction where blood circulation is increased, the affected area becomes swollen and hot, and the person may experience fever. When these chemical messengers are over-active it can result in conditions like colitis, arthritis and psoriasis.

Supporting this system is the adaptive immunity system that involves antibodies that recognise and then train the body to respond to threats. This is our memory immunity and the basis of how vaccinations work.

Scientists from the WEHI, with colleagues at the National Institutes of Health (NIH) in the United States, have been working to understand why patients from three families suffered from a history of painful swollen lymph nodes, fever and inflammation.

The families had a range of other inflammatory symptoms which began in childhood and continued into their adult years.

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This type of repeated fever often indicates an issue with the innate immune system and the same disease in an extended family can indicate genetic changes that are passed from parents to their children, explains Dr Lalaoui.

Previous tests didnt identify any known cause.

But by sequencing the patients genomes, the NIH team identified a mutation in DNA that codes for a molecule known as RIPK that they suspected might cause the disease.

RIPK is a critical regulator of inflammation and the cell death pathway responsible for cleaning up damaged cells or those infected by pathogens.

Professor John Silke from the Walter and Eliza Hall Institute and his team have been studying RIPK1 for more than 10 years. His team had previously shown that damaging the RIPK1 gene could lead to uncontrolled inflammation and cell death.

RIPK1 is a potent controller of cell death, which means cells have had to develop many ways of regulating its activity, Professor Silke says.

In this paper, we showed that one way that the cell regulates its activity is by cleaving RIPK1 into two pieces to disarm the molecule and halt its role in driving inflammation.

In this condition (CRIA), the mutations are preventing the molecule from being cleaved into two pieces, resulting in autoinflammatory disease. This helped confirm that the mutations identified by the NIH researchers were indeed causing the disease, he says.

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He explains that mutations in RIPK1 can drive both too much inflammation as in autoinflammatory and autoimmune diseases and too little inflammation, resulting in immunodeficiency.

There is still a lot to learn about the varied roles of RIPK1 in cell death, and how we can effectively target RIPK1 to treat disease.

In CRIA syndrome, the mutation in RIPK1 overcomes all of the normal checks and balances that exist, resulting in uncontrolled cell death and inflammation, says Dr Steven Boyden from the National Human Genome Research Institute at the NIH.

Dr Boyden says the first clue that the disease was linked to cell death was when they delved into the patients exomes the part of the genome that encodes all of the proteins in the body.

The team sequenced the entire exome of each patient and discovered unique mutations in the exact same amino acid of RIPK1 in each of the three families.

It is remarkable, like lightning striking three times in the same place. Each of the three mutations has the same result it blocks cleavage of RIPK1 which shows how important RIPK1 cleavage is in maintaining the normal function of the cell, says Dr Boyden.

Dr Lalaoui said the WEHI researchers then confirmed the link between the RIPK1 mutations and CRIA syndrome in laboratory models.

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We showed that mice with mutations in the same location in RIPK1 as in the CRIA syndrome patients, had a similar exacerbation of inflammation, she says.

Dr Dan Kastner from NIH widely regarded as the father of autoinflammatory disease says colleagues had treated CRIA syndrome patients with a number of anti-inflammatory medications, including high doses of corticosteroids and biologics, compounds that block specific parts of the immune system.

And although some of the patients markedly improved, others responded less well or had significant side effects.

Understanding the molecular mechanism by which CRIA syndrome causes inflammation provides an opportunity to get right to the root of the problem, Dr Kastner says.

Dr Kastner noted that RIPK1 inhibitors, which are already available on a research basis, may provide a focused, precision medicine approach to treating patients.

RIPK1 inhibitors may be just what the doctor ordered for these patients. The discovery of CRIA syndrome also suggests a possible role for RIPK1 in a broad spectrum of human illnesses, such as colitis, arthritis and psoriasis.

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The genetic mutation behind a new autoinflammatory disease - Pursuit

Cannadabis Medical INC they intend to create a healthier and more consciously aware environment for the cannabis industry, and its participants, to thrive in.

Did you know that Cannadabis are Partners with us? Discover their featured Partner Page about a healthier, environmentally conscious cannabis industry.

The company is a family run company that was founded in Humboldt, Saskatchewan.

Founders, Alexander Calkins, BSc and Markus Li, P.Chem, MBA, are personally and emotionally invested in the science of cannabis. They each have family members that are dealing with incurable ailments, complications of which can often become fatal.

