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Modifying DNA ‘will get humans on Mars’ 70 years after monkey in space – Daily Star

Posted: December 12, 2019 at 2:46 am

On the anniversary of an ill-fated monkey's journey into space, there's a growing belief that genetic engineering could hold the key to exploring the universe.

Seventy years ago today, a monkey named Albert IV was strapped into a small spacecraft, hooked up to monitors and propelled into orbit.

The US launched a series of V-2 rockets carrying monkey astronauts throughout the late 1940s and early 1950s as a precursor to the space race.

Albert II became the first monkey in space on June 14 1949, a year after the original Albert suffocated before his rocket could make it past the Karman line - the 100km height above Earth marking the beginning of space.

Albert II survived his flight, which reached a height of 134km, but died on impact after his parachute failed.

He was followed by Albert III, who made it just 10km up before his rocket exploded.

On December 12, 1949, Albert IV was launched from New Mexico and successfully made it into space. He stayed safe and well throughout the flight until it was time to land, when yet another parachute failure killed him on impact.

Albert IV was the last of the V-2 monkeys, but the experiments continued in other forms.

Eventually, advances in space technology meant that the US and the Soviet Union were able to send animals into space and bring them back alive.

But the enormous stress of space travel had a huge impact on them, with many suffering heart attacks brought on by dehydration.

The weightlessness also affected their bodily functions: when the European Space Agency sent crickets into space for 16 days in 1998, the insects failed to develop the organs needed for balance that they would on Earth.

Human astronauts suffer a huge range of side-effects as well, from muscle atrophy to congestion to eyesight problems.

The rise of the animal rights movement means that even as space agencies look to Mars as the next destination to conquer, they may refrain from testing the technology on animals due to public pressure.

But Elon Musk may have found a way around it. Last week SpaceX sent a 'crew' of genetically modified mice and worms into space.

The rocket docked at the International Space Station where its precious cargo will be used in a variety of experiments investigating how to improve space travel.

Of the 40 mice onboard the 'Dragon' capsule, eight have been genetically engineered to have twice the muscle mass of a normal mouse. They're known as 'mighty mice', and they'll be able to better cope with the muscle-shrinking and bone density-decreasing effects of space.

Scientists hope these results will help them to understand how to limit muscle and bone loss in humans while they're in space.

SpaceX intends to send humans to Mars in 2024, with the eventual goal of colonising the red planet into a "self-sustaining civilisation".

It would take between six and eight months for a spacecraft to travel from Earth to Mars. That's a long exposure to space radiation, which has been proven to have devastating effects on humans including an increased risk of cancer.

But if scientists were able to strengthen our cells to better withstand the radiation, astronauts could stay healthier in space for longer.

US geneticist Chris Mason recently spoke about the possibility of changing human DNA to allow us to explore the universe further than we are currently able to.

One potential method would involve splicing human DNA with that of tardigrades - tiny micro-animals capable of surviving extreme conditions including direct exposure to deep space.

While genetic engineering is controversial, Mr Mason says in the future it may be more unethical not to enhance our DNA.

"In terms of a question of liberty, you're engineering it [a future human] to have lots more opportunities, again assuming we haven't taken away opportunities," he told

"If we learned that, in some way, when we decided to try and prove the ability of humans to live beyond Earth, and we take away their ability to live on Earth, I think that would be unjust."

In his words: "It's not if we evolve, it's when we evolve."

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Modifying DNA 'will get humans on Mars' 70 years after monkey in space - Daily Star

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Eavesdropping on the human microbiome uncovers ‘potent’ new antibiotics – Newswise

Posted: December 12, 2019 at 2:46 am


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Newswise The microbes populating the human body play an important role in health and disease, but with few exceptions, how individual microbial species affect health and disease states remains poorly understood. A new study by Princeton researcherMohamed Abou Doniaand his colleagues, appearing in the Dec. 13 issue of the journalScience, gives scientists new tools to explore and understand the human microbiome.

Using a massive dataset drawn from the genomes of hundreds of people, the researchers identified two microbes that function as powerful antibiotics, said Donia, an assistant professor in the Department of Molecular Biology, "as potent as their clinically used relatives against neighboring microbes in the oral microbiome." Finding novel antibiotics is important because pathogens are evolving resistance to antibiotics currently in clinical use.

The human microbiome -- the identity and balance of bacterial species on human skin and mucosal surfaces -- influences a variety of disease conditions, from digestive ailments to halitosis, bacterial vaginosis and eczema. The microbiome also aids immune development and the fight against pathogens. However, the human microbiome is incredibly diverse; the communities of bacteria, viruses, fungi and other tiny organisms differ according to the tissue where they live, and across human populations and individuals. It's unclear what constitutes a normal, healthy microbiome, much less how one might go about bringing a sick one back into balance.

A common approach to solving this problem is to culture an individual microbe in the lab and explore how it contributes to health or disease states. Unfortunately, it can be difficult to identify and isolate very rare species, or find the conditions necessary to support their growth outside their natural niche. To do this with every species would be a daunting task. Alternatively, scientists can examine the microbiome in situ, with the aim of describing its individual components and how they interact.

One way microbes communicate -- and do battle -- with each other and with human cells is through biologically active small molecules.

"Our long-term goal is to define the chemical space of the human microbiome," explained Donia. His group set out to identify the set of genes that manufacture such chemicals (termed a biosynthetic gene cluster, or BGC) directly in clinical samples. This would allow scientists to listen in on the chemical conversation taking place, and discover who is speaking and when.

Led by co-first authors Yuki Sugimoto, a postdoctoral research associate, and graduate student Francine Camacho, the researchers developed computer algorithms that can detect BGCs by analyzing and interpreting data sets known as "metagenomic sequencing data," genetic sequences obtained from the tissues or excretions of hundreds of human subjects. Some metagenomic data sets are drawn from clinical samples taken from diverse populations, including persons in different states of health or disease, or people in different geographical locales. Intensive analysis is needed to make sense of the rich but often fragmentary information contained in these data sets.

Donia's team began by identifying genes essential for the synthesis of a particular molecule or chemical of interest, then using computational algorithms to sort through metagenomic data for similar (homologous) genetic sequences, and grouping these sequence fragments together. They then assessed the prevalence of each group in the human population, and used the grouped sequences to piece together full-length BGCs. Importantly, this approach allowed identification of novel BGCs even if they are extremely rare.

