Researchers from the Universities of Bonn and Opole examined a fossil that raises questions
Have you ever wondered why our hands have five fingers? And what about amphibians? They usually only have four. Until now it was assumed that this was already the case with the early ancestors of today’s frogs and salamanders, the Temnospondyli. However, a new find of the crocodile-like Temnospondyl Metoposaurus krasiejowensis from the late Triassic (about 225 million years old) in Poland shows five metacarpal bones and thus five fingers. As the researchers from the Universities of Bonn and Opole (Poland) note, this finding is very important, because until now, fossil animal tracks may have been wrongly assigned. The results have now been published in the Journal of Anatomy.
Modern amphibians usually have four fingers on the forelimb (and never more), which is called a “four-rayed hand”, as opposed to our five-rayed hand. Of all groups of terrestrial vertebrates, amphibians show the greatest variation in the number of frontfingers Reptiles are the most conservative and usually have five. In birds, the finger bones in the wing have been lost completely. In mammals, the number of toes in the forelimb also varies greatly: Primates and raccoons have five, in horses only the third has survived, while in cattle and other even-toed ungulates fingers three and four remain. What they all have in common, however, is that this loss of toes or fingers originates from a five-ray pattern, which is why amphibians cannot be the ancestors of all these terrestrial vertebrate groups.
Exact number of toes is controversial
It has been known for some time that the earliest quadrupeds had significantly more fingers than five, such as Acanthostega, which had eight in the forelimb, or Ichthyostega with seven in the hind foot. As early as 300 million years ago, all but the five-fingered forms became extinct. The five-ray pattern was then retained in the real land animals, but was reduced again and again (see horses). The ancestors of today’s amphibians, the Temnospondyli, presented contradictory evidence of skeletons with four fingers, but also tracks that had five.
Temnospondyli is an important group of the early, very diverse quadrupeds. Some temnospondyls became as big as crocodiles, others were rather small. However, like all amphibians, they were dependent on water during their larval stage. Their most famous representatives include Eryops or Mastodonsaurus. “It’s also important to understand the evolution of modern amphibians, as this group probably evolved from the Temnospondyli,” says Dr. Dorota Konietzko-Meier from the Institute for Geosciences at the University of Bonn, who discovered and prepared the left forelimb of a Metoposaurus krasiejowensis in Krasiejów (southwest Poland).
However, despite the long history of research, the exact number of fingers in Metoposaurus and other temnospondyls is still controversial. “It’s remarkable that even in the case of the very well-researched Eryops, the skeletal reconstruction exhibited at the Muséum National d’Histoire Naturelle in Paris has five fingers, while only four fingers can be seen at the National Museum of Natural History in Washington,” says Ella Teschner, a doctoral student from Bonn and Opole. Lately, science has assumed that, similar to most modern amphibians, all Temnospondyli have only four toes in their forelimbs. This resulted in the five-toed footprints common in the Permian and Triassic periods being almost automatically assumed to not belong to Temnospondyli.
“The find from the famous Upper Triassic site Krasiejów in Poland therefore offers a new opportunity to study the architecture and development of the hand of the early quadrupeds,” says paleontologist Prof. Dr. Martin Sander from the University of Bonn. A considerably broader view of the entire group of Temnospondyli did not show a clear trend with regard to the five-ray pattern and suggested that the number of digits was not as limited in the phylogenetic context as was assumed. “Evidently, the temnospondyls were already experimenting with the four-ray pattern, and the five-ray pattern died out before the emergence of modern amphibians,” adds Sander.
Five fingers on each hand?
“Even if the ossification of five metacarpal bones described here was only a pathology, it still shows that a five-ray pattern was possible in Temnospondyli,” says Konietzko-Meier. However, it could not be assumed with certainty that the reduction in the number of fingers/digits from five to four always affected the fifth place on the hand in these fossil taxa. The possibility that some of the four-fingered taxa were caused by the loss of the first ray cannot be excluded. Sander: “The new finding of a five-fingered hand is particularly important for the interpretation of tracks, as it shows that a five-fingered forefoot print could also belong to the Temnospondyli and thus indicate a considerably wider distribution area of these animals.”
These results are also of general importance, since limb development plays an important role in evolutionary biology and medicine, and fossils may therefore provide important information for the evaluation of theories of hand development.
