Tag Archives: genetics

This is not how science is done!

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Reading J. Craig Venter & David Ewing Duncan’s Microlands for the Telegraph

Scientists! Are you having fun? Then stop it. Be as solemn as an owl, or else. Your career depends on it. Discoveries are all very well for the young, but dogma is what gets you tenure. Any truths you uncover must be allowed to ossify through constant poker-faced repetition. And Heaven forbid that before your death, a new idea comes along, forcing you to recalculate and re-envision your life’s work!

Above all, do not read Microlands. Do not be captivated by its adventures, foreign places and radical ideas. This is not how science is done!

Though his book edges a little too close to corporate history to be particularly memorable, it is clear that science journalist David Duncan has had an inordinate amount of fun co-writing this account of ocean-going explorations, led by biotechnologist Craig Venter between 2003 and 2018, into the microbiome of the Earth’s oceans.

While it explains with admirable clarity the science and technology involved in this global ocean sampling expedition, Microlands also serves as Duncan’s paean to Venter himself, who in 2000 disrupted the gene sequencing industry before it was even a thing by quickly and cheaply sequencing the human genome. Eight years later he was sailing around the world on a mission to sequence the genome of the entire planet — a classic bit of Venter hyperbole, this, ”almost embarrassingly grandiose” according to Duncan — but as Duncan says, “did he really mean it literally? Does it matter?”

It ought to matter. Duncan is too experienced a journalist to buy into the cliche of Venter the maverick scientist. According to Duncan, his subject is less a gifted visionary than a supreme and belligerent tactician, who advances his science and his career by knowing whom to offend. He’s an entrepreneur, not an academic, and if his science was off by even a little, his ideas about the microbial underpinnings of life on Earth wouldn’t have lasted (and wouldn’t have deserved to last) five minutes.

But here’s the thing: Venter’s ideas have been proved right, again and again. In the late 1990s he conceived a technology to read a long DNA sequence: first it breaks the string into readable pieces, then, by spotting overlaps, it strings the pieces back into the right order. A decade later he realised the same machinery could handle multiple DNA strands — it would simply deliver several results instead of just one. And if it could produce two or three readings, why not hundreds? Why not thousands? Why not put buckets of seawater through a sieve and sequence the microbiome of entire oceans?

And — this is what really annoys Venter’s critics — why not have some fun in the process? Why not gather water samples while sailing around the world on a cutting-edge sailboat, “a hundred-foot-long sliver of fiberglass and Kevlar”, and visiting some of the most beautiful and out-of-the-way places on Earth?

It is amusing and inspiring to learn how business acumen has helped Venter to a career more glamorous than those enjoyed by his peers. More important is the way in which his ocean sampling project has changed our ideas of how biology is done.

For over a century, biology has been evolving from a descriptive science into an experimental one. Steadily, the study of living things has given ground to efforts to unpick the laws of life.
But Venters’ project has uncovered so much diversity in aquatic microbial worlds, the standard taxonomy of kingdom, phylum, and species breaks down in an effort to capture its richness. At the microbial scale, every tiny thing reveals itself to be a special and unique snowflake. Genes pass promiscuously from bacterium to bacterium, ferried there very often by viruses, since they survive longer, the more energy-producing powers they can “download” into their host cell. We already know microbial evolution takes place on a scale of hours. Now it turns out the mechanisms of that evolution are so various and plastic, we can barely formalise them. “Laws of biology” may go some way to explain creatures as big as ourselves, but at the scale of bacteria and viruses, archaea and protozoa, wild innovation holds sway.

The field is simply overwhelmed by the quantity of data Venter’s project has generated. Discovering whether microbes follow fundamental ecological ‘laws’ at a planetary scale will likely require massive, monolithic cross-environment surveys — and many further adventure-travel vacations posing as expeditions by provoking tycoons who love to sail.

Here’s the capping irony, and Duncan does it proud — that Venter, the arch-entrepreneur of cutting-edge genetic science, is returning biology to a descriptive science. We are just going to have to go out and observe what is there — and, says Venter, “that’s probably where biology will be for the next century at least.”

A truth told backwards

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Reading Disputed Inheritance by Gregory Radick for New Scientist, 23 August 2023

In 1865 Gregor Mendel, working to understand the mechanisms of hybridisation, discovered exquisitely simple and reliable patterns of inheritance in varieties of garden pea. Rediscovered in 1900, the patterns of inheritance described in his work revealed the existence of hereditary “particles”. Today, we call these particles “genes”.

