GENETICS: Unlocking Humanity's Past and Future

[Stormer0628]

Re: Gene editing breakthrough could destroy thousands of deadly diseases

In Under the Skin, Scarlett Johanssen plays an alien who seduces men in order to graft their skin to her black mass of a body. In Painted Skin 1 and 2, a demon seduces men in order to graft their skin over her original demonic form. The seven-year-old boy in the story is neither alien nor demon, but his story brings these sci-fi films easily to mind.

In Bochum, Germany, a small boy throws himself down a playground slide, landing triumphantly at the bottom. To the relief of his father, he is not bleeding. For seven-year-old Hassan, this is a very big day.

Two years earlier, in June 2015, Hassan was admitted to the burns unit of Ruhr University hospital in Bochum. Covered in blisters, 80 per cent of his skin was open and bleeding. It was one of the most severe cases that doctors had experienced. Attached permanently to a morphine drip, his pain was so extreme that doctors expected him to die.

In November 2016, Tobias Hirsch, a plastic surgeon at the university hospital, successfully transplanted new skin to almost the entirety of Hassan's body. All the skin was grown in a laboratory by Michele de Luca, a world-renowned expert in epithelial stem cell biology.

"As I saw the results after the first operation it was like a miracle to me," Hirsch says. "There really was new, solid skin". In October 2015, and to the surprise of all the surgeons working on the case, the first transplantation to Hassan's four limbs was a success. For the first time doctors were able to prove that transgenic stem cells could regenerate an entire tissue. In simple terms, they realised it was possible not just to grow skin, but also for the skin to thrive when transplanted.

Hassan had a severe case of a rare genetic skin disease known as junctional epidermolysis bullosa (JEB). His skin was so fragile he was covered in wounds, blisters and recurrent infections that were largely untreatable. The entirety of his back and legs were covered in open sores.

Hassan had been transferred to the specialist burns centre as a last resort when his condition began to rapidly deteriorate and the condition spread across his whole body. "When we got him in our burns centre he was in a septic state, so we had a lot of problems from the first day keeping this kid alive," Hirsch says.

First, Hirsch treated Hassan with antibiotics and an aggressive nutrition schedule, but with no success. The team of doctors treating him grew more concerned. Hirsch addressed various experts in the field, in Germany, Switzerland and the United States, in order to find the right experimental treatment. "We tried to transplant the patient some skin that we took from his father," says Hirsch, but this was rejected. "After nearly two months we were sure we could do nothing for this kid and that he would die."

That was when Hassan's father found the work of Michele de Luca. "We studied the literature again and approached Doctor Michele de Luca and his team."

The images on the left show Hassan's massive skin loss before treatment.
The images to the right demonstrate his recovery and the elasticity of his skin
Credit: Hirsch et. al, Nature Research​

Michele de Luca has worked in epithelial stem cell biology for 20 years. De Luca told the Bochum team that he could grow Hassan enough skin inside his lab to replace the 80 per cent of that he had lost. Scientists had never tried to transplant this magnitude of lab grown skin on to a human. De Luca agreed to take a four-centimetre-square biopsy from an unaffected part of Hassan's skin and began to grow the corrected cell population at his Centre for Regenerative Medicine in Bologna, Italy.

The process took four weeks. "The basic technology is very similar to burns treatment that we have been using in the past," de Luca says. "In other words, you take a biopsy, you isolate the polygenic cells, then the difference is that you genetically modify those cells and make genetic corrections to introduce the new copy of the gene, in this case LAMB3 which is needed to restore the original machinery in the skin." The sets of cells are grown in large numbers, half of them being used to prepare the culture grafts of different sizes. The grafts ranged from 50-100 centimetres in size. After a month, De Luca was ready to transport the graft to the hospital in Bochum, so they could be applied to Hassan.

Transplanting the skin was extremely meticulous and risky. "We first divided the wounds and open areas thoroughly in order to achieve a clean wound bath with a good cleaning situation," Hirsch says. It is essential to get rid of all the bacteria that is placed on the chronic wounds. Then Hirsch applied the grafts provided by De Luca. "What is quite challenging is to make sure the grafts attach properly to the wounds because in this patient you can't use any plastic strips to fix them." The transplanted skin naturally adheres to the wound bed with the help of the right medication. If kept in place, they fully engraft to the body in a few weeks. The team felt confident to proceed, completing the transplantation to the rest of his body the following month. The results of the work were published in the journal Nature.

