Book Review: A Crack in Creation by Jennifer Doudna and Samuel Sternberg

crack in creation

Shortly after I finished reading Jennifer Doudna and Samuel Sternberg’s book on the development of the CRISPR gene editing technology, CRISPR was leading the news headlines. Shoukhrat Mitalipov and his international team announced their successful and efficient correction of a mutant MYBPC3 gene which causes the condition hypertropic cardiomyopathy, the cause of many of the sudden heart attacks in young people, in non-viable human embryos.  Though it took some time for the news stories to use the word “CRISPR”, as it is not yet a household name, the news sparked many opinion pieces warning of  a slippery slop, down which we will be lead to “designer babies”. But these are the same arguments we have been having since the dawn of the recombinant DNA era in the 1970s, with little reconsideration in light of the actual facts of how the technology and the  human genome works. What I found lacking in these analyses was a thorough understanding of the actual scope and limits of CRISPR gene editing technology. Gladly, A Crack in Creation offers such a nuanced background straight from those deeply embedded in the science; Jennifer Doudna is one of the scientists leading the development of CRISPR gene editing and Samuel Sternberg started his career as Doudna’s doctoral student.

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Media coverage of the latest CRISPR story, from Eric Topol’s twitter.

The acronym CRISPR stands for the cumbersome phrase  “Clustered Regularly Interspaced Short Palindromic Repeats”. This refers to clustered stretches of base pairs in the genome of bacteria which are the same backwards as they are forwards, with non-repetitive “spacers” between them. Bacteria don’t tend to have superfluous parts to their genome, so researchers before Doudna were prompted to investigate their function. The spacer sequences were found to be derived from viral DNA, and the CRISPR sequences were found to be associated with the Cas proteins, which can cut DNA. With this information, the mechanism was pieced together. When the bacterium is infected with a virus, the cell copies this DNA and inserts it between the palindromic repeats. This acts as a cellular “memory”, so that when the same strain of virus infects the cell, it can transcribe into RNA the “memorised” sequence and use the RNA fragments to guide the Cas9 protein to the viral DNA. Cas9 then cuts the DNA with the characteristic double-strand cut. This allows bacteria to have something like the mammalian innate immune system, but unlike the immune system, CRISPR “immunity” involves infection leading to changes in DNA. This opens up the potential for this system of DNA editing, honed by evolution, to be adapted for human ends.

Doudna and Sternberg place CRISPR in the context of previous gene editing technologies, such as TALENs and zinc finger nucleases, which acted in a similar way to the CRISPR system, and the long history of largely unsuccessful gene therapies. This gives the reader the proper context of gene editing as not a quantum leap but a progression from cruder technologies. CRISPR seems startling only because we are now drawing on nature’s more efficient solutions rather than the fumbling designs of the human hand.

Jennifer Doudna was at the forefront of CRISPR emergence from obscure microbial trick to a potentially powerful tool. She and her colleagues modified Cas9 and produced a simpler guide RNA, allowing CRISPR to be used to alter the DNA of all organisms in which it has been attempted. Alongside their work, Doudna and Sternberg also stepped out from the shadows of academia and onto the public stage. These years of public engagement and consultation with policy makers have allowed Doudna and Sternberg to hone their explanations of the science and to explore the implication with skill, the great strength of the book.

Their main ethical concerns with CRISPR are in regards to its use in germ cells and embryos, as this would alter the genetic constitution of the person and their descendants permanently. Doudna and Sternberg don’t call for rigid ban on this editing in all cases, but would rather scientists refrain from implementing this until the safety and efficacy concerns are addressed and there has been a public conversation on whether we should alter the future of humanity in this manner. Instead, Doudna and Sternberg champion the therapeutic use of CRISPR by editing the DNA of somatic cells. This only alters the DNA of the organ or area treated in the patient, and cannot affect their offspring, and could potential eradicate HIV, hemophilia and similar diseases.