In the search for natural products that will improve the quality and longevity of life, the founders began working with cannabis. While there is no likelihood of a cure, the symptom management has been very positive for their family members. After witnessing the improvements, Cannadabis founders Calkins and Li, have dedicated themselves to furthering the medical cannabis movement.

Calkins and Li both have backgrounds in technical science and business. They are experienced cultivators and have a strong understanding of energy systems (practically essential for a power-hungry industry), process automation, and large-scale development.

Their familiarity with multi-industry supply chains has leveraged them into a cannabis development that is simultaneously high-tech, old school, and simple.

Through observation of established global industries, Cannadabis is building a multi-faceted business model based on sustainable practices, a strong genetics portfolio, disruptive technologies, hyper-specialisation, and holistic production.

Driven by a passion to help others in need, Calkins and Li took it upon themselves to bring their methods and expertise to the cannabis world. They recognise and praise the patient independence that medical cannabis can provide.

While they champion the practice of homegrown medicine, they have obligated themselves to providing the safest and highest quality medical products to those who are unable to grow for themselves.

Once Cannadabis has perfected its organic growing system, they will build and operate all future cultivation sites according to (EU) GMP and ISO:9001 2015 standards. By adopting these standards, Cannadabis will have the ability to share their cultivated passion with the world.

To meet the sanitary requirements of GMP and processing limitations of an organic certification, Cannadabis will be using a combination of reactive oxygen, electrolysed water, and radio frequency pasteurisation technologies.

Being a medically focused company, Cannadabis recognises that medical consumers have turned to cannabis because they are looking for natural remedies and are becoming increasingly weary of synthetic medicines.

For Cannadabis, producing medical cannabis using anything other than organic methods would transgress the fundamental sentiment that drives the global, medical movement. That is why Cannadabis is committed to attaining internationally recognised organic certifications on expanded production.

The companys flagship facility is intended to be an R&D focused proving ground for state-of-the-art organic cultivation methods. Cannadabis currently uses an inhouse blended soil, made only with organic ingredients. Their living soil has the benefit of creating terpene dense medicine, reducing cost, and simplifying processes.

With all the nutrients available in the soil, the plants require only water from transplant to harvest. Additionally, the growing medium and all organic waste can be recycled through vermicomposting, further reducing long term costs and needless waste.

Cannadabis will adopt various technologies to reduce energy demand and environmental impact. In addition to using LEDs and solar panels, Cannadabis will use combined heat and power (CHP) (or cooling combined heat power (CCHP)) at their cultivation facilities. CHP units burn natural gas to generate power and the waste heat is used to heat water and the workspace. CHPs are quickly becoming popular for reducing carbon emissions. In certain applications, CHPs reduce carbon emissions by 30-40%, compared to when power is taken from the grid.

Cannadabis will also divert the combustion CO2 into the growing space. CO2 supplementing supercharges growth naturally, increasing yield by 30-60%, and further reducing the carbon emissions from power generation. In the future, expanded cultivations may integrate pyrolysis of waste biomass, which will supply power and nutrient dense biochar to the living soil.

Cannadabis is aspiring to build a unique indoor growing system that uses a combination of solar power, water recycling, CHP (CCHP), pyrolysis, CO2 supplementation and vermicompost to create a no waste, carbon neutral, minimal input, self-regenerating nutrient, off grid, medical grade, organic, indoor cultivation.

Calkins and Li hope to validate the system and then apply the techniques to food cultivation; this type of system could revolutionise the food production in remote locations, like the northern territories, Alaska and would deliver food supply independence to small communities or reservations. Where biomass is abundant, this system would produce all year, requires only labour as inputs, self-generate power off-grid, and would also be carbon negative over extended time frames.

On their path to improving growing efficiency, Cannadabis has developed proprietary tissue culture methods specifically for cannabis. These methods are based upon the decades old horticultural practice that has been essential for the sterile propagation of ornamental and food cultivars; non seed propagation.

Developing an inhouse tissue culture system has the following benefits:1

Tissue culture revitalises cultivars and produces more vigorous plants Regeneration from meristem rids systemic disease; Propagation is significantly more efficient; Starting with 100 traditional cuttings; able to produce 70,000 annual clones; Start with 200 tissue culture vials; produce 2 million annual clones; Uses 1/10 the space of traditional cloning; Per square foot, tissue culturing is >100x more efficient; and Two million annual clones could be produced in less than 3000 square feet.

1000 mother cultivars could be stored inside a refrigerator with no care or maintenance for months, sometimes over a year; and Pest invasion would not affect mother cultures (many cultivators without tissue culture have lost their entire genetic inventory to viruses and fungi).

