Category Archives: Human Genetic Engineering

Casey Atkins for Nature

Aviv Regev likes to work at the edge of what is possible. In 2011, the computational biologist was collaborating with molecular geneticist Joshua Levin to test a handful of methods for sequencing RNA. The scientists were aiming to push the technologies to the brink of failure and see which performed the best. They processed samples with degraded RNA or vanishingly small amounts of the molecule. Eventually, Levin pointed out that they were sequencing less RNA than appears in a single cell.

To Regev, that sounded like an opportunity. The cell is the basic unit of life and she had long been looking for ways to explore how complex networks of genes operate in individual cells, how those networks can differ and, ultimately, how diverse cell populations work together. The answers to such questions would reveal, in essence, how complex organisms such as humans are built. So, we're like, 'OK, time to give it a try', she says. Regev and Levin, who both work at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, sequenced the RNA of 18 seemingly identical immune cells from mouse bone marrow, and found that some produced starkly different patterns of gene expression from the rest1. They were acting like two different cell subtypes.

That made Regev want to push even further: to use single-cell sequencing to understand how many different cell types there are in the human body, where they reside and what they do. Her lab has gone from looking at 18 cells at a time to sequencing RNA from hundreds of thousands and combining single-cell analyses with genome editing to see what happens when key regulatory genes are shut down.

The results are already widening the spectrum of known cell types identifying, for example, two new forms of retinal neuron2 and Regev is eager to find more. In late 2016, she helped to launch the International Human Cell Atlas, an ambitious effort to classify and map all of the estimated 37 trillion cells in the human body (see 'To build an atlas'). It is part of a growing interest in characterizing individual cells in many different ways, says Mathias Uhln, a microbiologist at the Royal Institute of Technology in Stockholm: I actually think it's one of the most important life-science projects in history, probably more important than the human genome.

Such broad involvement in ambitious projects is the norm for Regev, says Dana Pe'er, a computational biologist at Memorial Sloan Kettering Cancer Center in New York City, who has known Regev for 18 years. One of the things that makes Aviv special is her enormous bandwidth. I've never met a scientist who thinks so deeply and so innovatively on so many things.

When Regev was an undergraduate at Tel Aviv University in Israel, students had to pick a subject before beginning their studies. But she didn't want to decide. Too many things were interesting, she says. Instead, she chose an advanced interdisciplinary programme that would let her look at lots of subjects and skip a bachelor's degree, going straight to a master's.

A turning point in her undergraduate years came under the tutelage of evolutionary biologist Eva Jablonka. Jablonka has pushed a controversial view of evolution that involves epigenetic inheritance, and Regev says she admired her courage and integrity in the face of criticism. There are many easy paths that you can take, and it's always impressive to see people who choose alternative roads.

Jablonka's class involved solving complicated genetics problems, which Regev loved. She was drawn to the way in which genetics relies on abstract reasoning to reach fundamental scientific conclusions. I got hooked on biology very deeply as a result, she says. Genes became fascinating, but more so how they work with each other. And the first vehicle in which they work with each other is the cell.

Regev did a PhD in computational biology under Ehud Shapiro from the Weizmann Institute of Science in Rehovot, Israel. In 2003 she moved to Harvard University's Bauer Center for Genomics Research in Cambridge, through a unique programme that allows researchers to leapfrog the traditional postdoctoral fellowship and start their own lab. I had my own small group and was completely independent, she says. That allowed her to define her own research questions, and she focused on picking apart genetic networks by looking at the RNA molecules produced by genes in cells. In 2004, she applied this technique to tumours and found gene-expression patterns that were shared across wildly different types of cancer, as well as some that were more specific, such as a group of genes related to growth inhibition that is suppressed in acute lymphoblastic leukaemias3. By 2006, at the age of 35, she had established her lab at the Broad Institute and the Massachusetts Institute of Technology in Cambridge.

At Broad, Regev continued working on how to tease complex information out of RNA sequencing data. In 2009, she published a paper on a type of mouse immune cell called dendritic cells, revealing the gene networks that control how they respond to pathogens4. In 2011, she developed a method that could assemble a complete transcriptome5 all the RNA being transcribed from the genes in a sample without using a reference genome, important when an organism's genome has not been sequenced in any great depth.

It was around this time that Levin mentioned the prospect of sequencing the RNA inside a single cell. Up to that point, single-cell genomics had been almost impossible, because techniques weren't sensitive enough to detect the tiny amount of RNA or DNA inside just one cell. But that began to change around 2011.

