Category Archives: Human Genetic Engineering

Understand biology and engineer biology. These are the goals of synthetic biology in brief. Due to the developments in sequencing and DNA synthesis, scientists can construct genetic constructs and edit genomes. These tools answer basic research questions and provide biological applications. But synthetic biology can never reach its full potential until artificial genome writing becomes commonplace.

Chromosomes are the hard drives of cells. They contain most of the cells DNA and genes. Bacteria and archaea typically have a single circular chromosome, while eukaryotes contain several linear ones. Besides genetic information, a chromosome contains structural elements. Centromers (that participate in mitosis), telomers (that have a role in maintaining linear chromosome integrity), and origins of replication (that are where DNA replication starts in circular DNA pieces) are some well-known examples.

Artificial chromosomes are chromosomes that have been fully constructed in the lab and assembled within a cell. An important note: artificial chromosomes do not mean artificial life. They function normally within cells and the DNA used is the same as the one found in nature. What is different is their origin they dont come from a DNA template duplication and the genetic information they carry.

The advantages of building a chromosome align with both goals of synthetic biology. The role of many DNA elements is unknown. By recombining, adding, or deleting DNA sequences, we can understand if a genetic part is essential and what does it do. By rewriting a genome from scratch, we can obtain a cell with specific properties and only them! Such cells are invaluable tools for applied and fundamental research.

Current DNA technology makes the construction of short DNA pieces easy and available to most research labs, but the same cannot be said for chromosome assembly. And this is not surprising: a plasmid with a few genes contains a few thousand base pairs; a chromosome several million or billion! As a result, there are very few reported artificial chromosomes reported. The emblematic Yeast 2.0 consortium reported the construction and assembly of six of the yeasts chromosomes. A research group from Switzerland designed and assembled a full bacterial chromosome with its genome minimized to the essential components; so far, they havent managed to insert the chromosome to the organism. A minimal bacterial cell with a synthetic genome was nevertheless announced in 2016 by J. Craig Venter Institute scientists. And recently the molecular biology workhorse, the bacterium E. coli, got its genome replaced by a synthetic variant.

All these works required a huge amount of resources and faced tremendous challenges. And despite the successes, we are a long way from mastering the craft of genome writing. In a recent article, Nili Ostrov and her collaborators in the field of synthetic genomics outline the technological advances needed to reach this goal. They list the following areas of focus: genome design, DNA synthesis, genome editing, and chromosome assembly.

Designing the synthetic chromosome is the first step of a construction workflow. And this step is probably the most critical, as an error there will condemn the whole effort into failure. The information hidden into a genome is too vast to be handled manually. This requires computer aided design tools, which are currently under development. These tools should also predict the effect of alterations in the sequence. Ideally, design software should model how a cell will behave when the synthetic genome replaces its native one.

Chemical DNA synthesis can provide DNA oligos a few hundred base pairs long. This is simply not good enough for chromosome synthesis. DNA synthesis will need to reach the scale of several thousand base pairs, decrease its error rate. And the assembly workflows should minimize the need of iterative cloning steps.

Genome editing is the key to generate many synthetic genome variants. Constructing a chromosome de novo will always be laborious. Genome editing will reduce the need of reconstructing from scratch when we need to insert a few (say, a few thousand) mutations to mimic a certain phenotype. Multiplex genome editing already exists. But instead of 20-50 edits, the techniques should allow for many thousand.

The last step of chromosome writing is the assembly of the final construct. Throwing the smaller DNA parts inside a bakers yeast cell and use its DNA repair system to stitch them up is how its currently done, and it works well. However, the yeast has limitations on what kind of DNA sequences it can work with. For a bigger variety of constructs, we will need more hosts and transformation methods.

Genome writing will accelerate the synthetic biology and genetic engineering applications. In medicine, engineered cells could become accurate disease models, increasing therapeutic efficiency and reducing the need for animal testing. In agriculture, plant cells with engineered genome or plastome can guide breeding and editing efforts to increase productivity and crop robustness. In metabolic engineering, cells will produce compounds optimally. And if we want to adapt organisms for life beyond earths boundaries, chromosome editing will let us test radical redesigns and insert novel properties.

Ostrov and collaborators write that many of the technological breakthroughs can be achieved within the next years. It sounds a bit optimistic, but lets hope we will be pleasantly surprised. Chromosome engineering has the potential to benefit all humankind, but we should be careful to not overhype the potential and promise things we cant deliver. And as the authors say and I couldnt agree more we have to be transparent, ethical, and share the advances globally.

Kostas Vavitsas, PhD, is a Senior Research Associate at the University of Athens, Greece. He is also community editor for PLOS Synbio and steering committee member of EUSynBioS. Follow him on Twitter @konvavitsas

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For synthetic biology to reach its potential, building new chromosomes from scratch must become commonplaceand we may be getting close - Genetic...

An open letter signed by more than 150 New Zealanders under 30 who specialise in biological or environmental science says the current law hinders efforts to tackle the climate crisis, and urges the Greens to change their position and take a lead on reform.

A group of more than 150 young New Zealand scientists has laid down a challenge to the Green Party to revisit its position on genetic modification.

In an open letter, the signatories urge Green Party members and MPs to take a lead in overhauling strict legislation, enacted 16 years ago, that regulates GM research. To do so is urgent, they argue, in light of the climate crisis.

Climate change is one of the greatest crises in human history, and our current law severely restricts the development of technologies that could make a vital difference, reads the letter.

GM based study in New Zealand was bridled by one of the toughest regulatory environments in the world for this field of research, they write. We believe that GM based research could be decisive in our efforts to reduce New Zealand and global climate emissions as well as partially mitigating some of the impacts of climate change.

The letter read it in full here is signed 155 people under 30 who either have or are studying for a PhD or Masters degree in biological or environmental science. It pokes a stick at a potential hornets nest for the Green Party, pitching members who are staunchly opposed to genetic engineering against the more resolutely evidence-based camp keen to see science deployed in the fight against climate change.

The Greens had been targeted, according to the open letter, because of a history of leading in science based policy such as climate action, even when that path is difficult.

Responding to the letter, the Greens spokesperson for science and technology, Gareth Hughes, said: Were comfortable with keeping GE in the lab but were always open to a facts-based public conversation about GE.

Green Party policy calls for keeping genetic research organisms completely contained in a secure indoor laboratory and prohibiting genetically modified and transgenic organisms that are intended for release into the environment or food chain.

The signatories say that the existing 2003 law is a handbrake on GM related research in areas including agricultural efficiency, carbon capture, and the production of alternative proteins.

The existing regulation in New Zealand inhibits application of advances such as these, blocking not only the development of green technology, but the potential for a just transition away from extractive and polluting industries. New Zealand has the opportunity to be a world leader in such a transition: for example, the development and demonstration of effective technologies to reduce agricultural emissions could have an international impact and set an example for other countries.

The letter notes that among those calling for a public discussion around reforms to genetic modification laws are the expert panel on gene editing set up by the Royal Society Te Aprangi, which reported back in August, the prime ministers chief science advisor, and the interim climate change committee.

The Greens have been strong advocates of both climate action and evidence based policy informed by science, concludes the letter.

In this light we call upon its members, supporters, ministers, and MPs to add their voices to the cause of a science-based approach to climate, on behalf of the people and environment of both Aotearoa and the world.

Approached for comment, the Green Party leadership directed questions to science and technology spokesperson Gareth Hughes.

We acknowledge the letter and appreciate the message, Hughes told The Spinoff in an email.

Were comfortable with keeping GE in the lab but were always open to a facts-based public conversation about GE to ensure our environment and species are protected and consumers are safe and informed.

Hughes noted that the prime ministers chief science adviser, Juliet Gerrard, had recently pointed out that GE regulation isnt just a scientific question, it has ethical and economic dimensions too. Risks to New Zealands fast-growing organics sector and national agricultural reputation need to be considered.