Cannadabis will be sharing its tissue culture methods with industry members who want to stay one step ahead of pests and systemic disease. Following more development, they will also be making their organic formulations available.

Having collected and grown a large variety of cultivars, both through seed and clone, the Cannadabis founders have noticed a distinct lack of quality in the genetics market. Over time, most of the popular cultivars of the world have been slowly degraded by deleterious breeding practices like selfing (feminising), backcrossing, and poor mother plant maintenance which promotes genetic drift.

The current genetics market is rife with breeders that take prized clones and spray them with colloidal silver to produce feminised seed, or they are crossed onto their own cultivars and backcrossed until stable seed is produced.

While these name sake creations may capture some of the qualities of the original strain, like trichome density or terpene profile, the progeny will lack the genetic diversity needed to produce healthy plants. Often, these weakened strains have reduced yield, potency, and pest resistance. In response to this, Cannadabis has focused on breeding their own high yield, high potency, flavour dense strains for commercial production.

The Cannadabis team is eager to unveil their propriety strains to the domestic and international medical markets. Over the past few years, the founders have started breeding their own cultivars. Currently, the team has focused on a selection of stabilised true breeds (landrace or F5+) for creating original F1 breeds.

Where the F1 generation is created by breeding male and female plants that are distinctly unique from each other; traditional F1s are created by crossing landrace indicas with landrace sativas.

These crosses need to be done with highly stable and uniquely different parents to produce a true F1 progeny that has abundant hybrid vigour. A plant with true hybrid vigour will typically have higher potency, increased pest resistance, and a higher yield than both parent plants; on average yield can be as high as 20% more than either parent.

Due to the nature of the F1 progeny, very few breeders release true F1 seeds. If highly stable progenitors are not used, the seedstock will be incredibly variable, which is unfavourable for consumers, who typically want consistency in their seed. However, as commercial cultivators, Cannadabis believes that F1 hybrids are essential for producing at large scale. The breeding and phenotyping can be a long and arduous process, the fruits of labour are not without commercial benefit.

Building upon the tissue culture and breeding practices, Cannadabis is quickly developing polyploidisation methods for creating ultra-premium cultivars. Polyploidisation is another common horticultural practice that Cannadabis expects to apply to their cannabis breeding projects.

Polyploidisation is a naturally occurring mechanism where the chromosomes of the plant cells become doubled within the same nucleus. This mechanism has played a significant role in speciation of crops, occurring frequently in nature, usually due to stress response.

In the 100 years since scientists discovered polyploidy, there has been rapid development of polyploid breeds. It is estimated that up to 80% of all flowering plants have polyploid varieties.2 Common polyploid cultivars includes wheat, coffee, banana, strawberry, potato, etc.

Polyploidy has been researched since the early 1900s. Scientists first used heat and electrical stress to induce those mechanisms. Today polyploidy is more commonly, and consistently, induced with radiation and stressing chemicals. Interestingly, induced polyploidy is explicitly exempt by most organic certification bodies. These types of breeds typically do not fall under genetically modified until foreign, non-similar species, DNA is introduced to the plant cell.

These polyploids are called autopolyploid (same species), and plants made with dissimilar species are called allopolyploids. Cannadabis will also be exploring organic permitted cell fusion; this would allow breeding with two male plants, or two female plants.

In the past, the following horticulture benefits have been derived from polyploidy and cell fusion, which Cannadabis hopes to similarly apply to the cannabis plant:3

The same can apply to cannabis. Strains can be developed that would never seed regardless of direct pollination; massive utility available to outdoor or indoor cultivators with seeding problems.

Cannadabis hopes to release their first polyploid strains in late 2020.

Cannadabis has begun manufacturing premade tissue culture mediums and are currently distributing them to Western Canadian horticulture stores and Amazon Marketplace; the mediums are a standard blend that works on 95%+ of the founders cultivars. The founders tissue culture experience is being provided to the public in both consumer and commercial grade products.

The introductory products show unfamiliar users how to do tissue culture at home, using proven methods that do not require expensive laboratory equipment. Besides what comes in the starter kit, the everyday home grower will usually have all the remaining materials at home. Commercial format mediums are intended for growers that want the best value and space savings.

Cultivators of any background can find information or help on tissue culture through the Cannadabis homepage. They are posting helpful videos and literature on cannabis tissue culture and hope to share the benefits with every grower. All horticulturalists, cannabis or not, can benefit from having their cloning area be 100x more efficient, through stackable containers. Furthermore, their mother plants can easily be maintained with minimal care. 100-1000 mother cultures can be stored within a refrigerator for 4-8 months, no adding nutrient or water. For larger cultivators, Cannadabis provides PGR matrices to more easily troubleshoot difficult cultivars. They also will custom blend and sterilise mediums to customer preference.