The study with the 18 immune cells also dendritic cells was meant to test the method. I had kind of insisted that we do an experiment to prove that when we put the same cell types in, everything comes out the same, says Rahul Satija, Regev's postdoc at the time, who is now at the New York Genome Center in New York City. Instead, he found two very different groups of cell subtypes. Even within one of the groups, individual cells varied surprisingly in their expression of regulatory and immune genes. We saw so much in this one little snapshot, Regev recalls.

I think even right then, Aviv knew, says Satija. When we saw those results, they pointed the way forward to where all this was going to go. They could use the diversity revealed by single-cell genomics to uncover the true range of cell types in an organism, and find out how they were interacting with each other.

In standard genetic sequencing, DNA or RNA is extracted from a blend of many cells to produce an average read-out for the entire population. Regev compares this approach to a fruit smoothie. The colour and taste hint at what is in it, but a single blueberry, or even a dozen, can be easily masked by a carton of strawberries.

By contrast, single-cell-resolved data is like a fruit salad, Regev says. You can distinguish your blueberries from your blackberries from your raspberries from your pineapples and so on. That promised to expose a range of overlooked cellular variation. Using single-cell genomics to sequence a tumour, biologists could determine which genes were being expressed by malignant cells, which by non-malignant cells and which by blood vessels or immune cells potentially pointing to better ways to attack the cancer.

The technique holds promise for drug development in many diseases. Knowing which genes a potential drug affects is more useful if there's a way to comprehensively check which cells are actively expressing the gene.

Regev was not the only one becoming enamoured with single-cell analyses on a grand scale. Since at least 2012, scientists have been toying with the idea of mapping all human cell types using these techniques. The idea independently arose in several areas of the world at the same time, says Stephen Quake, a bioengineer at Stanford University in California who co-leads the Chan Zuckerberg Biohub. The Biohub, which has been funding various biomedical research projects since September 2016, includes its own cell-atlas project.

Around 2014, Regev started giving talks and workshops on cell mapping. Sarah Teichmann, head of cellular genetics at the Wellcome Trust Sanger Institute in Hinxton, UK, heard about Regev's interest and last year asked her whether she would like to collaborate on building an international human cell atlas project. It would include not just genomics researchers, but also experts in the physiology of various tissues and organ systems.

I would get stressed out of this world, but she doesn't.

Regev leapt at the chance, and she and Teichmann are now co-leaders of the Human Cell Atlas. The idea is to sequence the RNA of every kind of cell in the body, to use those gene-expression profiles to classify cells into types and identify new ones, and to map how all those cells and their molecules are spatially organized.

The project also aims to discover and characterize all the possible cell states in the human body mature and immature, exhausted and fully functioning which will require much more sequencing. Scientists have assumed that there are about 300 major cell types, but Regev suspects that there are many more states and subtypes to explore. The retina alone seems to contain more than 100 subtypes of neuron, Regev says. Currently, consortium members whose labs are already working on immune cells, liver and tumours are coming together to coordinate efforts on these tissues and organs. This is really early days, says Teichmann.

In co-coordinating the Human Cell Atlas project, Regev has wrangled a committee of 28 people from 5 continents and helped to organize meetings for more than 500 scientists. I would get stressed out of this world, but she doesn't, Jablonka says. It's fun to have a vision that's shared with others, Regev says, simply.

It has been unclear how the project would find funding for all its ambitions. But in June, the Chan Zuckerberg Initiative the philanthropic organization in Palo Alto, California, that funds the Biohub contributed an undisclosed amount of money and software-engineering support to the Human Cell Atlas data platform, which will be used to store, analyse and browse project data. Teichmann sees the need for data curation as a key reason to focus on a large, centralized effort instead of many smaller ones. The computational part is at the heart of the project, she says. Uniform data processing, data browsing and so on: that's a clear benefit.

In April, the Chan Zuckerberg Initiative had also accepted applications for one-year pilot projects to test and develop technologies and experimental procedures for the Human Cell Atlas; it is expected to announce which projects it has selected for funding some time soon. The applications were open to everyone, not just scientists who have participated in planning meetings.

Some scientists worry that the atlas will drain both funding and effort from other creative endeavours a critique aimed at many such international big-science projects. There's this tension, says Atray Dixit, a PhD student in Regev's lab. We know they're going to give us something, and they're kind of low-risk in that sense. But they're really expensive. How do we balance that?