Gerrard has also said, however, that New Zealands existing law on genetic engineering is not fit for purpose. Speaking to the Spinoff shortly after her appointment, she said: The act was written before the technologies were discussing were even invented. So I think what we need to do is have a calm look at sorting out the language and the legal and regulatory framework.

Her predecessor as PMs science adviser, Sir Peter Gluckman, has gone further, saying, If our country does not periodically consider how to use or not use evolving technologies, we run the risk of becoming a backwater with a declining competitive position. We must to find a way to have ongoing conversations about fast moving and evolving technologies; burying our heads in the sands of short-termism can have serious long-term costs.

An expert panel, cited by the letter writers, set up by Royal Society Te Aprangi to consider implications of new technologies which allow more controlled and precise gene editing, called for an overhaul of the regulations and an urgent need for wide discussion and debate about gene editing within and across all New Zealand communities.

Hughes added: There are emissions reduction practices available right now without needing hypothetical, future GE-based technologies. We believe regenerative and organic agriculture is a better future for New Zealand and our environment.

Green Party policies are developed by our members and any change would have to come from the membership.

The strength of divergent views within the Greens bubbled to the surface last week, when a member went public over a rejected op-ed submission to the party magazine, Te Awa.

In the proposed piece, which he provided to the NZ Herald, GE opponent and non-toxic pesticide developer Chris Henry had called for the resignation of James Shaw, writing: We simply cannot have someone weak on the issue leading the political side.

He had been motivated by an appearance by Shaw on Q&A, in which the Greens co-leader said he would be led by the science in assessing the arguments for GM technology in reducing methane emissions in agriculture.

The editor of the magazine, which is independent from the party caucus, told Henry: Your piece conflicts with many of our principles and values when it asks for James resignation. The Green Partys non-violence and appropriate decision-making principles preclude me from publishing your article. You have chosen a confrontational and violent approach to getting attention to your concerns.

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Young scientists call on Greens to rethink GM stance in the cause of the climate - The Spinoff

Its so metaphorical! Kim Ki-woo exclaims early in Parasite, Bong Joon Hos new film. Ki-woo is the college-aged son of one of the two families the impoverished Kims and the wealthy Parks whose fates entwine with horrible and hilarious results. He uses the phrase a few times, most notably with reference to the large, decorative landscape rock that is a gift from a better-off friend. In the interpretation of Parasite that emphasizes the movies fairy-tale aspects, the stone brings good fortune to Ki-woo, his sister and their parents, even as, like so many magical objects, it also curses them. (Spoilers follow, for Parasite and other Bong movies.)

Before long, Ki-woo stops talking about metaphors. Maybe because things start getting real. He takes a job tutoring the Parks teenage daughter, Da-hye, and pretty soon his whole family is employed, under dubious premises and fake identities, in the Park household. His sister, pretending to be a highly trained art therapist, starts working with Da-hyes younger brother, Da-song. The Kim patriarch, Ki-taek, replaces the chauffeur who drives Mr. Park to and from his fancy tech job. Kim Chung-sook, the mother of the clan (a former Olympic-level hammer-thrower), takes over as housekeeper.

Or maybe and it might amount to the same thing the Kims reality has turned into an unsettling allegory of modern life, and Ki-woo doesnt see metaphors in the way that a fish doesnt notice water. What started out as a clever scam has turned into a fable.

In South Korea, where Parasite is already a blockbuster (having taken in more than $70 million at the box office), it has contributed to that countrys continuing debate about economic inequality. In the United States, where similar arguments are swirling, it has begun to turn Bong from an auteur with a passionate cult following into a top-tier international filmmaker. Fifty years old, with seven features to his name most of them available on North American streaming platforms he combines showmanship with social awareness in a way that re-energizes the faded but nonetheless durable democratic promise of movies.

The cramped, leaky semi-basement apartment the Kims call home is a metaphor of sorts, and so is the spacious, modern, architecturally significant mansion where they work. The Park home in particular comes with built-in symbols, including a deep subbasement where inconvenient secrets can be stashed away, like dead bodies or hidden meanings in an Edgar Allan Poe story. And Parasite, which won the top prize in Cannes in May and has recently become the rare subtitled release to be mentioned as an Oscar contender beyond the foreign film category, plays out like a parable of contemporary social relations. Its part horror film, part satire and part tragedy, conveying a sharp lesson about class struggle in South Korea and just about everywhere else.

But the houses in the film like every office, alley, field, railroad car and precinct house in Bongs expanding cinematic universe are also actual physical places. And their inhabitants are anything but symbols or ciphers. Bong likes to choreograph wildly improbable chases and fights, but he doesnt cheat at physics. A reason for the frequent comparisons to Alfred Hitchcock and Steven Spielberg is the ruthless precision of his technique. But for all his love of whimsy and absurdity, he doesnt play games with human psychology. The actions and reactions in his movies are often surprising, but they are never nonsensical. His characters have gravity, density, grace and a decent share of stupidity.

To call Bong a realist, though, would be crazy. The movie of his that first caught the attention of genre geeks on a global scale was his third feature, The Host (released here in 2007), about a giant, carnivorous mutant fish spreading terror along the Han River in Seoul. In 2014 came Snowpiercer (based on a French graphic novel), which confirmed Bongs status as an international action auteur. A gaggle of movie stars from Hollywood and beyond (including Chris Evans, Tilda Swinton and Song Kang Ho, the solid South Korean Everyman who has appeared in four of Bongs movies and who plays the Kim patriarch in Parasite) were packed into a high-speed train zooming around an apocalyptically frozen earth. The passengers were sorted into haves and have-nots, rebels and sellouts, and their struggles were both surprising and grimly familiar.

That was followed by Okja (2017), an antic updating of the basic Charlottes Web material (a young farm girl fights to save the life of her beloved piglet) for an age of genetic engineering, mass media and multinational capitalism. Swinton returned, playing twin moguls, but the real stars were Ahn Seo Hyun, as the young girl, and the digitally rendered shoat whose soul was at stake in the hectic battles among scientists, executives, animal-rights activists and other motley human specimens.

In obvious ways, Parasite is more realistic than those films. It returns Bong to the workaday Korean settings of his first two features, the grotesque comedy Barking Dogs Never Bite and the detective drama Memories of Murder, and also of Mother, his masterpiece (released here in 2010) about a woman whose mentally challenged adult son is accused of killing a schoolgirl. Parasite is more noir than science fiction, farcical until it turns melodramatic.

But to sort Bongs work by genre or style is to miss both its originality and consistency. His movies are bold and bright, infused with rich colors and emphatic performances. They are funny, suspenseful and punctuated by kinetic sequences that can make even jaded multiplex-potatoes sit up and gasp. There are at least a half-dozen such moments in Parasite, perhaps the most thrilling of which involves three people hiding under a living-room coffee table while another camps out in a tent in the backyard.

At the same time, his movies are dark and subtle, burrowing deep into sticky ethical problems and hot zones of social dysfunction. You could say that he uses blockbuster means to advance art-house ends. You could also say the opposite. His real achievement, though, is to scramble such facile distinctions, and a host of others as well.

His stories are often tragic, but the mood tends to be more exuberant than somber, an emotional effect that can be hard to describe. The full awfulness of human beings and their circumstances is on vivid display: venality, vanity, deception and outright cruelty. But the aim isnt mockery or glib sensationalism, or the routine fusion of the laughable and the grotesque that has been a staple of Hollywood cool since the mid-1990s. The most shocking thing about Bongs films might be their sincerity, the warm humanism that flickers through the chronicles of spite, sloth and self-delusion.

The flickers are sometimes faint. In Bongs debut feature, Barking Dogs Never Bite (2000), the humanism is all but buried in a gruesome, urban-legend-inflected conceit. A beleaguered graduate student, desperate to become a professor an advancement that depends on his ability to come up with a large bribe for a senior figure in his field is tormented by the barking of a neighbors dog. Since he lives in a vast, impersonal apartment block (the first of Bongs metaphorical architectural spaces), he cant identify the offending creature. The wrong dog ends up dying, more than once, and being eaten by a janitor with a taste for stewed canine flesh. Meanwhile the students marriage starts to crumble.