Cannadabis has begun developing an automated cell culture process for mass propagation of cultivars. The economies of scale of which are expected to change the supply chain of the entire cannabis industry. Automated cell culturing will provide starting materials to the industry at a fraction of the cost of inhouse cloning. Clones produced through cell culturing will also have the benefit of being totally sterile and free from disease.

Cannadabis has been offered an NRC-IRAP grant for initial developments of the process and are in early negotiations with a Canadian cannabis company to commercialise. The founders are expecting to file patents, mid 2020, and begin construction of a commercial scale process by mid-2021. Cannadabis anticipates that a 5000 sq ft facility will produce 5+ million clones annually, with minimal labour.

The project is looking to possibly incorporate the production of artificial seeds, which would simplify transportation and ease of storage for cultivators. They will also be developing cryogenic preservation methods. Cultivators around the world are encouraged to reach out to Cannadabis if they are looking to simplify their process, access cell culture benefits, and maximise growing space.

Working with Cannadabis cultured clones will be the most affordable, safe, and efficient way of acquiring starting material. Their services would include meristem culturing to remove systemic disease, and long-term storage of genetic inventory. Partners who end up with a pest could rest easy knowing their mother cultures will be perfectly preserved in tissue culture, and fifty thousand clones for the next crop are still on the way.

Cannadabis Medical and Delta 9 Cannabis have teamed up to provide an affordable, turnkey, tissue culture laboratory, complete with operating procedures, equipment, and cannabis medium recipes.

The two companies have co developed this system for their own commercial use and have recently made the system available for other cultivators. Both companies have recognised that the cannabis industry is still reliant on black market methods of propagation, and as a result, there have been countless incidents of crop and genetic loss in the legal industry; many of the stories circulating are understandably refuted by the companies experiencing such loss.

Rather than ignore the inevitable pest problems, the two companies are going toe to toe with mother nature, developing half century old technology and making it specifically for cannabis. Hopefully delivering the same modicum of control to the rest of the industry; cultivators slow to develop tissue culture science may soon find their genetics and crop totally destroyed by a single, often microscopic pest. On a commercial scale, these pests become essentially impossible to remove without the use of tissue culture.

With feet rooted in genuine care, Cannadabis and Delta 9 are prepared and excited to deliver a tissue culturing system to the global cannabis industry. They recognise the value and utility available to growers, and they also recognise that learning tissue culturing can feel out of reach for cultivators with no prior knowledge, or excess funding to hire an inhouse specialist.

Instead of missing out or paying specialists, cultivators can rely on Cannadabis and Delta 9 to deliver a ready to use laboratory, the development of which was based on maximising value for the growers.

The laboratory comes with only bare essentials and extensive, yet simple, operating procedures. Training materials will detail cannabis specific mediums, sanitation protocols, along with troubleshooting methods for finicky cultivars; an inexperienced grower will be comfortably blending and using mediums on the same day of commissioning. The whole system, equipment and all, will be much more affordable than hiring a tissue culture specialist.

Over the next three years, Cannadabis will be working to establish an expanded cultivation with the hope of supplying medical, organic, indoor grown cannabis to domestic and international markets.

They will also pioneer an original cell culture process that expects to be the most affordable source for starting materials in the world; Cannadabis is especially excited to deliver their polyploid cultivars as starting materials to industry members.

Cannadabis would like to offer an open invitation to all scientists, entrepreneurs, and industry professionals for collaboration. We are actively seeking partners who share a similar vision for the cannabis industry. Any professionals who are driven by a sense of genuine care and have a passion for cannabis medicine are encouraged to reach out.

References

1 hempindustrydaily.com/hemp-cultivators-tissue-culture-increase-propagation-preserve-genetics/2 Meyers, L. A., and Levin, D. A. (2006). On the abundance of polyploids in flowering plants. Evolution 60, 11981206. doi: 10.1111/j.0014 3820.2006.tb01198.x3 http://www.slideshare.net/ranganihennayaka/plant-polyploids4 http://www.frontiersin.org/articles/10.3389/fpls.2019.00476/full5 plantbreeding.coe.uga.edu/index.php?title=5._Polyploidy

Alexander CalkinsCEOCANNADABIS Medical INC+1 306 552 4242alexander@cannadabismedical.caTweet @cannadabiscannadabismedical.ca

This article will appear in the first issue ofMedical Cannabis Networkwhich will be out in January.Clickhereto subscribe.