Doudna and Sternbrg do stress throughout the book that the technology is currently imprecise and produces a mosaic of altered and unaffected cells in treated tissues. However, the work done by Mitalipov et al and others show that these challenges are being rapidly overcome. The authors’ reliance on the current inefficiencies of CRISPR technologies to suggesting that it will not be the path to designer babies does lack persuasive power. For the non-specialists seeing seemingly miraculous developments emerge every month now, technical barriers seem only temporary, until the next bit of lab-based magic happens. They give little consideration to the main concerns of those predicting a eugenic future, not just that the genes of embryos may be edited but that they will be altered so as to produce a monoculture of blue-eyed Übermensch. This is unlikely to happen not necessarily due to technological limits, but most importantly due to the extreme ambiguity of human development and gene expression. There is no gene for musical virtuosity, and even a relatively simple trait like eye colour is determined and influence by a myriad of different genetic pathways, perturbations in any of which may or may not alter the outcome. And then there are the environmental influences which can make the difference between the virtuoso and the tone-deaf.

For all of these reasons, gene editing will have a limited impact on the complex traits that cause middle-class parents so much anxiety, but it could have a significant impact on the incidence of traits and diseases with simple or Mendelian genetic causes. CRISPR could never bring about the Übermensch, but if germ cell and embryonic editing occurs, if only in China, for example as there is already the desire to do so, then diseases like Huntington’s, but also deafness and some learning disabilities, could begin to disappear from the population.  CRISPR gene editing of embryos poses questions regarding the diversity of the human gene pool,  whether we can propose to alter it, and if so, what of the limited amount of diversity we can affect do we want to alter?

Stylistically, the book is written in Doudna’s voice, but I gather it was Sternberg’s idea to write it. This gives the work some anchoring in the life of human beings, conveying the collaborative nature of the field as well as the human frailties that lie behind the top-tier publications. The book opens with Doudna’s anxiety dream of being subsumed by a wave, which she suggests symbolises her being overwhelmed by the enormous ethical implications of her work. Later, they recount a far more unsubtle dream in which a pig-faced Hitler asks Doudna to explain the CRISPR technology to him, which needs no explanation. This gives the book an accessible moral sensibility, the ethics are not discussed entirely dispassionately and academically, but from the viewpoint of someone who do not want their work to be used for evil. But the personal slant is limited and Doudna’s emotional responses feel mediated as the book is co-authored, and so lose some of their power. I would have liked to have seen more of the mind of the scientist at work, to understand a real-life Victor Frankenstein, though given how soon after the introduction of CRISPR gene editing the book was written, the first Doudna et al. CRISPR paper was only published in 2012, it is too early to expect a tell-all memoir like Watson’s The Double Helix.

On the whole, A Crack in Creation is a very clear explanation of the science and considered and non-diadactic exploration of associated ethical concerns, inviting the reader to stop and consider the implications in an informed manner rather than being swept up in an ill-informed media furor. And at the very least, it will provide a wealth of material fro Doudna to draw upon when she makes her no-doubt forthcoming Nobel Prize acceptance speech.

 

 

Book Review: The Secret Life of Flies by Erica McAlister

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In his vibrant ‘social history’ of the Natural History Museum Dry Store Room Number 1, Richard Fortey gives the reader a glimpse into the more obscure corners of the museum. Some of the more curious researchers disturbed by Fortey’s prying, like woodlice fleeing an upturned rock, are the dipterist. Fly experts have a reputation for spending their days counting hairs on legs down a microscope, one of the key identification features for fly species. Erica McAlister is a dipterists of a very different generation to the solitary creatures of Fortey’s study. Modern curators must leave their dusty corners and go out into the world to justify their obscure interests to the general public.

With public engagement in mind, the Natural History Museum has published a number of popular science books by their researchers on topics ranging from lichens to bats, the latest of which is McAlister’s The Secret Life of Flies. From the outset, McAlister faces the challenge of the poor public image of flies, as most consider them to be filthy pests which should be swatted quickly and not studied. But McAlister is a persuasive champion of flies in all their forms, and the book gives an overview of this surprisingly diverse and fascinating group.

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Forcipomyia sp.

McAlister stresses early on in the book the useful roles flies play in providing some of our favourite foods. Flies are important pollinators of many plants including mango, black pepper and carrots. But the choicest evidence for the pro-fly case is the chocolate midge Forcipomyia, pollinator of chocolate. But the flies have their pollinating prowess overlooked in favour of the bees, which McAlister clearly thinks is unfair.

