Posts Tagged ‘genetics’
“The most outstanding feature of life’s history is a constant domination by bacteria”*…
Jennifer Kahn interviews biochemist Jennifer Doudna (who won the Noel Prize for the gene-editing engine Crispr) on her new focus– our microbiomes, tackling everything from immune disorders and mental illness to climate change—all by altering microbes in the digestive tract…
… what isn’t the microbiome responsible for? It’s been all the rage for the past few years, with scientists hoping it could help treat everything from immune disorders to mental illness. How exactly that will work is something we’re just starting to explore. This spring, the effort got a boost when UC Berkeley biochemist and gene-editing pioneer Jennifer Doudna, who won a Nobel Prize in 2020 for coinventing Crispr, joined the pursuit. Her first order of business, spearheaded by Berkeley’s Innovative Genomics Institute: fine-tuning our microbiome by genetically editing the microbes it contains while they’re still inside us to prevent and treat diseases like childhood asthma. (Full disclosure: I teach at Berkeley.) Oh, she also wants to slow climate change by doing the same thing in cows, which are collectively responsible for a shocking amount of greenhouse gas.
As someone who has written about genetic engineering in the past, I have to admit that my first reaction was: No way. The gut microbiome contains around 4,500 different kinds of bacteria plus untold viruses, and even fungi (so far: in practice we’ve only just started counting) in such massive quantities that it weighs close to half a pound. (Microbes are so tiny that 30 trillion bacteria would weigh roughly 1 ounce. So half a pound is a lot.)
Figuring out which ones are responsible for which ailments is tricky. First you need to know what’s causing the problem: like maybe something is producing too much of a particular inflammatory molecule. Then you have to figure out which microbe—or microbes—is doing that, and also which gene within that microbe. Then, in theory, you can fix it. Not in a petri dish, but in situ—meaning in our fully active, roiling, squishing stomach and intestines while they continue to do all the stuff they usually do.
Until recently, it would have seemed insane—not to mention literally impossible—to edit all the microbes belonging to a species within a vast ecosystem like our gut. And to be fair, Doudna and her collaborator, Jill Banfield, still don’t know quite how it will work. But they think it can be done, and in April, TED’s Audacious Project donated $70 million to support the effort. My own gut feeling (right?) was that this was either brilliant or terrifying, or possibly both at once. Brilliant because it had the potential to head off or treat diseases in an incredibly targeted and noninvasive way. Terrifying because, well, you know … releasing a bunch of inert viruses equipped with gene-editing machinery into the vital ecosystem that is our gut microbiome—what could go wrong? With that in mind, I invited Jennifer Doudna to my house for a chat about the future of microbiome medicine…
Fascinating– and encouraging: “Crispr Pioneer Jennifer Doudna Has the Guts to Take On the Microbiome,” in @WIRED.
(Image above: source)
* Stephen Jay Gould
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As we investigate our intestines, we might spare a thought for Guido Pontecorvo; he died on this date in 1999. A geneticist, he discovered the process of genetic recombination in the common soil fungus Aspergillus— and as a result the parasexual cycle— in what became the model for the genetic studies in many other fungi. This cycle gives rise to genetic reassortment by means other than sexual reproduction; its discovery provided a method of genetically analyzing asexual fungi…. which, as noted above, populate our microbiomes.
“History repeats itself, in part because the genome repeats itself. And the genome repeats itself, in part because history does.”*…
The original Human Genome Project map of the human genome was largely based on the DNA of one mixed-race man from Buffalo, with inputs from a few dozen other individuals, mostly of European descent. Now, researchers have released draft results from an ongoing effort to capture the entirety of human genetic variation…
More than 20 years after the first draft genome from the landmark Human Genome Project was released, researchers have published a draft human ‘pangenome’ — a snapshot of what is poised to become a new reference for genetic research that captures more of human diversity than has been previously available. Geneticists have welcomed the milestone, while also highlighting key ethical considerations surrounding the effort to make genome research more inclusive…
The draft genome, published in Nature on 10 May, was produced by the Human Pangenome Reference Consortium. Launched in 2019, the international project aims to map the entirety of human genetic variation, to create a comprehensive reference against which geneticists will be able to compare other sequences. Such a reference would aid studies investigating potential links between genes and disease.
