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Great Ormond Street Hospital: Baby Who Received Genetic Therapy Has Cancer Reversed

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Great Ormond Street Hospital: Baby Who Received Genetic Therapy Has Cancer Reversed

A new treatment that uses ‘molecular scissors’ to edit genes and create designer immune cells programmed to hunt out and kill drug resistant leukaemia has been used at Great Ormond Street Hospital (GOSH).

The treatment, previously only tested in the laboratory, was used in one-year-old, Layla, who had relapsed acute lymphoblastic leukaemia (ALL). She is now cancer free and doing well.

This breakthrough comes from GOSH and UCL Institute of Child Health’s (ICH) pioneering research teams, who together are developing treatments and cures for some of the rarest childhood diseases.

Chemotherapy successfully treats many patients with leukaemia but it can be ineffective in patients with particularly aggressive forms of the disease where cancer cells can remain hidden or resistant to drug therapy. Recent developments have led to treatments where immune cells, known as T-cells, are gathered from patients and programmed using gene therapy to recognise and kill cancerous cells. Multiple clinical trials are underway, but individuals with leukaemia, or those who have had several rounds of chemotherapy, often don’t have enough healthy T-cells to collect and modify meaning this type of treatment is not appropriate.

A team at GOSH has now used modified T-cells from donors, known as UCART19 cells, to treat a one-year-old child with an aggressive form of ALL who had unsuccessful chemotherapy and for whom palliative care was deemed the only option left.

The treatment works by adding new genes to healthy donor T-cells, which arm them against leukaemia. Using molecular tools (TALEN®) that act like very accurate scissors, specific genes are then cut in order to make the T-cells behave in two specific ways. Firstly, the cells became invisible to a powerful leukaemia drug that would usually kill them and secondly they are reprogrammed to only target and fight against leukaemia cells.

The team at GOSH and the UCL ICH, along with investigators at University College London and biotech company Cellectis, had been developing ‘off-the-shelf’ banks of these donor T-cells and the first of which was due to be used for final stage testing ahead of clinical trials. But, after hearing about this infant, the team received special permission to try the new treatment early.

Professor Waseem Qasim, Professor of Cell and Gene Therapy at UCL ICH and Consultant Immunologist at GOSH, explains: “The approach was looking incredibly successful in laboratory studies, and so when I heard there were no options left for treating this child’s disease, I thought ‘why don’t we use the new UCART19 cells?’

“The treatment was highly experimental and we had to get special permissions, but she appeared ideally suited for this type of approach.”

The patient’s parents were also keen to try the treatment. Mum, Lisa, says: “We didn’t want to accept palliative care and so we asked the doctors to try anything for our daughter, even if it hadn’t been tried before.”

The treatment consisted of 1ml of UCART19 cells delivered via intravenous line in around 10 minutes. After the cells had been delivered, the patient spent several months in isolation to protect her from infections while her immune system was extremely weak. Throughout this time, the patient stayed generally well.

After several weeks there were signs that the treatment was working. Professor Paul Veys, Director of bone marrow transplant at GOSH and the patient’s lead clinician, says: “As this was the first time that the treatment had been used, we didn’t know if or when it would work and so we were over the moon when it did. Her leukaemia was so aggressive that such a response is almost a miracle.”

Once doctors were confident that the leukaemia cells had been removed, the patient was given a bone marrow transplant to replace her entire blood and immune system which had been wiped out by the treatment. The child is now recovering well at home, although she returns to GOSH regularly to check that her bone marrow cells are healthy and blood counts continuing to normalise.

Professor Qasim says: “We have only used this treatment on one very strong little girl, and we have to be cautious about claiming that this will be a suitable treatment option for all children. But, this is a landmark in the use of new gene engineering technology and the effects for this child have been staggering.

“If replicated, it could represent a huge step forward in treating leukaemia and other cancers.”

Full clinical trials funded by Cellectis are now being planned to test UCART19 cells in larger groups of patients and are set to begin early in 2016.

“Cellectis main objective is to provide cancer patients with an accessible, cost-effective, off-the-shelf allogeneic CAR-T therapies across all geographies. With clinical trial for the first gene-edited UCART on the horizon, it could be the beginning of a revolution in cancer immunotherapy,” says Dr. André Choulika, Chairman and CEO of Cellectis.