A measure of redemption or at least a twinkle of mischief, innocence and decency arrives via a subplot concerning a young woman in the building, and her friend, who works in a convenience store. They represent archetypal Bong characters: socially marginal, loyal to each other, but not necessarily heroic or noble by virtue of their poverty. Bongs sense of class solidarity, which threads through every one of his movies, doesnt involve romanticizing the people on the losing end of an increasingly ruthless economic competition.

The Kims in Parasite arent necessarily nicer, more loving or more honest than the bourgeois Parks. The small-town police officers in Memories of Murder are hardly pillars of virtue. The snack vendor played by Song in The Host, who enlists his father and his siblings in a valiant crusade to save his daughter from the monster, is a bit of an oaf. The mother in Mother, who sells herbs and practices acupuncture without a license, pushes maternal devotion to the point of homicide.

To sentimentalize or idealize any of these people would not only be a form of condescension. It would strip their stories of dramatic and moral interest, making them less disturbing, and also a lot less fun. The pleasure and the discomfort cant be separated. We are watching players compete in a rigged game with potentially mortal stakes and unreliable referees. Institutions schools, companies, governments are comically and also lethally useless. There is no legitimate authority, only raw power. Family connections are the only bonds that count, but families are a mess. The only answer is a kind of wily resourcefulness, an on-the-fly problem-solving knack that can deliver at best small, local victories. That those can be satisfying is a tribute to Bongs own wily resourcefulness and also to his radical compassion.

What makes Parasite the movie of the year what might make Bong the filmmaker of the century is the way it succeeds in being at once fantastical and true to life, intensely metaphorical and devastatingly concrete.

There doesnt seem to be much distance, in other words, between the dire futures projected in Snowpiercer and Okja nightmares of technology and greed run amok and the class-specific domestic spaces of Parasite, Mother and Memories of Murder. A much-remarked-on feature of human existence at the moment is how dystopian it feels, as some of the most extreme and alarming fantasies of fiction reappear as newsfeed banalities. Fires and hurricanes feel less like symbols than signals, evidence of a disaster thats already here rather than omens of impending catastrophe. Monsters walk among us. Corruption is normal. Trust, outside a narrow circle of friends or kin, is unthinkable. Whether we know it or not, its Bongs world were living in. Literally.

Parasite: In theaters now.

Okja: Stream it on Netflix.

Snowpiercer: Stream it on Netflix; buy or rent it on iTunes, Vudu, Amazon and YouTube.

Mother: Buy or rent it on iTunes, Amazon and Vudu.

The Host: Buy or rent it on iTunes, Vudu and YouTube.

Memories of Murder: Buy or rent it on iTunes and YouTube.

Barking Dogs Never Bite: Buy or rent it on iTunes.

Top Art: Associated Press (Bong); Magnolia Pictures (Mother); Netflix (Okja); Radius-TWC (Snowpiercer); CJ ENM Corporation, Barunson E&A and Neon (Parasite)

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Its Bong Joon Hos Dystopia. We Just Live in It. - The New York Times

Artists from Brooklyn to So Paulo will travel to UB to beautify open water sewers, engineer living perfumes, construct an evolutionary tree of skulls, craft sculptures made of bacteria-dyed llama wool and more.

The seven artists are the fourth cohort of art residents in the UB Coalesce: Center for Biological Art, which helps artists, scientists, architects and designers explore and examine the cultural meanings of their work.

The residents will have the opportunity to form partnerships with UB faculty in the life sciences, gain access to laboratory equipment, and take advantage of the creative space and technical support to study genomic and microbiomic concepts.

Artists selected for this years residency embrace projects situated within the Anthropocene, our Earths most recent geological era defined by overwhelming evidence of dramatic human alteration of atmospheric, geologic and hydrologic systems on our planet, says Paul Vanouse, Coalesce director and professor in the Department of Art in the UB College of Arts and Sciences. The theme is explored through projects that begin both inside and outside the laboratory, and also inspire questions about the human and non-human divide.

Coalesce is a collaboration between UBs Genome, Environment and Microbiome (GEM) Community of Excellence and the Department of Art. An initiative of GEM, the program aims to expand public understanding of and participation in the life sciences.

Over the past four years, the UB and Western New York communities have benefited from thought-provoking installations, workshops and discussions focused on social and ethical questions surrounding the genome and microbiome, says Jennifer Surtees, GEM co-director and associate professor in the Department of Biochemistry in the Jacobs School of Medicine and Biomedical Sciences at UB. These artists creative research informs public science literacy, helping to make the science more accessible, and has made UB a top research destination for biological art. I look forward to seeing how this years projects evolve and develop through artist interactions at Coalesce.

In-progress projects and explorations will be on view during a Coalesce open house from 1-3 p.m. Nov. 1 in the Coalesce BioArt Lab, 308 Hochstetter Hall, North Campus. The event will feature previews and experiments of ongoing projects by residents and associated researchers.

The 2019-20 class of artists-in-residence:

Zeelie Brown: The worlds most beautiful septic tank

Thousands of people nationwide, many of whom are among the countrys poorest, are believed to live near open sewers. The unsanitary conditions are prevalent in rural African American communities in Alabama, where Brown was raised.

The worlds most beautiful septic tank seeks to resurrect these areas by converting open sewers into lush septic gardens filled with lavender, basil and various flowers. The garden will also contain mosquito repellant plants to counter the risk of mosquito-borne illnesses, one of many diseases that people face living near the putrid waters.

Made from commonly found materials, the permaculture septic garden will filter and recycle human waste. The project aims to increase public thought surrounding how waste is managed and experienced, as the management of waste products has increasingly become one of societys greatest social, scientific and aesthetic problems.

Brown is a Brooklyn-based, interdisciplinary visual artist and cellist.

Tiare Ribeaux and Ruth Schmidt: Microbial Scents and Olfactory Prosthesis for the Future

As climate change threatens to alter the habitats in which humans live, Microbial Scents and Olfactory Prosthesis for the Future hopes to preserve natures scents for future generations through living perfumes and 3D-printed filtration masks.

The project will recreate geosmin a compound with an earthy aroma that is produced by bacteria in soil and other natural scents, as well as craft new odors using communities of microbes. The scents will be encased in vials as living perfumes.

The artists will also place the scents in 3D-printed filtration masks and prosthesis that can be worn under the nose or around the neck. The devices could improve air quality or be used to house customized familiar aromas.

Ribeaux is a San Francisco-based, new media and interdisciplinary artist; Schmidt is a Montreal-based microbial ecologist.

Sun Young Kang: Humans place in the evolutionary tree of life

Humanitys location in the evolutionary tree will be explored through Humans place in the evolutionary tree of life, a display of hundreds of hanging primate and human skulls made of paper materials aged at varying degrees.

At Coalesce, Kang will focus on discovering soil and paper qualities that facilitate aging and decay of the paper, as well as understanding the roles of microbes. Using time as the central theme, the skulls will be hung from the ceiling in a tree-like arrangement, and organized based on genetic and physical similarities between the species.

Ancestral skulls will be situated at the roots, genetically younger species will occupy the branches, and hypothetical skull shapes representing theoretical evolutionary paths for humans and primates will radiate from the tree as rays of light.

Kang is a book and installation artist based in Buffalo. She is collaborating on the project with evolutionary anatomist Jack Tseng, assistant professor of pathology and anatomical sciences in the Jacobs School; and Patrick Ravines, associate professor and director of the Art Conservation Department at SUNY Buffalo State.

Laura Splan: Conformations

Using photography, video, sound, digital animation, sculpture and textiles, Conformations will examine the institutionalized notion of boundaries, and the hidden materiality and labor of biotechnology through a performance of language, image and movement.