Developmental biologist Azim Surani at the University of Cambridge, UK, is not sure that the project will adeptly balance quantity and depth of information. With the Human Cell Atlas, you would have a broad picture rather than a deeper understanding of what the different cell types are and the relationships between them, he says. What is the pain-to-gain ratio here?

Surani also wonders whether single-cell genomics is ready to converge on one big project. Has the technology reached maturity so that you're making the best use of it? he asks. For example, tissue desegregation extracting single cells from tissue without getting a biased sample or damaging the RNA inside is still very difficult, and it might be better for the field, some say, if many groups were to go off in their own directions to find the best solution to this and other technical challenges.

And there are concerns that the project is practically limitless in scope. The definition of a cell type is not very clear, says Uhln, who is director of the Human Protein Atlas an effort to catalogue proteins in normal and cancerous human cells that has been running since 2003. There may be a nearly infinite number of cell types to characterize. Uhln says that the Human Cell Atlas is important and exciting, but adds: We need to be very clear, what is the endpoint?

Regev argues that completion is not the only goal. It's modular: you can break this to pieces, she says. Even if you solve a part of a problem, it's still a meaningful solution. Even if the project just catalogues all the cells in the retina, for example, that's still useful for drug development, she argues. It lends itself to something that can unfold over time.

Regev's focus on the Human Cell Atlas has not distracted her from her more detailed studies of specific cell types. Last December, her group was one of three to publish papers6, 7, 8 in which they used the precision gene-editing tool CRISPRCas9 to turn off transcription factors and other regulatory genes in large batches of cells, and then used single-cell RNA sequencing to observe the effects. Regev's lab calls its technique Perturb-seq6.

The aim is to unpick genetic pathways very precisely, on a much larger scale than has been possible before, by switching off one or more genes in each cell, then assaying how they influence every other gene. This was possible before, for a handful of genes at a time, but Perturb-seq can work on 1,000 or even 10,000 genes at once. The results can reveal how genes regulate each other; they can also show the combined effects of activating or deactivating multiple genes at once, which can't be predicted from each of the genes alone.

Dixit, a co-first author on the paper, says Regev is indefatigable. She held daily project meetings at 6 a.m. in the weeks leading up to the submission. I put in this joke sentence at the end of the supplementary methods a bunch of alliteration just to see if anyone would read that far. She found it, Dixit says. It was 3 a.m. the night before we submitted.

Regev's intensity and focus is accompanied by relentless positivity. I'm one of the fortunate people who love what they do, she says. And she still loves cells. No matter how you look at them, they're just absolutely amazing things.

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How to build a human cell atlas - Nature.com

On a hill above the cold waters around Prince Edward Island, technicians painstakingly create fertilized Atlantic salmon eggs that include growth-enhancing DNA from two other fish species. The eggs will be shipped to tanks in the high rainforest of Panama, where they will produce fish that mature far more quickly than normal farmed salmon.

More than 20 years after first seeking approval from the USFood and Drug Administration, AquaBounty Technologies of Maynard, Massachusetts, plans to bring these AquAdvantage fish to the USand Canadian markets next year. And in the small village of Albany, Indiana, workers will soon begin converting a land-based aquaculture facility to produce about 1,300 UStonsof these salmon annually, in the first USfacility to generate GE animals for human consumption.

The company also plans to open a second aquaculture facility at Prince Edward Island if it can can rise above its latest round of legal battles and persuade grocery stores and restaurants to snap up the genetically engineered fish.

Before the FDA cleared the salmon for consumption in 2015, in its first approval of GE animal protein as human food, it received 1.8 million messages opposing these fish. Perhaps more substantively, many outside researchers remain concerned about AquaBountys plans.

Aquaculture specialists generally arent skeptical about whether the fish will be healthy to eat, although thats one issue hinted at in a lawsuit multiple organizations, including Friends of the Earth, have filed against the FDA.

Dana Perls, senior food and technology campaigner with Friends of the Earth in Berkeley, California, says the FDA didnt fully examine questions about eating the salmon initially raised by Health Canada, that countrys public health department including susceptibility to disease and potential allergic reactions.

This is a poorly studied, risky and unlabeled genetically engineered fish, she says, adding that more than 80 USgrocery chains havecommitted not to buy it.