Crucially for Hassan, this treatment set his recovery apart from previous skin transplant procedures. Usually, due to the severity of the skin damage, burn victims are unable to grow hair on their transplanted skin or develop functioning sweat glands. For these patients, an ointment must be applied to the transplanted skin twice a day for the rest of their life. "We found here that the appendages in the skin didn't need any ointment for the child, we saw hair regrowth and no further need for ointment which is fantastic," Hirsch says. Hassan's parents were overwhelmed. "They told me this was like a dream," Hirsch says.

Eight months after his surgery, Hassan was discharged from hospital. Now, Hassan plays football, goes to school and enjoys life with his siblings. For the past two years, De Luca and Hirsch have kept a close eye on him. Now, they are finally confident his recovery has been successful. "To move from constantly being on morphine to playing football is obviously quite an improvement," Hirsch says. "For me, as Hassan`s surgeon, it is a great success to save his life and bring him back to an almost normal daily life," he adds.

But the impact of this groundbreaking procedure goes beyond a single case. "For the first time we are able to show that an insufficient solid organ has been successfully replaced by genetically-modified stem cells," Hirsch explains. "I worked during my whole research career on gene transfer in skin and wounds. However, we have never applied such a treatment to a patient before."

Michele De Luca is now undertaking trials on two more patients with similar genetic diseases. "We might have problems that we did not encounter before," he says. "This is going to be discovered only after a phase one clinical trial. We are running other clinical trails at the moment." But for Hassan, very simply, it means a new life.


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[Stormer0628]

In the Shadow of Darwin's Finches: Evolution in Action

Finches in the Galapagos Islands have evolved into a new species, which is the first example ever seen by scientists, effectively making the theory of evolution an empirically measurable theory. Prior, the theory primarily relied on fossil records and species hybridisation, though an existing species had never been observed evolving into an entirely new species.

After decades of hybridisation, a group of finches on the Daphne Major island in the Galapagos Island chain developed closed breeding.

The various groups of finches in the Galapagos had been aptly named ‘Darwin’s finches’ to commemorate Charles Darwin, the famous scientist who developed his theory of evolution by way of natural selection after spending time on the islands, one of the most biologically diverse places in the world, and observing the species, especially the finches which he wrote about extensively in his personal journals.

Scientists note that in 1981, a male large cactus finch that is believed to have come from the nearby island of Espanola, mated with a native finch on Daphne Major and produced offspring.

"We didn't see him fly in from over the sea, but we noticed him shortly after he arrived. He was so different from the other birds that we knew he did not hatch from an egg on Daphne Major," Princeton zoology professor Peter Grant told Phys.org.

This gave rise to a population of finches, about 30 of them, that are distinctively different in appearance and behavior on the island of Daphne Major. This population has been called the ‘Big Bird’ group by zoologists and researchers.

Professors Rosemary and Peter Grant of Princeton University collaborated with Prof Leif Andersson of Sweden's Uppsala University to genetically analyze the mixed-species population, and published their findings in Science journal on Nov. 23.

“From the second generation onwards the lineage bred endogamously, and despite intense inbreeding, was ecologically successful and showed transgressive segregation of bill morphology,” they wrote. “This example shows that reproductive isolation, which typically develops over hundreds of generations, can be established in only three.”

This is a remarkable observation which is demonstrated by the fact that native females do not recognize the mating calls of the new species, which is a form of behavioral isolation, meaning that the two species can no longer breed and are distinct.

"The surprise was that we would expect the hybrid would start to breed with one of the other species on the island and be absorbed,” Andersson told the BBC. “We have confirmed that they are a closed breeding group."

Even more remarkably, hybrid species have been long believed to be sterile, meaning that they are unable to reproduce and become a viable species, however this observation demonstrates that it is possible.

Ironically, the discovery was published on the eve of the anniversary of the publication of Charles Darwin’s magnum opus titled On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life, which was released in 1859 and largely inspired by his time on the Galapagos Islands.



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[Stormer0628]

We've Just Added New Letters to the Genetic Code

DNA stores our genetic code in an elegant double helix. But some argue that this elegance is overrated. “DNA as a molecule has many things wrong with it,” said Steven Benner, an organic chemist at the Foundation for Applied Molecular Evolution in Florida.