Layla’s story

Layla was born healthy at 7lb 10 in June 2014. There were no problems during pregnancy and when she was born she was happy and content. At three months old, Layla was taken to the doctors as she was off her milk crying lots and her heart beat was fast. At first doctors suspected a tummy bug but after a blood test a few days later, it was confirmed that Layla had Infant Acute Lymphoblastic Leukaemia (ALL.) Layla was just 14 weeks old.

The family were immediately sent to GOSH in a CATS ambulance and Layla was taken to intensive care with what doctors described as “one of the most aggressive forms of the disease we have ever seen.” The next day Layla was moved to Elephant Ward where chemotherapy started straight away. She had several rounds of treatment to try and get rid of the cancer and was then given a bone marrow transplant (BMT) so her damaged blood cells could be replaced.

Seven weeks later the family were told that despite the transplant Layla’s cancer had returned. As the strong doses of chemotherapy that Layla had already received hadn’t killed off the cancer cells, a second round of treatment wasn’t an option. After travelling to Sheffield and taking part in an experimental treatment that sadly didn’t work for Layla, the family returned to London the day before her first birthday.

Doctors at GOSH explained that there were no treatment options left for Layla that would cure her and suggested palliative care. Mum, Lisa, says: “Doctors don’t want to say that there’s nothing we can do and offer palliative care but sometimes that’s the only option.

“We didn’t want to accept palliative care and give up on our daughter though so we asked the doctors to try anything.”

The family were then told that a very recent and experimental treatment, which had only been trialled in mice, was being developed in the hospital and could be used to try and treat the aggressive form of cancer that Layla had. Only one vial of the treatment was available for Layla but in order for that to be given, an emergency ethics committee meeting had to be called to discuss whether it was the right thing to do for her. Dad, Ashleigh, says: “It was scary to think that the treatment had never been used in a human before but even with the risks, there was no doubt that we wanted to try the treatment. She was sick and in lots of pain so we had to do something.

“Doctors explained that even if we could try the treatment, there was no guarantee that it would work but we prayed it would.”

After ethical approval was gained, doctors explained to mum and dad what the treatment would involve, consent forms were signed and treatment could begin. Treatment involved Layla being given a small 1ml infusion of genetically engineered cells through her Hickman line, which took a couple of minutes followed by a five minute flush. “Layla didn’t notice anything was going on, and was bouncing around her cot all the way through!”

Ashleigh says: “We thought that the little bit of liquid in the syringe was nothing, and asked ‘what is that going to do when bags and bags of chemo haven’t worked.’ The nurse said this was about quality and not quantity though.”

Within one to two weeks doctors expected to see an immune response – usually in the form of a rash or a fever – to show that the treatment was working but when there was no change in Layla at two weeks, medical staff were unsure whether it had been successful. Doctors were preparing to send Layla home when she got ‘the rash’. Something seemed to be happening.

The rash got worse but aside from that Layla remained well. Lisa says: “We didn’t know she was going to be so well. We were preparing ourselves for her to be in intensive care and were constantly waiting to pull the crash bell.

“It was terrifying because you think that if she hasn’t gone to intensive care then it’s not working. When she didn’t, we couldn’t believe it.”

A few weeks later, Lisa was picking up her elder daughter from school when Ashleigh called. “He said that the consultants had been in with results of the treatment and told me to sit down.

“I thought it was bad news but then he said ‘it’s worked’ and I just cried happy tears.”

Around two months later and cancer free, Layla came back to GOSH for a second BMT to replace her bone marrow which had also been affected by the treatment. Her blood cell numbers increased from that point and one month after the transplant, she was well enough to go home.

Ashleigh says: “Even though she is well at the moment, we still don’t know what the future holds. She will still have monthly bone marrow checks for now and might be on some medicines for the rest of her life.

“It’s always at the back of your mind. It’s not like chickenpox that clears away, this is constant. You always have doubts.”

But Lisa says: “I consider ourselves lucky that we were in the right place at the right time to get a vial of these cells. We always said that we had to try new things as we didn’t want to be saying ‘what if?

“Hopefully Layla will stay well and lots more children can be helped with this new treatment.”

Entrepreneur, contributor, writer, and editor of Sostre News. With a powerful new bi-lingual speaking generation by his side, Sostre News is becoming the preferred site for the latest in Politics, Entertainment, Sports, Culture, Tech, Breaking and World News.