However, Health Canada eventually concluded that fillets derived from AquAdvantage salmon are as safe and nutritious as fillets from current available farmed Atlantic salmon, and approved the fish for consumption in 2016.

Theres no reason to suspect these fish from a food safety perspective, says Cyr Couturier, chair of aquaculture programs at Memorial Universitys Marine Institute in St. Johns, Newfoundland. They have no unnatural products that humans wouldnt otherwise consume.

Similar transgenic salmon created by a decades-long Fisheries and Oceans Canada research program tested well within normal salmon variations, adds Robert Devlin, engineering research scientist at the agency in North Vancouver, British Columbia.

But critics do raise two other main concerns about AquaBountys quest: the economic sustainability of the land-based approach, and the environmental risk to ecosystems if the fish escape.

AquaBounty will raise its GE fish in land-based recirculating aquaculture systems, known as RAS basically huge aquaria designed to minimize water use, maximize resources and accommodate high stocking densities.

While farming salmon in sea cages is less expensive and less technologically complex than a land-based farm, the companys website points out, sea cages are susceptible to a number of hazards such as violent storms, predators, harmful algal blooms, jellyfish attacks, fish escapes, and the transmission of pathogens and parasites from wild fish populations.

Given the potential opportunity to achieve greater production control and avoid some of the environmental concerns of sea farms, many RAS projects have launched around the world in the past decade. However, most of these projects are small, and many have failed or are struggling.

The big problem is cost. RAS facilities need much more capital than ocean farms with similar production rates, and theyre expensive to operate.

Land-based systems use a lot of freshwater, even though its recirculated, and a lot of electricity, notes Couturier. Such systems operate at an economic disadvantage because much of their cost goes toward creating growing conditions occurring naturally within the ocean, summed up one 2014 report that found producing Atlantic salmon in Nova Scotia would not be economically feasible.

AquaBounty, which is buying its Indiana plant from a collapsed RAS venture, expects to beat these odds mainly because its GE salmon reach market size in about half the time of normal farmed salmon in 1618 months rather than 2836 months, the company says. Ravenous as they are, with their growth hormones continually wired on, the fish still require about a quarter less feed than normal fish. (Although farmed salmon are very efficient at converting food to flesh a pound of feed converts to close to a pound of flesh feed remains a major expense.)

The company also says that salmon in its RAS facilities wont need vaccines or antibiotics because it will tightly control conditions. However, they will have some disease issues of course, as will any animal thats reared in high densities, Couturier predicts.

If AquaBounty can compete on cost, there will be some justification for promoting its product as the worlds most sustainable salmon. In addition to requiring less feed, growing fish in Indiana or Prince Edward Island can slash the high carbon costs of flying fish from Norway or Chile, two leading suppliers of farmed salmon in the US.

Still, says Couturier, I wish them all the best, but I think it will be a small-scale niche for at least a decade.

Many aquaculture scientists remain uneasy about the environmental risk to wild ecosystems if transgenic fish slip out of their farms.

Although other agencies will presumably be involved in assessing risk as the projects advance, the FDA has no in-house capacity to evaluate or understand the ecological consequences of transgenics in an aquatic ecosystem, says Conner Bailey, professor emeritus of rural sociology at Auburn University in Alabama. And once you get anything into an aquatic ecosystem, its really hard to control.

AquaBountys protection scheme begins with multiple levels of physical barriers in its RAS facilities. Additionally, the salmon are all female and triploid (their DNA is in three rather than two sets of chromosomes) so they cant reproduce. However, scientists say neither of these measures can be 100 percent effective at preventing transgenic fish from escaping, disrupting local ecosystems and potentially breeding in the wild.

More generally, while AquaBounty is committed to land-based systems, there are concerns that its also creating far more GE eggs than it needs for its own production. Other industry groups, such as the Atlantic Salmon Federation, worry that other producers AquaBounty sells to might not be so careful, or that other companies around the world might move ahead with similar projects but without the same precautions. And all bets on risk are off if GE fish are raised in the ocean, where fish routinely escape, sometimes in large numbers.

Devlins group has extensively modeled the results of accidental releases, studying groups of transgenic and non-transgenic fish in naturalized aquatic test beds that are exposed to variations in conditions, such as food supply. Transgenic fish often behave quite differently, and the results have varied from peaceful coexistence to one experiment in which fully transgenic fish killed off all their competitors.

In the multitude of different environments that exist in nature, the uncertainty is too great to make a reliable prediction of what the impact would be, he says.