To validate this approach, the researchers investigated whether they could detect BGCs involved in the synthesis of type II polyketides. This class of chemicals, which includes the anti-cancer drug doxorubicin and several antibiotic drugs, was previously found in soil bacteria but had never before been found in bacteria of the human microbiome.

"To our surprise, we discovered 13 such gene clusters, which are widely distributed in the gut, oral and skin microbiome of people all the way from the U.S. to Fiji," said Donia. To test if these newly identified BGCs actually make type II polyketides, the researchers selected two of the BGCs and inserted their genes into bacteria that can be easily grown in the lab, then used mass spectrometry to detect any new chemical products. These compounds were then purified and tested for antibiotic or anticancer activity.

"Two of the five new molecules we discovered are potent antibiotics," said Donia, "revealing a potential mechanism for niche competition and defense against intruders and pathogens." More work will be needed to discover the biological activity of the other three molecules, and the role of all five in human health or disease. Such studies may uncover new pathways for interaction between microbes, or between the microbiome and its human host.

With this technology, it is now possible to mine our own microbiomes for drug discovery or novel biological interactions. What other treasures might this type of analysis reveal? As Donia observed, "This was only one clinically important class of molecules that we went after -- there are dozens more to do, and we can't even start to predict what we will discover!"


"A metagenomic strategy for harnessing the chemical repertoire of the human microbiome," by Yuki Sugimoto, Francine R. Camacho, Shuo Wang, Pranatchareeya Chankhamjon, Arman Odabas '17, Abhishek Biswas, Philip D. Jeffrey and Mohamed S. Donia, appears in the Dec. 13 issue of the journalScienceand was released online Oct. 3 (DOI: 10.1126/science.aax9176). This work was supported the National Institutes of Health Director's New Innovator Award (1DP2AI124441), the Pew Biomedical Scholars Program, and a Focused Research Team on Precision Antibiotics Award by the School of Engineering and Applied Science at Princeton University. The researchers are all at Princeton University, in the Department of Molecular Biology, the Lewis-Sigler Institute for Integrative Genomics, the Department of Chemical and Biological Engineering, or Princeton Research Computing.


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Eavesdropping on the human microbiome uncovers 'potent' new antibiotics - Newswise

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Disney’s Bob Iger Was Just Named Time’s Businessperson of the Year and Baby Yoda Is Exactly the Reason Why – Inc.

Posted: December 12, 2019 at 2:46 am

And speaking of both Disney+ and Star Wars, that combination resulted in the most-watched show of any of the streaming services, The Mandalorian. Oh, and then there's Baby Yoda. Which brings us to the most recent reason Iger is having a good year: he was just named Time's Businessperson of the Year. Make no mistake, Baby Yoda is a perfect example of why that honorwas well-earned.

The Time article tells a brief story of how Iger knew immediately Baby Yoda would be an enormous hit with fans. For Disney, by the way, enormous hits are the standard operating procedure. In fact, the entire strategy looks something like this:

Create a story with adorable characters. Mass market both the story and the characters. Manufacture merchandise featuring adorable characters. Stuff more cash than you can imagine into the bank account.

In the case of Baby Yoda, Iger not only knew that the character would lead to huge sales, but also that the best play was radio silence until after the first episode of The Mandalorian streamed, so as not to spoil the reveal.

He wasright, of course.

Look, regardless of what you think of the mysterious green alien that has become the star of the Disney+ service and the mascot of the internet, there's really no arguing that from a business standpoint, Baby Yoda is brilliant. And it's a great lesson for entrepreneurs.

Here's why: Bob Iger isn't a storyteller--at least not in the classic sense of someonewho writesa scriptor directs a film. That isn't his role.But he has one thing that might be even more important--a sense of how stories connect with audiences. I'm not sure anyone would disagree that Iger knows his audience, and knows how to steward both the Disney brand as a whole, as well as the individual stories within it (Star Wars, Marvel, etc.)to make sure they resonate with that audience.

But Iger didn't create The Mandalorian or its most famous character. He didn't invent streaming video. He didn't dream upthe Star Wars universe. He isn't a comic book illustrator.

The puzzle that makes up Disney has an extraordinary number of pieces, none of which originated with its CEO. Instead, Iger's job is to see how all of those pieces fit together, and sell the resulting picture tothe rest of us.

And, just because you aren't running the world's largest media and entertainment company, doesn't mean that you don't have a story to tell.And, it doesn't mean you can't learn from what made Bob Iger so successful this year.

In most of the areas Disney competes, it is the apex predator. It's the biggest player in theme parks. It's the biggest licensor of toy characters. It's the biggest sports broadcaster. It's the biggest animation studio. It's the biggest family-friendlymovie producer.

It is not the biggeststreaming video service. It isn't the biggest player--Netflix has over 150 million subscribers--a number that dwarfs Disney+. But it made a huge bet that owning its own platform to stream its own library of content would pay off in a big way.

So far it has. And the lesson here is that when you align your story with your audience, you will win.

That's one of the most important qualities in any marketer, but also in every entrepreneur. Your primary job, at least at first,is to figure out how to tell the story of your brand, and then tell it to the right audience.

And you don't even need Baby Yoda for that--but it can'thurt.

The opinions expressed here by columnists are their own, not those of

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Disney's Bob Iger Was Just Named Time's Businessperson of the Year and Baby Yoda Is Exactly the Reason Why - Inc.

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The Great Barrier Grief and countless other marine disasters –

Posted: December 12, 2019 at 2:46 am

In the last, wrenching episode of BBCs Blue Planet 2, theres a distressing moment when a young Australian diver, expert in his patch of the Great Barrier Reef, admits I cried in my mask as he swam over an ossuary of recently bleached-out coral bones. Professor Callum Robertss memoir of a life devoted to the study of our oceans, and in particular their coral reefs, is a ravishing, alarming account of these underwater palaces of wonder, and the existential threat they face from humanity and our warming climate.