The project will include sculptures made from 200 pounds of hand-spun, laboratory llama and alpaca wool. The textiles will be dyed with pigments extracted from bacteria harvested for drug development.

The wool will serve as a synecdoche a figure of speech in which a part is used to reference the whole for the use of immunized animals to produce antibodies for human drugs.

Splan is a Brooklyn-based mixed media artist.

Cesar Baio and Lucy H.G. Solomon: Thinking within Ecosystems: Collective Cell Consciousness

The project will explore what is human through an artwork that merges cellular and digital networks to enable communication between microbiomes, the human body and machine.

The artists aim to better understand the relationship between human and non-human entities through a pragmatic rethinking of a human-centered ontology, which is the philosophical study of being and existence.

To explore what they call collective cell consciousness, Baio and Solomon will draw on computer science and engineering approaches to create an integrated cellular and technological network that would accommodate cross-network or inter-species communication.

Baio, a Brazil-based media artist, and Solomon, a California-based media artist, form the art collective Cesar & Lois.

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Artists to explore waste, evolution, climate change and more through UB bioart residencies - UB Now: News and views for UB faculty and staff -...

Women wait with their malaria-struck babies for treatment in Angola. Will opponents of gene ... [+] engineering deny prevention to families like these?

Mosquitoes are not just obnoxious summer pests they are a serious health threat to most of the world. In fact, the WHO calls mosquitoes one of the deadliest animals in the world.

Why? Mosquitoes carry and spread diseases to humans that cause millions of deaths every year. The biggest threat is malaria: a half a million lives are lost annually, and Africa alone loses $12 billion in health care, productivity, investment, and tourism to the disease. Then theres Zika, dengue, chikungunya, and yellow fever each carried by mosquitoes, and each extracting their toll in human lives and livelihood.

But now, there is hope that biotechnology can help solve this crisis. The solution lies in genetically modifying a small population of mosquitoes and releasing them into malaria-prone areas. These mosquitoes carry a lethal gene that kills larvae before they reach adulthood and carry malaria to others, just stunting human illness.

Oxitec is a British biotechnology company doing just this. Over the last fifteen years or so the company has introduced Friendly Technology. Oxitecs latest results back up historic successes in Brazil, which saw dengue cases in one area reduced by 91% in a small trial. Their latest study showed a 96% reduction in mosquito numbers, this time using a more effective strategy of targeting the biting, egg-laying females - albeit leaving non-biting males to survive and reproduce. A great success, on the face of it.

The anti-GM backlash

However, Oxitec and others are taking a lot of flak from the anti-GM lobby, which according to the Genetic Literacy Project spent $850 million in the last five years alone opposing everything from the way we label genetically engineered food to fabric thats fermented from sugar.

The backlash was triggered by a paper that, ironically, seems likely to be retracted (or at least highly modified) due to exaggerated predictions of more robust mosquitoes, among others. Though reports of genetic mixing between surviving introduced mosquitoes and local mosquitoes were valid, the lethal gene was not actually present - which was the most likely outcome considering the lethality of the gene in question. A lethal gene will naturally diminish in frequency among a population.

But another consideration is to ask: does it even matter, all things considered, when eradication of disease should be the goal?

The risk of inaction

Mosquitoes are utterly deadly, and even when theyre not they provide among the largest disease burden on the planet. Tuberculosis may kill more people (around 1.3 million per year, compared with around 450,000 for malaria). But malaria infects 20 times that number of people.

Those 219 million annual malaria cases cost low income countries a significant chunk of their GDP up to 1.3% in the worst affected while just a 10% reduction in malaria was associated with a 0.3% growth in a much cited study on the economic burden of malaria. For Uganda, the economic gain from eradicating malaria would total around $50 million USD.

This doesnt take into account emerging diseases such as dengue and Zika virus, among others. In Brazil, the focus of Oxitecs recent trials aiming to reduce numbers of Aedes aegypti, 1.2 million people were infected with dengue in the first six months of 2019 six times more than in 2018 with an associated 388 deaths. Zika virus, carried by the same mosquito, exploded onto the scene in 2015 and has been associated with a range of effects on babies born to infected mothers in 10% of cases.

Yes, there are likely some knock-on ecosystem effects of releasing Oxitec mosquitoes. There might well be reduced prey for fish that eat the larvae, or less food for some of the birds that eat the flying insects. However, mosquitoes are not irreplaceable as far as the wider ecosystem is concerned, especially pests such as Aedes aegypti. There are another 3000 species of mosquito other than the three which primarily cause disease in people.

The World Health Organization (WHO) brands Aedes aegypti mosquitoes as being exquisitely adapted to city life, and that they prefer to breed in artificial containers. Given this information, it makes it even less important that lethal genes might persist among the wider population of these costly pests, less so that they might be eradicated - an opinion seemingly shared by researchers who have looked into the potential environmental costs associated with getting rid of the worst species of disease-bearing mosquitoes.

It all boils down to a cost/benefit analysis. Is the risk of some genetically modified mosquitoes passing on transgenes to wild populations worse than the risk of millions of people being infected with haemorrhagic fever and malaria, or babies being born with abnormally small heads (microcephaly)?

In any case, we will always have to take measures to reduce the burden of disease. What about the alternative forms of pest control and their relatively indiscriminate, off-target effects?

What is natural?

Oxitec, the company responsible for releasing genetically modified mosquitoes, have always known and stated - explicitly so - that some mosquitoes would survive to breed and pass on their genes. They have also taken measures to ensure that populations containing the lethal gene eventually go their predestined way.

In fact, their latest mosquitoes are meant to pass on genes to wild populations, this time to reverse the naturally occurring genetic mechanisms that render mosquitoes resistant to pesticides such as DEET. (Incidentally, multi drug resistance in the malaria parasite itself is also increasing).

To put our collective minds at ease, its worth pointing out that nature is weirder than what Oxitec is doing. mosquitoes perform their own version of enforced sterilisation, whereby male tiger mosquitoes (of the species Aedes albopictus) can mate with, and sterilize, female Aedes aegypti mosquitoes.

The fact that diseases such as Zika and dengue are present in Brazil in the first place is evidence that we are about as far removed from whatever natural used to mean as we can possibly be. Zika was introduced by a traveller from French Polynesia. The only way it got to Brazil was by aeroplane.

Its not just Zika traversing the globe in such a manner. There are emergent diseases popping up left, right and center, and it is not an easy task to keep them in check. The WHO warned us over ten years ago that infectious diseases are emerging at a rate not seen before. (One example is West Nile Virus, a mosquito-borne disease first described in 1937 in Uganda but discovered in New York in the summer of 1999. It is becoming more prevalent in California and will soon reach Silicon Valley and the San Francisco biotech region.)

It is no wonder. We live in a globally connected world with a rapidly expanding population that is a hotbed for disease-causing agents to emerge, mix, and spread (from viruses and bacteria to malaria parasites), which means that we need highly innovative, modern solutions to control them. Its an evolutionary arms race, and we need all the tools we can muster. If one of them happens to include lethal genes that successfully wipe out local populations of disease-causing mosquitoes, so be it.

Mosquito-borne diseases already threaten half of the global population.And as the climate warms and favors the mosquito, these diseases could spread to a billion more people.

Clearly, our current methods of control havent quite been enough to stop 219 million people becoming afflicted with malaria each year, or an increasing number suffering and dying from dengue and other diseases. Its not genes escaping that is the problem, but the sheer difficulty in eradicating mosquitoes and their diseases at all.

We must proceed carefully with new genetic engineering technologies, but we must also weigh the risks of inaction: each year hundreds of millions of people mostly children needlessly die, get sick, or suffer genetic defects. GMO mosquitoes are something we can do about it.

So what would you rather have: GMO mosquitoes or dying babies?

Acknowledgement: Thank you to Peter Bickerton for additional research and reporting in this post.

