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Biotechnology / CRISPR

China’s CRISPR babies: Read exclusive excerpts from the unseen original research

He Jiankui’s manuscript shows how he ignored ethical and scientific norms in creating the gene-edited twins Lulu and Nana.

by Antonio RegaladoDec 3, 2019

Earlier this year a source sent us a copy of an unpublished manuscript describing the creation of the first gene-edited babies, born last year in China. Today, we are making excerpts of that manuscript public for the first time.

Titled “Birth of Twins After Genome Editing for HIV Resistance,” and 4,699 words long, the still unpublished paper was authored by He Jiankui, the Chinese biophysicist who created the edited twin girls. A second manuscript we also received discusses laboratory research on human and animal embryos.

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The metadata in the files we were sent indicate that the two draft papers were edited by He in late November 2018 and appear to be what he initially submitted for publication. Other versions, including a combined manuscript, may also exist. After consideration by at least two prestigious journals, Nature and JAMA, his research remains unpublished.

The text of the twins paper is replete with expansive claims of a medical breakthrough that can “control the HIV epidemic.” It claims “success”—a word used more than once—in using a “novel therapy” to render the girls resistant to HIV. Yet surprisingly, it makes little attempt to prove that the twins really are resistant to the virus. And the text largely ignores data elsewhere in the paper suggesting that the editing went wrong.

We shared the unpublished manuscripts with four experts—a legal scholar, an IVF doctor, an embryologist, and a gene-editing specialist—and asked them for their reactions. Their views were damning. Among them: key claims that He and his team made are not supported by the data; the babies’ parents may have been under pressure to agree to join the experiment; the supposed medical benefits are dubious at best; and the researchers moved forward with creating living human beings before they fully understood the effects of the edits they had made.

Because these documents relate to one of the most important public interest issues of all time—the ability to change human heredity using technology—we here present excerpts from the “twins” manuscript, together with some of the experts’ comments, and explain the questions they raise. The excerpts are in the order in which they appear in the paper.

To understand why the manuscripts have remained unpublished up to now, read the accompanying article on He’s attempts to get them into scientific journals. For the case for making their content public, read the op-ed by Kiran Musunuru, a gene-editing specialist at the University of Pennsylvania, who argues the Chinese data shows that gene-editing for reproduction is unsafe and premature. 

1. Why aren’t the doctors among the paper’s authors?

The manuscript begins with a list of the authors—10 of them, mostly from He Jiankui’s lab at the Southern University of Science and Technology, but also including Hua Bai, director of an AIDS support network, who helped recruit couples, and Michael Deem, an American biophysicist whose role is under review by Rice University. (His attorney previously said Deem never agreed to submit the manuscript and sought to remove his name from it.)

It’s a small number of people for such a significant project, and one reason is that some names are missing—notably, the fertility doctors who treated the patients and the obstetrician who delivered the babies. Concealing them may be an attempt to obscure the identities of the patients. However, it also leaves unclear whether or not these doctors understood they were helping to create the first gene-edited babies.

To some, the question of whether the manuscript is trustworthy arises immediately.

Hank Greely, professor of law, Stanford University: We have no, or almost no, independent evidence for anything reported in this paper. Although I believe that the babies probably were DNA-edited and were born, there’s very little evidence for that. Given the circumstances of this case, I am not willing to grant He Jiankui the usual presumption of honesty. 

2. The researchers’ own data don’t support their main claims

The abstract, or summary, lays out the aim of the project—to generate humans resistant to HIV—and the main results. It states that the team was “successfully” able to “reproduce” a known mutation in a gene called CCR5. The small percentage of people born naturally with this mutation, known as CCR5 delta 32, can be immune to infection by HIV.

But the summary goes well beyond what the data in the paper can back up. Specifically, as we’ll see later, the team didn’t actually reproduce the known mutation. Rather, they created new mutations, which might lead to HIV resistance but might not. They never checked to see, according to the paper.

Fyodor Urnov, genome-editing scientist, Innovative Genomics Institute, University of California, Berkeley: The claim they have reproduced the prevalent CCR5 variant is a blatant misrepresentation of the actual data and can only be described by one term: a deliberate falsehood. The study shows that the research team instead failed to reproduce the prevalent CCR5 variant. The statement that embryo editing will help millions is equal parts delusional and outrageous, and is akin to saying that the 1969 moonwalk “brings hopes to millions of human beings seeking to live on the moon.” 