Reefs take up just 0.1 per cent of our planets surface, yet provide home and breeding grounds for more than a quarter of all sea life. They are also the canaries in the carbon dioxide coal mine. As ocean temperatures rise, corals bleach and die, the tiny organisms that feed them (zooxanthellae) expelled from their chalky hosts. Further, the acidification of the seas weakens the very structures the coral relies on for support and reduces the amount of calcium carbonate available in the seawater to make new coralline homes.

Robertss first student dives in 1982 were made off the Saudi coast of the Red Sea, counting reef fish with a waterproof whiteboard. He writes of the traditional Arab attitude towards the desert as an endless waste disposal and how one of his heroes, Jacques Cousteau, saw the sea the same way. Cousteau regretted this much later, writing: Water and air, the two essential fluids on which all life depends, have become global garbage cans.

The chief pleasure of this book is Robertss rich descriptive power. He was an adviser for Blue Planet 2, and his writing does more than justice to those stunning films. Natures throne rooms are thrown open by Robertss prose. Here he describes a dive in the Hol Chan Marine Reserve off Belize:

Coral outcrops rise through the canopy like Mayan temples above rainforest A group of batfish swim past, their bodies like pewter plates. Passing into the channel, fish coalesce into shoals of hammered copper, slate and sulphur, liveried with royal blue.

Roberts visits some of the most idyllic places on earth, and finds them under threat from mining, tourism and war. Most human development seems to spell doom. He surveys reefs in Egypt and sets up a marine centre, before being shunted off for the massive Sharm-el-Sheikh resort. He inspects Arab reefs hit by Saddams deliberate release of oil in Kuwait in 1991 and finds that local fishing fleets have inflicted even more terrible damage.

Flying back to Kuwait City, he looks out of the window to see the aftermath of Saddams obscene tactic:

In the suns glare, the spills shine like pools of water on the dry earth. Thousands of migrating birds fell for the same illusion, alighting on the waters surface only to find themselves mired in oil.

Shadows cast by burning wells cause the sea temperatures to fall and blot the sun so the coral struggles to photosynthesise.

One Saudi fertiliser plant flushes 5.8 million cubic metres of water poisoned with ammonia and heavy metals into the sea every year. The Saudi city of Al Khobar expels ten million cubic metres of raw sewage into the gulf annually. In Bonaire, a Caribbean island off the coast of Venezuela, Roberts finds a massive wipe-out of the coral, up to 99 per cent. The culprit: human gut bacteria from sewage sloshed into the sea. Fertilisers and spillage from land developments and the overfishing of grazing fish cause seaweed to explode, smothering reefs and boosting the numbers of Crown of Thorns starfish, who feast on corals corpses like looters after a massacre.

Extreme weather events like El Nio, their frequency and impact aggravated by the climate crisis, also play a part. By the end of 1998, roughly 70 to 95 per cent of all corals had perished across a vast swathe of the Indian Ocean from the Seychelles to Sri Lanka, Kenya to the Maldives. This catastrophe had no historical precedent. One Australian professor Roberts quotes believes all is lost: reefs have become a zombie ecosystem set to collapse by the centurys end.

Roberts and his colleagues rake through the ashes of a desolate future, looking for embers of hope. Some corals have been found that can live in acidified water, and perhaps natural selection will throw up heat-tolerant corals, although the adaptation might be slower than the oceans rate of warming. Perhaps there will be less diverse, but more resilient reefs, like the hardier corals Roberts encountered in the Arabian Gulf.

Maybe technology could use molecular or genetic engineering to make heat-proof corals. Theres also evidence in the Caribbean that the manageable stresses of pollution, overfishing and development are hurting coral more than the climate crisis, and the creation of marine parks could help mitigate this. Reducing fishing, fertilisers, pulling development back from the coasts these would all be local actions not hamstrung by the inertia of global agreements on greenhouse gas reduction.

Roberts is wary of putting a capital value on reefs, despite the services reefs provide being worth billions of dollars worldwide: the risk of monetising nature is that markets will assume that the loss of habitats is just a cost of doing business. For Callum Roberts, its the moral argument that we have a duty of care to preserve as many species as we can: What right do we have to rob future generations of their chance to revel as we do in the sheer joy of what is, arguably, the greatest show on Earth?

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Five technologies that may alter India in 2020 – Livemint

Posted: December 12, 2019 at 2:46 am

Bengaluru: What must it have felt like to be a cotton spinner or an iron maker in England in the 1820s in the midst of an industrial revolution? Exactly 200 years later, we may be on the verge of another era of momentous change: the internet revolution. With internet access expanding dramatically post the early 1990s, a slew of new technologies have now matured to a point where fundamental change constantly seems to be right around the corner.

On the doorstep of a brand new decadethe 2020swhat new frontiers may Artificial Intelligence (AI) or gene editing open up? Will we soon have robot bosses? Will mixed reality change the way we consume entertainment and sports? Will we be able to cure 90% of all genetic diseases by the end of the decade? We take a look at five technologies that could alter India and the world. This may not be a definitive or even exhaustive list, but it is a list of things that could change the way we live, work, and play sooner than we think.

Mixed reality

Imagine watching a football match, not on your TV but on a virtual reality (VR) headset that streams the match live and projects interesting stats on the fly with the help of augmented reality (AR). Mumbai-based VR startup Tesseract, now owned by Mukesh Ambanis Reliance Jio, is promising a future like that with its Quark camera, Holoboard headset, and the high internet speeds of Jio Fiber. Similarly, a Hyderabad-based mixed reality startup called Imaginate enables cross-device communication over VR and AR wearables for better enterprise collaboration in the industrial sector.

Despite the much-hyped yet unmet expectations from the likes of Google Glass, Microsoft HoloLens and Facebooks Oculus, Tesseract and Imaginate simply underscore how the fusion of AR and VR technologies the combination of which is popularly known as Mixed Reality or MR is coming of age and is no longer in the realm of just sci-fi movies like Blade Runner 2049, where Officer K played by Ryan Gosling develops a relationship with his artificial intelligence (AI) hologram companion Joi.

For instance, AI-powered chatbots today can not only conduct a conversation in natural language via audio or text but they can be made more powerful with a dose of mixed reality. Last May, Fidelity Investments created a prototype VR financial advisor named Cora to answer client queries using a suite of tools from Amazon Web Services. Researchers in Southampton have built a device that displays 3D animated objects that can talk and interact with onlookers.