Flies are far more diverse a group than those familiar only with the house fly would think. One in ten of every species described is a fly, and McAlister stresses throughout the book the understudied nature of the group, even in compared to the beetles, let alone the mammalian charismatic megafauna. Therefore, McAlister makes a case for the charismatic minifauna.

The book is structured so that each chapter details one of the ways of life that flies have evolved to carry out. There are the detritivores, who help rid the world of rotting vegetation, such as the adorable drain fly. The coprophages include the living punchline to the old joke “what do you call a fly with no wings?”. It is referred to as the bat fly, or Mystacinoba zelandica, rather than a walk, and has lost its wings in favour of clinging to the fur of bats. Then there are the more grisly species; the predators like the fearsome soldier flies and the parasites including the flesh-eating bot fly larva and the parasitoid thick-headed fly larvae who kill their hymenopteran hosts. But even these species can be useful, as McAlister stresses that the parasite of a pest is an ally. Then there are the bloodsuckers, most infamously the mosquitos. McAlister never vilifies the species she describes, and she finds beauty in even the more unlikable groups, such as the vivid metallic female Sabethes tarsopus mosquito.

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Sabethes tarsopus

The book is written in an informal style. I counted two “by gum”s, included presumably to fulfill the publisher’s quota of delightful British idioms. McAlister takes an intellectual and aesthetic delight in her topic. She finds charisma in her minifauna, the grey bee fly and Cuterebra emasculator must be vying for the honor of being McAlister’s cutest flies.  The book does not try to be a textbook introduction to the dipterans, rather takes interesting or illustrative species. This does run the risk of not giving the reader a conceptual understanding of the topic, so the case studies become unmoored without the appropriate context. McAlister does provide this basic information throughout the book, but often later than would be most appropriate. For instance, halteres are only mentioned over two hundred pages in, is a key distinguishing feature of the flies, though not terribly interesting, I admit.

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Grey bee fly

The book is lively and richly illustrated and gives an impression both of the enormous complexity of the order Diptera and the life of a curator, which is spent as much collecting flies in far flung locations as pushing pins through specimens. The profession has come a long way since the days of curators hiding away in dusty corners, now more curators enter the public stage to defend their work and earn their keep. This book shows that public engagement is not merely a box ticking exercise but a vital part of shaping knowledge and helping preserve biodiversity.

The Poison Chronicles: Bryony – Deadly Margins

I’ve written a blog post on White Bryony for the Manchester Museum Herbarium.

Herbology Manchester

Guest Post by Laura Cooper

WP_20170307_08_08_25_Pro Margin Illustrations from The Hours of Jeanne de Navarre. Image Source.

The Hours of Jeanne de Navarre is one of the most famous and beautiful illuminated manuscripts. It is a collection of prayers and psalms for each of the hours of the medieval religious day made for the personal use of the Queen of Navarre somewhere between 1328-1343. The book is lavishly and elegantly decorated with images of saints and angels framed by a naturalistic border. This curling foliage has been referred to as ivy, but was identified by Christopher de Hamel actually white bryony, Bryonia dioica.

Bryony is a notoriously poisonous plant, so the scenes the illuminator painted are far from idyllic. As de Hamel writes in his book Meetings with Remarkable Manuscripts,“The world in the medieval margins is not a comfortable place, any more than the gilded life of Jeanne de…

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Book Review: Tristimania by Jay Griffiths

tristamania

Writing a good memoir of mental illness must be like navigating rough seas. It is easy to have your boat buffeted by the storms of trite melodrama, glamourising of sickness (or accusation of), boring the reader with the wasteland of depression or a scaring them off by a display of wounds still bleeding. But with her latest book Tristimania, Jay Griffiths sails as if on a smooth lake. She at once conveys the raw truth of her experiences of mental illness and synthesises it into a network of literary and cultural associations to form an effortless whole.