—Rita Vassena, scientific director, Eugin Group: Approaching this document, I was hoping to see a reflective and mindful approach to gene editing in human embryos. Unfortunately, it reads more like an experiment in search of a purpose, an attempt to find a defensible reason to use CRISPR/Cas9 technology in human embryos at all costs, rather than a conscientious, carefully thought through, stepwise approach to editing the human genome for generations to come. As the current scientific consensus indicates, the use of CRISPR/Cas9 in human embryos destined to give rise to a pregnancy is, at this stage, unjustified and unnecessary, and should not be pursued.

3. Gene-editing embryos won’t bring HIV under control, especially in the worst-affected countries

The end of the abstract and beginning of the main text is where the authors justify their research. They suggest that gene-editing babies could save millions of people from HIV infection. Our commenters call this claim “preposterous” and “ludicrous,” and point out that even if the CRISPR method works to create people who are HIV resistant, it’s unlikely to be practical in places where HIV is rampant, such as in the southern part of Africa.

—Rita VassenaThis work offers little justification for the editing and subsequent transfer of human embryos to generate a pregnancy. The idea that editing-derived embryos may one day be able to “control the HIV epidemic,” as the authors claim, is preposterous. Public health initiatives, education, and widespread access to antiviral drugs have been shown to control the HIV epidemic.

—Hank GreelyThat this is a plausible way to “control the HIV epidemic” seems ludicrous. If every baby in the world were given this variation (beyond unlikely), it would begin to affect HIV infection substantially in 20 to 30 years, by which time we should have much better methods of stemming the epidemic—as well as existing methods that have substantially, if not yet sufficiently, slowed it. The 64% increase in infections in China (if true) is from a very low base. China has a substantially lower rate of HIV infection than Western countries. The situation in some developing countries remains more serious. But that this high-tech response is likely to be helpful in those countries is not plausible.

4. The parents might have wanted to take part for the wrong reasons

Contrary to some interpretations, the point of using CRISPR on the babies’ DNA wasn’t to prevent them from catching HIV from their father, who was infected. As the paper describes, this was achieved by sperm washing, a well-established technique. Instead, the purpose of the editing was to give the children immunity to HIV later in life. Thus, the experiment didn’t provide clear, immediate medical benefits to either the parents or the children. Why did the couple agree? One reason may have been to access fertility treatment at all.

—Rita VassenaI find it worrying that the husband in the couple offered this experimental genome editing was positive to HIV infection, as one can imagine the unnecessary emotional pressure on the couple to consent to a procedure offering no improvement to the patient and their children’s health, but carrying a potential risk of negative consequences. It is worth remembering that HIV infection is not passed on through generations like a genetic disease; the embryo needs to “catch” the infection. For this reason, preventive measures such as controlling the viral load of the patient with appropriate drugs, and careful handling of the gametes during IVF, can avoid contagion very efficiently. Current assisted reproductive techniques ensure safe procreation for HIV-positive men and women, avoiding both horizontal (between partners) and vertical (between parent and embryo/fetus) transmission, making the editing of embryos in these cases unnecessary. In fact, the couple in the experiment did undergo such ART procedures, consisting in this case of an extended wash of semen to remove all seminal fluid, which may harbor HIV. Extended sperm washing has been used for almost two decades in IVF laboratories worldwide and in thousands of patients; in ours and others’ experience, it is safe for both parents and their future children and does not entail invasive manipulation of embryos.

—Jeanne O’Brien, reproductive endocrinologist, Shady Grove Fertility: Being HIV-positive in China carries a significant social stigma. In spite of intense familial and societal obligations to have a child, HIV-positive patients have no access to treatment for infertility. The social context in which the clinical study was carried out is problematic and it targeted a vulnerable patient group. Did the study provide a genetic treatment for a social problem? Was this couple free from undue coercion?

5. The gene edits weren’t the same as the mutations that confer natural HIV resistance

Here, the researchers describe the changes CRISPR actually made to the twins. They removed a few cells from the IVF embryos to look at their DNA, and found that edits intended to disable the CCR5 gene had indeed taken hold.

But while they “expect” these edits to confer HIV resistance by nullifying the activity of the gene, they can’t know for sure, because the edits are “similar” but not identical to CCR5 delta 32, the mutation that occurs in nature. Moreover, only one of the embryos had edits to both copies of the CCR5 gene (one from each parent); the other had only one edited, giving partial HIV resistance at best.