The Chinese government-run Xinhua News Agency has the worlds first AI-powered news anchor, whose voice has been modelled to resemble a real human anchor working for the agency. Going a step further, Japan-headquartered DataGrid Inc. uses generative adversarial networks (GANs) to develop its so-called whole body model automatic generation AI" that automatically generates full-length images of non-existent people with high resolutions.

Nevertheless, challenges abound when dealing MR-and AI-powered robots, humanoids, and human avatars. For one, whenever a company generates human bodies and faces, concerns over deep fakes and cheap fakes will always rear their heads. Second, data collection will continually raise concerns over security and privacy. Third, theres always the concern regarding the fairness of an AI algorithm when it is deployed to do human tasks like giving financial advice. Last, but not the least, theres also the question of whether AI bots should be allowed to pose as humans. This will continually pose a challenge and opportunity for technologists and policy makers.

Future of solar

Heliogen, a company that has billionaire philanthropist Bill Gates as one of its investors, says it has created the worlds first technology that can commercially replace fuels with carbon-free, ultra-high temperature heat from the sun. With its patented technology, Heliogens field of mirrors acts as a multi-acre magnifying glass to concentrate and capture sunlight.

This is just a case in point that solar technologies have evolved a lot since they first made their debut in the 1960s. For instance, solar roadwayspanels lining the surface of highwayshave already popped up in the Netherlands. Floating solar, on its part, is providing a credible option to address land use concerns associated with wide scale solar implementations. A French firm called Ciel et Terre, for instance, has projects set up in France, Japan, and England. Other parts of the world, including India and California in the US, are piloting similar floating solar initiatives.

Space-based solar technology is another exciting arena. India, China and Japan are investing heavily in these technologies right now. The Japan Aerospace Exploration Agencys (JAXA) Space Solar Power Systems (SSPS) aims to transmit energy from orbiting solar panels by 2030. Further, researchers at the VTT Technical Research Centre in Finland have used solar and 3D printing technologies to develop prototypes of what they have christened as energy harvesting trees".

With solar power cheaper than coal in most countries in the world, its worth scaling up these technologies.

Indians and robot bosses

Between 400 and 800 million individuals around the world could be displaced by automation and would need to find new jobs by 2030, predicted a December 2017 survey by consultancy firm McKinsey. The Future of Jobs 2018 report by the World Economic Forum (WEF) suggests that 75 million jobs may be lost to automation by 2022, but adds that another 133 million additional new roles will be created.

Given that many of the automated jobs are being taken away by AI-powered chatbots and intelligent robots, would humans eventually have to work for a robo boss? This, however, may not be as big a concern as it is made out to be. According to the second annual AI at Work study conducted by Oracle and Future Workplace, people trust robots more than their managers. The study, released this October, notes that workers in China (77%) and India (78%) have adopted AI over 2X more than those in France (32%) and Japan (29%). Further, workers in India (60%) and China (56%) are the most excited about AI, while men have a more positive view of AI at work than women.

Oracle and Future Workplace also found that 82% of the workers believe robot managers are better at certain tasks, such as maintaining work schedules and providing unbiased information, than their human counterparts. And almost two-thirds (64%) of workers worldwide say they would trust a robot more than their human manager. In China and India, that figure rises to almost 90%.

On the other hand, the respondents felt managers can outdo robots when it comes to understanding their feelings, coaching them, and creating a healthy work culture. Whether humans eventually serve a robo boss or not remains to be seen. However, we can be certain of one thing: in the near future, we will increasingly see humans collaborating with smart robots.

Future of payments

Everyone can be a merchant, and every device can be an acceptance device," Accenture noted in its 2017 Driving the Future of Payments report. This trend has only accelerated over the last two years, especially with banks coming to terms with the fact that young customers, especially those living in urban areas, prefer net banking and mobile banking and would seldom, or never, want to visit a bank branch if offered that choice.

Bitcoin and cryptocurrency investors, for instance, have not lost faith in this disruptive currency despite the run with volatility, and despite the industry being viewed with a lot of suspicion by most governments around the world, including India. Fintechs too, with their innovative technology solutions like AI-powered bots and contactless payments to name a few, have only made the payments ecosystem more inclusive, disruptive, and challenging. In India, especially, the governments Aadhaar-enabled payments system and the Unified Payments Interface (UPI) have revolutionized the payments ecosystem. The total volume of UPI transactions in the third quarter of calendar 2019 touched 2.7 billiona 183% rise over the same July-September quarter a year ago. In terms of value, UPI clocked 4.6 trillionup 189% over the same period a year ago, according to the Worldlines India Digital Payments Report-Q3 2019.

However, the number of transactions done on mobile wallets was 1.04 billiononly a 5% rise over the previous year period.

QR codes, according to the report, will continue to be used for payments, and the internet of things (IoT) is set to dominate micro payments by transforming connected devices into payment channels, though the pace of adoption of 5G by countries like India will be the key.

Nevertheless, cash that has been in existence for over 3000 years in different forms is not going to disappear in a hurry. Trust and security will continue to remain the operative words in digital payments.

Making sense of gene editing

When Dolly the sheep made news for becoming the first mammal ever to be cloned from another individuals body cell, many expected human cloning to follow soon. Dolly died over 16 years ago, and subsequently animals, including monkeys and dogs, continue to be cloned successfully. Yet, no human being has yet been cloned in real life.

While human cloning, which may or may not eventually happen, is bound to raise a lot of alarm bells given the moral implications surrounding the issue, the fact is that human genomes, or genes, are being routinely edited in a bid to find solutions for what are today considered to be incurable genetically inherited diseases.

Researchers are using a gene editing tool known as CRISPR-Cas9. CRISPR, which stands for Clusters of Regularly Interspaced Short Palindromic Repeats, is a tool that allows researchers to easily alter DNA sequences and modify gene function. The protein Cas9 (CRISPR-associated, or Cas) is an enzyme that acts like a pair of molecular scissors capable of cutting strands of DNA.

CRISPR-Cas9 is primarily known for its use in treating diseases like AIDS, amyotrophic lateral sclerosis (ALS), and Huntingtons disease. Two patients, one with beta thalassemia and one with sickle cell disease, have potentially been cured of their diseases, reveal results from clinical trials that were jointly conducted by Vertex Pharmaceuticals and CRISPR Therapeutics. The results released this November involved using Crispr to edit the genes of these patients.