The book is subtitled A Diary of Manic Depression, evidently added by the publisher to make plain the subject of the book; the term “tristimania” is a now obscure 18th century term for manic depression. Referring to the book as a diary is probably to fit it into the market for confessional non-fiction writing. The book does have a large element of this, but anyone expecting it to be a journal written in an acute hypomanic episode will be misled. As Griffiths would no doubt point out, the word “diary” derives from the Latin diarium, translating as daily allowance. Tristimania has few dates and the this retrospective charting of a rough chronology of a recent year of hypomania is frequently interspersed with exploration of the figure of the manic-depressive in culture. She draws upon myths of Mercury, the trickster and the shaman and explores etymology and Shakespeare. The book shows a mind agile and eager to make sense of herself in the world, but this does give the narrative a sense of disjointedness..There is not a clear tug of narrative through much of it; it meanders and I found myself flicking through the book to see where exactly this was going and little would have been lost by excising some discussion of Mercury and trickster. But such nebulous writing is rather like acute mental illness itself. A spell of illness is a break from the narrative flow of life as planned, in its place are days that all run into one another, which is why sculpted mental illness narratives so often ring false. The book is complicated and knotty, it is not a matey autobiography of a comedian or a celebrity self-help memoir, but much more can be learnt from this than something more easily digestible.

Griffiths has mixed-state manic-depression, an under-discussed condition where mood cycling is rapid and rather than the summit of mania, there is hypomania in the foothills. She acknowledges her hypomania and depression is not as dramatic and destructive as it can be for some. A more pedestrian telling of her experience would be rather dull, she spends the year hunkered down at home with friends and her wonderful doctor, no gambling, promiscuity or drug use. Eventually the medication starts to work and whilst she is still rallying she sets out solo to walk the Camino de Santiago de Compostela. It is not a story of a miraculous recovery; she is incredibly fortunate to have a good doctor that leads her out of her acute spell of madness as well as meds that work and supportive friends, as well as of course the written word.

She takes a romantic, humanistic approach to mental illness. She doesn’t dwell on her brain misfiring and neurotransmitter imbalance, instead talks of the psyche, myth and etymology, digging down into the hidden histories of the words in our mouths. She is a writer enraptured with words, their meaning and importance. She is most luminous on metaphor: “’Meta-phor’, in its etymology, means a carrying-across of attributes from one thing to another. […] If a person uses a metaphor, they are carrying themselves over, towards the listener, but in madness this need becomes infinitely more intense. In a manic-depressive episode, metaphors are heavy with meaning, and the metaphors one chooses must carry an almost unbearable weight. This, I think, is why people are so stubborn about repeating the precise metaphors which tell their truth.” She places her doctor’s following of her metaphors as key to her recovery. The book is profoundly literary, though naturally my library has shelved it in the “Shelf Help” section, as this is rapidly becoming the NHS mental health services. But worthy of the librarians’ decision, this literarity is tied to a belief in the healing power of words, texts and stories.

The retrospective layering of scholarship and intertextual references is making plain what all recollections of a personal spell of madness are, a reconstruction. The prose is not from the eye of the storm, she makes it clear she would have not been able to, but at a few years’ distance. What struck me within the first fifty pages was the poeticism of the prose, and surely Griffiths writes “What does it want, this madness? Language. In my case, specifically, poems.” She yearns for and writes poems during her months of hypomania, and on the Camino de Santiagio de Compostela reads and gives out poems to fellow pilgrims from an anthology compiled by friends. After the prose testimony, where we leave Griffiths “small but alive”, there are a series of luminous, acute poems written during hypomania. The poetry and prose deal with the same events, such as the night thoughts of suicide were scuppered by the cat bringing in a dead treecreeper from the snow, but with different aspects of authorial mood, form and temporal relation. It is an interesting exploration of the two forms, but the unexepected appearance of the poems could lead the prose to feel superfluous, especially to the reader bored by Griffiths banging on about Mercury and The Winter’s Tale.

What is so often left out of the “miracle recovery” mental illness narratives is how even illnesses that can manifest so acutely as Griffiths’ does cannot be comparentmentalised from the self. As she writes: “To me, the experience of having manic depression can never be separated from my sense of who I am. It runs through me like wine through water: everything is coloured (or tainted) by it.” She certainly doesn’t glamourise her hypomania, it makes her dependent and physically weak, but also takes a rather culturally relative stance on the nature of illness and society. In the right environment, the manic-depressive aspects of her personality that are always there can be an asset; in the past they were for the court jester, the shaman and to an extent the modern artist. As she writes “it seems to me that we, the bipolar-mad of today, take the role of the unemployed court jester, crying for our demeaned status as living ruins when, in the remains of magic, mystery and majesty, we are reduced to pathology. If we do not have a role worthy of our wodness [an Old English term, referring to a frenzied madness] , then we will be ill, for illness is the only category which our culture allows us in this age of literalism […]”. The task of society is not to ameliorate the dysfunctioning mind, but to make viable ways for these people to apply themselves to what they do best, art or magic or both, for the sake of the wellness of all in society. Those with the skill, vision, bravery and honest of Griffiths must tell their stories and reveal their minds in order for us to inch day by day closer to such as world.

