(Roughly) Daily

Posts Tagged ‘genetics

“Life is a whim of several billion cells to be you for a while”*…

An AI-designed xenobot (parent organism, C shape, red) sweeping up stem cells that have been compressed into a ball (incipient offspring, green)

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.

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’.

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…

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.)

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Written by (Roughly) Daily

September 12, 2022 at 1:00 am

“I have all these great genes, but they’re recessive. That’s the problem here.”*…

DNA Sequence chromatograms produced by automated sequencing machines

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.”

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Written by (Roughly) Daily

June 21, 2022 at 1:00 am

“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.

WIB Beveridge

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Happy Shakespeare’s Birthday!

“The world is bound in secret knots”*…

Everyone knows what a knot is. But knots have special significance in math and science because their properties can help unlock secrets hidden within topics ranging as widely as the biochemistry of DNA, the synthesis of new materials, and the geometry of three-dimensional spaces. In his podcast, The Joy of Wh(Y), the sensational Steven Strogatz explores the mysteries of knots with his fellow mathematicians Colin Adams and Lisa Piccirillo

How do mathematicians distinguish different types of knots? How many different kinds of knots are there? And why do mathematicians and scientists care about knots anyway? Turns out, there’s lots of real-world applications for this branch of math, now called knot theory. It started out with the mystery of the chemical elements about 150 years ago, which were, at the time, thought to be different kinds of knots tied in the ether. Nowadays, knot theory is helping us understand how enzymes can disentangle strands of linked DNA. And also, knot theory has potential in basic research to create new kinds of medicines, including some chemotherapy drugs. But in math itself, knot theory is helping mathematicians work out the riddles of higher-dimensional spaces…

The study of knots unites the interests of researchers in fields from molecular biology to theoretical physics: “Untangling Why Knots Are Important,” from @stevenstrogatz in @QuantaMagazine. Listen here; read the transcript here.

Athanasius Kircher

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As we take stock of tangles, we might might send nicely-tied birthday greetings to a beneficiary and user of knot theory, Francis Collins; he was born on this date in 1950. A physician and geneticist, he discovered the genes associated with a number of diseases, led the Human Genome Project, and served as the director of the National Institutes of Health.

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“How is it that you keep mutating and can still be the same virus?”*…

Thale cress (Arabidopsis thaliana)

A common plant has yielded insights that question a fundamental assumption in biology– more specifically, an assumption about the mechanism of natural selection…

A simple roadside weed may hold the key to understanding and predicting DNA mutation, according to new research from University of California, Davis, and the Max Planck Institute for Developmental Biology in Germany.

The findings, published today in the journal Nature, radically change our understanding of evolution and could one day help researchers breed better crops or even help humans fight cancer.

Mutations occur when DNA is damaged and left unrepaired, creating a new variation. The scientists wanted to know if mutation was purely random or something deeper. What they found was unexpected.

“We always thought of mutation as basically random across the genome,” said Grey Monroe, an assistant professor in the UC Davis Department of Plant Sciences who is lead author on the paper. “It turns out that mutation is very non-random and it’s non-random in a way that benefits the plant. It’s a totally new way of thinking about mutation.”

Knowing why some regions of the genome mutate more than others could help breeders who rely on genetic variation to develop better crops. Scientists could also use the information to better predict or develop new treatments for diseases like cancer that are caused by mutation.

“Our discoveries yield a more complete account of the forces driving patterns of natural variation; they should inspire new avenues of theoretical and practical research on the role of mutation in evolution,” the paper concludes.

Evolutionary theory revised? A new study challenges the received wisdom that that DNA mutations are random. Read the underlying paper here.

* Chuck Palahniuk, Invisible Monsters

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As we contemplate change, we might send micro-biological birthday greetings to Ruth Sager; she was born on this date in 1918. A geneticist, she had two careers in science.

In the 1950s and 1960s, she pioneered the field of cytoplasmic genetics by discovering transmission of genetic traits through chloroplast DNA, the first known example of genetics not involving the cell nucleus. The academic community did not acknowledge the significance of her contribution until after the second wave of feminism in the 1970s.

Then, in the early 1970s, she moved into cancer genetics (with a specific focus on breast cancer); she proposed and investigated the roles of tumor suppressor genes.

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