Researchers are now looking to extend its use to tackle famine, lend a hand in creating antibiotics, and even wipe out an entire species such as malaria-spreading mosquitoes. Further, by genetically engineering a persons bone marrow cells, researchers can reprogram their immune and circulatory systems. Some new cancer treatments are based on this. Moreover, looking at the DNA of the collection of microbes in your gut can help with digestive disorders, weight loss, and even help understand mood changes.

Closer home, scientists at the Institute of Genomics and Integrative Biology (IGIB) and the Indian Institute of Chemical Biology (CSIR-IICB) are trying to correct genetic mutations in their laboratories using CRISPR Cas9 with encouraging preliminary results. But due to regulatory and ethical concerns, it may take a while before they can use this on humans.

IGIB also sells CRISPR products such as Cas9 proteins and its variants to educational institutes at reduced prices in a bid to encourage use of the technology.

The US Food and Drug Administration (FDA), on its part, considers any use of CRISPR-Cas9 gene editing in humans to be gene therapy and rules that the sale of DIY kits to produce gene therapies for self-administration is illegal. India, too, has banned the use of stem cell therapy for commercial use following concerns over rampant malpractice".

CRISPR-Cas9, thus, remains a work in progress and countries should have policies to govern its use. Meanwhile, one can watch out for an upgrade to CRISPR called Prime, which theoretically has the ability to snip out more than 90% of all genetic diseases.

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Five technologies that may alter India in 2020 - Livemint

Recommendation and review posted by G. Smith

ASH 2019: Second-gen CAR T-Cell Therapy Overcome Resistance, Reduce Toxicity and Simplify Treatment – OncoZine

Posted: December 12, 2019 at 2:46 am

Using immunotherapy with genetically modified T cells that express chimeric antigen receptors or CARs designed to target tumor-associated molecules, have impressive efficacy in the treatment hematological malignancies.

A CAR is a synthetic construct that, when expressed in T cells, mimics T cell receptor activation and redirects specificity and effector function toward a specified antigen.[1]

In the treatment of cancer, this process is accomplished by linking an extracellular ligand-binding domain specific for a tumor cell surface antigen to an intracellular signaling module that activates T cells upon antigen binding.[1]

The presented studies include results from emerging second-generation cellular immunotherapy products that strive to overcome the limitations of existing products such as resistance and reduce toxicity and simplify treatment.

Cellular immunotherapy uses genetic engineering to enhance the ability of the immune system the bodys defense system against infection and disease to kill malignant cells in the blood, the bone marrow, and other sites, in order to keep cancer from coming back.

CAR T-cell TherapyChimeric antigen receptor T-cell therapies, better known as CAR T-cell therapies, are developed by harvesting a patients own T-cells, the immune systems primary cancer-killing cells, engineering them to target proteins specific to the surface of cancer cells, and reintroducing these modified T-cells back into the patients immune system to kill the cancer cells.

First generationFirst-generation CAR T-cell therapies primarily target CD-19, a protein found on the surface of most normal and malignant B cells in B cell cancers such as lymphoma. These therapies have been shown to produce long-term remissions in about one-third of patients with B-cell lymphomas that have not responded to prior therapies.

We are now seeing efforts to enhance the effectiveness of CAR T-cell therapy by designing products capable of attacking multiple targets, expand the availability of cellular immunotherapy to other blood cancers such as multiple myeloma and replace the complex manufacturing process required for CAR T-cell therapy with a uniform off-the-shelf product, noted Gary Schiller, MD, UCLA Health, an academic medical center which includes a number of hospitals and an extensive primary care network in the Los Angeles, California, region.

One of the phase I studies evaluates an off-the-shelf cellular immunotherapy product that targets two proteins found on the surface of lymphoma cells, including its potential to revive previously administered CAR T-cells that have stopped working.

Another study presents preclinical results for one of the first cellular immunotherapies to be based on off-the-shelf natural killer (NK) cells and the first, according to its manufacturer, to be genetically engineered to contain three active anti-tumor components.

The other two studies, also phase I studies, assess novel CAR T-cell therapies for multiple myeloma that test different dual-target strategies.

One investigational agent is genetically engineered to contain two proteins that attach to BCMA, a protein found almost exclusively on the surface of plasma cells, the immune-system cells that become cancerous in multiple myeloma.

The other is designed to target both BCMA and CD-38, another protein found on the surface of plasma cells. In both studies, many patients achieved minimal residual disease (MRD) negativity, which means that using highly sensitive testing fewer than one myeloma cell per 100,000 cells was identified in the bone marrow. Previous studies have shown that patients who achieve this milestone have a lower risk of relapse after more than three years of follow-up.

Dual-targeted CAR T-cell therapiesThe three phase I studies also hint at the possibility that dual-targeted CAR T-cell therapies might result in fewer patients experiencing moderate to severe cytokine release syndrome (CRS), a known adverse effect caused by an immune response in the body to the activated T cells that are attacking the cancer. CRS causes flu-like symptoms such as fever, body aches, and fatigue, and in severe cases can be life-threatening. Treatment with the drug tocilizumab can reduce CRS symptoms.

Dual-Targeted Antibody Elicits Durable ResponsesPatients with B-cell Non-Hodgkin Lymphoma (NHL) that had returned after or failed to respond to a median of three prior therapies showed complete responses (CR) and durable remissions after being treated with an investigational drug called mosunetuzumab (RG7828; Genentech/Roche). [2]

This investigational agent is a humanized, T-cell bispecific antibody designed to engage T cells and redirect their cytotoxic activity against malignant B cells. The drug works by activating the patients own T-cells, stimulating them to attack and kill cancerous B cells to which they have been introduced by the novel antibody.

Mosunetuzumab simultaneously binds to CD3 epsilon (CD3), a component of the T-cell receptor (TCR) complex, and to CD20, a B-cell surface protein expressed in a majority of B-cell malignancies. This results in crosslinking of the TCR, inducing downstream signaling events that leads to B-cell killing.

Among patients whose lymphoma progressed after treatment with CAR T-cell therapy, 22% had complete remissions when treated with mosunetuzumab. This new drug targets two proteins, one on the surface of tumor cells and the other on the surface of the recipients Tcells.

