The proteins needed to create limb progenitor cells are marked with different colors under a microscope.
Images: Yuji Atsuta/Tabin lab
Visit any site of a supposed Marian miracle, such as Lourdes, now selling 'miracle cures' that almost never work and those that do can be attributed to the medication the pilgrim was receiving prior to the visit, or to spontaneous regression, the placebo effect or a psychosomatic condition, and you may find lots of crutches supposedly left there as testament to the cure of mobility disorders, but what you will never find is the artificial limb discarded by someone who had a spontaneous regeneration of an amputated limb.
Or visit any of the lucrative travelling, carefully stage-managed 'faith healing circuses' where people appear to be 'cured' of all manner of ailments at the touch of a 'healer', who, for perhaps obvious reasons, never works in a hospital, and you will never witness the regeneration of a limb, or even part of a limb. Not even a finger or toe.
And before some-one cites, the 'Miracle of Calanda', this is such an obvious hoax that it's a miracle anyone believes it.
Despite having allegedly created a universe from nothing and all living things from dirt, creationism's god appears to be incapable, even with the help of his miracle-working mother, to be able to regrow a human limb.
The problem is one of the designer's own making (if you believe creationists) because it would involve the epigenetic resetting of the cells at the end of the stump, so they become stem cells again, capable of making all the different specialist cells in a limb, like bone, muscle, skin, nerves and blood vessels and growing to the right shape in the right place. That was a once-only ability in the developing embryo.
Epigenetics, as I have written about many times, is necessary because the cells of a multicellular organism replicate the same way our single-celled ancestors did - by replicating the entire genome every time in every daughter cell. But the benefit of multicellularity is that cells are specialised so only need a few genes, not the entire genome and having the wrong genes active in a specialist cell would be detrimental, so most of them need to be switched off by the epigenetic system. A problem which could have been avoided by any omniscient, omnipotent designer by just replicating those genes that were going to be needed by the specialist cells, but not something a mindless, natural process with no foresight, no reverse gear and no means of scrapping a bad design and starting again, could have avoided.
And yet medical scientists investigating the problem believe they have discovered the basic principles involved, which turn out to be "surprisingly simple", so well within the capabilities of even creationism's rather limited god.
The scientists, led by Harvard Medical School geneticists, have published their findings in an open access paper in a Cell Press journal, Developmental Cell and explain it in a Harvard Medical School news release by Stephanie Dutchen:
At a glance:And from the paper in Developmental Cell:
- In a first, scientists have identified the proteins needed to kick-start limb formation in mice and chicks.
- The findings allow researchers for the first time to turn non-limb-forming cells into limb-forming ones and keep them alive in the lab for far longer than once possible.
- Work deepens understanding of early limb development and could contribute to the long-term goal of regenerating limbs lost to injury and disease.
As described Feb. 5 in Developmental Cell, the researchers identified the special ingredients needed to kick off limb creation in mice and chicks.
“People in the field have known a lot of the proteins critical for limb formation, but we found that there are proteins we missed,” said study co-first author ChangHee Lee, research fellow in genetics in the lab of Cliff Tabin at HMS.
The team found that a combination of just three proteins — Prdm16, Zbtb16, and Lin28a — is necessary and sufficient to turn certain non-limb-forming stem cells into limb-forming ones. A fourth protein, Lin41, speeds the process along.
Part of a family called gene transcription factors, these proteins activate a handful of genes inside certain cells in embryonic tissue known as mesenchyme, the researchers revealed. This change in gene activity is what transforms the cells into limb progenitor cells, the team showed.
Limb progenitor cells then bud out where a limb will form and provide a framework for the future arm, leg, wing, or fin.
“We’ve found the proteins that imbue ‘limbness’ to this subgroup of mesenchymal cells,” said Lee. “People didn’t know how to make mesenchymal stem cells into limb progenitors before. Now we can do this and study early limb differentiation.”
Future work needs to confirm whether the same transcription factors are at play in human development. Early work is promising, the team said.
It also remains to be discovered which other ingredients need to be added for limb progenitor cells to mature into the limb’s connective tissues, such as tendons, ligaments, and the middle layer of skin.
How the work advances stem cell research
The discovery makes it possible for the first time for scientists to take mouse fibroblasts — connective tissue cells commonly used to explore how stem cells mature into different tissues — and direct them to become limb progenitors.
The work also now allows scientists to keep limb progenitor cells alive in the lab for far longer than was possible before — weeks instead of a day or two. That’s enough time to start really digging into the mechanisms of early limb development, Lee said.
Members of the Tabin lab made all of this possible by building a tool to grow limb progenitor cells in 3D structures and then optimizing nearly 30 cell-culture conditions until the cells thrived.
The team was delighted to finally make limb progenitor cells “survive, proliferate, and, critically, maintain their limb progenitor identity after extended culture,” said co-senior author Tabin, the George Jacob and Jacqueline Hazel Leder Professor of Genetics and head of the Department of Genetics in the Blavatnik Institute at HMS.
The set of optimal growth parameters is a more important contribution to the field than the 3D scaffold, Lee said. The team made the protocols available for free online.
“We tested a lot of conditions to see what the cells like and what they don’t like. We found they are particularly finicky about stiffness,” said Lee. “The only limitation we’ve found so far is that the cells grow so well that they fill up the containers we use, which is a good problem to have.”
Questions that limb development studies could now answer
Developmental and evolutionary biologists and regenerative medicine scientists are now better positioned to answer questions such as:
- The roles the three gene transcription factors play in other organ systems and organisms.