Publication: Dorota Konietzko-Meier, Elzbieta M. Teschner, Adam Bodzioch, P. Martin Sander: Pentadactyl manus of the Metoposaurus krasiejowensis from the Late Triassic of Poland, the first record of pentadactyly among Temnospondyli, Journal of Anatomy, DOI:10.1111/joa.13276
Dr. Dorota Konietzko-Meier
Institut für Geowissenschaften
E-mail: [email protected]
Prof. Dr. Martin Sander
Institut für Geowissenschaften
E-mail: [email protected]
Thermo Fisher’s $12.5B deal for Qiagen falls through, as COVID-19 test demand lights new path forward
While many companies have faltered under the spread of COVID-19, others may be doing a little too well for some tastes—with Qiagen’s investors turning down Thermo Fisher’s multibillion-dollar takeover proposal, following rocketing demand for its testing products.
Late last year, Qiagen was missing revenue targets and saying goodbye to its long-time CEO, and planned to walk away from developing its own diagnostic hardware under a multi-year reorganization that would favor tests built for Illumina’s sequencing machines.
Still, the Dutch manufacturer was coy about being acquired; Qiagen rebuffed multiple takeover offers in the last days of December—describing them all as “not compelling”—despite press reports that Thermo Fisher had been after the company for weeks, if not years. The lab equipment giant finally broke through in early March, and the two announced a $11.5 billion deal slated for early 2021—a 23% premium above the stock price at the time.
Five months and one global pandemic later, Qiagen found itself back in the spotlight. With the world clamoring for its COVID-19 diagnostic reagents and molecular testing supplies, the company’s shares outpaced the original offer as sales jumped nearly 20%. Thermo Fisher even sweetened the deal, adding an extra $1 billion after one of Qiagen’s hedge fund investors urged the company to hold out for more.
But it wasn’t enough. Investors rejected Thermo Fisher’s offer, with only 47% of shares signing up for the deal before the August 10 deadline, falling below the two-thirds minimum.
“The magnitude and duration of the global coronavirus pandemic have proven the increasingly critical importance of molecular testing to society,” Qiagen CEO Thierry Bernard said. The company previously rolled out plans to quadruple its reagent production, to support millions of COVID-19 tests per month with the necessary chemicals to help sequencing machines gain access to the virus’ RNA.
“Qiagen’s business prospects have improved significantly, as shown in our performance for the first half of 2020 and the strong outlook for the rest of this year and for 2021,” Bernard added.
The New York-based investment fund Davidson Kempner—which recently increased its stake in Qiagen to 8%, making it its second-largest investor, and had pushed for a higher price of about $13.4 billion—did not take up the final offer, and said that fewer than half of the company’s shares lining up to be traded showed “widespread confidence in the long-term prospects of Qiagen.”
Instead, Qiagen will move forward with an acquisition of its own: The company plans to pick up the remaining stake of NeuMoDx Molecular, makers of a test for COVID-19 as well as a multiplexed panel that detects the novel coronavirus plus influenza and respiratory syncytial virus—an important tool for telling infections apart as the pandemic begins to collide with this year’s oncoming flu season.
The $234 million deal was first announced in September 2018, with Qiagen previously owning about 20% of NeuMoDx and agreeing to commercialize its tests and systems. Qiagen said it would deliver more details alongside its third-quarter earnings report.
Meanwhile, Thermo Fisher showed no signs of plans to come back to the table after announcing last week that its price would be its “best and final offer.”
“Thermo Fisher is a disciplined acquirer with a strong track record of executing value-creating transactions,” President and CEO Marc Casper said in a statement after the deal fell through. “We remain extremely well-positioned to deliver on our proven growth strategy and continue to generate significant returns for our shareholders.”
MicuRx gets $7.8M top-up to push new antibiotic into the clinic
Just last week, MicuRx nabbed nearly $43 million in venture funding to expand its antibiotics pipeline and gear up for its first launch in China. Now, the Sino-American biotech is topping that up with $7.78 million from a nonprofit focused on antimicrobial resistance to push another asset into human trials.
The funding comes from Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator, or CARB-X, which previously funded IND-enabling studies for the prospect, dubbed MRX-8. The cash will bankroll a phase 1 study of the drug, a novel antibiotic in the polymyxin class, and cover “related R&D activities” for phase 2 trials.