Well, of course, there’s more to the story than this. In his ambitious and spirited history of the genetic idea, Leeds-based geneticist Gregory Radick accounts for our much more nuanced, sophisticated ideas of what genetics actually is, and in so doing he asks a deceptively simple question: why, knowing what we know now, do we still bother with Mendel? Why, when we explain genetics to people, do we reach for experiments conducted by a man who had no interest in heritability, never mind evolution, and whose conclusions about heritability (in as much as he ever made any) were quite spectacularly contradicted in experiments by Darwin’s favourite plantsman Thomas Laxton in 1866? (“Where Mendel’s pea hybrids always showed just the one parental character in colour and shape, Laxton’s,” says Radick, “were sometimes blended, sometimes wholly like the one parent, sometimes wholly like the other, and sometimes mosaically like both.”)

The evidence against Mendelian genetics began accumulating almost immediately after its 20th-century rediscovery. The “genetics” we talk about today isn’t Mendelian, it’s molecular, and it arose out of other sciences: microbiology, biochemistry, X-ray crystallography, and later a whole host of data-rich sequencing technologies. “Today’s genome,” Radick explains, “the post-genomic genome, looks more like… a device for regulating the production of specific proteins in response to the constantly changing signals [the cell] receives from its environment.”

The point is not that Mendel was “wrong”. (That would be silly, like saying Newton was “wrong” for not coming up with special relativity.) The point is that we have no real need to be thinking in Mendelian terms at all any more. Couching almost the whole of modern genetics as exceptions to Mendelian’s specious “rules” is to be constantly having to explain everything backwards.

Radick explains why this has happened, and what we can do about it. The seed of trouble was first sown in the battle (at first collegiate, then increasingly cantankerous) between the Cambridge-based William Bateson, who made it his mission to reshape biology in the image of Mendel’s experiments, and Oxford-based Walter Frank Raphael Weldon, who saw that Mendel (whose interest was hybrids, not heredity) had removed from his experiments as many ordinary sources of variability as he could. Real pea seeds are not always just yellow or green, or just round or wrinkled, and Weldon argued that actual variability should not be just idealised away.

“It seems to me that every character is at once inherited and acquired,” Weldon wrote, and of course he was right. The difficulty was what to do with that insight. “It is easy to say Mendelism does not happen,” he remarked to his friend Karl Pearson in March 1903, “but what the deuce does happen is harder every day!”

What Weldon needed, and what he pursued, was an alternative theory of heredity, but the book manuscript setting out his alternative vision was left unfinished at his death, from pneumonia, in April 1906.

Radick’s book champions the underdog, Weldon, over the victorious Bateson. Whether his account smacks of special pleading will depend on the reader’s education and interests. (Less than a century ago, geneticists in the Soviet Union faced ruin and even persecution as they defended the Mendelian idea, insufficient as that idea may seem to us now; temperatures in this field run high.)

This is not the first attempt to lay history’s ghosts to rest, and reset our ideas about genetics. That said, I can’t think of one that’s better argued, more fair-minded or more sheerly enjoyable.

Citizen of nowhere

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Watching Son of Monarchs for New Scientist, 3 November 2021

“This is you!” says Bob, Mendel’s boss at a genetics laboratory in New York City. He holds the journal out for his young colleague to see: on its cover there’s a close-up of the wing of a monarch butterfly. The cover-line announces the lab’s achievement: they have shown how the evolution and development of butterfly color and iridescence are controlled by a single master regulatory gene.

Bob (William Mapother) sees something is wrong. Softer now: “This is you. Own it.”
But Mendel, Bob’s talented Mexican post-doc (played by Tenoch Huerta, familiar from the Netflix series Narcos: Mexico), is near to tears.

Something has gone badly wrong in Mendel’s life. And he’s no more comfortable back home, in the butterfly forests of Michoacán, than he was in Manhattan. In some ways things are worse. Even at their grandmother’s funeral, his brother Simon (Noé Hernández) won’t give him an inch. At least the lab was friendly.

Bit by bit, through touching flashbacks, some disposable dream sequences and one rather overwrought row, we learn the story: how, when Mendel and Simon were children, a mining accident drowned their parents; how their grandmother took them in, but things were never the same; how Simon went to work for the predatory company responsible for the accident, and has ever since felt judged by his high-flying, science-whizz, citizen-of-nowhere brother.

When Son of Monarchs premiered at this year’s Sundance Film Festival, critics picked up on its themes of borders and belonging, the harm walls do and all the ways nature undermines them. Mendel grew up in a forest alive with clouds of Monarch butterflies. (In the film the area, a national reserve, is threatened by mining; these days, tourism is arguably the bigger threat.) Sarah, Mendel’s New York girlfriend (Alexia Rasmussen; note-perfect but somewhat under-used) is an amateur trapeze artist. The point — that airborn creatures know no frontiers — is clear enough; just in case you missed it, a flashback shows young Mendel and young Simon in happier days, discussing humanity’s airborne future.