Originally posted here:
Cannadabis: tissue culture and the future of cannabis cultivation - Health Europa

Prescient Medicine holding Inc has collaborated with the department of clinical chemistry, Erasmus MC (CC-EMC) to study the risks of opioid addiction in the Netherlands. The announcement was made today. This new partnership will be centered on Prescient Medicines novel genetic testing technology that is designed to accurately assess the risks of opioid addiction before exposure to opioids. To confirm the positive outcomes of the research in the United States, clinical research will be conducted on the patients in Netherlands.

A previous study from this year reveals that between the years 2008 and 2017 the number of prescription opioid users in the Netherland become double and hospital admission related to opioids become tripled.

Prescient Medicine, a private company that mainly focused on the development of diagnostic tools. It advances the healthcare movement of precision. The mission of Prescient Medicine is to accelerate the commercialization, development, and deployment of advanced clinical diagnostics for addressing the public health issues in the U.S. and around the world. The company has built up a strong test and proposed analytical solutions. This gives insight to the doctors and patients to assess the data so that they can make a better decision for clinical to achieve the best possible outcomes.

Also read- FDA Posts Warning Letter for No Mention of Serious Risks in Drug Advertisement

According to Professor Ron HN Van Schaik at Erasmus, that in the U.S. the number of opioid addictions is devastating, and we are worried about the increased number of opioid users and addiction that is similar to the Netherland. It is a vital step to evaluate the potential of Prescient Medicines diagnostic technology.

This step is helpful in the future for addressing and minimizing the risks of opioid addictions in The Netherlands. It is a tool for the clinical to determine the risks related to opioid addiction for a person before going for medicine. The test would give an easy way to the prescriber for choosing the best drug to treat the patient.

The Erasmus MC University Medical Center is an organization that is aimed to achieve a healthy population and excellence in healthcare through education and research. It has employed 17,000 members in 2019.

Also read- US FDA To Approve Clinical Trials for Type 2 Diabetes By Global Institute of Stem Cell Therapy and Research (GIOSTAR)

It rapidly grew in many fields including studying clinical and fundamental domains along with public prevention. The main goal of research at Erasmus is the heart of a society that results in innovation, improving the quality and effectiveness of patient care.

Keri Donaldson, the medical director and CEO of Prescient Medicine said that this type of test is important and valuable for anyone to prescribe opioids that are not only restricted to the U.S. We are trying to expand the usage of this test in The Netherlands. It may play a part in helping to combat the opioid crisis that develops in The Netherlands and throughout the world.

To learn the assessment of a patients genetic risk for opioid addiction we use the genetic panel that may leverage the power of the machine. The Federal Drug and Administration gave Breakthrough Device Designation to the test in the U.S. in Feb 2018.

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Prescient Medicine To Collaborate With Erasmus For Studying Opioid Addiction in Netherlands - TheHealthMania

ByGreg Rienzi

STOCKHOLMDuring his distinguished career, Gregg Semenza has given hundreds of lectures. In fact, for general scientific audiences, the Johns Hopkins University School of Medicine professor often gives a longer version of the very talk he presented on Sundaydetailing his discovery of the HIF-1 protein's role in human cell oxygen level regulationduring his Nobel Prize lecture at the Karolinska Institutet's Aula Medica auditorium.

But he's never presented to such a large crowd, let alone for such a crowning career achievement.

At the end of his Nobel Prize lecture, where in 30 minutes he effortlessly synthesized three decades of research on how the human body adapts to changes in oxygen availability, Semenza took ample time to thank the many people responsible for bringing him to this moment.

He dedicated his lecture to his high school biology teacher, Rose Nelson, pictured prominently in a slide of the many scientists whom he learned from.

Video credit: Len Turner and Dave Schmelick

"Dr. Nelson was my inspiration in science. I'm here because of her," Semenza told the crowd. He also thanked his early mentors at Johns Hopkins, chiefly professors of genetic medicine Haig Kazazian and Stylianos Antonarakis, both in the audience, and the late Victor McKusick, hailed as the "father of medical genetics." Indeed, the list of acknowledgments was long and detailed, naming nearly 150 faculty colleagues as well as students and postdocs who have collaborated with him over the years.