Nearly 30 years ago, Benner sketched out better versions of both DNA and its chemical cousin RNA, adding new letters and other additions that would expand their repertoire of chemical feats. He wondered why these improvements haven’t occurred in living creatures. Nature has written the entire language of life using just four chemical letters: G, C, A and T. Did our genetic code settle on these four nucleotides for a reason? Or was this system one of many possibilities, selected by simple chance? Perhaps expanding the code could make it better.

Benner’s early attempts at synthesizing new chemical letters failed. But with each false start, his team learned more about what makes a good nucleotide and gained a better understanding of the precise molecular details that make DNA and RNA work. The researchers’ efforts progressed slowly, as they had to design new tools to manipulate the extended alphabet they were building. “We have had to re-create, for our artificially designed DNA, all of the molecular biology that evolution took 4 billion years to create for natural DNA,” Benner said.

Now, after decades of work, Benner’s team has synthesized artificially enhanced DNA that functions much like ordinary DNA, if not better. In two papers published in the Journal of the American Chemical Society last month, the researchers have shown that two synthetic nucleotides called P and Z fit seamlessly into DNA’s helical structure, maintaining the natural shape of DNA. Moreover, DNA sequences incorporating these letters can evolve just like traditional DNA, a first for an expanded genetic alphabet.

The new nucleotides even outperform their natural counterparts. When challenged to evolve a segment that selectively binds to cancer cells, DNA sequences using P and Z did better than those without.

“When you compare the four-nucleotide and six-nucleotide alphabet, the six-nucleotide version seems to have won out,” said Andrew Ellington, a biochemist at the University of Texas, Austin, who was not involved in the study.

Benner has lofty goals for his synthetic molecules. He wants to create an alternative genetic system in which proteins — intricately folded molecules that perform essential biological functions — are unnecessary. Perhaps, Benner proposes, instead of our standard three-component system of DNA, RNA and proteins, life on other planets evolved with just two.

Better Blueprints for Life
The primary job of DNA is to store information. Its sequence of letters contains the blueprints for building proteins. Our current four-letter alphabet encodes 20 amino acids, which are strung together to create millions of different proteins. But a six-letter alphabet could encode as many as 216 possible amino acids and many, many more possible proteins.

Why nature stuck with four letters is one of biology’s fundamental questions. Computers, after all, use a binary system with just two “letters” — 0s and 1s. Yet two letters probably aren’t enough to create the array of biological molecules that make up life. “If you have a two-letter code, you limit the number of combinations you get,” said Ramanarayanan Krishnamurthy, a chemist at the Scripps Research Institute in La Jolla, Calif.

On the other hand, additional letters could make the system more error prone. DNA bases come in pairs — G pairs with C and A pairs with T. It’s this pairing that endows DNA with the ability to pass along genetic information. With a larger alphabet, each letter has a greater chance of pairing with the wrong partner, and new copies of DNA might harbor more mistakes. “If you go past four, it becomes too unwieldy,” Krishnamurthy said.

But perhaps the advantages of a larger alphabet can outweigh the potential drawbacks. Six-letter DNA could densely pack in genetic information. And perhaps six-letter RNA could take over some of the jobs now handled by proteins, which perform most of the work in the cell.

Proteins have a much more flexible structure than DNA and RNA and are capable of folding into an array of complex shapes. A properly folded protein can act as a molecular lock, opening a chamber only for the right key. Or it can act as a catalyst, capturing and bringing together different molecules for chemical reactions.

Adding new letters to RNA could give it some of these abilities. “Six letters can potentially fold into more, different structures than four letters,” Ellington said.

Back when Benner was sketching out ideas for alternative DNA and RNA, it was this potential that he had in mind. According to the most widely held theory of life’s origins, RNA once performed both the information-storage job of DNA and the catalytic job of proteins. Benner realized that there are many ways to make RNA a better catalyst.

“With just these little insights, I was able to write down the structures that are in my notebook as alternatives that would make DNA and RNA better,” Benner said. “So the question is: Why did life not make these alternatives? One way to find out was to make them ourselves, in the laboratory, and see how they work.”

It’s one thing to design new codes on paper, and quite another to make them work in real biological systems. Other researchers have created their own additions to the genetic code, in one case even incorporating new letters into living bacteria. But these other bases fit together a bit differently from natural ones, stacking on top of each other rather than linking side by side. This can distort the shape of DNA, particularly when a number of these bases cluster together. Benner’s P-Z pair, however, is designed to mimic natural bases.