Does the fast growth of AquAdvantage salmon justify taking on these unknown risks?

Scientists point out that todays selective breeding research programs, built on genomics and other tools of modern biology, also have turbocharged fish development. Some strains of rainbow trout, which have been selected for fast growth for 150 years, grow incredibly fast compared to wild-type fish, Devlin says. In fact, he says, his lab work across various species suggests that the absolute fastest growth you can achieve either by domestication or by transgenesis seems to be very similar.

Todays farmed salmon have had more than 10 generations of selection applied to them, and they are growing at more than double the rate compared to the 1970s, says Bjarne Gjerde, senior scientist at Nofima in Troms, Norway.

Farmed fish also must excel in many traits besides growth, such as disease resistance and food quality, he emphasizes. Most of the traits we are breeding for are governed by many, many genes with small effects, he says. Thats a real challenge if you just want to take short cuts with genetic engineering.

When and if AquaBounty rises above all its challenges into a groundbreaking success in North America, the firm will send a signal around the world to unleash efforts for commercializing GE fish, observers say.

Friends of the Earths Perls remains hopeful that legal barriers and consumer boycotts will stop AquaBounty in its tracks. If not, GE salmon could set a precedent to the approval of other GE animals in the pipeline, from fish to chickens, pigs and cows, she says. It is critical that we dont approve other GE animals without robust regulations and full environmental reviews to ensure that were prioritizing human and environmental safety over profit.

Fish are probably where transgenic animals will emerge, because its much cheaper to maintain a herd of catfish or salmon than cattle or sheep or pigs, says Bailey.

This story was first published by Ensia, an environmental news magazine from the University of Minnesota.

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After decades of work, Americans may soon be eating genetically engineered salmon - PRI

We long to transcend the human condition

baona/Getty

By Joanna Kavenna

Death, be not proud, though some have called thee

Mighty and dreadful, for thou art not so;

For those whom thou thinkst thou dost overthrow

Die not, poor Death, nor yet canst thou kill me.

Here we are discussing transhumanism, defined by evolutionary biologist Julian Huxley in 1957 as the belief that the human species can and should transcend itself by realizing new possibilities of and for human nature. What relevance could the poet John Donne have to such a discussion?

A more recent explanation of transhumanism, by Oxford University philosopher Nick Bostrom, calls it a loosely defined movement that has developed gradually over the past two decades Attention is given to both present technologies, like genetic engineering and information technology, and anticipated future ones, such as molecular nanotechnology and artificial intelligence. This formulation resembles the poetry of English clerics even less than Huxleys did.

But though Bostrom does not express himself in quite the same fashion as Donne, the overarching sentiment is not dissimilar: Death, thou shalt die, or at least thou shalt be postponed as far as possible. Bostrom continues: Transhumanists view human nature as a work-in-progress, a half-baked beginning that we can learn to remold in desirable ways.

In other words, before death postponed or otherwise, life might be made considerably nicer: less fraught with disease and suffering, and altogether less half-baked. This is a metaphor from cooking, and transhumanist rhetoric is awash with such, at times treacherous, metaphors.

Transhumanists hope that by responsible use of science, technology, and other rational means we shall eventually manage to become posthuman, beings with vastly greater capacities than present human beings have. Bostroms lovely sentiment that the half-baked human must be improved by the responsible use of science has driven humanity for millennia, ever since we began using technologies of flint and fire and so on, and through innumerable and utterly vital developments in medicine and science. So one key question that we must pose and seek to discuss is how, specifically, the transhumanist movement will depart from or further enhance this consistent strain in human history?

Transhumanisms signature ambition, that we may become posthuman, leads us to a baroque and venerable question: what does it mean to be human, anyway? If we want to go beyond something, to transcend it, it is clear we must understand our starting point, the point beyond which we desire to go. The quest to fathom the self, to understand what it means to be human, is fundamental to almost every civilisation known to us. It defines one of the earliest works of literature, the Epic of Gilgamesh from ancient Mesopotamia, in which our protagonist embarks on a quest to understand who on earth he is and what hes meant to do with his mortal span of years. In ancient religious texts such as the Upanishads, all creation begins with the moment of becoming: I am! That is, the world comes from mind itself.

In many global religions, the human self is divided into body and soul, a material and an immaterial part. During the Enlightenment, Descartes famously tried to reconcile this ancient distinction and also placate the church by proposing that the material and immaterial somehow communicated or mingled via the pineal gland.