But before he was done, Semenza flashed a slide of his familyof him with his wife and three childrentaken on the beach during a vacation to Maine this past summer. "And last but not least, I'd like to thank " he began before pausing, tears welling in his eyes, voice cracking. He bowed his head briefly. In an instant, the emotion of the moment overtook him. Sensing the heartfelt struggle, the packed house of more than 800 attendees came to his aid with a roar of applause.

"Thank you," Semenza said, before pausing to take in a deep breath. "OK. I've got it together. I'd like to thank my wife, Laura; my sons, Evan and Gabe; my daughter, Allie, for always being there for me. Giving me unconditional love and support."

The moment was out of character for the usually reserved physician-scientist, but it gave a hint of the many emotions bubbling just beneath the surface during perhaps the most momentous week of his life.

"At that moment, I was feeling the power of my feelings for those people, particularly for my family, and it just became really kind of overwhelming," Semenza said the next morning. "That's never happened to me before. ... It caught me by surprise."

Video credit: Nobel Prize

On many occasions, Semenza has said sharing this Nobel Prize experience with family and friends is the pinnacle of the trip. A group of 30 family members and close friends have traveled to Stockholm to celebrate the week with him, including his four siblings, his mother, and her twin sister.

Beth Murphy, Semenza's sister, said it was both touching and surprising to see her older brother break down on stage, if only for a moment.

"It's not like him, for him to tear up like that," she said. "But obviously he went someplace deep inside of him."

She added that it's already been an emotional few days for their family as they share this unique experience with him, touring Stockholm and taking part in Nobel Week activities.

"I really, really love seeing how happy Gregg is," she said. "This is his life's work. To see him smiling from ear to ear the whole time is just fabulous."

Image caption: Gregg Semenza and two of his children, Allie (left) and Evan

Image credit: Will Kirk / Johns Hopkins University

Semenza's siblings have said the fame and attention of receiving science's highest honor have certainly not gotten to their brother, who has been celebrated at nearly every turn since he received news of the award in early October.

"He's the same humble, hardworking, and quiet guy he's always been," said brother Matt Semenza. "For us, it's been very exciting. I got to see him win the Gairdner Award [for Biomedical Research] in Toronto and the 2016 Albert Lasker Basic Medical Research Award in New York. So this is like the apogee of the award road trip we've been on with him."

Laurene Graig, Semenza's sister, added that while the emotional moment on stage might have been out of character, her brother's unselfishness and humility are not.

"I really appreciate that [Gregg] has recognized all the people who have helped and supported him along the way," she said. "I think it takes a certain amount of grace to do that. I'm very proud of him. We all are. There's been a lot of 'we' when he talks, not 'I' or "my.'"

Image caption: Semenza (center) with his family

Image credit: Will Kirk / Johns Hopkins University

When asked about his accomplishments and research, Semenza frequently credits others, and considers himself fortunate to happen upon the discoveries that brought him to this point. He traces it all back to his days growing up in New York.

Born in New York City in 1956, Semenza spent his formative years in Tarrytown, New York, a village located in Westchester County along the Hudson River. Semenza called it a "great place to grow up," a small-town atmosphere only a few train stops away from New York City where he would often go on the weekends to tour museums. His mother, Kathryn, taught at an elementary school, so learning and education were always priorities for the young Semenza.

At Sleepy Hollow High School, he learned to love science from Nelson, who during his junior year alerted him to an opportunity to take part in a National Science Foundation summer program at the Boyce Thompson Institute for Plant Research, an independent research institute then located in Yonkers, New York, and now located on the campus of Cornell University in Ithaca.

There he would do simple experiments like exposing plants to viruses and detailing the signs of infection.

"I was all thumbs back then because this was the first time I'd done it," Semenza said. "But I still enjoyed it. And this experience was really important for me because it showed me this was something I'd like to do for a career. It was just one more link in the chain of events that led me on the path that ended up here."

This exposure to science at such a young age, and the mentoring he received from Nelson, is largely why Semenza now champions STEM education and the teaching profession. That was what compelled him to not only dedicate his Nobel Prize lecture to Nelson, he said, but also to share the long list of undergraduate students, graduate students, and postdocs who have worked with him over the past three decades at Johns Hopkins.

"I stopped doing experiments in my lab back in 1996," he said. "Since then, all the data has been generated by students and trainees. I can have all the greatest ideas in the world, but science is about generating data. If I didn't have all these people doing that, all these ideas wouldn't matter. We're not philosophers. We're scientists. If we have an idea, if we have a hypothesis, we have to prove it."