Unlike CAR T-cell therapy, mosunetuzumab is an off-the-shelf immunotherapy product that can be given to patients without having to genetically modify their T cells, noted lead author Stephen J. Schuster, MD, of Abramson Cancer Center at the University of Pennsylvania in Philadelphia.

Mosunetuzumab generates long-lasting responses with a very tolerable safety profile in patients with B-cell non-Hodgkin lymphomas for whom multiple prior treatments have failed and whose prognosis is poor. Of particular interest, we are seeing durable complete remissions in patients whose lymphomas progressed after CAR T-cell therapy, he added.

The researchers observed many remissions continue after patients stop receiving the drug.

I have stopped therapy in some patients after six months and they have remained in remission. Some patients have remained in remission without additional therapy for more than a year, Schuster said.

New treatment options are needed not only for patients in whom CAR T-cell therapy has failed, but also for those patients whose lymphomas are getting worse so quickly that they cannot wait for CAR T-cell manufacturing, which takes several weeks, Schuster explained.

The data presented during the annual meeting of the American Society of Hematology included 270 patients (median age 62, 172 men) enrolled in the phase I trial in seven countries (the United States, Australia, Canada, Germany, South Korea, Spain, and the United Kingdom). All participating patients had B-cell lymphomas that had come back or not responded to a median of three prior therapies. Two-thirds of patients (67%) had fast-growing lymphomas; 85 (31%) patients had more slow-growing forms of the disease. In 30 patients (11%), the cancer was resistant to or returned after an initial response to CAR T-cell therapy; in 77 patients (29%), the disease had progressed after a stem cell transplant.

All patients were treated with mosunetuzumab by intravenous infusion. They had an imaging test at either six weeks or three months after starting therapy to assess the initial response to treatment, and responses continued to be followed every three months thereafter.

Forty-six of 124 patients with fast-growing lymphomas (37%) had measurable decreases in the extent of their cancer (objective response); 24 of 124 patients (19%) saw all detectable tumors disappear (complete response). A higher response rate was observed in patients with higher exposure to mosunetuzumab. Among patients with slow-growing lymphomas, 42 of 67 (63%) had objective responses and 29 of 67 (43%) had complete responses. Both objective response rate and complete response rate were maintained in subgroups of patients at high risk for relapse.

Complete remissions appear to be long lasting, Schuster said.

With a median follow-up of six months since first complete remission, 24 of 29 patients (83%) who achieved complete remissions of their slow-growing lymphomas and 17 of 24 patients (71%) who achieved complete remissions of their fast-growing lymphomas remain free of disease. In some patients whose cancers progressed after receiving CAR T-cell therapy, highly sensitive molecular testing showed that the previously administered CAR T cells increased in number.

This suggests that, in addition to its ability to kill cancerous B cells, mosunetuzumab may also help augment the effect of the prior CAR-T treatment, Schuster noted.

Cytokine-release syndromeIn this study, 29% of patients treated with mosunetuzumab experienced cytokine-release syndrome that was mostly mild.

Cytokine release syndrome or CRS is caused by a large, rapid release of cytokines into the blood from immune cells affected by the immunotherapy. While most patients have a mild reaction, sometimes patients may have a severe, life threatening, reaction.

In 3% of patients, CRS was treated with tocilizumab (Actemra; Genentech/Roche). Four percent of patients experienced moderately severe neurologic side effects. Patients who received higher doses of mosunetuzumab were no more likely to have CRS or neurologic side effects than patients treated at lower doses.

A study of a higher dose of mosunetuzumab is now enrolling patients and long-term follow-up of these patients will ultimately help to better evaluate the durability of response data.

Larger, randomized trials are needed to further confirm these promising data and determine whether the treatment benefit of mosunetuzumab is enhanced when it is used earlier in the course of lymphoma therapy or in combination with other agents, Schuster concluded.

Novel Off-the-Shelf CARPreclinical studies provide the first evidence that cellular immunotherapy for B cell cancers could ultimately become an off-the-shelf product, capable of being uniformly manufactured in large quantities as prescription drugs are.

We have taken the concept of traditional pharmaceutical drug development and applied it to cellular therapy, explained senior author Bob Valamehr, Ph.D, of Fate Therapeutics, a San Diego biopharmaceutical company.

The product called FT596, is among the first cellular immunotherapies to be based on off-the-shelf NK cells the first line of defense of the immune system and is the first cellular immunotherapy to be genetically engineered to contain three active anti-tumor components, Valamehr explained.

Comparable with standard CAR T-cell therapyFT596 demonstrated comparable ability to kill cancerous white blood cells as standard CAR T-cells and, when combined with the drug rituximab (Rituxan; Genentech/Roche), killed cancerous white blood cells that were no longer responding to standard CAR T-cell therapy due to loss of the CD19 antigen target.

The U.S. Food and Drug Administration (FDA) approved Fate Therapeutics Investigational New Drug Application for FT596 in September 2019 and the company hopes to begin a first-in-human phase I clinical trial for the treatment of B-cell lymphoma and chronic lymphocytic leukemia in the first quarter of 2020.

The primary purpose of this trial will be to assess the safety and activity of FT596 in patients.

ManufacturingThe development and manufacturing of FT596 begins with human induced pluripotent stem cells (iPSCs) that are uniquely capable of unlimited self-renewal and can differentiate into more than 200 types of human cells. These iPSCs are genetically engineered, after which a single genetically engineered cell or clone is selected and multiplied in the laboratory to create a master engineered cell line that can be repeatedly used to generate cancer-fighting immune-system cells such as NK and T cells.

Natural Kiler Cells or NK cells are a type of lymphocyte and a component of innate immune system, the bodys first line of defense against infection and disease. Unlike T-cells, which have to be trained to recognize their target and can kill only cells that display that target on their surface, NK cells do not need special preparation before going on the attack and can kill many different types of transformed or infected cells.

NK cells are multifaceted and can be viewed as a jack-of-all-trades when it comes to protecting the host, whereas T cells can act in only one way, Valamehr explained.

But NK cells are also different in other ways. They are inherently limited in their capacity to multiply and expand when infused into patients, and they have a shorter lifespan.