—Hank Greely“Successfully” is iffy here. None of the embryos got the 32-base-pair deletion to CCR5 that is known in millions of humans. Instead, the embryos/eventual babies got novel variations, whose effects are not clear. As well, what does “partial resistance” to HIV mean? How partial? And was that enough to justify transferring the embryo, with a CCR5 gene never before seen in humans, to a uterus for possible birth?

6. There could have been other, unwanted CRISPR edits

CRISPR isn’t a perfect tool. Trying to edit one gene can sometimes create other, unintended changes elsewhere in the genome. Here the team discusses their search for such unwanted edits, called “off-target” mutations, and say they found just one.

The search was incomplete, however, and the manuscript also glosses over a key point: any cells the researchers took from the early-stage embryos to test didn’t, therefore, actually contribute to the twins’ bodies. The remaining cells, the ones that would multiply and grow to become the twins, could have harbored off-target effects too, but there would have been no way to know that in advance of starting the pregnancy.

—Fyodor UrnovAn egregious misrepresentation of the actual data that can, again, only be described as a blatant falsehood. It is technically impossible to determine whether an edited embryo “did not show any off-target mutations” without destroying that embryo by inspecting every one of its cells. This is a key problem for the entirety of the embryo-editing field, one that the authors sweep under the rug here.

7. The doctors treating the couple may not have known what was going on

Reporting by a variety of news outlets, including the Wall Street Journal, has charged that He’s team tricked doctors by switching blood samples and that not all of them knew they were involved in creating gene-edited children. If true, that’s a problem, since it’s the duty of doctors to do what is in the best interest of the patient.

—Jeanne O’BrienThe IVF procedure described follows the same steps and time line whether or not CRISPR is used for genome editing. The Chinese physicians who performed the IVF may have been unaware of the father’s HIV status or that the embryos were genetically modified. He Jiankui would have only needed a willing embryologist to inject CRISPR at the time of insemination. He’s comments make it appear as if the physicians who performed the IVF were not involved in the subsequent decision regarding which embryos to select for transfer. This is a wake-up call to physicians involved in IVF: the science and technology will continue to progress, and desperate couples with infertility may overlook the unknowns or believe the technology is proven safe. Once we, the infertility physicians, knowingly transfer an embryo with germline editing, we are in essence confirming the safety of the modification to the parents and the future child. Is it ever possible to know that?

8. The manuscript misrepresents when the babies were born

By now, several media reports and people familiar with the research have established that the twins were born in October, not November. Why did He’s team include a false date? It may have been to protect the anonymity of the patients and their twins. In a country the size of China, there could be more than ten thousand sets of twins born each month. The falsified date may have been an attempt to make their reidentification even more difficult.

9. It’s not clear if there was a proper ethics review

The paper includes an exceptionally brief discussion of ethics. It says the research plan was registered with the China Clinical Trial Registry, but in fact the public registration occurred only after the twins were born. 

—Hank GreelyRegistered when? The answer is on November 8, 2018, after the births and very shortly before they were announced, and probably in order to increase publication potential. This was not a normal registration. Maybe there was an ethics approval—though that hospital has denied it. Who is telling the truth? Not sure we’ll ever know. The phrase “we were told” about a comprehensive ethics review is not very powerful evidence. The article also does not discuss the Chinese ban on assisted reproductive services for HIV-positive parents. It has been reported that He had other men pretend to be the intended fathers for purpose of the required HIV tests. The article doesn’t say this. It seems to me likely to be true—and damning. If true, it means He defrauded the Chinese regulatory process.

10. The researchers didn’t test whether the HIV immunity worked before creating living human beings

Here the Chinese team outlines their plan to collect blood from the twins to see if their edited cells really resist HIV. That is something they could have tried to learn ahead of time, before creating the girls. Before transferring the embryos, they could have kept them frozen while they made identical edits in laboratory  cells and tested the effects of HIV on those cells.

—Fyodor UrnovThis statement proves that the research team placed their interests above those of the couple who donated the embryos and of their prospective children. There is zero evidence in the manuscript supporting the essential expectation that the new forms of CCR5 would be HIV-protective. It was essential to have determined that before the embryos were implanted. They could have done so using a known assay: introduce the same edits into immune system cells in the laboratory and then infect them with HIV. Only the cells that have HIV-protective variants of CCR5 survive. The research team chose not to do that assay. Instead, they made children out of embryos that had forms of CCR5 of entirely uncertain functional impact. Were the researchers in a rush? Did they simply not care? Whatever the explanation, this egregious violation of elementary norms of ethics and of research borders on the criminal.