Book Review: Flower Hunters by Mary Gribbin and John Gribbin

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I’ve spent a fair amount of the last six months in the quiet corridors of the Manchester Museum Herbarium, helping with a lengthy transfer of packets of the General Moss collection from filing cabinet to boxes. Sifting through sheets and packets, I can trace the patterns that the personalities of the different collectors etch in the collection. I see the differences in packeting; ‘stuffers’ who see the size of the envelope as the minimum target and the ‘folders’, who encase tiny scraps in tissue-thin paper, the localities visited and the specimens selected which different personalities pick. It is inevitable that any Herbarium collection is filtered through the collectors’ passions and whims. Therefore, when I found a copy of Mary and John Gribbin’s Flower Hunters in the library, I picked it up out of a desire to learn more about the collectors whose specimens fill the shelves of herbaria throughout the world.

The book traces a history of botany up until the 20th century, when there still existed territories unaltered by human hands. There is a distinct horticultural slant, but does cover scientific and economic botany which interests me more. There is also more of a stress on Hunters than Flowers; biographic minutiae trumps botanical detail. I would have liked to have seen more on the bryophytological loves of Richard Spruce, for example, to get a feel for his mind and passions.

Across the biographical chapters of individual botanists, what piqued my interest was how class influence how these collectors could practice and were rewarded for their work. Whilst all suffered on arduous, years long journeys around the world, the gentleman (and gentlewoman) naturalist had a retinue and global connections. Their resources permitted the intellectual freedom to see global patterns in vegetation, which fueled evolutionary and ecological thinking. In contrast, working-class commercial plantsmen were sent out on their own and expected to keep their heads down, looking for the economically not intellectually fruitful, but only seeing the smallest slice of the profits their seeds and plants made.

The book is structured roughly chronologically, with each chapter on the life of a plant collector (or collaborating pair), hence showing the changing shape of science and adventure. The structure works well in the beginning, the early classification system of John Ray (1627-1705) is followed by the more familiar classification of Linnaeus (1707 – 1778). I was surprised to learn that Ray’s somewhat cumbersome classification based on essential features of the plant (such as the dicotyledon/ monocotyledon division still current) blended with Linnaeus’ user-friendly classification system based on somewhat arbitrary features (Crytogamia, anybody?) to create the bones of modern plant taxonomy. Linnaeus is not the origin of plant taxonomy, he had his own forerunners as well. We then move to Joseph Banks (1743 – 1820), the de facto first director of the Royal Botanic Gardens at Kew and friend of George III who accompanied Captain Cook on the Endeavour. Here scientific curiousity is inseparable from imperial ambition, Banks saw the land and flora of the Pacific as ripe for “improvement” and exploitation.

Then follows the plantsmen, sent as the somewhat disposable employees of private companies into unmapped territory. These include David Douglas (1799-1834) sent alone on starvation pay by the Royal Horticultural Society to discover and collect plants including his eponymous fir and the Sugar Pine in North America. Expected to live on the land and employ local guides, his health was ruined, losing most of his vision and becoming rheumatic. He died in a bizarre, tragic manner; on Hawaii, his poor eyesight caused him to fall into an animal trap where he was gored by the trapped bull.

We then move onto a pair of similarly intrepid plantsmen, William and Thomas Lobb, who also brought large trees back to their employers. But with the later plant hunter, Robert Fortune (1812-1880), the voyages become more routine. His work involved trading, officially and unofficially, with other plant breeders in China. His notable achievement was in service of the British Empire, he was the first to take viable tea seeds out of China to establish successful plantations in India, ending China’s monopoly on tea. Though economic considerations went into even Linnaeus’ botanising, consideration of profit becomes more naked and unscrupulous.