In a strongly scripted film, such gestures would have been painfully heavy-handed. Here, though, they’re pretty much all the viewer has to go on in this sometimes painfully indirect film.
The plot does come together, though, through the character of Mendel’s old friend Vicente (a stand-out performance by the relative unknown Gabino Rodríguez). While muddling along like everyone else in the village of Angangueo (the real-life site, in 2010, of some horrific mine-related mudslides), Vicente has been developing peculiar animistic rituals. His unique brand of masked howling seems jolly silly at first glance — just a backwoodsman’s high spirits — but as the film advances, we realise that these rituals are just what Mendel needs.

For a man trapped between worlds, Vicente’s rituals offer a genuine way out: a way to re-engage imaginatively with the living world.

So, yes, Son of Monarchs is, on one level, about identity, about how a cosmopolitan high-flier learns to be a good son of Angangeo. But more than that, it’s about personality: about how Mendel learns to live both as a scientist, and as a man lost among butterflies.

French-Venezuelan filmmaker Alexis Gambis is himself a biologist and founded the Imagine Science Film Festival. While Son of Monarchs is steeped in colour, and full of cinematographer Alejandro Mejía’s mouth-watering (occasionally stomach-churning) macro-photography of butterflies and their pupae, ultimately this is a film, not about the findings of science, but about science as a vocation.

Gambis’s previous feature, The Fly Room (2014) was about the inspiration a 10-year-old girl draws from visits to T H Morgan’s famous (and famously cramped) “Fly Room” drosophila laboratory. Son of Monarchs asks what can be done if inspiration dries up. It is a hopeful film and, on more than the visual level, a beautiful one.

We may never have a pandemic again

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Reading The Code Breaker, Walter Isaacson’s biography of Jennifer Doudna, for the Telegraph, 27 March 2021

In a co-written account of her work published in 2017, biochemist Jennifer Doudna creates a system that can cut and paste genetic information as simply as a word processor can manipulate text. Having conceived a technology that promises to predict, correct and even enhance a person’s genetic destiny she says, not without cause, “I began to feel a bit like Doctor Frankenstein.”

When it comes to breakthroughs in biology, references to Mary Shelley are irresistible. One of Walter Isaacson’s minor triumphs, in a book not short of major triumphs, is that, over 500 pages, he mentions that over-quoted, under-read novel less than half a dozen times. In biotechnology circles, this is probably a record.

We explain science by telling stories of discovery. It’s a way of unpacking complicated ideas in narrative form. It’s not really history, or if it is, it’s whig history, defined by a young Herbert Butterfield in 1931 as “the tendency… to praise revolutions provided they have been successful, to emphasise certain principles of progress in the past and to produce a story which is the ratification if not the glorification of the present.”

To explain the science, you falsify the history.
So all discovers and inventors are heroes on the Promethean (or Frankensteinian) model, working in isolation, and taking on the whole weight of the world on their shoulders!

Alas, the reverse is also true. Telling the true history of discovery makes the science very difficult to unpack. And though Walter Isaacson, whose many achievements include a spell as CEO of the Aspen Institute, clearly knows his science, his account of the most significant biological breakthrough since understanding the structure of DNA is not the very best account of CRISPR out there. His folksy cajoling — inviting us to celebrate “wily bacteria” and the “plucky little molecule” RNA — suggests exasperation. Explaining CRISPR is *hard*.

The Code Breaker excels precisely where, having read Isaacson’s 2011 biography of Steve Jobs, you might expect it to excel. Isaacson understands that all institutions are political. Every institutional activity — be it blue-sky research into the genome, or the design of a consumer product — is a species of political action.

The politics of science is uniquely challenging, because its standards of honesty, precision and rigour stretch the capabilities of language itself. Again and again, Doudna’s relationships with rivals, colleagues, mentors and critics are seen to hang on fine threads of contested interpretation. We see that Doudna’s fiercest rivalry, with Feng Zhang of the Broad Institute of MIT and Harvard, was conducted in an entirely ethical manner — and yet we see both of them stumbling away, bloodied.

Isaacson’s style of biography — already evident in his appreciations of Einstein and Franklin and Leonardo — can be dubbed “qualified hagiography”. He’s trying to hit a balance between the kind of whig history that will make complex materials accessible, and the kind of account that will stand the inspection of academic historians. His heroes’ flaws are explored, but their heroism is upheld. It’s a structural device, and pick at it however you want, it makes for a rattlingly good story.

Jennifer Doudna was born in 1964 and grew up on Big Island, Hawaii. Inspired by an old paperback copy of The Double Helix by DNA pioneer James Watson, she devoted her life to understanding the chemistry of living things. Over her career she championed DNA’s smaller, more active cousin RNA, which brought to her notice a remarkable mechanism, developed by single-celled organisms in their 3.1-million-year war with viruses. Each of these cells used RNA to build their very own immune system.