11. An American Nobelist may have helped He justify his experiment

The article’s conclusion contains an unexpected digression that puts forth an entirely new justification for the research, one that connects the project to the heart of the HIV epidemic in Africa. It’s that many uninfected children of African mothers with HIV suffer a syndrome called “HEU” that makes them more susceptible to a variety of childhood illnesses. The authors say genome editing could be a “novel strategy” against HEU.

There isn’t any evidence for this idea, but there are some clues about where He got it. In an email he sent on November 22 to Craig Mello, a biologist at the University of Massachusetts who at the time was an advisor to one of his companies, He thanked Mello for suggestions on the topic and enclosed in his email the same paragraph above.

Does that mean Mello, a winner of the 2006 Nobel Prize for medicine, contributed a key idea to the paper? Mello was told about the twins project early on but, through a spokesman, says he never gave He advice on how to write the paper. According to He’s email, however, any such interaction was meant to remain unacknowledged. “Again, I won’t tell people you know what is happening here,” he wrote to Mello.

12. The project had other supporters, but some key information is missing

The manuscript concludes by thanking a list of people who, according to He, gave him direct feedback on draft versions of the text or other advice. In an acknowledgement for “editing” the text, he names Mark Dewitt, a researcher at the University of California. Dewitt didn’t reply to emails but earlier gave a description of his role, saying he had warned against the project. William Hurlbut, an ethicist at Stanford, says he gave ethics advice to He but didn’t know that the Chinese scientist had created children.

He also thanks W.R. “Twink” Allen, an equine reproduction specialist in the United Kingdom, and Allen’s onetime student Jin Zhang, also known as John Zhang, who is now head of New Hope Fertility Center in New York, one of the largest in the US. According to reports, Zhang was planning with He late last year to open a medical tourism business for gene-edited babies.

Of these names, only Allen’s has not previously been cited in connection with the CRISPR-baby research. Allen did not reply to attempts to contact him by email. Zhang, who has not been forthcoming about his role, told us he was not familiar with the manuscript. “I have never seen it,” he told us in October.

The version of the twins manuscript we have is missing two critically important disclosures usually present in scientific papers. First, it gives no information about who funded the project or what financial interests the authors have in the outcome. Also missing is a section in which each author’s scientific contribution is detailed. This means the text does not explicitly describe the role of the single non-Chinese author, Michael Deem of Rice University in Texas. The nature of Deem’s role—particularly any hands-on involvement with the patients—could determine penalties that Deem, or his university, could face. Deem’s lawyers did not answer questions, including a request for copies of his past statements, which sought to minimize his role in the research. Rice says its investigation is ongoing.

13. The researchers ignored evidence that the gene edits weren’t uniform

In data attached to the paper, in the so-called “supplementary” material, are tables that He previously showed publicly. It shows chromatograms, or the readout of the DNA sequences found in the embryos and birth tissues of the twins (the umbilical cord and placenta) when his team tried to measure what editing had happened to the CCR5 gene.

Some observers, including Musunuru in our accompanying op-ed, say these data show clearly that the embryos are “mosaic,” meaning that different cells in the embryo were edited differently. He says presence of multiple edits is visible in the chromatograms, where several distinct readings are registered in overlapping signals at a given DNA position.

The implication of the data is that the twins’ bodies could be composites of cells edited in different ways, or not at all. That, Musunuru points out, means only some of their cells might have the HIV-resistant gene edit; it also means some might have undetected “off-target” edits, which could potentially cause health problems. The problem of mosaicism was well known to He from his experiments on animal embryos. One of the mysteries of the research project is why He chose to proceed with embryos if they were flawed in this way.

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In his manuscript, He doesn’t resolve the mystery. It says only, “The CCR5 gene was deep sequenced for all samples to examine the mosaicism of gene editing.” There’s no interpretation of what was found, and no acknowledgement that the data seem to show mosaicism or that it’s a problem.