The draft pangenome follows the 2022 publication of the first complete sequence of the human genome, which filled gaps that had been left by the original Human Genome Project. But unlike the original draft human genome and its successor, both of which were derived mostly from the DNA of just one person, the draft pangenome represents a collection of sequences from a diverse selection of 47 people from around the globe, including individuals from Africa, the Americas, Asia and Europe…
More at “First human ‘pangenome’ aims to catalogue genetic diversity,” in @Nature.
See the paper on the Pangenome Project here; and for more background, “This new genome map tries to capture all human genetic variation.”
* Siddhartha Mukherjee, The Gene: An Intimate History
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As we go wide on genetics, we might send microscopic birthday greetings to Christian Anfinsen; he was born on this date in 1916. A biochemist, he won the 1972 Nobel Prize for Chemistry for his research on the shape and primary structure of ribonuclease (the enzyme that hydrolyses RNA), in whihc he found that found that its shape and consequently its enzymatic power could be restored– leading him to conclude that ribonuclease must retain all of the information about its configuration within its amino acids.
“Life is a whim of several billion cells to be you for a while”*…
The more we understand how cells produce shape and form, Philip Ball explains, the more inadequate the idea of a genomic blueprint looks…
Where in the embryo does the person reside? Morphogenesis – the formation of the body from an embryo – once seemed so mystifying that scholars presumed the body must somehow already exist in tiny form at conception. In the 17th century, the Dutch microscopist Nicolaas Hartsoeker illustrated this ‘preformationist’ theory by drawing a foetal homunculus tucked into the head of a sperm.
This idea finds modern expression in the notion that the body plan is encoded in our DNA. But the more we come to understand how cells produce shape and form, the more inadequate the idea of a genomic blueprint looks, too. What cells follow is not a blueprint; if they can be considered programmed at all, it’s not with a plan of what to make, but with a set of rules to guide construction. One implication is that humans and other complex organisms are not the unique result of cells’ behaviour, but only one of many possible outcomes.
This view of the cell as a contingent, constructional entity challenges our traditional idea of what a body is, and what it can be. It also opens up some remarkable and even disconcerting possibilities about the prospects of redirecting biology into new shapes and structures. Life suddenly seems more plastic and amenable to being reconfigured by design. Understanding the contingency and malleability of multicellular form also connects us to our deep evolutionary past, when single-celled organisms first discovered the potential benefits of becoming multicellular. ‘The cell may be the focus of evolution, more than genes or even than the organism,’ says Iñaki Ruiz-Trillo of the Institute of Evolutionary Biology in Barcelona. Far from the pinnacle of the tree of life, humans become just one of the many things our cells are capable of doing.
In one of the most dramatic demonstrations to date that cells are capable of more than we had imagined, the biologist Michael Levin of Tufts University in Medford, Massachusetts and his colleagues have shown that frog cells liberated from their normal developmental path can organise themselves in distinctly un-froglike ways. The researchers separated cells from frog embryos that were developing into skin cells, and simply watched what the free cells did.
Culturing cells – growing them in a dish where they are fed the nutrients they need – is a mature technology. In general, such cells will form an expanding colony as they divide. But the frog skin cells had other plans. They clustered into roughly spherical clumps of up to several thousand cells each, and the surface cells developed little hairlike protrusions called cilia (also present on normal frog skin). The cilia waved in coordinated fashion to propel the clusters through the solution, much like rowing oars. These cell clumps behaved like tiny organisms in their own right, surviving for a week or more – sometimes several months – if supplied with food. The researchers called them xenobots, derived from Xenopus laevis, the Latin name of the African clawed frog from which the cells were taken.
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Levin and colleagues have recently found a new type of behaviour that xenobots can exhibit. They discovered that these pseudo-organisms can even replicate, after a fashion. Xenobots placed in a dish of cells will move to marshal those loose cells into piles that, over the course of a few days, cluster into new xenobots that then take off through the liquid themselves. Left to their own devices, the xenobots typically manage to produce only a single generation of offspring. But the researchers wondered if they could do better. They made computer simulations to search for xenobot shapes that were better at making new xenobots, using an AI program devised by their team member Josh Bongard of the University of Vermont. The simulations suggested that structures like C-shaped half-doughnuts could sweep up cells more efficiently than the spheroidal xenobots could, making larger (spherical) clusters of ‘offspring’.