Skipping boldly through a few centuries of thought, we might arrive (blinking in surprise) at the philosophical novels of Philip K. Dick and his brilliant Do Androids Dream of Electric Sheep? This poses the ancient question again: what does it mean to be human? When is someone/something convincingly human and when are they not? Is your version of being human the same as mine? Or the same as the next humans?

As the Australian philosopher David Chalmers has said, consciousness this mysterious thing that every human possesses or feels they possess remains the hard problem of philosophy. We lack a unified theory of consciousness. We dont understand how consciousness is generated by the brain, or even whether this is the right metaphor to use. We speak of such mysteries in a funny system of squeaks and murmurs that we call language and that swiftly drops into the blackness of prehistory when we seek to trace its origins. We dont know who the first humans were: that fascinating quest likewise drives us straight into a great void of unknowing.

There is nothing wrong with unknowing: it is the ordinary condition of all humanity, so far. Yet, undeterred, we devise bold, elegant theories and advance them in many disciplines of thought. We develop beautiful and exciting almost-human machines and speculate about uploading consciousness. And in so doing, we are consistently rebaking, reheating or refrying the ancient philosophical dilemma: what does it mean to be human?

Pace Bostrom, transhumanism has not developed over the past few decades. Its predilections and concerns have developed over several millennia, and possibly further back, within civilisations we no longer recall. To go back in time to Ecclesiastes, there is nothing new under the sun. We are still here, and human, with our paradoxical longing to transcend the human condition.

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Who do we think we are? - New Scientist

A new study by Transparency Market Research indicates that the degree of competitive rivalry in genome engineering rivalry market is likely to remain moderate over the forecast period owing to the presence of a limited number of international and regional players. Sigma-Aldrich Corporation, Thermo Fisher Scientific Inc., and Sangamo Biosciences Inc. are among the prominent revenue contributors to the market. The entry of small regional players in the arena is prompting global players to pay high attention to product innovation.

To develop innovative, technologically advanced and differentiated products, the leading companies are banking on agreements with laboratories and research institutes and pouring funds into ongoing research and development projects, says the author of the report. The global market for Genome Engineering is anticipated to reach a valuation of US$7.21 bn by 2023 from US$2.30 bn in 2015, expanding at a remarkable CAGR of 14.2% from 2015 to 2023.

North America to Remain Ahead through 2023, thanks to Upswing in Research and Development Activities

By end user, the market will be dominated by the biotechnology and pharmaceutical companies throughout the forecast period. The growth of the segment can be attributed to the rising use of genome engineering technologies in drug discovery and therapeutics. North America will continue to be the frontrunner in the global arena until 2023, rising to a valuation of US$3.68 bn. The widening applications of genome engineering resulting from the increasing research and development activities are contributing to the growth of the region. Asia Pacific will be the most promising regional market, thanks to the increasing government incentives.

Increasing Funding by Biotechnology and Pharmaceutical Organizations to Augment Genome Engineering Market

Pharmaceutical and biotechnology companies worldwide are increasingly realizing the need for advanced gene editing technologies for detecting genetic anomalies. As a result, the number of research and development activities is rising at a significant pace. Large organizations are focusing towards cell mutation to curb genetic and cell diseases. To encourage the development of technologies relating to gene editing, pharmaceutical companies are either funding ongoing projects of medical firms or entering into a collaboration with them, says a TMR analyst. Therefore, the increasing research and development activities in the field of gene editing is paving for genome engineered techniques.

The growing investments by governments and non-government organizations in genome research and technological advancements along with the funding by pharmaceutical and biotechnology are providing a fillip to the global genome engineering market.

Rising Opposition on Ethical Grounds to Hamper Growth Prospects

Over the past few years, genetic engineering has received a lot of opposition on ethical grounds from several health, social, and religious organizations. According to the U.S. National Institute of Health (NIH), genetic engineering of human embryos leads to complications in human genes and has, therefore, prohibited its funding. In addition, various social organizations are persistent about the ban of genetic engineering as the alteration in animal genes can adversely affect the genetic makeup of the coming generations of the animal along with hampering the lifespan of the genetically engineered animal.

Along with the rising ethical concerns, the stringent regulatory framework for the approval of genetic modifications in plants, animals, and human genome are acting as a major bottleneck in the growth of the global genome engineering market. Nevertheless, the growing adoption of genome engineering technologies in agriculture for crop improvement is opening new avenues for players in the market.