—Fyodor UrnovThey should have worked and worked and worked until they reduced mosaicism to as close to zero as possible. This failed completely. They forged ahead anyway.Read the whole story  3456 words

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Friday, Dec 13th 2019 6AM 18°C 9AM 25°C 5-Day Forecast

Doctors bring a DEAD heart ‘back to life’ by pumping it full of oxygen, blood and electrolytes in groundbreaking procedure that could save the lives of thousands waiting for an organ transplant

  • Duke University doctors have re-animated a heart after its donor died in a first for the US 
  • Every day, 20 Americans die waiting for donated organs  
  • Worldwide, there is a constant shortage of donor organs, and many go to waste because they can’t be transplanted quickly enough 
  • Typically a donor heart must be harvested from a brain dead donor whose heart is still beating to keep the tissue from dying too fast 
  • Now, doctors can use a technique called warm perfusion to reinvigorate the organ with blood, oxygen and electrolytes 
  • It was first done in the UK ion 2015, and Duke has now become the first US hospital to complete a donation after cardiac death heart transplant  

By NATALIE RAHHAL DEPUTY HEALTH EDITOR FOR DAILYMAIL.COM

PUBLISHED: 16:15 GMT, 2 December 2019 | UPDATED: 16:16 GMT, 2 December 2019

151kshares91View comments

Doctors have now brought an adult heart back to life to transplant it into a person in need of a new organ for the first time in the US. 

Duke University surgeons harvested the heart from a dead donor whose blood had already stopped circulating through their body. 

They then used a pioneering technique to run blood back into the disembodied heart, so it would beat once more, a process documented in a surreal video tweeted by one of the doctors involved in the historic operation. 

The heart was successfully transplanted into a recipient, a win that suggests far more will be eligible for donation in the future as doctors are able to beat the clock and keep the organ alive for outside of a body. Duke doctors bring dead heart back to life for transplantLoaded: 0%Progress: 0%0:00PreviousPlaySkipMuteCurrent Time0:00/Duration Time0:18FullscreenNeed Text

A human heart was transplanted for the first time ever in 1967 in South Africa. A year later, Stanford University doctors performed the first such transplant in the US. 

By 2018, over 3,400 heart transplants were performed across the US. 

Heart transplants are now relatively common, but there’s a constant shortage of organs – hearts as well as others, like livers, lungs and kidneys – in the US and worldwide.  

Less than half of Americans in the US – about 45 percent – are registered as organ donors. 

The pool shrinks further after they pass away. 

Many organs are too damaged or in poor conditions that render them unusable. 

Still others may be cast aside based on their donors’ medical histories, lifestyles or infections they’ve contracted. 

The transplant wait list in the US is over 100,000 people long, and 20 die every day waiting for new organs.

In an effort to address this, doctors are constantly working on new ways to broaden the donor pool. 

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Simply asking more Americans to register as organ donors isn’t enough. In recent years, the transplant community has expanded that pool most significantly by allowing the transplantation of organs from donors who tested positive for hepatitis C.  

In addition to meeting health criteria, time plays a significant role in the viability of organs. 

The tissue that makes up the heart starts to die shortly after it stops beating, making it unusable. In fact, by the time a heart stops naturally, it’s already been running on a low supply of oxygen, that the tissue has been dying before circulatory death could be proclaimed. 

So transplant surgeons are confined to using hearts from donors who are declared brain dead, but whose other vital organs are still functioning. 

Historically, the best defense against the heart’s decay has been keeping the organ at very cold temperatures. Even then, hearts are only viable after spending four to six hours outside the body. 

But if doctors can instead get a heart beating again after removing it from the donor’s body, the organ will be ‘alive’ once more, independent of the person who has died. 

And they won’t have to harvest solely from brain dead donors with still-beating hearts. 

The so-called heart-in-a-box technique keeps the organ beating by keeping it warm and pumped full of blood, oxygen and electrolytes, potentially adding hours to its viability period

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The so-called heart-in-a-box technique keeps the organ beating by keeping it warm and pumped full of blood, oxygen and electrolytes, potentially adding hours to its viability period

To do so, surgeons remove the heart and quickly connect it to a series of tubes that mechanically feed it blood, oxygen and electrolytes. 

Nurtured once more, the heart muscle is ‘reanimated,’ and jumps back into action. 

The technique, called warm perfusion, was used to do a human heart transplant for the first time ever at Royal Papworth Hospital in the UK in 2015. 

Since then, the hospital, which is the nation’s main center for both heart and transplants, has performed some 75 heart transplants after the donor’s circulation stopped, estimates Dr Jacob Schroder, one of the heart surgeons involved in the Duke University procedure. 