- What factors contribute to later limb development, such as fingers and toes.
- What distinguishes fore- and hind limb development.
- How these insights can inform efforts to regrow different organs to treat injury or disease.
“It’s important to understand the basic properties of cells that have a therapeutic value,” said Lee. “Culturing and maintaining limb progenitor cells and directing them to more specific lineages is fundamentally important for the long-term goal of replenishing cells in the clinic.”
The work also supports an underdog argument that mammals can serve as useful model organisms for limb regeneration even though they can’t regrow limbs after birth.
“Understanding and harnessing mammalian limb progenitors is a first step toward considering mammals as models for regenerating amputated limbs, as an alternative to the amphibians and other limb-regenerating critters being studied today,” said Tabin.
Although there is a long way to go yet before medical science can begin to regrow amputated limbs, it now looks well withing the capabilities of science to do so, or possibly to grow a limb that can be attached to the original stump.HighlightsGraphical abstract
- Established a primary 3D limb culture system that maintains early limb progenitor cells
- Used a reprogramming approach to identify factors imbuing a limb progenitor state
- Together, Prdm16, Zbtb16, and Lin28a can convert non-limb cells to limb progenitors
- Trajectory analysis identifies Lin41 as facilitating reprogramming by the other factors
Summary
The early limb bud consists of mesenchymal limb progenitors derived from the lateral plate mesoderm (LPM). The LPM also gives rise to the mesodermal components of the flank and neck. However, the cells at these other levels cannot produce the variety of cell types found in the limb. Taking advantage of a direct reprogramming approach, we find a set of factors (Prdm16, Zbtb16, and Lin28a) normally expressed in the early limb bud and capable of imparting limb progenitor-like properties to mouse non-limb fibroblasts. The reprogrammed cells show similar gene expression profiles and can differentiate into similar cell types as endogenous limb progenitors. The further addition of Lin41 potentiates the proliferation of the reprogrammed cells. These results suggest that these same four factors may play pivotal roles in the specification of endogenous limb progenitors.
Atsuta, Yuji; Lee, ChangHee; Rodrigues, Alan R.; Colle, Charlotte; Tomizawa, Reiko R.; Lujan, Ernesto G.; Tschopp, Patrick; Galan, Laura; Zhu, Meng; Gorham, Joshua M.; Vannier, Jean-Pierre; Seidman, Christine E.; Seidman, Jonathan G.; Ros, Marian A.; Pourquié, Olivier; Tabin, Clifford J.
Direct reprogramming of non-limb fibroblasts to cells with properties of limb progenitors
Developmental Cell 59(3), p 415-430.e8. DOI: 10.1016/j.devcel.2023.12.010.
© 2023 Elsevier Inc.
Reprinted under the terms of s60 of the Copyright, Designs and Patents Act 1988.
For some reason, although this is possible in some vertebrates such as amphibians like the axolotl, creationism's putative designer either found it too difficult to do what biological science is beginning to do or chose not to allow humans to have that ability.
The scientific explanation of course is that the increased specialisation in mammals that proved to be such a benefit meant the loss of a rarely used ability because the epigenetic programming became too complex to simply switch off and start again at the level of a whole limb. The loss of the ability to regenerate the occasional loss of a limb or part of a limb, which might have meant almost certain death for our early mammalian ancestors, was not strong enough selection pressure to prevent the evolution of less dependence on water to reproduce than our amphibian ancestors.
So, the question creationists need to address is why is medical science beginning to achieve something their putative omnipotent designer is incapable of achieving, or chooses not to? I wonder if they can produce something better than the knee-jerk response, "It's a mystery, but God obviously did it for a reason not given to us to understand".
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ID is not a problem for science; rather science is a problem for ID. This book shows why. It exposes the fallacy of Intelligent Design by showing that, when examined in detail, biological systems are anything but intelligently designed. They show no signs of a plan and are quite ludicrously complex for whatever can be described as a purpose. The Intelligent Design movement relies on almost total ignorance of biological science and seemingly limitless credulity in its target marks. Its only real appeal appears to be to those who find science too difficult or too much trouble to learn yet want their opinions to be regarded as at least as important as those of scientists and experts in their fields.
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The Malevolent Designer: Why Nature's God is Not Good
This book presents the reader with multiple examples of why, even if we accept Creationism's putative intelligent designer, any such entity can only be regarded as malevolent, designing ever-more ingenious ways to make life difficult for living things, including humans, for no other reason than the sheer pleasure of doing so. This putative creator has also given other creatures much better things like immune systems, eyesight and ability to regenerate limbs that it could have given to all its creation, including humans, but chose not to. This book will leave creationists with the dilemma of explaining why evolution by natural selection is the only plausible explanation for so many nasty little parasites that doesn't leave their creator looking like an ingenious, sadistic, misanthropic, malevolence finding ever more ways to increase pain and suffering in the world, and not the omnibenevolent, maximally good god that Creationists of all Abrahamic religions believe created everything. As with a previous book by this author, "The Unintelligent Designer: Refuting the Intelligent Design Hoax", this book comprehensively refutes any notion of intelligent design by anything resembling a loving, intelligent and maximally good god. Such evil could not exist in a universe created by such a god. Evil exists, therefore a maximally good, all-knowing, all-loving god does not.
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Available in Hardcover, Paperback or ebook for Kindle
Illustrated by Catherine Webber-Hounslow.
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