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Genome Engineering Market: Leading Players Need to Focus on Product Innovation to Maintain their Prominence - Edition Truth

Research published in the journal Nature has analysed the DNA of 10,503 Pakistanis who were participating in a Pakistan Risk of Myocardial Infarction Study (PROMIS) and discovered 1,317 disabled or knocked-out genes.

People who are natural knockouts, that is, they were born missing one or more genes without any obvious medical problems are few and far between.

Humans inherit two copies of every gene one from the mother and one from the father.

If one copy is damaged or inactivated, then the presence of the other fully functional copy may help alleviate most problems.

However, if the parents are biologically related, then the chances of inheriting two inactivated copies are much higher.

The person with two inactivated copies may not have the functioning protein at all and will be a natural knockout for that specific gene.

The high number of human knockouts found in the country is due to the cultural tradition of cousin marriages that is prevalent here.

A search for human knockouts has also been conducted in other countries including Iceland and the United Kingdom.

In order to study what a particular gene does, scientists have traditionally made use of genetic engineering to breed mice with a mutation in that gene (as this type of experimentation is not possible with humans).

Once they have discovered what the gene does, it is possible to make new drugs that can either block a gene if it is harmful or enhance its positive functions if it turns out to be useful.

However, while such research is informative, evidence from studies in animal knockouts often does not hold for humans.

This is explained by a substantial number of failures seen in recent clinical trials that tested new drugs for the prevention of coronary heart disease.

Read more: The Tech Healthcare Revolution Pakistan Needs

Studies in human knockouts can provide data regarding whether natural inhibition of a given pathway is useful or not, says Dr. Danish Saleheen, lead author and principal investigator of the study published in Nature.

This evidence could be translated to develop new drugs, and prioritise or deprioritise existing drug programs.

Some knocked-out genes protect against disease.

Absence of the gene ALOX5 protects against stress-induced memory deficits, synaptic dysfunction and tauopathy which can help prevent Alzheimers disease or lower its progression.

The discovery of a human PCSK9 knockout who had astonishingly low levels of LDL cholesterol and up to 90 per cent less chances of getting a heart attack has resulted in the development of a new class of drugs that could prevent heart disease.

The Nature research study discovered that individuals without the gene APOC3 were protected against coronary heart disease.

The protein Apo-CIII is encoded by the APOC3 gene and inhibits hepatic uptake of fats called triglycerides.

The team was able to study a family of Pakistanis missing both copies of the APOC3 gene.

The human knockouts were given an oral fat load in the form of a milkshake.

When compared to other family members who had the gene, individuals with an absence of APOC3 didnt get a significant postprandial rise in their blood fat levels and were perfectly healthy.

This showed the human knockouts had little artery-clogging fat in their body and had a considerably lower risk of getting a heart attack.

So the research team was able to reason that ApoC-IIIblocking drugs that are currently in clinical trials could be beneficial in preventing heart disease.

The team was only able to make this discovery after identifying an entire family of natural knockouts for APOC3 in Pakistan.

They had been searching for the past four years for someone who was missing both copies of the gene but hadnt found a single person in the United States and Europe.

It was only in Pakistan that they were able to discover a family with both parents and nine children all of whom were missing the gene.

Read more: Is a permanent cure for diabetes on the cards?

This Pakistani research study is reportedly the first time where the knockouts found have been tested and their blood biomarkers like cholesterol have been studied to discover more about their health.

As part of this study, knockouts have been found that have not been seen anywhere else in the world.

This includes knockouts for NRG4, A3GALT2 and CYP2F1 among others.

In addition, the study found 734 genes where both copies were affected by predicted loss-of-function mutations (double knock-outs) which had never been described before.

This cohort of individuals provides a great opportunity for further study and more extensive phenotyping, says Dr. James Peters, Clinical Research Fellow at the British Heart Foundation.

A particular strength of this study is that individuals with a specific mutation can be contacted and brought back for further detailed measurements, he adds.

However, some geneticists caution that drugs made from this kind of genetic analysis might not be effective.

In an article, geneticist Stephen Rich from the University of Virginia in Charlottesville says that inhibiting ApoC-III late in life may not mimic being born with an APOC3 mutation, which protects for a lifetime.

The research team is now calling for a human knockout project to make one complete database for all the information coming from new genetics studies.

The project would make it possible to systematically conduct deep phenotyping studies on human knockouts and learn more about the natural deletion of those genes in humans.