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As Johns Hopkins physician-scientist Gregg Semenza travels to Stockholm to accept his Nobel Prize, the Hub takes readers along for the journey, from his arrival in Sweden to his Nobel lecture at the Karolinska Institutet to the grand Nobel Award Ceremony and Banquet

Mentoring students, he says, has been vitally important to him, as he feels the need to repay the debt of what his mentors did for him and pay it forward to the next generation.

That next generation was notably present at his Nobel Prize lecture, a celebration of science that many consider the most exciting part of the week as people get to hear directly from the Nobel laureates about their significant contributions to their fields. A long line of mostly students and young researchers snaked around the Aula Medica building that day, down steps and around the block, students such as Stephanie Chanda, a first-year biomedicine master's student at the Karolinska Institutet who had been in line with friends for hours to ensure she got in and got a good seat. "Of course, we are very interested in the Nobel lecture because we want to be researchers ourselves one day," Chanda said.

Also in the crowd were Semenza's family and friends and colleagues, including several of those he thanked in his talk.

"Having family and friends here is really the most important part of this experience, sharing this with them," Semenza said. "It's been great to have [my mom] here. Nobody has been more excited than she has. She's become something of a local celebrity back in Tarrytown, appearing in all the media, newspaper and television. ... She's very into it. And she deserves the attention.

"It's been an exciting week," he added, "from the time we stepped out of the car at the Grand Hotel to the throng of autograph seekers standing out in the cold waiting for us to come, to the thrill of giving the Nobel lecture yesterday. And having so many friends and family here to enjoy it with. That's really what has made it most special for me."

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A Nobel journey a lifetime in the making - The Hub at Johns Hopkins

The landscape of precision medicine has changed dramatically over the years. The completion of the Human Genome Project in 2003 has greatly accelerated our understanding of individual genomes, leading to the idea of precision medicine: medical care tailored to the individual.

Since then, science has progressed greatly. Today, we are able to look beyond identifying mutations and instead gain a very comprehensive view of the molecular biology taking place in tumor cells. We nowunderstand that each person has a unique genetic and molecular setup, and each cell in the human body is different. Based on this knowledge, single-cell analysis tools are being developed to analyze the genetic, transcriptomic, proteomic, and epigenetic features of each cell.

As a relatively new suite of technologies, single-cell analysis can greatly improve precision medicine, a feat that is especially important in cancer biology. By providing deeper insights into each individuals disease, single-cell analysis can address many of the current challenges in precision medicine.

One area in which single-cell analysis is starting to make a difference is personalized cancer treatment. Tumors often contain very heterogeneous cell populations, which makes selecting treatments extremely challenging. Conventional diagnostic techniques often rely on the bulk analysis of cells. By taking the average of all cells in a sample, it is easy to miss a cell subpopulation that can become resistant to treatment and cause a relapse.

Now one company has taken it upon itself to improve precision medicine using single-cell analysis: Proteona. Among its first targets are blood cancers, such as multiple myeloma. As one of the most aggressive blood cancers, the treatment of multiple myeloma comes with a number of challenges.

Myeloma is a very difficult disease to treat because it constantly relapses, explains Chng Wee Joo, Senior Consultant and Head of Department of Haematology-Oncology at the National University Cancer Institute Singapore. The tumor cells are highly heterogeneous, and the immune microenvironment also plays an important role, creating additional complexity. Typically, patients are treated with multiple drugs at the same time, which triggers side effects and is extremely costly. There is definitely a need for better precision medicine here.

While the traditional bulk analysis of a tumor biopsy only provides information on the average of all cells present in a sample, single-cell analysis allows clinicians to analyze different tumor cell subpopulations, which might be resistant to a specific treatment and could cause a recurrence of the disease. In the case of multiple myeloma, single-cell proteogenomics can also be used to analyze the malignant plasma cells gene and protein expression and can be used to decide what treatments are plausible for the individual patient.

By adding protein expression analysis to single-cell sequencing, clinicians can gain valuable information on protein and gene expression as well as a better resolution between different cell types compared to analyzing gene expression alone. This is important for understanding patient cell heterogeneity.

For example, single-cell proteogenomics can provide a detailed analysis of the immune cells involved in a disease, can help clinicians understand possible resistance, and can be used for patient stratification in precision medicine trials.

There is a huge value in combining total mRNA profiling and proteomics in single-cell sequencing, says Andreas Schmidt, CEO of Proteona. While single-cell proteogenomics can be applied in various fields, what we find most interesting is the ability to gain a good snapshot of the immune cells as well as of tumor cells in the same sample. And that is valid for solid tumors as well as for liquid tumors. The information we are dealing with is already directly relevant for immuno-oncology, immunotherapy, and cell therapy. But despite the huge clinical value that we can already see on the horizon, there are no commercial solutions that can move single-cell sequencing into the clinic. And that is where we see the sweet spot.