Please note: I am the founder ofSynBioBeta, and some of the companies that I write about are sponsors of theSynBioBeta conference(click herefor a full list of sponsors).

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British Biotech Company Sees Hope In Reducing Mosquito-Borne Diseases And Deaths With GMOs - Forbes

An unexpected early morning phone call from the hospital is never good news. When Joy Johnson answered, her first thought was that Sharon Birzer, her partner of 15 years, was dead. Her fears were amplified by the voice on the other end refusing to confirm or deny it. Just come in and talk to one of the doctors, she remembers the voice saying.

Johnson knew this was a real possibility. A few weeks earlier, she and Birzer sat in the exam room of a lymphoma specialist at Stanford University. Birzers cancer had grown, and fast first during one type of chemotherapy, then through a second. Out of standard options, Birzers local oncologist had referred her for a novel treatment called chimeric antigen receptor T-cell therapy or CAR-T. Birzer and Johnson knew the treatment was risky. They were warned there was a chance of death. There was also a chance of serious complications such as multi-organ failure and neurological impairment. But it was like warning a drowning person that her lifeboat could have problems. Without treatment, the chance of Birzers death was all but certain. She signed the consent form.

Johnson hung up the phone that early morning and sped to the hospital. She met with a doctor and two chaplains in a windowless room in the cancer ward, where happy photos of cancer alumni smiled down from the walls. This is getting worse and worse, Johnson thought. As she remembers it, the doctor went through the timeline of what happened for 10 minutes, explaining how Birzer became sicker and sicker, before Johnson interrupted with the thought splitting her world in two: I need you to tell me whether shes alive or dead.

Birzer wasnt dead. But she was far from okay. The ordeal began with Birzer speaking gibberish. Then came seizures so severe there was concern she wouldnt be able to breathe on her own. When it took a few different medications to stop Birzer from seizing, her doctors sedated her, put a breathing tube down her throat, and connected her to a ventilator. Now, she was unconscious and in the intensive care unit (ICU).

Birzer was one of the early patients to receive CAR-T, a radical new therapy to treat cancer. It involved removing Birzers own blood, filtering for immune cells called T-cells, and genetically engineering those cells to recognize and attack her lymphoma. CAR-T made history in 2017 as the first FDA-approved gene therapy to treat any disease. After three to six months of follow-up, the trials that led to approval showed response rates of 80 percent and above in aggressive leukemias and lymphomas that had resisted chemotherapy. Patients on the brink of death were coming back to life.

This is something I often dream of seeing but rarely do. As a doctor who treats cancer, I think a lot about how to frame new treatments to my patients. I never want to give false hope. But the uncertainty inherent to my field also cautions me against closing the door on optimism prematurely. We take it as a point of pride that no field of medicine evolves as rapidly as cancer the FDA approves dozens of new treatments a year. One of my biggest challenges is staying up to date on every development and teasing apart what should and shouldnt change my practice. I am often a mediator for my patients, tempering theoretical promises with everyday realism. To accept a research finding into medical practice, I prefer slow steps showing me proof of concept, safety, and efficacy.

CAR-T, nearly three decades in the making, systemically cleared these hurdles. Not only did the product work, its approach was also unique among cancer treatments. Unlike our usual advances, this wasnt a matter of prescribing an old drug for a new disease or remixing known medications. CAR-T isnt even a drug. This is a one-time infusion giving a person a better version of her own immune system. When the FDA approved its use, it wasnt a question of whether my hospital would be involved, but how we could stay ahead. We werent alone.

Today, two FDA-approved CAR-T products called Kymriah and Yescarta are available in more than 100 hospitals collectively across the U.S. Hundreds of clinical trials are tinkering with dosages, patient populations, and types of cancer. Some medical centers are manufacturing the cells on-site.

The FDA approved CAR-T with a drug safety program called a Risk Evaluation and Mitigation Strategy (REMS). As I cared for these patients, I quickly realized the FDAs concerns. Of the 10 or so patients Ive treated, more than half developed strange neurologic side effects ranging from headaches to difficulty speaking to seizures to falling unconscious. We scrambled to learn how to manage the side effects in real time.

Johnson and Birzer, who I didnt treat personally but spoke to at length for this essay, understood this better than most. Both had worked in quality control for a blood bank and were medically savvier than the average patient. They accepted a medical system with a learning curve. They were fine with hearing I dont know. Signing up for a trailblazing treatment meant going along for the ride. Twists and bumps were par for the course.

* * *

Cancer, by definition, means something has gone very wrong within a cell has malfunctioned and multiplied. The philosophy for fighting cancer has been, for the most part, creating and bringing in treatments from outside the body. Thats how we got to the most common modern approaches: Chemotherapy (administering drugs to kill cancer), radiation (using high energy beams to kill cancer), and surgery (cutting cancer out with a scalpel and other tools). Next came the genetics revolution, with a focus on creating drugs that target a precise genetic mutation separating a cancer cell from a normal one. But cancers are genetically complex, with legions of mutations and the talent to develop new ones. Its rare to have that one magic bullet.

Over the last decade or so, our approach shifted. Instead of fighting cancer from the outside, we are increasingly turning in. The human body is already marvelously equipped to recognize and attack invaders, from the common cold to food poisoning, even if the invaders are ones the body has never seen before. Cancer doesnt belong either. But since cancer cells come from normal ones, theyve developed clever camouflages to trick and evade the immune system. The 2018 Nobel Prize in Physiology or Medicine was jointly awarded to two researchers for their work in immunotherapy, a class of medications devoted to wiping out the camouflages and restoring the immune systems upper hand. As I once watched a fellow oncologist describe it to a patient: Im not treating you. You are treating you.

What if we could go one step further? What if we could genetically engineer a patients own immune cells to spot and fight cancer, as a sort of best hits of genetic therapy and immunotherapy?

Enter CAR-T. The technology uses T-cells, which are like the bouncers of the immune system. T-cells survey the body and make sure everything belongs. CAR-T involves removing a persons T-cells from her blood and using a disarmed virus to deliver new genetic material to the cells. The new genes given to the T-cells help them make two types of proteins. The first giving the technology its name is a CAR, which sits on the T-cells surface and binds to a protein on the tumor cells surface, like a lock and key. The second serves as the T-cells caffeine jolt, rousing it to activate. Once the genetic engineering part is done, the T-cells are prodded to multiply by being placed on a rocking device that feeds them nutrients while filtering their wastes. When the cells reach a high enough number a typical dose ranges from hundreds of thousands to hundreds of millions they are formidable enough to go back into the patient. Once inside, the cancer provokes the new cells to replicate even more. After one week, a typical expansion means multiplying by about another 1,000-fold.

Practically, it looks like this: A person comes in for an appointment. She has a catheter placed in a vein, perhaps in her arm or her chest, that connects to a large, whirring machine which pulls in her blood and separates it into its components. The medical team set the T-cells aside to freeze while the rest of the blood circulates back into the patient in a closed loop. Then, the hospital ships the cells frozen to the relevant pharmaceutical companys headquarters or transports them to a lab on-site, where thawing and manufacturing takes from a few days to a few weeks. When the cells are ready, the patient undergoes about three days of chemotherapy to kill both cancer and normal cells, making room for the millions of new cells and eradicating normal immune players that could jeopardize their existence. She then gets a day or two to rest. When the new cells are infused back into her blood, we call that Day 0.

* * *

I remember the first time I watched a patient get his Day 0 infusion. It felt anti-climactic. The entire process took about 15 minutes. The CAR-T cells are invisible to the naked eye, housed in a small plastic bag containing clear liquid.

Thats it? my patient asked when the nurse said it was over. The infusion part is easy. The hard part is everything that comes next.