First discovered in the 1940s, polymyxins have been used for decades to fight off infections caused by gram-negative bacteria. But their side effects, including acute kidney injury and neurological issues like dizziness and prickling sensations in various parts of the body, has sidelined them in favor of newer, less toxic antibiotics.
However, the rise of multidrug-resistant strains of gram-negative bacteria, such as Pseudomonas aeruginosa, and Acinetobacter baumannii, has “forced” doctors to put polymyxins back in the mix, Swiss researchers wrote in a 2017 study.
MicuRx believes that MRX-8 could be even better than two commonly used polymyxins, polymyxin B and colistin, thanks to its safety profile. The drug showed “improved renal safety” in monkey studies, as well as better efficacy than polymyxin B in “certain nonclinical models of Gram-negative infections, such as urinary tract and lung infection in animal models,” the company says. Now, it has the cash to try to prove that out in humans.
Besides MRX-8, MicuRx has two other programs in its pipeline: contezolid, an oral antibiotic against gram-positive bacteria that has been filed for approval in China, and contezolid acefosamil, an oral and intravenous antibiotic for gram-positive bacteria. Both programs are in phase 2 studies in the U.S.
The funding comes a month after a laundry list of Big Pharma companies joined forces on a $1 billion fund to bolster the development of much-needed antibiotics.
Despite the rise of antibiotic-resistant bacteria, very few antibiotics have been approved over the last 30 years. Multiple pharma companies, including Novartis, AstraZeneca and Eli Lilly, have bowed out of antimicrobials research, while smaller biotechs trying to fill the gap have struggled to stay afloat. In the span of one year, antibiotics makers Aradigm, Achaogen, Melinta and Tetraphase all filed for bankruptcy protection; all but Melinta had approved products.
The new fund, known as the AMR Action Fund, should be up and running by the fourth quarter and aims to see two to four new antibiotics through approval by 2030.
Scholar Rock’s experimental SMA therapy nabs speedy review voucher
The FDA has handed Scholar Rock a rare pediatric disease designation voucher, which can allow the biotech a speedy review of its leading of spinal muscular atrophy (SMA) hopeful SRK-015.
The drug targets the progressive, rare genetic disease that leads to motor function impairments in young children. For decades there were no treatments, but there are now three, all coming in the past few years.
The latest, Roche’s Evrysdi, a survival motor neuron-2 splicing modifier, was approved in the past week, and allows patients to take the drug at home. The other two drugs are Biogen’s Spinraza, an antisense oligonucleotide, and Novartis’ gene therapy Zolgensma.
Those companies have been battling for market share and working to grow sales, as Spinraza sales reached $2.1 billion last year, while Zolgensma generated $361 million during its launch year.
Scholar Rock’s SRK-015 works as a selective inhibitor of the activation of myostatin, and say its drug “may promote a clinically meaningful increase in muscle strength.” It’s a similar theory behind research in another devastating childhood disease, Duchenne Muscular Dystrophy (DMD), although both Roche and Pfizer have in the past tried and failed in this approach.
The biotech will hope to have better luck in SMA, and says it is “on track” report six-month interim efficacy and safety data from the ongoing TOPAZ phase 2 clinical trial of its med, in patients with Type 2 and Type 3 SMA, in the fourth quarter. Top-line data for the 12-month treatment period are expected in the first half of 2021.
There are four main types of SMA, with Type 2 affecting older babies and toddlers, with symptoms less severe than Type 1. Type 2 SMA can shorten life expectancy, but most children with it survive into adulthood.
Type 3 meanwhile usually develop symptoms after 18 months of age, but this is very variable and sometimes it may not appear until late childhood or early adulthood. It doesn’t impact life expectancy.
Now, the Scholar Rock has that rare pediatric disease designation for its rare drug. Under this program, a biopharma that gains approval for a rare pediatric disease can grab a voucher that can be redeemed to receive a priority review of a new, separate marketing application for a different drug.
Recently, these have become hot property and sold off for $100 million-plus to another buyer, given the seller a quick cash grab and the buyer a potentially quicker approval.
We’ll have to wait and see whether the biotech decides to hold on to the voucher for its other programs, many of which are partnered with an array of biopharmas.
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