Proteona has developed a suite of technologies called the Enhanced Single-Cell Analysis with Protein Expression (ESCAPETM) platform. ESCAPE uses DNA-barcoded antibodies to obtain protein and gene expression information from individual cells. Available as an in-house service or a kit, the ESCAPE platform has been used extensively for peripheral blood mononuclear cells (PBMC) profiling, whole tumor analysis, and cell therapy characterization.

One of the key challenges of single-cell analysis is the enormous amount of data generated. Even the sequencing of a single tumor results in hundreds of millions of data points that have to be analyzed and interpreted.

Combining datasets from different sources is also challenging. Cross-experimental comparison is often impeded by batch-to-batch differences. Moreover, single-cell analysis often results in the detection of previously unknown cell populations. Manual intervention is often needed for cell clustering and cell annotation, which demands specialist expertise, takes time and is susceptible to human error and bias.

Proteona definitely evolved from being a wet lab company with a bit of IT to a company that is equal parts bio and tech, says Schmidt. With single-cell proteogenomics you end up with thousands of mRNAs and potentially hundreds of proteins. If you were to gate them all by yourself and annotate that data, it would take a long time and it would create a lot of bias. We try to avoid this by using machine learning and automatic algorithms. One key point of our work is that we started with the wet lab and have a very deep understanding of the techniques and biology. At the end of the day, the biology is what informs us, not the algorithms.

In a partnership with AI Singapore, Proteona is further developing its computational workflows to support the knowledge-driven analysis of single-cell proteogenomics data to create unbiased data sets. The collaboration aims to further the development of artificial intelligence (AI) tools for single-cell multi-omics data analysis.

In Autumn 2019, Proteona issued an oncology challenge, co-sponsored by NovogeneAIT, in which it called for proposals from scientists and clinicians working on major clinical problems in oncology. Participants were asked to send in an abstract describing how they would use the ESCAPE platform with the chance to win $50.000 worth of single-cell analysis services from Proteona and NovogeneAIT.

The grant was awarded to Cesar Rodriguez Valdes from the Wake Forest School of Medicine in Winston-Salem, US. The proposal aims to tackle the issue of treatment selection for multiple myeloma.

By applying single-cell proteogenomics in their patient-derived 3D organoid models, the team will compare cell populations in response to multiple drugs, identifying the difference in protein and gene expression patterns. These studies will help to elucidate the mechanism of chemo-sensitivity, and potentially help to choose the suitable chemotherapy combination for each patient.

We are excited about combining Proteonas single-cell proteogenomic analysis with our patient-derived organoid screening platform, says Rodriguez Valdes. Our ambition is to develop a predictive, validated test that will facilitate clinical decision-making and improve the outcome of multiple myeloma treatment. This grant will help us to move closer to that goal.

One major challenge in multiple myeloma management is how to select the most suitable treatment strategy for each patient, given the wide range of available therapies, adds Hartmut Goldschmidt, Head of Hemato-oncology in Heidelberg. Currently, the decision of which drug to use and when depends largely on the clinicians experience. There is an urgent need for tools that help clinicians make evidence-based choices. That is where single-cell multi-omics can be extremely valuable.

Other awardees of Proteonas challenge include the runner-up, Sanjay de Mel (National University Cancer Institute, Singapore), and the finalists Nicholas Gascoigne (National University of Singapore, Singapore), Steve Bilodeau (Universit Laval, Canada), and Aaron Tan (National Cancer Centre Singapore, Singapore).

With the growing complexity of drug development and the advancement of cell therapies and gene editing techniques, the need for single-cell proteogenomics in research and the clinic is increasing. A key application of single-cell proteogenomics will be the quality control of cell therapies.

Furthermore, although there is already genomic monitoring in place for many clinical trials, oncology trials would greatly benefit from single-cell proteogenomics monitoring.

Besides blood cancers, we see multiple potential areas where single-cell multi-omics will make a clinical impact, Schmidt says. By providing in-depth data on cell heterogeneity and combining that with powerful analysis tools, we are in the best position to help clinicians to decipher complex cases, from cell therapy to solid tumors. We are only starting to harness the power of single-cell analysis.

Are you interested in learning more about single-cell proteogenomics? Check out Proteonas website for more information or get in touch with its team of experts at [emailprotected]!

Images via Shutterstock.com and Proteona

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