Science

New Study Solves Mystery of Salt Buildup on Bottom of Dead Sea

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New Study Solves Mystery of Salt Buildup on Bottom of Dead Sea

New research explains why salt crystals are piling up on the deepest parts of the Dead Sea’s floor, a finding that could help scientists understand how large salt deposits formed in Earth’s geologic past.

The Dead Sea, a salt lake bordered by Jordan, Israel and the West Bank, is nearly 10 times as salty as the ocean. Humans have visited the Dead Sea for thousands of years to experience its purported healing properties and to float in its extremely dense, buoyant waters, and mention of the sea goes back to biblical times.

Much of the freshwater feeding the Dead Sea has been diverted in recent decades, lowering the sea’s levels and making it saltier than before. Scientists first noticed in 1979, after this process had started, that salt crystals were precipitating out of the top layer of water, “snowing” down and piling up on the lakebed. The salt layer on the lake floor has been growing about 10 centimeters (4 inches) thicker every year.

The process driving this salt crystal “snow” and buildup of salt layers on the lakebed has puzzled scientists because it doesn’t make sense according to the laws of physics. Now, a new study in AGU’s journal Water Resources Research proposes that tiny disturbances in the lake, caused by waves or other motion, create “salt fingers” that slowly funnel salt down to the lakebed. Watch a video about this research here.

“Initially you form these tiny fingers that are too small to observe… but quickly they interact with each other as they move down, and form larger and larger structures,” said Raphael Ouillon, a mechanical engineer at the University of California Santa Barbara and lead author of the new study.

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“The initial fingers might only be a few millimeters or a couple of centimeters thick, but they’re everywhere across the entire surface of the lake,” said Eckart Meiburg, also a mechanical engineer at UC Santa Barbara and co-author of the new study. “Together these small fingers generate a tremendous amount of salt flux.”

The new finding helps researchers better understand the physics of the Dead Sea but also helps explain the formation of massive salt deposits found within Earth’s crust.

The Dead Sea is only hypersaline water body on Earth today where this salt fingering process is happening, so it represents a unique laboratory for researchers to study the mechanisms by which these thick salt deposits have formed, according to the authors.

“Altogether this makes the Dead Sea a unique system,” said Nadav Lensky, a geologist with the Geological Survey of Israel and co-author of the new study. “Basically, we have here a new finding that we think is very relevant to the understanding of the arrangement of these basins that were so common in Earth’s history.”

A salty mystery

As the Dead Sea has become saltier in , much of that salt has become concentrated near its surface. During the summer, extra heat from the Sun warms the surface of the Dead Sea and divides it into two distinct layers: A warm top layer sitting atop a colder lower layer. As water evaporates from the top layer in the summer heat, it becomes saltier than the cooler layer below.

Researchers realized the salt snow they observed was originating in this top salty layer, but this warm water doesn’t mix with the cooler water below because it’s so much warmer and less dense. So they were puzzled as to how salt from the surface was entering the cooler layer and plummeting to the bottom of the lake.

Lensky and his colleagues proposed an explanation in 2016, and the new research tests this theory for the first time.

They propose that when the top layer of the lake is disturbed by waves or other motion, tiny parcels of warm water enter the cooler pool of water below. Heat diffuses more rapidly than salt, so this warm water parcel rapidly cools. But as it cools it holds less salt, so the salt precipitates out and forms crystals that sink to the bottom. Watch an animation of the salt fingers here.

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In the new study, researchers created a computer simulation of how water and salt would flow in the Dead Sea if the salt fingers theory was correct. They found the salt fingers theory correctly predicted the downward flow of salt snow and buildup of salt layers in the middle of the lake’s floor. Because the level of the lake is declining, due to pumping of freshwater from the nearby Jordan River, the salt layers are concentrated in the central part of the lake, according to the authors.

New Study Solves Mystery of Salt Buildup on Bottom of Dead Sea

Satellite images of the Dead Sea taken in 1972 and 2011, showing how much water levels have dropped since Israel and Jordan began diverting much of the freshwater entering the Dead Sea. Credit: NASA.

Understanding salt deposits elsewhere

The new finding also helps explain the formation of massive salt deposits found within Earth’s crust.

“We know that many places around the world have thick salt deposits in the Earth’s crust, and these deposits can be up to a kilometer thick,” Meiburg said. “But we’re uncertain how these salt deposits were generated throughout geological history.”