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The work shows that, by combining biological xenobots with the exploratory power of AI, it’s possible to make a kind of ‘living machine’ devised for a purpose. ‘AI can be brought in to exaggerate an innate capability,’ says Bongard. ‘The AI can “program” new behaviours into organisms by rearranging their morphology rather than their genes.’ The researchers wonder if the simulations might identify other shapes that can assemble different structures, or perhaps perform other tasks entirely. ‘One of my primary interests in this project is exactly how ‘far’ from the wild type [the natural, spontaneously arising form of xenobots] an AI can push things,’ says Bongard. ‘We’re now working on incorporating several new behaviours into xenobots via AI-driven design.’
This perspective entails a new way of thinking about cells: not as building blocks assembled according to a blueprint, but as autonomous entities with skills that can be leveraged to make all manner of organisms and living structures. You might conceive of them as smart, reprogrammable, shapeshifting robots that can move, stick together, and signal to one another – and, by those means, build themselves into elaborate artifacts.
This might also be a better way to conceptualise how our own bodies are built during embryogenesis…
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The generative potential of cells equipped for multicellular construction was evident almost as soon as this became a lifestyle option, in evolutionary terms. In the Cambrian explosion around 540 million years ago, all manner of strange body shapes appeared, many of which are no longer exhibited by any creatures on Earth. Perhaps we should regard those forgotten ‘endless forms most beautiful’, to borrow Charles Darwin’s resonant phrase, as an illustration of the constructive potential of the metazoan cell – an exuberant expression of the palette of solutions to the problem of cell assembly, which natural selection then stringently pruned.
Acknowledging that the human form is a contingent outcome of the way our cells are programmed for construction raises some mind-bending questions. Are there, for example, human xenobots (perhaps we might call them anthrobots)? If so, are they truly ‘human’? Might there be a kind of organ or tissue that our cells could make but don’t normally get the chance to? Might our still cells ‘remember’ older evolutionary body shapes?…
How our understanding of genetics is changing– a fascinating dispatch from the frontiers of experimental biology: “What on earth is a xenobot?,” from @philipcball in @aeonmag. Eminently worth reading in full.
* Groucho Marx
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As we ponder possibility, we might spare a thought for Hans Spemann; he died on this date in 1941. An embryologist, he was awarded the Nobel Prize for Physiology and Medicine in 1935 for his discovery of embryonic induction, an effect involving several parts of the embryo in directing the development of the early group of cells into specific tissues and organs.
In a way that can be said to have foreshadowed the work described above, Spemann showed that the in the earliest stage, tissue may be transplanted to different areas of the embryo, where it then develops based on the new location and not from where it came. (For example, early tissue cut from an area of nervous tissue might be moved to an area of skin tissue where it then grows into the same form as the surrounding skin.)
“I have all these great genes, but they’re recessive. That’s the problem here.”*…
When the Human Genome Initiative published its first findings in 2002, the world was shocked. Genetic biologists, however, had long ago come to realize that DNA sequences are only part of the story of how organisms develop…
Fueled by the expectation that knowing the sequence of our DNA would tell us who we are, US funding agencies launched one of the most ambitious scientific efforts of all time in 1990. I refer, of course, to the Human Genome Initiative. Since then, the pace of that effort has been furious:even before the decade was over, the finishing line was clearly in view. When in February 2001, two rival teams announced the results of their first analysis of this invaluable information, their report made front-page headlines around the world. Humans, it seems, have far fewer genes than had been expected — in fact, only a third more than the lowly roundworm. How can this be? And what does it mean? Are we really so similar to, and so little more than, mere worms? News of the extent of our commonality with all living species is as stunning as it is humbling. But at the same time, it invites a certain incredulity — and that not merely because of human pride. Simple observation of the manifest diversity of life also makes us resist, for it is impossible not to wonder: what is it, if not the number (and in many cases, even the structure) of the ‘genes’ encoded in our DNA that accounts for the extraordinary differences among living organisms? For the answer to this question, it seems that we will have to look to the regulatory dynamics that determine how the sequence information of the DNA is to be used by the cell. Here, in the complex regulation of genetic transcription, of translation, of protein structure and function, is where we will find what makes us human beings rather than worms, flies or mice. Knowledge of the sequence of our DNA can tell us an enormous amount, but it can almost certainly not tell us who we are.