He and his team are now the first in the US to perform a donation after cardiac death (DCD) heart transplantation in the US. 

Proof of concept that doctors here can do the procedure, Dr Schroder hopes, will mean more hearts will be viable for more patients.

‘This is the first time in the US, which is a huge deal because transplant need and volume is so high, but a few centers around the world, including Papworth, have pioneered this effort,’ he told DailyMail.com in an email.          

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Doctors bring a dead heart ‘back to life’ for groundbreaking transplant

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Batak accordion book of spells.
This Batak accordion book of spells was used in rituals, spellcasting and healing, according to librarian Emilie Hardman. It was often worn draped across the body of the practitioner, she said. Photos by Stephanie Mitchell/Harvard Staff Photographer

Whether a spell book or Edison bulb, Houghton’s treasures charm students and illuminate research

BY Anna Fisher-PinkertGSAS Communications

DATEJanuary 5, 2018SHARE 

It’s hard to imagine even the most jaded student entering the Houghton Library without a sense of awe. Within these walls, you can read a letter signed personally by Vladimir Lenin, unfold a book of spells from Indonesia, and marvel at Emily Dickinson’s writing desk and chair.

As Houghton celebrates its 75th anniversary, scholars take a look back at how some of the library’s rare holdings have inspired their research. Their stories are paired with audio clips from Houghton librarian Emilie Hardman, who provides some context for the the objects.

* * *

Katherine Leach, a Ph.D. student in Celtic languages and literatures, took her students to Houghton to explore medieval and early modern tracts against witchcraft.

Librarian Emilie Hardman showed them original sources from the period such as the Malleus Maleficarum but to the delight of the class, she also rolled out an Indonesian spell book, bamboo sticks engraved with spells, and an Armenian charm scroll.

“The class changed because of what Emilie brought in to show my students,” Leach says. “There were two Armenian students in the class. Seeing that scroll blew their minds. They were posting on Instagram and texting other Armenian students.”

Leach says that as a medievalist, she’s often focused exclusively on texts and manuscripts but “seeing these artifacts made the topic more relatable, more real” for her students.

“I was so impressed with the collection and with Emilie,” Leach says.

Malleus Maleficarum, open page

‘Malleus Maleficarum’

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Armenian charm scroll from 1708.

Armenian charm scroll

PlaySeek00:00Current time00:30Toggle MuteVolume“There were two Armenian students in the class. Seeing that scroll blew their minds. They were posting on Instagram and texting other Armenian students.”— Katherine Leach

Spell-engraved bamboo stick

PlaySeek00:00Current time00:23Toggle MuteVolume

* * *

Today, we can zoom in on any part of the world through Google Maps and Street View.

When German cosmographer Sebastian Münster made his Cosmographia, a book intended to capture the world as he knew it in the 16th century, he did not have the benefit of Google’s tools.

Instead, Münster recruited a resident from every German burg to provide him with drawings of their cities, says Jasper van Putten ’15.

A Ph.D. student in the history of art and architecture when he found the text at Houghton, van Putten launched a research project that would have astonished Münster.

Using GIS mapping tools — with landmarks such as church spires and old city walls as his guide — he overlaid the antique drawings from Münster’s book over modern satellite maps of German cities.

Surprisingly, the old illustrations were fairly accurate, van Putten says. However, in some, important landmarks were nudged into positions that made the cities look more important.

“One city moved a castle about 300 meters to put it in the center of the view,” according to van Putten.

The Cosmographia stayed in print for about 90 years with maps added or redesigned in later editions, van Putten says, so he stacked up the views in GIS to flip back and forth and see how the cities had changed over time. He has put his work online, giving researchers and history buffs anywhere a bird’s eye view of the way that 16th century Germans saw their world.

Cosmographia

Cosmographia

PlaySeek00:00Current time00:27Toggle MuteVolume

* * *

Jeremy Zallen ’14 wanted to write about the history of illumination for his Ph.D. dissertation. While exploring the earliest forms of electric light in the United States he came across the records of the Bijou Theatre.

In the 1880s, the Boston venue became the first fully electrified theater in the country. A single, fragile light bulb survived from that era and sits in Houghton alongside the theater’s financial records.

If you put this tiny bulb on a shelf in Home Depot, you might not notice that it is a relic from the 1880s, with a bamboo, rather than tungsten, filament.