In the future, the team plans on testing the genomes of 200,000 participants from Pakistan to find knockouts of approximately 8,000 genes.

Such studies provide unprecedented opportunities to understand the function of genes and provide important insights into the development of drugs, says Dr. Saleheen.

This research study was the result of an international collaboration between scientists from Pakistan, the United Kingdom and the United States.

This story originally appeared on MIT Tech Review Pakistan and has been reproduced with permission.

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Study finds 1317 knocked-out genes in DNA samples from Pakistanis - DAWN.com

In BriefCRISPR technology is transforming biomedical research and isat the heart of numerous recent discoveries but if no one can payfor treatments it produces, how will we make use of it? Expertshave a range of ideas to solve this knotty problem. Paying For Cures

CRISPR, a gene editing tool, is at the heart of numerous new medical treatments and technologies. Some of the incredible uses of CRISPR weve seen in the past year alone include editing phagesto kill antibiotic-resistant bacteria; targeting cancers command centerin mice, boosting survival rates from 0 to 100 percent; repairing the gene defects that cause sickle cell disease; and copying the T-cells of naturally HIV-immune individuals.

However, even as CRISPR moves toward clinical trials and practical use, its future remains unclear. This is due to the extreme cost of CRISPR treatments; most people simply cannot afford them, and whether insurance carriers will pay the tab is uncertain. Some insurance companies have already implemented no coverage policies for gene therapies; the American healthcare system is ever-changing, and its seeming increasingly likely that these extremely expensive therapies might be out of reach even for people with insurance.

StatNews reports that oncologist and author Dr. Siddhartha Mukherjee, who wrote the bestseller Emperor of All Maladies, told the American Society of Clinical Oncology in spring that the world would soon be divided into the rich who can afford personalized cancer treatment and the poor who cannot. The case of Glybera, a gene therapy infamously called the most expensive drug in the world, adds more credence to this concern. At a whopping $1.4 million per patient, Glybera was sold only once in Germany, abandoned in the EU, and never came to the US market due to its cost.

Much of the issue arises as we try to treat and cure rare diseases, which the United States defines as diseases that affect fewer than 200,000 people and the European Union defines as one that affects fewer than 1 in 2,000 people. However, cumulatively, rare diseases effect an estimated 25 to 30 million Americans, and there could be up to7,000 rare diseases.

The tension comes at the nexus between multiple market forces: drug companies who want to invest in research and profit from their investment; insurance companies who must maximize profit for shareholders while insuring as many people as possible; governments and leaders with different policies about intervention into the system; scientists who may have independent interest in conducting research but must find a way to fund it; and patients (some with insurance, some without) who are interested or, in some cases, desperate for treatments and cures. How to relieve the tension and allow science to progress in the best way for the most people is a difficult question, but various experts have ideas.

University of Alberta law and policy expert Tania Bubela suggests toStatNews that insurers should be allowed to reimburse drug companies for gene therapies before they receive FDA approval, requiring them to amass more data before increasing drug costs to full price. Another partial solution might be to grant CRISPR licenses one gene at a time rather than issuing exclusive patents on tools like CRISPR. Other creative intellectual property strategies have been proposed by the Rare Genomics Institute. Pediatric oncologist Stuart Orkin and Phillip Reilly, a Third Rock Ventures partner, along with FDA commissioner Scott Gottlieb, advocate for spreading insurer payments to companies out over years of time contingent upon the drugs continued performance, a sort of annuities structure; this would recognize the value in paying for even expensive drugs rather than years of care and treatment for expensive diseases.

Some form of government intervention is probably inevitable, according to most experts. The US Orphan Drug Act, for example, facilitates the development of treatments and drugs for rare diseases; Orkin and Reilly argue that funds from the Act could pay for gene therapies. The 2009 Biologics Price Competition and Innovation Act made generic biologics, called biosimilars, possible. However, generic forms of CRISPR are not likely to come for decades. Where does this leave us?

StatNews writer Jim Kozubek frames the ultimate issue, suggesting two possible outcomes. One of two things will happen: either we will embrace a national health care system with broad access but that severely limits expensive new drugs, gene therapies, and CRISPR-based biologics; or these treatments will be available to only the wealthiest among us who can pay for them, a dystopian vision which is perverse but perhaps more realistic considering the pressures for a return on investment.

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Is Getting Genetically Engineered a Human Right? - Futurism