But not everyone was taken aback by this news. While readers of the popular press may have been stunned, few biologists working at the frontiers of research in molecular genetics were astonished. True, they had expected a larger number of human ‘genes’, but they had long ago come to realise that DNA sequences are only part of the story of how organisms develop, and even of what we mean by a ‘gene’. They recognise, for example, that the spatial and temporal patterns of expression of a gene are even more crucial to the specification of an organism than the structure of that ‘gene’ is. They also know that no single definition of this word ‘gene’ can suffice. Of the many different definitions that are required to make sense of current usage, two stand out with particular clarity: one referring to a particular region of the DNA, and another to the unit of messenger RNA that is used in the synthesis of a particular protein. The number of genes of the second kind is in fact very much larger than that of the first kind (current estimates suggest more than ten times as many), for the fact is that many different ‘genes’ can be constructed out of a single specified region of the DNA. Because the particular context in which they use the word makes its meaning quite clear, ambiguities in usage rarely create problems for practising biologists. Not so, however, for most readers. Outside the laboratory, such linguistic uncertainties can lead to both confusion and misunderstanding — not only around the question of how many genes we have, but also of what genes are made of, where they reside, what they do and, perhaps most important, what genes are for.
The good news is that research in genetics has never been more exciting, and over the last few decades both the depth and the breadth of our understanding of the nature of genetic activity have grown spectacularly. With each advance, the picture of the role of genes in development that biologists learn to draw grows ever more complex and sophisticated, and in ever more conspicuous defiance of the simple mantra with which they began. The word ‘gene’ does not begin to do justice to the ingenuity of the mechanisms required to put biological organisms together — no more than the concept of the neuron does to the ingenuity and dynamic complexity of neural organisation, and no more than talk of individual minds to the complexities of language and cognition…
Unpacking the genome hasn’t turned out to be the master key to understanding life that many thought it would be– but that’s no reason not to celebrate what it does illuminate: “The century of the gene,” from Evelyn Fox Keller in @EngelsbergIdeas.
* Calvin, in Calvin and Hobbes (Bill Watterson)
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As we investigate inheritance, we might spare a thought for D’Arcy Wentworth Thompson; he died on this date in 1948. A classics scholar who was also an accomplished biologist and mathematician, Thompson is best remembered for On Growth and Form (1917, new ed. 1942), a profound consideration of the shapes of living things, starting from the simple premise that “everything is the way it is because it got that way.” Thus one must study not only finished forms, but also the forces that molded them: “the form of an object is a ‘diagram of forces’, in this sense, at least, that from it we can judge of or deduce the forces that are acting or have acted upon it.”
The book paved the way for the scientific explanation of morphogenesis, the process by which patterns are formed in plants and animals. Thompson’s description of the mathematical beauty of nature inspired thinkers as diverse as Alan Turing and Claude Levi-Strauss, and artists including Henry Moore, Salvador Dali, and Jackson Pollock. Peter Medawar, the 1960 Nobel Laureate in Medicine, called On Growth and Form “the finest work of literature in all the annals of science that have been recorded in the English tongue.”
“It is sad to go to pieces like this but we all have to do it”*…
Still, some species “do it” differently than others…
It is well known that somatic mutations — mutations in our body’s genetic code that accumulate over time — can cause cancer, but their broader role in ageing is less clear.
Now a team of researchers have measured the somatic mutation rates of a range of mammals and discovered a striking correlation between mutation rate and lifespan. Lending evidence to the theory that somatic mutations are a cause of ageing rather than a result of it…
Ageing is linked to accumulated mutations: “The lifespan secret: why giraffes live longer than ferrets,” from @Nature.
* Mark Twain, on aging
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As we grow old gracefully, we might send carefully-deduced birthday greetings to William Ian Beardmore (WIB) Beveridge; he was born on this date in 1908. A veterinarian who served as director of the Institute of Animal Pathology at Cambridge, he identified the origin of the Great Influenza (the Spanish Flu pandemic, 1918-19)– a strain of swine flu.
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