“The bulb would have been made in Menlo Park, under the direction of Thomas Edison. In those days, they were experimenting with a number of filament types,” Zallen says. “The bamboo filament would have been less bright than previous electric light bulbs, but it would have lasted at least a few days — which was a big improvement.”

The bulb brought up more questions than answers for Zallen: Why did someone save this solitary light bulb? Were the electric lights’ primary purpose functional, or were they really just props to publicize Edison’s invention?

Llight bulb from the 1880s.
Photo courtesy of Harvard University Library

Light bulb from the 1880s

PlaySeek00:00Current time00:45Toggle MuteVolume

* * *

Andrea Bohlman, Ph.D. ’12 in music, unexpectedly discovered a series of underground recordings at Houghton while preparing for a trip to Poland that she says, “changed my research methodology forever.”

“I was probably on page 57 of search results in the HOLLIS catalog when I stumbled upon the Solidarity Collection,” Bohlman said.

Comprising dozens of cassette tapes belonging to Poles who resisted or subverted the Communist government as a part of the Solidarity movement of the 1980s, the collection opened up a whole new world of research for Bohlman.“Now everywhere I go to conduct research, I look for weird sound recordings.”— Andrea Bohlman

Bohlman heard everything from politically conscious Polish rock music to bootlegged news reports from broadcasters sympathetic to the Solidarity movement.

“Cassette tapes are convenient materials for politically subversive communication — you can wipe them with a magnet, you can record over them, but you can also copy them infinitely,” Bohlman said.

Solidarity-related cassette tapes became the cornerstone of Bohlman’s dissertation, now a forthcoming book, “Musical Solidarities: Political Action and Music in Late Twentieth-Century Poland.”

“Now everywhere I go to conduct research, I look for weird sound recordings,” Bohlman says. “They’re an untapped resource.”

To read the full story, visit the Graduate School of Arts and Sciences website.

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2019 Top 10 Innovations
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2019 Top 10 Innovations

From a mass photometer to improved breath biopsy probes, these new products are poised for scientific success.

Dec 1, 2019
THE SCIENTIST STAFF

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On the winding road to successful innovation, there are many diversions and dead ends. But companies and independent researchers consistently navigate those pitfalls, developing products that have the potential not just to revolutionize the creation of new drugs or to ease the work of life scientists in the lab, but to offer a clearer picture of how biology works. This year’s Top 10 Innovations, which come from companies both large and small, include an instrument that uses a new technology called mass photometry to simultaneously analyze several biomolecules within a cell and a novel system that improves multiplexed antibody detection.

You’ll notice familiar names—such as Pacific Biosciences, Horizon Discovery, and 10x Genomics—among our 2019 winners, as instrument makers continue to advance their platforms and protocols to better meet the needs of biologists. New players also made the cut this year. Companies including Owlstone Medical and Berkeley Lights appear in our Top 10 Innovations list for the first time with products that wowed The Scientist’s independent panel of judges with their potential to enable new discoveries.

This year has proven to be a great one for the life sciences, and the 2010s have been an exciting decade. Here, The Scientist presents the fine-tuned tweaks and brand-new technologies that make up our Top 10 Innovations for 2019.

RefeynRefeyn OneMP

In 2018, Philipp Kukura at the University of Oxford and his colleagues announced a technology they had developed, called mass photometry, that measures the weight of single molecules by the way they scatter light. The approach offered an entirely novel way to analyze biomolecules, with a few key advantages. Instead of moving samples into a vacuum as native mass spectrometry requires, mass photometry allows them to stay in their buffer solution. And unlike chromatography, which requires rather large sample volumes, mass photometry can read just a few microliters of a nanomolar concentration solution. To top it all off, the processing time is about a minute or two, compared to an hour or so for chromatography.

In short order, the University of Oxford spun out Refeyn to commercialize mass photometry, and its Refeyn OneMP instruments went on the market in March of 2019, starting at roughly $150,000. Matthias Langhorst, the chief marketing officer of the company, says applications for the tool range from simple tests of purity—the number of mass peaks will indicate how many types of protein are in a sample, for example—to more sophisticated analyses of how biomolecule assemblies behave under different conditions.

Thomas Schwartz, who studies the cell’s nuclear pore complex at MIT, was an early tester of the device, reaching out to Kukura as soon as he heard about mass photometry. “The most valuable thing with this instrument is that we can look at complex proteins-macromolecular complexes and figure out what are the components in that mixture, and do we detect any issue with stability,” he says. “It’s a very time-consuming process in typical workflow.”