One notable example is the thick salt layer underneath the Mediterranean Sea. Researchers know that about six million years ago, the Strait of Gibraltar closed off, because of the movements of Earth’s tectonic plates. This cut off the supply of water from the Atlantic Ocean to the Mediterranean, creating a giant shallow inland sea.

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After several hundred thousand years, the Mediterranean’s water levels dropped so much that the sea partly or nearly dried out, leaving behind thick deposits of salt. The new finding suggests these deposits formed during this time in a similar manner to what is happening right now in the Dead Sea. When the Strait of Gibraltar opened up again, water flooded the basin and the salt deposits were buried under new layers of sediment, where they remain today.

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Using Handheld Devices May Cause Young Children’s Speech Delay, new study claims

While technology offers convenience on one’s life, it could also impose negativity on its users especially on children.

A new study presents the possible speech delay in children upon usage of handheld devices last May 6 during 2017 Pediatric Academic Societies (PAS) meeting…

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Using Handheld Devices Cause Young Children’s Speech Delay, new study claims

While technology offers convenience on one’s life, it could also impose negativity on its users especially on children.

A new study presents the possible speech delay in children upon usage of handheld devices last May 6 during 2017 Pediatric Academic Societies (PAS) meeting.

The study was presented as an abstract entitled, “Is handheld screen time use associated with language delay in infants?” which claims that a thirty-minute daily usage of such devices increases the risk of a child’s speech delay by 49 percent.

“Handheld devices are everywhere these days,” said Dr. Catherine Birken, MD, MSc, FRCPC, the study’s principal investigator and a staff pediatrician and scientist at The Hospital for Sick Children (SickKids).

A total of 894 children from ages six to twenty-four months participated in the study, conducted from 2011 to 2015.

Dr. Birken, says in a news release, the research findings could reinforce the policy recommendation of the American Academy of Pediatrics (AAP) to limit any type of screen media in children primarily on the younger ones, 18 months and below.

However, she also added that more research is required to have a clearer understanding of how screen devices affect a child’s speech delay – like knowing what type of content children indulge with.

Lead by the author Julia Ma, HBSc, an MPH student at the University of Toronto, the study is the first to probe the correlation between handheld screen time and risk of expressive language delay.

AAP Policy

Last year, November 2016, AAP issued their three policy statements, which detailed how children should use media and avoid unnecessary repercussions: “Media and Young Minds,” “Media Use in School-Aged Children and Adolescents,” and “Children, Adolescents and Digital Media.”

In these policy statements, AAP encourages parents to be vigilant as they play an integral role if technology would benefit their children or not.

“Families should proactively think about their children’s media use and talk with children about it, because too much media use can mean that children don’t have enough time during the day to play, study, talk, or sleep,” said Jenny Radesky, MD, FAAP, lead author of the policy statement, “Media and Young Minds.”

AAP policy statements elaborated the effects of media on children, prominently on health issues.

With different age group as subjects, the “Media and Young Minds” included infants, toddlers and pre-school children while “Media Use in School-Aged Children and Adolescents” focused from ages 5 to 18.

In addition, AAP released a Family Media Plan Tool on October 2016, which can be used to help parents in guiding their children for using media.

AAP Recommendations

AAP have also laid several recommendations for avoiding overexposure of children on media. These are divided into three subgroups: pediatricians, families, and industries.

See: Media and Young Minds

Source: PAS (news release), AAP (news release)

 

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Greenland Shark may live up to 250 years

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In the freezing waters of the sub-Arctic ocean lurks a mysterious and slow-moving beast known as the Greenland shark. It’s a massive animal that can grow up to six metres in length. Now, new research suggests it may have a massive lifespan as well.

According to a paper published recently in Science, the Greenland shark could live for well over 250 years, making it the longest-living known vertebrate on Earth.

“I am 95 percent certain that the oldest of these sharks is between 272 and 512 years old,” said lead author Julius Nielsen, a marine biologist at the University of Copenhagen.

 

“That’s a big range, but even the age estimate of at least 272 years makes it the oldest vertebrate animal in the world.”

The oldest-animal record holder is a clam called Ming that was dredged up from the ocean floor off the coast of Iceland. It was said to be 507 years old when it died in 2006.