Understanding that mechanism was Doudna’s triumph, shared with her colleague Emmanuelle Charpentier; both conspicuously deserved the Nobel prize awarded them last year.

Showing that this mechanism worked in cells like our own, though, would change everything, including our species’ relationship with its own evolution. This technology has the power to eradicate both disease (good) and ordinary human variety (really not so good at all).

In 2012, the year of the great race, Doudna’s Berkeley lab knew nothing like enough about working with human cells. Zhang’s lab knew nothing like enough about the biochemical wrinkles that drove CRISPR. Their rivalrous decision not to pool CRISPR-Cas9 intellectual property would pave the way for an epic patent battle.

COVID-19 has changed all that, ushering in an extraordinary cultural shift.. Led by Doudna and Zhang, last year most academic labs declared that their discoveries would be made available to anyone fighting the virus. New on-line forums have blossomed, breaking the stranglehold of expensive paywall-protected journals.

Doudna’s lab and others have developed home testing kits for COVID-19 that have a potential impact beyond this one fight, “bringing biology into the home,” as Isaacson writes, “the way that personal computers in the 1970s brought digital products and services… into people’s daily lives and consciousness.”

Meanwhile genetic vaccines powered by CRISPR — like the ones developed for COVID-19 by Moderna and BioNTech/Pfizer — portend a sudden shift of the evolutionary balance between human beings and viruses. Moderna’s chair Noubar Afeyan is punchy about the prospects: “We may never have a pandemic again,” he says.

The Code Breaker catches us at an extraordinary moment. Isaacson argues with sincerity and conviction that, blooded by this pandemic, we should now grasp the nettle, make a stab at the hard ethical questions, and apply Doudna’s Promethean knowledge, now, and everywhere, to help people. Given the growing likelihood of pandemics, we may not have a choice.

 

Worth losing sleep over

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Watching Human Nature, directed by Adam Bolt, for New Scientist, 27 November 2019.

Mature and intelligent, Human Nature shows us how gene editing works, explores its implications and – in a field awash with alarmist rhetoric and cheap dystopianism – explains which concerns are worth losing sleep over.

This gripping documentary covers a lot of ground, but also works as a primer on CRISPR, the spectacular technology that enables us to cut and paste genetic information with something like the ease with which we manipulate text on a computer. Human Nature introduces us to key start-ups and projects that promise to predict, correct and maybe enhance the genetic destinies of individuals. It explores the fears this inspires, and asks whether they are reasonable. Its conclusions are cautious, well-argued and largely optimistic.

Writers Regina Sobel and Adam Bolt (who also directs) manage to tell this story through interviews. Key players in the field, put at their ease during hours of film-making, speak cogently to camera. There is no narration.

Ned Piyadarakorn’s graphics are ravishing and yet absurdly simple to grasp. They need to be, because this is an account hardly less complex than those in the best popular science books. As the film progressed, I began to suspect that the film-makers assume we aren’t idiots. This is so rare an experience that it took a while to sink in.

There are certain problems the film can’t get round, though. There are too many people in white coats moving specks from one Petri dish to another. It couldn’t be otherwise, given the technology involves coats, specks, Petri dishes and little else by way of props the general viewer can understand. That this is a source of cool amusement rather than irritation is largely due to the charisma of the film’s cast of researchers, ethicists, entrepreneurs, diagnosticians, their clients and people with conditions that could be helped by the technique, such as schoolboy David Sanchez, who has sickle-cell anaemia. We learn that researchers are running clinical trials using CRISPR to test a therapy for his condition.

Foundational researchers like Jennifer Doudna and Jill Banfield, Emmanuelle Charpentier and Fyodor Urnov provide star quality. Provocateurs like Stephen Hsu, a cheerful promoter of designer babies, and the longevity guru George Church are given room to explain why they aren’t nearly as crazy as some people assume.

Then the bioethicist Alta Charo makes the obvious but frequently ignored point that the Brave New World nightmare CRISPR is said to usher in is a very old and well-worn future indeed. Sterilisations, genocide and mass enslavement have been around a lot longer than CRISPR, she says, and if the new tech is politically abused, we will only have our ourselves to blame.

There is, of course, the possibility that CRISPR will let loose some irresistibly bad ideas. Consider the mutation in a gene called ADRB1, which allows us to get by on just 4 hours’ sleep a night. I would leap at the chance of a therapy that freed up my nights – but I wonder what would happen if everyone else followed suit. Would we all live richer, more fulfilled lives? Or would I need a letter from my doctor when I applied for a 16-hour factory shift?

The point, as Human Nature makes all too clear, is that the questions we should be asking about gene editing are only superficially about the technology. At heart, they are questions about ourselves and our values.