One of the new papers by Benner’s team shows that Z and P are yoked together by the same chemical bond that ties A to T and C to G. (This bond is known as Watson-Crick pairing, after the scientists who discovered DNA’s structure.) Millie Georgiadis, a chemist at Indiana University-Purdue University Indianapolis, along with Benner and other collaborators, showed that DNA strands that incorporate Z and P retain their proper helical shape if the new letters are strung together or interspersed with natural letters.

“This is very impressive work,” said Jack Szostak, a chemist at Harvard University who studies the origin of life, and who was not involved in the study. “Finding a novel base pair that does not grossly disrupt the double-helical structure of DNA has been quite difficult.”

The team’s second paper demonstrates how well the expanded alphabet works. Researchers started with a random library of DNA strands constructed from the expanded alphabet and then selected the strands that were able to bind to liver cancer cells but not to other cells. Of the 12 successful binders, the best had Zs and Ps in their sequences, while the weakest did not.

“More functionality in the nucleobases has led to greater functionality in nucleic acids themselves,” Ellington said. In other words, the new additions appear to improve the alphabet, at least under these conditions.

But additional experiments are needed to determine how broadly that’s true. “I think it will take more work, and more direct comparisons, to be sure that a six-letter version generally results in ‘better’ aptamers [short DNA strands] than four-letter DNA,” Szostak said. For example, it’s unclear whether the six-letter alphabet triumphed because it provided more sequence options or because one of the new letters is simply better at binding, Szostak said.

Benner wants to expand his genetic alphabet even further, which could enhance its functional repertoire. He’s working on creating a 10- or 12-letter system and plans to move the new alphabet into living cells. Benner’s and others’ synthetic molecules have already proved useful in medical and biotech applications, such as diagnostic tests for HIV and other diseases. Indeed, Benner’s work helped to found the burgeoning field of synthetic biology, which seeks to build new life, in addition to forming useful tools from molecular parts.

Why Life’s Code Is Limited
Benner’s work and that of other researchers suggests that a larger alphabet has the capacity to enhance DNA’s function. So why didn’t nature expand its alphabet in the 4 billion years it has had to work on it? It could be because a larger repertoire has potential disadvantages. Some of the structures made possible by a larger alphabet might be of poor quality, with a greater risk of misfolding, Ellington said.

Nature was also effectively locked into the system at hand when life began. “Once [nature] has made a decision about which molecular structures to place at the core of its molecular biology, it has relatively little opportunity to change those decisions,” Benner said. “By constructing unnatural systems, we are learning not only about the constraints at the time that life first emerged, but also about constraints that prevent life from searching broadly within the imagination of chemistry.”

Benner aims to make a thorough search of that chemical space, using his discoveries to make new and improved versions of both DNA and RNA. He wants to make DNA better at storing information and RNA better at catalyzing reactions. He hasn’t shown directly that the P-Z base pairs do that. But both bases have the potential to help RNA fold into more complex structures, which in turn could make proteins better catalysts. P has a place to add a “functional group,” a molecular structure that helps folding and is typically found in proteins. And Z has a nitro group, which could aid in molecular binding.

In modern cells, RNA acts as an intermediary between DNA and proteins. But Benner ultimately hopes to show that the three-biopolymer system — DNA, RNA and proteins — that exists throughout life on Earth isn’t essential. With better-engineered DNA and RNA, he says, perhaps proteins are unnecessary.

Indeed, the three-biopolymer system may have drawbacks, since information flows only one way, from DNA to RNA to proteins. If a DNA mutation produces a more efficient protein, that mutation will spread slowly, as organisms without it eventually die off.

What if the more efficient protein could spread some other way, by directly creating new DNA? DNA and RNA can transmit information in both directions. So a helpful RNA mutation could theoretically be transformed into beneficial DNA. Adaptations could thus lead directly to changes in the genetic code.

Benner predicts that a two-biopolymer system would evolve faster than our own three-biopolymer system. If so, this could have implications for life on distant planets. “If we find life elsewhere,” he said, “it would likely have the two-biopolymer system.”




MORE:

'Alien' life form is grown in a lab: Scientists add unnatural DNA strands to the genetic code of bacteria to create a new strain




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[hardcorekid03]

Re: We've Just Added New Letters to the Genetic Code

patambay ulit dito TS, daming bago ah, basa muna ulit