Shortraker rockfish off the Alaskan coast and orange roughy off Namibia are both estimated to live up to 200 years or longer. Harriet, a Galapagos tortoise from the Australia Zoo, lived to be about 170 years old.

Still, if Nielsen’s estimates are correct, the Greenland shark would be a record breaker.

Greenland sharks are among the largest sharks on the planet. They are dark brown or purple with small, beady eyes. They inhabit the Arctic and sub-Arctic waters, as well as cold, deep water in other oceans throughout the world.

Because they spend most of their time in the darkness their eyesight is thought to be very poor, but a vast network of neurons in their snouts suggests they hunt and scavenge using their powerful sense of smell.

“They are basically a giant swimming nose,” said Aaron Fisk, a professor at the University of Windsor who has studied the Greenland shark for two decades.

Scientists have long suspected that these lethargic giants have extremely long lifespans in part because previous research shows that they grow very slowly – possibly as little as a centimetre per year.

“In colder temperatures, growth slows and fish tend to get older,” said Fisk, who was not involved in the study.

“It’s not hard to imagine that they could be 200 or 400 years old.”

But determining the exact age of the Greenland shark is a tricky business. When scientists determine the age of fish such as cod, rockfish and salmon, they usually look at the otolith – a bony structure that grows in the ear of a fish.

Otoliths have seasonal growth rings, kind of like the rings in tree trunks. If researchers can figure out how long it took the animal to lay down one ring, they can easily determine the age of the fish.

Sharks and rays don’t have otoliths, so scientists have found other ways to determine their ages. For some species of sharks, it’s possible to tell how old they are by looking at growth layers deposited in calcified parts of their vertebra or fin spines. But the Greenland shark doesn’t have fin spines, and its cartilage skeleton is extremely soft with almost no calcified material, so there are no layers to count.

To overcome this hurdle, Nielsen and his collaborators turned to a more complicated technique called eye lens radiocarbon dating, which has been used to determine the age of other animals.

The eye lenses of all vertebrates continue to grow with the animal through its life, adding layers like an onion. However, the core of the eye lens is formed before the animal is born and remains metabolically stable throughout its life, Nielsen explained. That means that embedded in this small piece of tissue in the centre of a shark’s eye is a chemical signature from the environment just before it was born.

In the late 1950s, atmospheric tests of thermonuclear weapons caused a big and easily detectable spike in the amount of radiocarbon that eventually made its way into the sea. Scientists call this bump “the bomb pulse,” and it has become a handy way to verify the age of marine organisms.

If the amount of radiocarbon in a shark’s lens represents post bomb-pulse levels, that’s a pretty clear indicator that the animal was born after 1960. (It took a few years for the radiocarbon to filter down into the deep water.)

For this study, Nielsen examined the eye lenses of 28 female specimens that were caught off the coast of Greenland between 2010 and 2013.

The radiocarbon levels in the lenses of the two smallest sharks had a clear post-bomb pulse signature, suggesting that these animals were 50 or younger. The radiocarbon levels of the third-smallest shark put it right on the onset of the bomb pulse. The researchers say this means the third shark was likely born in the early 1960s.

However, the centre of the eye lenses of the 25 larger sharks all had pre-bomb-pulse radiocarbon levels, leading the authors to conclude that they were more than 60 years old.

The group’s next step was to determine how long before 1960 the other 25 sharks were born, and here’s where they had to get creative. They measured the radiocarbon levels in each of the remaining eye lens samples and then compared them to a published reference of how radiocarbon levels in the ocean have changed over time.

This chronology of much more subtle radiocarbon fluctuations goes back 50,000 years and is usually used to date corals and other organisms that are thousands of years old. When it is used to date more recent organisms, it shows a wide range of error.

To further constrain their results, the authors made the assumption that the longer a shark is, the older it is.

When they added the lengths of the specimens to their model, they found that the biggest shark in the data set – a 16-footer – would have been 392 years old, give or take 120 years.

The authors concede that the margin of error is still very large, but they say their findings demonstrate that the Greenland shark is extremely long-lived and that its population would take a long time to bounce back to normal if the animals were exploited by humans.

Aaron MacNeil, a research scientist at the Australian Institute of Marine Science who was not involved in the work, said the study represents an interesting approach to a difficult biological problem, but added that the findings are not necessarily conclusive.

“I don’t think this is the final word on Greenland shark ages,” he said.

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