Once the cells are in, they cant turn off. That this may cause collateral damage was evident from the start. In 2009 working in parallel with other researchers at Memorial Sloan Kettering Cancer Center in New York and the National Cancer Institute in Maryland oncologists at the University of Pennsylvania opened a clinical trial for CAR-T in human leukemia patients. (Carl June, who led the CAR-T development, did not respond to Undarks interview request.) Of the first three patients who got CAR-T infusions, two achieved complete remission but nearly died in the process. The first was a retired corrections officer named Bill Ludwig, who developed extremely high fevers and went into multi-organ failure requiring time in the ICU. At the time, the medical teams had no idea why it was happening or how to stop it. But time passed. Ludwig got better. Then came the truly incredible part: His cancer was gone.

With only philanthropic support, the trial ran out of funding. Of the eligible patients they intended to treat, the Penn doctors only treated three. So they published the results of one patient in the New England Journal of Medicine and presented the outcomes of all three patients, including Ludwig, at a cancer conference anyway. From there, the money poured in. Based on the results, the Swiss pharmaceutical company Novartis licensed the rights of the therapy.

The next year, six-year-old Emily Whitehead was on the brink of death when she became the first child to receive CAR-T. She also became extremely ill in the ICU, and her cancer was also eventually cured. Her media savvy parents helped bring her story public, making her the poster child for CAR-T. In 2014, the FDA granted CAR-T a breakthrough therapy designation to expedite the development of extremely promising therapies. By 2017, a larger trial gave the treatment to 75 children and young adults with a type of leukemia B-cell acute lymphoblastic leukemia that failed to respond to chemotherapy. Eighty-one percent had no sign of cancer after three months.

In August 2017, the FDA approved a CAR-T treatment as the first gene therapy in the U.S. The decision was unanimous. The Oncologic Drugs Advisory Committee, a branch of the FDA that reviews new cancer products, voted 10 to zero in favor of Kymriah. Committee members called the responses remarkable and potentially paradigm changing. When the announcement broke, a crowd formed in the medical education center of Penn Medicine, made up of ecstatic faculty and staff. There were banners and T-shirts. A remarkable thing happened was the tagline, above a cartoon image of a heroic T-cell. Two months later, in October 2017, the FDA approved a second CAR-T formulation called Yescarta from Kite Pharma, a subsidiary of Gilead Sciences, to treat an aggressive blood cancer in adults called diffuse large B-cell lymphoma, the trial of which had shown a 54 percent complete response rate, meaning all signs of cancer had disappeared. In May 2018, Kymriah was approved to treat adults with non-Hodgkin lymphoma.

That year, the American Society of Clinical Oncology named CAR-T the Advance of the Year, beating out immunotherapy, which had won two years in a row. When I attended the last American Society of Hematology meeting in December 2018, CAR-T stole the show. Trying to get into CAR-T talks felt like trying to get a photo with a celebrity. Running five minutes late to one session meant facing closed doors. Others were standing room only. With every slide, it became difficult to see over a sea of smartphones snapping photos. At one session I found a seat next to the oncologist from my hospital who treated Birzer. Look, she nudged me. Do you see all these non-member badges? I turned. Members were doctors like us who treated blood cancers. I couldnt imagine who else would want to be here. Who are they? I asked. Investors, she said. It felt obvious the moment she said it.

For patients, the dreaded c word is cancer. For oncologists, its cure. When patients ask, Ive noticed how we gently steer the conversation toward safer lingo. We talk about keeping the cancer in check. Cure is a dangerous word, used only when so much time has passed from her cancer diagnosis we can be reasonably certain its gone. But that line is arbitrary. We celebrate therapies that add weeks or months because the diseases are pugnacious, the biology diverse, and the threat of relapse looming. Oncologists are a tempered group, or so Ive learned, finding inspiration in slow, incremental change.

This was completely different. These were patients who would have otherwise died, and the trials were boasting that 54 to 81 percent were cancer-free upon initial follow-up. PET scans showed tumors that had speckled an entire body melt away. Bone marrow biopsies were clear, with even the most sensitive testing unable to detect disease.

The dreaded word was being tossed around could this be the cure weve always wanted?

* * *

When a new drug gets FDA approval, it makes its way into clinical practice, swiftly and often with little fanfare. Under the drug safety program REMS, hospitals offering CAR-T were obligated to undergo special training to monitor and manage side effects. As hospitals worked to create CAR-T programs, oncologists like me made the all too familiar transition from first-time user to expert.

It was May 2018 when I rotated through my hospitals unit and cared for my first patients on CAR-T. As I covered 24-hour shifts, I quickly learned that whether I would sleep that night depended on how many CAR-T patients I was covering. With each treatment, it felt like we were pouring gasoline on the fire of patients immune systems. Some developed high fevers and their blood pressures plummeted, mimicking a serious infection. But there was no infection to be found. When resuscitating with fluids couldnt maintain my patients blood pressures, I sent them to the ICU where they required intensive support to supply blood to their critical organs.

We now have a name for this effect cytokine release syndrome that occurs in more than half of patients who receive CAR-T, starting with Ludwig and Whitehead. The syndrome is the collateral damage of an immune system on the highest possible alert. This was first seen with other types of immunotherapy, but CAR-T took its severity to a new level. Usually starting the week after CAR-T, cytokine release syndrome can range from simple fevers to multi-organ failure affecting the liver, kidneys, heart, and more. The activated T-cells make and recruit other immune players called cytokines to join in the fight. Cytokines then recruit more immune cells. Unlike in the early trials at Penn, we now have two medicines to dampen the effect. Steroids calm the immune system in general, while a medication called tocilizumab, used to treat autoimmune disorders such as rheumatoid arthritis, blocks cytokines specifically.

Fortuity was behind the idea of tocilizumab: When Emily Whitehead, the first child to receive CAR-T, developed cytokine release syndrome, her medical team noted that her blood contained high levels of a cytokine called interleukin 6. Carl June thought of his own daughter, who had juvenile rheumatoid arthritis and was on a new FDA-approved medication that suppressed the same cytokine. The team tried the drug, tocilizumab, in Whitehead. It worked.

Still, we were cautious in our early treatments. The symptoms of cytokine release syndrome mimic the symptoms of severe infection. If this were infection, medicines that dampen a patients immune system would be the opposite of what youd want to give. There was another concern: Would these medications dampen the anti-cancer activity too? We didnt know. Whenever a CAR-T patient spiked a fever, I struggled with the question is it cytokine release syndrome, or is it infection? I often played it safe and covered all bases, starting antibiotics and steroids at the same time. It was counterintuitive, like pressing both heat and ice on a strain, or treating a patient simultaneously with fluids and diuretics.

The second side effect was even scarier: Patients stopped talking. Some, like Sharon Birzer, spoke gibberish or had violent seizures. Some couldnt interact at all, unable to follow simple commands like squeeze my fingers. How? Why? At hospitals across the nation, perfectly cognitively intact people who had signed up to treat their cancer were unable to ask what was happening.

Our nurses learned to ask a standardized list of questions to catch the effect, which we called neurotoxicity: Where are we? Who is the president? What is 100 minus 10? When the patients scored too low on these quizzes, they called me to the bedside.

In turn, I relied heavily on a laminated booklet, made by other doctors who were using CAR-T, which we tacked to a bulletin board in our doctors workroom. It contained a short chart noting how to score severity and what to do next. I flipped through the brightly color-coded pages telling me when to order a head CT-scan to look for brain swelling and when to place scalp electrodes looking for seizures. Meanwhile, we formed new channels of communication. As I routinely called a handful of CAR-T specialists at my hospital in the middle of the night, national consortiums formed where specialists around the country shared their experiences. As we tweaked the instructions, we scribbled updates to the booklet in pen.

I wanted to know whether my experience was representative. I came across an abstract and conference talk that explored what happened to 277 patients who received CAR-T in the real world, so I emailed the lead author, Loretta Nastoupil, director of the Department of Lymphoma and Myeloma at the University of Texas MD Anderson Cancer Center in Houston. Fortuitously, she was planning a trip to my university to give a talk that month. We met at a caf and I asked what her research found. Compared to the earlier trials, the patients were much sicker, she said. Of the 277 patients, more than 40 percent wouldnt have been eligible for the very trials that got CAR-T approved. Was her team calling other centers for advice? They were calling us, she said.