Valamehr and his colleagues used genetic engineering to address these shortcomings. In addition to engineering FT596 to carry a CAR targeting the CD19 protein, which is produced by nearly all B-cell lymphomas and leukemias, they inserted two other novel proteins: CD16, which boosts and broadens the NK cells ability to kill cancer cells, and IL15, which stimulates FT596 to proliferate and persist.

Valamehr explained that FT596 has been designed to address two more limitations of CAR T-cell therapy .

The investigational agent is an off-the-shelf product. As a result, it significantly improves the current patient-by-patient CAR T-cell treatment paradigm by eliminating the time-consuming and costly process that is currently required to treat a patient with CAR T-cells.

The addition of the CD16 protein gives FT596 broader therapeutic activity and versatility. In combination with rituximab, FT596 has the potential to lead to deeper and more durable responses and overcome resistance that hampers the long-term efficacy of CAR T-cell therapy.

Eliminating the high production cost, weeks of manufacturing time, and complex manufacturing process required for CAR T-cell therapy and replacing it with a mass-produced, off-the-shelf product, promises to expand access to effective cell-based cancer immunotherapy to many more patients who may benefit from it, Valamehr concluded.

Results from CARTITUDE-1 in R/R Multiple MyelomaPatients with multiple myeloma who had received a median of five prior therapies, and for whom standard-of-care treatments were no longer working, had a high response rate when treated with the investigational CAR T-cell therapy JNJ-68284528 (JNJ-4528), which targets BCMA, a protein commonly found on the surface of multiple myeloma cancer cells.

These patients participated in a clinical trials (NCT03548207), supported by Janssen Research & Development, designed to characterize safety of and establish the recommended Phase II dose (RP2D) (Phase Ib) and to evaluate the efficacy of JNJ-68284528 (Phase II).

We are seeing a high response rate, with most patients achieving MRD negativity, noted lead study author Deepu Madduri, MD, of The Tisch Cancer Institute at Mount Sinai in New York.

Considering these patients have all received multiple prior therapies, these results are extremely encouraging, Madduri added.

All evaluable patients receiving this CAR T-cell therapy have achieved MRD-negative disease state and 27 of 29 patients are progression free at a median follow-up of six months, Madduri said.

Multiple myeloma is a cancer of plasma cells, which are found in the bone marrow and are part of the immune system, the bodys defense system against infection. Typical signs and symptoms of multiple myeloma may be bone pain or fractures, high levels of calcium in the blood, kidney damage, and anemia. Multiple myeloma affects an estimated 160,000 people each year, occurs most often in people over 60. The disease is slightly more common in men than in women.

Although new therapies for multiple myeloma have recently become available that can extend patients life expectancy, a cure for the disease remains elusive.

We can get the disease into remission, but most patients unfortunately relapse, and outcomes are very poor for patients who have relapsed multiple times, she said.

Researchers explained that JNJ-4528 is a novel CAR T-cell therapy featuring two molecules that bind to BCMA, a protein found on the surface of multiple myeloma cells.

We are learning that every CAR T-cell therapy is different, Madduri said.

JNJ-4528 has a unique CAR T-cell composition in patients, preferentially enriched in CD8 T cells, which are believed to be one of the most important T cells in killing cancer cells, she noted.

This phase Ib/II trial is continuing to enroll patients.

During the 2019 annual meeting of the American Society of Hematology, Madduri reported results for the first 29 patients enrolled.

Patients T-cells were collected and sent to a laboratory where they were genetically engineered to express JNJ-4528. Prior to re-infusing these CAR T-cells, the patients received three days of chemotherapy to make room in their immune systems for the engineered T-cells.

Following chemotherapy, each patient received a single infusion of the JNJ-4528 CAR T-cells.

After a minimum of 28 days, these patients had blood and bone marrow exams, which was followed by exams at six months, and one year after treatment to assess their response. The primary aims of the trial are to assess the therapys safety and to confirm the dose to be tested in a larger, phase II trial.

The median follow-up time in the current analysis is six months. Overall, 100% of patients had a clinical response to JNJ-4528. Moreover, 66% had a stringent complete response, meaning that sensitive laboratory and microscopic tests found no evidence for myeloma proteins or cells in blood, urine, or bone marrow.

Most patients (93%) experienced some form of CRS. One patient had severe (grade 3) CRS, and one patient died from its complications 99 days after the CAR T-cell infusion. In 76% of patients, CRS was treated with tocilizumab.

To see some patients in this heavily pretreated population surviving for a year or more with a one-time treatment and a manageable safety profile is remarkable, Madduri explained.

These patients feel that they have their quality of life back. They no longer have to come into the clinic for weekly treatments and some are well enough to travel, Madduri concluded.

The phase II portion of this study is ongoing to evaluate the overall response rate of patients treated with JNJ-68284528 (JNJ-4528). Additional clinical studies are evaluating the safety and efficacy of JNJ-4528 in different multiple myeloma treatment settings.

BreakthroughEarlier this week the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for JNJ-68284528 (JNJ-4528).

The granting of Breakthrough Therapy Designation for JNJ-68284528 (JNJ-4528) is a significant milestone as we continue to accelerate the global development of this innovative CAR-T therapy in collaboration with Legend Biotech, noted Sen Zhuang, MD, Ph.D., Vice President, Oncology Clinical Development, Janssen Research & Development.

We look forward to continuing to work closely with the U.S. Food and Drug Administration to advance the clinical development program for JNJ-68284528 (JNJ-4528) and ultimately bring this BCMA-targeted immunotherapy to patients living with multiple myeloma who are in need of a new therapeutic option, Zhuang concluded.

Encouraging Results for Dual-Targeted CAR T-Cell TherapyMore than three out of four patients with multiple myeloma that returned or did not respond to at least two therapies remained in remission seven months after treatment with a novel CAR T-cell therapy targeting two proteins that are frequently found on myeloma cells.

Nine patients experiencing sustained remissions in this study, which ws supported by the National Natural Science Foundation of China, the Major Technological Innovation Special Project fund of Hubei Province of China, and Cellyan Therapeutics, were diagnosed with a difficult-to-treat form of multiple myeloma in which the disease has spread beyond the bone marrow.