Bucking the arch of the narrative is the figure of Marianne North (1830-1890). A wealthy woman, she circled the globe without the expected chaperone, not plant hunting for profit or for a scientific institute (as none would employ a woman to do so) but for her art. She was an incredible prolific botanical artist who, unusually for the time, painted plants in situ. She worked rapidly and in oils, producing what the Gribbins describe as not highly detailed but more importantly accurate. They are not plants “murder[ed] to dissect” but alive in their habitat, an ecological not an anatomical painter. I am hesitant to criticize the inclusion of North as I admire her as an intrepid artistic woman. But she does stick out of a narrative trend of increasing commercialization of plants precisely because she was not a plant hunter, with all it’s masculine connotations. She did not bring back the plants themselves as trophies, but her own impressions of the plants and their environments captured in the paintings. If her story was in the context of a discussion of the growing ecological understanding, amongst the stories of Alexander von Humboldt and Alfred Russell Wallace for example, it would make sense. But here it feels like she was shoehorned as “the woman” in a history of a period and profession which was more or less uniformly masculine. The best way to appreciate women’s contribution to science is to place them in their intellectual context, not to include them in a place where their lives seem superfluous and dismissable.

The final story is that of Joseph Dalton Hooker (1817-1911), who I know best for the Bentham & Hooker System of classifying seed plants which the Manchester Museum Herbarium (and many other herbaria) arrange their specimens by to this day. This is not discussed in the book, sadly, as it would make a nice narrative circle from Ray and Linnaeus to Hooker. The focus is instead upon Hooker’s botanising in the Himalayas. He was one of the earliest Europeans to explore the Tibetan Plateau, and is largely responsible for the flourishing of rhododendrons in the gardens (and countryside!) of Britain. Less destructively, his collections form integral parts of many herbaria in Britain, including Manchester’s.

A book such as this does run the threat of superficiality and glaring omission (Darwin is conspicuously but understandably absent, but aside from Linnaeus there is an absent of the non-Britons). But more important is cohesion, which it ultimately lacks. It doesn’t make any conclusions about the state of botanical science in this period, merely presenting fascinating stories.  A book which treated the hunters and their plants on the same level, giving biographical and evolutionary detail alongside each other, would have made maybe a more enjoyable, tightly structured book.

 

The Poison Chronicles: Calabar Bean – A Life-Saving Ordeal

Another of my posts on the Manchester Museum Herbarium blog, on when an ordeal can become a remedy.

Herbology Manchester

calabar-bean-1 Calabar beans and seed cases from the collection of the Manchester Museum Herbarium. 

Guest Post by Laura Cooper

For much of human history, people have sought to find a way to prove or disprove a person’s guilt. Today, we hope evidence and a fair trial will do this, but people have always wanted a quick and definitive way of doing this. This is where the idea of the trial by ordeal came in. Most people are familiar with the practice of dunking suspected witches in bodies of water in parts of 17th century Europe; if they floated they were guilty and if they sunk they were innocent. But in what was then called the Calabar region (now North-East Nigeria) in the 19th century, a particularly poisonous seed was used in these trials by ordeal. This plant, known as the Calabar bean, Physostigma venenosum, became notorious as a…

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The Poison Chronicles: Cyanide -Cassava’s Built in Pesticide

Another post on the Manchester Museum’s Herbarium blog, on cyanide and cassava.

Herbology Manchester

Guest Post by Laura Cooper

wp_20170109_11_56_21_proManihot esculenta leaf sewn onto this Herbarium sheet.

I remember hearing as a small child the rumour that swallowing a single apple seed would kill you. Whilst I later learnt that this was false, it is true that the cyanide in apple seeds means that theoretically, chewing a large number could cause poisoning.

Cyanide is a simple chemical produced by many organisms, often as an unwanted by-product. But cyanide is found in relatively high levels in many plant species, including the seeds of many common food plants, such as peaches, almonds, and legumes.

cassava Manihot esculenta tubers, sold as cassava or yuca. Source.

The cyanogenic plant I will focus on here is cassava, Manihot esculenta, also known as yucca. It’s tubers are a major carbohydrate source throughout the tropics due to its drought tolerance and ability to thrive in poor soil. It is probably most…

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