Patients included in clinical trials are carefully selected. They tend not to have other major medical problems, as we want them to survive whatever rigorous new therapy we put them through. Nastoupil admits some of it is arbitrary. Many criteria in the CAR-T trials were based on criteria that had been used in chemotherapy trials. These become standard languages that apply to all studies, she said, listing benchmarks like a patients age, kidney function, and platelet count. But we have no idea whether criteria for chemotherapy would apply to cellular therapy.

Now, with a blanket FDA approval comes clinical judgment. Patients want a chance. Oncologists want to give their patients a chance. Young, old, prior cancer, heart disease, or liver disease without strict trial criteria, anyone is fair game.

When I was making rounds at my hospital, I never wandered too far from these patients rooms, medically prepared for them to crash at any moment. At the same time, early side effects made me optimistic. A bizarre truism in cancer is that side effects may bode well. They could mean the treatment is working. Cancer is usually a waiting game, requiring months to learn an answer. Patients and doctors alike seek clues, but the only real way to know is waiting: Will the next PET scan show anything? What are the biopsy results?

CAR-T was fundamentally different from other cancer treatments in that it worked fast. Birzers first clue came just a few hours after her infusion. She developed pain in her lower back. She described it as feeling like she had menstrual cramps. A heavy burden of lymphoma lay in her uterus. Could the pain mean that the CAR-T cells had migrated to the right spot and started to work? Her medical team didnt know, but the lead doctors instinct was that it was a good sign.

Two days later, her temperature shot up to 102. Her blood pressure dropped. The medical team diagnosed cytokine release syndrome, as though right on schedule, and gave her tocilizumab.

Every day, the nurses would ask her questions and have her write simple sentences on a slip of paper to monitor for neurotoxicity. By the fifth day, her answers changed. She started saying things that were crazy, Johnson explained.

One of Birzer's sentences was guinea pigs eat greens like hay and pizza. Birzer and Johnson owned two guinea pigs, so their diet would be something Birzer normally knew well. So Johnson tried to reason with her: They dont eat pizza. And Birzer replied, They do eat pizza, but only gluten-free.

Johnson remembers being struck by the certainty in her partners delirium. Not only was Birzer confused, she was confident she was not. She was doubling down on everything, Johnson described. She was absolutely sure she was right.

Johnson vividly remembers the evening before the frightening early-morning phone call that brought her rushing back to the hospital. Birzer had said there was no point in Johnson staying overnight; she would only watch her be in pain. So Johnson went home. After she did, the doctor came by multiple times to evaluate Birzer. She was deteriorating and fast. Her speech became more and more garbled. Soon she couldnt name simple objects and didnt know where she was. At 3 a.m., the doctor ordered a head CT to make sure Birzer wasnt bleeding into her brain.

Fortunately, she wasnt. But by 7 a.m. Birzer stopped speaking altogether. Then she seized. Birzers nurse was about to step out of the room when she noticed Birzers arms and legs shaking. Her eyes stared vacantly and she wet the bed. The nurse called a code blue, and a team of more doctors and nurses ran over. Birzer was loaded with high-dose anti-seizure medications through her IV. But she continued to seize. As nurses infused more medications into her IV, a doctor placed a breathing tube down her throat.

Birzers saga poses the big question: Why does CAR-T cause seizures and other neurologic problems? No one seemed to know. My search of the published scientific literature was thin, but one name kept cropping up. So I called her. Juliane Gust, a pediatric neurologist and scientist at Seattle Childrens Hospital, told me her investigations of how CAR-T affects the brain were motivated by her own experiences. When the early CAR-T trials opened at her hospital in 2014, she and her colleagues began getting calls from oncologists about brain toxicities they knew nothing about. Where are the papers? she remembered thinking. There was nothing.

Typically, the brain is protected by a collection of cells aptly named the blood-brain-barrier. But with severe CAR-T neurotoxicity, research suggests, this defense breaks down. Gust explained that spinal taps on these patients show high levels of cytokines floating in the fluid surrounding the spine and brain. Some CAR-T cells circulate in the fluid too, she said, but these numbers do not correlate with sicker patients. CAR-T cells are even seen in the spinal fluid of patients without any symptoms.

What does this mean? Gust interprets it as a patients symptoms having more to do with cytokines than the CAR-T cells. Cytokine release syndrome is the number one risk factor for developing neurotoxicity over the next few days, she said. The mainstay for neurotoxicity is starting steroids as soon as possible. In the beginning we didnt manage as aggressively. We were worried about impairing the function of the CAR-T, she added. Now we give steroids right away.

But the steroids dont always work. Several doses of steroids didnt prevent Birzer from seizing. The morning after Johnsons alarming phone call, after the meeting at the hospital when she learned what had happened, a chaplain walked her from the conference room to the ICU. The first day, Johnson sat by her partners bedside while Birzer remained unconscious. By the next evening, she woke up enough to breathe on her own. The doctors removed her breathing tube, and Birzer looked around. She had no idea who she was or where she was.

Birzer was like a newborn baby, confused and sometimes frightened by her surroundings. She frequently looked like she was about to say something, but she couldnt find the words despite the nurses and Johnsons encouragement. One day she spoke a few words. Eventually she learned her name. A few days later she recognized Johnson. Her life was coming back to her, though she was still suspicious of her reality. She accused the nurses of tricking her, for instance, when they told her Donald Trump was president.

She took cues from the adults around her on whether her actions were appropriate. The best example of this was her I love you phase. One day, she said it to Johnson in the hospital. A few nurses overheard it and commented on how sweet it was. Birzer was pleased with the reaction. So she turned to the nurse: I love you! And the person emptying the trash: I love you! Months later, she was having lunch with a friend who asked, Do you remember when you told me you loved me? Birzer said, Well, I stand by that one.

When she got home, she needed a walker to help with her shakiness on her feet. When recounting her everyday interactions, she would swap in the wrong people, substituting a friend for someone else. She saw bugs that didnt exist. She couldnt hold a spoon or a cup steady. Johnson would try to slow her down, but Birzer was adamant she could eat and drink without help. Then peas would fly in my face, Johnson said.

Patients who experience neurotoxicity fall into one of three categories. The majority are impaired but then return to normal without long-term damage. A devastating handful, less than 1 percent, develop severe brain swelling and die. The rest fall into a minority that have lingering problems even months out. These are usually struggles to think up the right word, trouble concentrating, and weakness, often requiring long courses of rehabilitation and extra help at home.

As Birzer told me about her months of rehab, I thought how she did seem to fall somewhere in the middle among the patients Ive treated. On one end of the spectrum was the rancher who remained profoundly weak a year after his infusion. Before CAR-T, he walked across his ranch without issue; six months later, he needed a walker. Even with it, he fell on a near weekly basis. On the other end was the retired teacher who couldnt speak for a week she would look around her ICU room and move her mouth as though trying her hardest and then woke up as though nothing happened. She left the hospital and instantly resumed her life, which included a recent trip across the country. In hindsight, I remember how we worried more about giving the therapy to the teacher than the rancher, as she seemed frailer. Outcomes like theirs leave me with a familiar humility I keep learning in new ways as a doctor: We often cant predict how a patient will do. Our instincts can be just plain wrong.

I asked Gust if we have data to predict who will land in which group. While we can point to some risk factors higher burdens of cancer, baseline cognitive problems before therapy the individual patient tells you nothing, she confirmed.

So we wait.

* * *

Doctors like me who specialize in cancer regularly field heart-wrenching questions from patients. They have read about CAR-T in the news, and now they want to know: What about me? What about my cancer?

So, who gets CAR-T? That leads to the tougher question who doesnt? That depends on the type of cancer and whether their insurance can pay.