Roughly one in 10 patients with multiple myeloma develop tumors in the organs or soft tissues such as the blood vessels, muscles, and nerves. These so-called extramedullary tumors respond poorly to treatment, and patients who develop them have a poor outlook and poor health related quality of life (hrQoL)

Our results show that this CAR T-cell product can effectively achieve elimination of extramedullary tumors, said study author Yu Hu, MD, Ph.D, of Union Hospital, Huazhong University of Science and Technology in Wuhan, China.

Although these are preliminary data, they are encouraging for patients with multiple myeloma who have not responded to other therapies, Hu added.

Hu and his colleagues are developing the first CAR T-cell therapy to be genetically engineered to target BCMA and CD38, two proteins found on the surface of plasma cells. Multiple myeloma is a cancer of plasma cells, which are found in the bone marrow and are part of the immune system, the bodys defense system against infection and disease.

Our thinking was that targeting both of these proteins would improve treatment efficacy without increasing toxicity, and induce deeper, more durable remissions, Hu noted.

The first-in-humans phase I trial enrolled 22 patients whose average age was 59, of whom 11 were men. All had multiple myeloma that had returned or not responded to at least three therapies. Nine of the 22 patients had extramedullary tumors. The study aims were to determine the safest and most effective dose of the CAR T-cell therapy as well as to initially evaluate its effectiveness.

Just like in other trials with CAR T-cell therapies, the participating patients received three days of chemotherapy to make room in their immune systems for the engineered T-cells. Then each patient was infused with the dual-targeted CAR T cells. Patients were divided into five groups, with each group receiving a higher dose than the previous one. Depending on the cell dose, patients received either one or two infusions.

At a median of 36 weeks of follow-up, 18 patients (90.9%) had MRD-negative disease. Twelve patients (54.5%) had a stringent complete response, meaning that no plasma cells were detected in the bone marrow. Seven patients (31.8%) had a good or very good partial response, meaning that the level of M-protein (an abnormal protein produced by cancerous plasma cells) in the blood or urine was reduced but still detectable. In eight of the nine patients with extramedullary lesions, these tumors were undetectable on their computed tomography scans. For the 17 patients who remained in remission at seven months after treatment, the median duration of response was 28.8 weeks.

The adverse events observed included 20 patients who experienced CRS, of whom six needed treatment. No serious adverse neurologic effects such as seizures, movement impairment, difficulty speaking or understanding speech, or fatal swelling in the brain were reported.

With this dual-targeted CAR T-cell therapy, we have demonstrated a high response rate, especially a higher rate and longer duration of stringent complete response, compared with other therapies, as well as effective elimination of extramedullary lesions, with no serious neurologic adverse effects and manageable levels of other adverse effects, Hu concluded.

The investigators continue to follow the patients for the next two years. They are also planning to conduct a phase II trial in both China and the United States to test the treatments effectiveness in a larger number of patients.

Clinical trialsA Study of JNJ-68284528, a Chimeric Antigen Receptor T Cell (CAR-T) Therapy Directed Against B-Cell Maturation Antigen (BCMA) in Participants With Relapsed or Refractory Multiple Myeloma (CARTITUDE-1) NCT03548207

References[1] Srivastava S, Riddell SR. Chimeric Antigen Receptor T Cell Therapy: Challenges to Bench-to-Bedside Efficacy. J Immunol. 2018;200(2):459468. doi:10.4049/jimmunol.1701155 [Abstract][2] Schuster SJ, Bartlett NL, Assouline S, Yoon SS, Bosch F, Sehn LH, Cheah CY, Shadman M, et al. Mosunetuzumab Induces Complete Remissions in Poor Prognosis Non-Hodgkin Lymphoma Patients, Including Those Who Are Resistant to or Relapsing After Chimeric Antigen Receptor T-Cell (CAR-T) Therapies, and Is Active in Treatment through Multiple Lines. 61st annual meeting of the American Society of Hematology. Program: General Sessions. Session: Plenary Scientific Session. Hematology Disease Topics & Pathways: antibodies, Follicular Lymphoma, CRS, Diseases, Biological, Therapies, neurotoxicity, Adverse Events, CAR-Ts, Non-Hodgkin Lymphoma, DLBCL, immunotherapy, Lymphoid Malignancies. [Abstract][3] Goodridge JP, Mahmood S, Zhu H, Gaidarova S, Blum R, Bjordahl R, Cichocki F, et al. FT596: Translation of First-of-Kind Multi-Antigen Targeted Off-the-Shelf CAR-NK Cell with Engineered Persistence for the Treatment of B Cell Malignancies. 61st annual meeting of the American Society of Hematology. Program: Oral and Poster Abstracts. Type: Oral. Session: 625. Lymphoma: Pre-ClinicalChemotherapy and Biologic Agents: Targeting Apoptosis Pathways in Lymphoma.[Abstract][4] Madduri D, Usmani SZ, Jagannath S, Singh I, Zudaire E, Yeh TM, Allred AJ, Banerjee A, et al. Results from CARTITUDE-1: A Phase 1b/2 Study of JNJ-4528, a CAR-T Cell Therapy Directed Against B-Cell Maturation Antigen (BCMA), in Patients with Relapsed and/or Refractory Multiple Myeloma (R/R MM). 61st annual meeting of the American Society of Hematology. Program: Oral and Poster Abstracts. Type: Oral Session: 653. Myeloma: Therapy, excluding Transplantation: Novelty in CAR T in Relapsed/Refractory Multiple Myeloma. [Abstract][5] Li C, Mei H, Hu Y, Guo T, Liu L, Jiang H, Tang L, Wu Y, et al. A Bispecific CAR-T Cell Therapy Targeting Bcma and CD38 for Relapsed/Refractory Multiple Myeloma: Updated Results from a Phase 1 Dose-Climbing Trial61st annual meeting of the American Society of Hematology. Program: Oral and Poster Abstracts. Type: Oral. Session: 653. Myeloma: Therapy, excluding Transplantation: Novel Therapy for Relapsed Myeloma. Hematology Disease Topics & Pathways: Biological, Diseases, Adult, Therapies, Lymphoma (any), Adverse Events, CAR-Ts, Elderly, Biological Processes, Technology and Procedures, Cell Lineage, Study Population, Clinically relevant, Lymphoid Malignancies.

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