CAR-T is approved to treat certain leukemias and lymphomas that come from the blood and bone marrow. Since the initial approval, researchers have also set up new CAR-T trials for all sorts of solid tumors from lung cancer to kidney cancer to sarcoma. But progress has been slow. While some promising findings are coming from the lab and in small numbers of patients on early phase trials, nothing is yet approved in humans. The remarkable responses occurring in blood cancers just werent happening in solid tumors.

Cancer is one word, but its not one disease. Its easier to prove why something works when it works than show why it doesnt work when it doesnt work, said Saar Gill, a hematologist and scientist at the University of Pennsylvania who co-founded a company called Carisma Therapeutics using CAR-T technology against solid tumors. That was his short answer, at least. The longer answer to why CAR-T hasnt worked in solid cancers involves what Gill believes are two main barriers. First, its a trafficking problem. Leukemia cells tend to be easier targets; they bob through the bloodstream like buoys in an ocean. Solid tumors are more like trash islands. The cancer cells stick together and grow an assortment of supporting structures to hold the mound together. The first problem for CAR-T is that the T-cells may not be able to penetrate the islands. Then, even if the T-cells make it in, theyre faced with a hostile environment and will likely die before they can work.

At Carisma, Gill and his colleagues look to get around these obstacles though a different immune cell called the macrophage. T-cells are not the only players of the immune system, after all. Macrophages are gluttonous cells that recognize invaders and engulf them for destruction. But studies have shown they cluster in solid tumors in a way T-cells dont. Gill hopes genetically engineered macrophages can be the stowaways that sneak into solid tumor and attack from the inside out.

Another big challenge, even for leukemias and lymphomas, is resistance, where the cancers learn to survive the CAR-T infusion. While many patients in the trials achieved remission after a month, we now have two years worth of data and the outlook isnt as rosy. For lymphoma, that number is closer to 40 percent. Patients celebrating cures initially are relapsing later. Why?

The CAR-T cells we use target a specific protein on cancer cells. But if the cancer no longer expresses that protein, that can be a big problem, and were finding thats exactly whats happening. Through blood testing, we see that many patients who relapse lose the target.

Researchers are trying to regain the upper hand by designing CAR-Ts to target more than one receptor. Its an old idea in a new frame: An arms race between our medicines and the illnesses that can evolve to evade them. Too much medical precision in these cases is actually not what we want, as it makes it easier for cancer to pinpoint whats after it and develop an escape route. So, the reasoning goes, target multiple pieces at once. Confuse the cancer.

Then theres the other dreaded c word: Cost. Novartis Kymriah runs up to $475,000 while Kite Pharmas Yescarta is $373,000. That covers manufacturing and infusion. Not included is the minimum one-week hospital stay or any complications.

They are daunting numbers. Some limitations on health care we accept maybe the patients are too sick; maybe they have the wrong disease. The wrong cost is not one we as a society look kindly upon. And drug companies shy away from that kind of attention.

Cost origins in medicine are notoriously murky. Novartis, confident in its technology, made an offer to offset the scrutiny in CAR-T. If the treatment didnt work after one month, the company said it wouldnt send a bill.

Not everyone agrees that cost is an issue. Gill, for example, believes the concern is over-hyped. Its not a major issue, he told me over the phone. Look, of course [with] health care in this country, if you dont have insurance, then youre screwed. That is no different when it comes to CAR-T as it is for anything else, he said. The cost conversation must also put CAR-T in context. Gill went on to list what these patients would be doing otherwise months of chemotherapy, bone marrow transplants, hospital stays for cancer-associated complications and the associated loss of income as patients and caregivers miss work. These could add up to far more than a one-time CAR-T infusion. A bone marrow transplant, for example, can cost from $100,000 to more than $300,000. The cancer-fighting drug blinatumomab, also used to treat relapsed leukemia, costs $178,000 a year. Any discussion of cost is completely irresponsible without weighing the other side of the equation, Gill said.

How the system will get on board is another question. Logistics will be an issue, Gill conceded. The first national Medicare policy for covering CAR-T was announced in August 2019, two years after the first product was approved. The Centers for Medicare and Medicaid Services has offered to reimburse a set rate for CAR T-cell infusion, and while this figure was recently raised, it remains less than the total cost. Despite the expansion of medical uses, at some centers referrals for CAR-T are dropping as hospitals worry its a net loss. And while most commercial insurers are covering CAR-T therapies, companies less accustomed to handling complex therapies can postpone approval. Ironically, the patients considering CAR-T are the ones for whom the window for treatment is narrowest. A delay of even a few weeks can mean the difference between a cure and hospice.

This, of course, poses a big problem. A breakthrough technology is only as good as its access. A major selling point of CAR-T besides the efficacy is its ease. Its a one-and-done treatment. Engineered T-cells are intended to live indefinitely, constantly on the alert if cancer tries to come back. Compare that to chemotherapy or immunotherapy, which is months of infusions or a pill taken indefinitely. CAR-T is more akin to surgery: Cut it out, pay the entire cost upfront, and youre done.

Birzer was lucky in this respect. I asked her and Johnson if cost had factored into their decision to try CAR-T. They looked at each other. It wasnt an issue, said Johnson. They remembered getting a statement in the mail for a large sum when they got home. But Birzer had good insurance. She didnt pay a cent.

* * *

One year after Birzers infusion, I met her and Johnson at a coffee shop near their home in San Francisco. They had saved a table. Johnson had a newspaper open. Birzer already had her coffee, and I noticed her hand trembling as she brought it to her mouth. She described how she still struggles to find exactly the right words. She sometimes flings peas. But shes mostly back to normal, living her everyday life. She has even returned to her passion, performing stand-up comedy, though she admitted that at least for general audiences: My jokes about cancer didnt kill.

People handed a devastating diagnosis dont spend most of their time dying. They are living, but with a heightened awareness for a timeline the rest of us take for granted. They sip coffee, enjoy their hobbies, and read the news while also getting their affairs in order and staying on the lookout, constantly, for the next treatment that could save them.

Hoping for a miracle while preparing to die are mutually compatible ideas. Many of my patients have become accustomed to living somewhere in that limbo. It is humbling to witness. They hold out hope for a plan A, however unlikely it may be, while also adjusting to the reality of a plan B. They live their lives; and they live in uncertainty.

I see patients in various stages of this limbo. In clinic, I met a man with multiple myeloma six months after a CAR-T trial that supposedly cured him. He came in with a big smile but then quietly began praying when it was time to view PET results. He asked how the other patients on the trial were doing, and I shared the stats. While percentages dont say anything about an individual experience, theyre also all patients have to go on. When someone on the same treatment dies, its shattering for everyone. Was one person the exception, or a harbinger of anothers fate? Who is the outlier?

I look at these patients and think a sober truth: Before CAR-T, all would likely die within six months. Now, imagine taking 40 percent and curing them. Sure, a naysayer might point out, its only 40 percent. Whats the hype if most still succumb to their cancer? But there was nothing close to that before CAR-T. I agree with how Gill described it: I think CAR-T cells are like chemotherapy in the 1950s. Theyre not better than chemotherapy theyre just different. For an adversary as tough as cancer, well take any tool we can get.

There remain many questions. Can we use CAR-T earlier in a cancers course? Lessen the side effects? Overcome resistance? Streamline manufacturing and reimbursement? Will it work in other cancers? Patients will sign up to answer.

For now, Birzer seems to be in the lucky 40 percent. Her one-year PET scan showed no cancer. I thought of our last coffee meeting, where I had asked if she ever worried she wouldnt return to normal. She didnt even pause. If youre not dead, she said, youre winning.

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Ilana Yurkiewicz, M.D., is a physician at Stanford University and a medical journalist. She is a former Scientific American Blog Network columnist and AAAS Mass Media Fellow. Her writing has also appeared in Aeon Magazine, Health Affairs, and STAT News, and has been featured in "The Best American Science and Nature Writing."

This article was originally published on Undark. Read the original article.

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