Wiley: “The principles are not new, but the implementation in this new device is quite clever and powerful because it can measure every particle in a field. Very powerful and potentially revolutionary instrument.”

NeuBaseJanus bases

Researchers can silence RNA by designing antisense oligonucleotides that complement the target sequence; the first therapeutics based on this approach are just hitting the market. (See “Oligonucleotide Therapeutics Near Approval,” The Scientist, December 2016.) But manufacturing long oligonucleotides and delivering them to cells are not easy tasks, says Carnegie Mellon synthetic organic chemist Danith Ly. Researchers can also target RNA with small molecules, which are easier to manufacture and deliver but don’t selectively bind to the targeted RNA. “We thought we might be able to find a sweet spot between the two traditional methods,” says Ly, who with his former postdoc Shivaji Thadke developed double-sided Janus bases (Comm Chem, 1:79, 2018).

These bases are covalently linked to a charge-neutral peptide nucleic acid backbone, rather than a negatively charged sugar backbone, so the molecules can get cozy with target RNA or DNA. Janus bases also have two binding faces, allowing them to slip between the two sides of double-stranded nucleic acids, and bind to both of the complementary strands with stronger affinity than the two natural strands have to each other. Janus base therapeutics can therefore be highly specific to their targets even at lengths much shorter than traditional oligonucleotides. 

NeuBase Therapeutics, founded in 2018 to develop peptide nucleic acid (PNA) therapeutics, exclusively licensed Janus bases from Carnegie Mellon last year and took Thadke on as its director of chemistry. The company now has two Janus-based drugs in early development, for Huntington’s disease and for myotonic dystrophy type 1. Each drug is just three Janus bases long and binds to two sides of an aberrant hairpin that forms in mutant RNAs that underlie disease pathogenesis. The company is now beginning mouse experiments, says Dietrich Stephan, cofounder, chairman, and CEO of NeuBase, with clinical trials projected to begin in 2021. He adds, “We’ve got a pipeline of other targets below that.”

Kamdar: “Development of a new gene modifying therapy with ability to target neurological and neuromuscular disorders. Combines the advantages of small molecules with the selectivity of antisense oligonucleotides.”

Berkeley LightsLightning optofluidic platform

Berkeley Lights’s Lightning optofluidic platform enables researchers to precisely study the behaviors of single cells within a defined time period by recording video of them throughout the data collection process. The platform, released in June, works via a microfluidic section with a postage stamp–sized silicon chip containing miniscule NanoPens, long and narrow chambers that isolate and culture individual cells. “If you were the size of a cell, a conference room is about the size of a NanoPen,” says Mark White, senior director of marketing at Berkeley Lights. He declined to name the product’s price, saying that it varies based on applications. “The platform is in the ballpark of a very high-end microscope,” he says.

Medical oncologist Cassian Yee, a consultant for Berkeley Lights who studies endogenous T cell therapy, uses the device in his lab at the University of Texas MD Anderson Cancer Center. “Every single cell is tracked from beginning to end. . . . This not only allows you to analyze a lot of different parameters at once, even with a few cells, but also if you’re interested in using this as quality control for your T cell product, it’s probably as rigorous as you can get,” he says. 

Researchers using other optofluidic devices have to use multiple instruments to perform cell assays and take a snapshot of the cells on each instrument. In addition to consolidating equipment, the Lightning platform runs protocols on Python script, making it access-ible to researchers worldwide. “You can give [a protocol] to somebody else halfway around the world who can run exactly the same protocol,” says Yee. “That’s the beauty of a device like this. . . . This is a sort of quantum leap from what people were doing.”

Cruickshank-Quinn: “Being able to visualize phenotypes and perform functional assays on thousands of individual cells simultan-eously allows users to obtain results in a fraction of the time. Very promising technology for cancer research.”

Pacific BiosciencesSequel II

Pacific Biosciences has multiplied the capacity of its previous DNA- and RNA-sequencing instrument, Sequel, which won a spot in The Scientist’s 2016 Top 10 Innovations. The new Sequel II, priced at $495,000 in the US, can generate about eight times as much data as its predecessor. Inside each of its sample chambers, termed zero-mode waveguides, the instrument detects bases as a polymerase adds them to a nucleotide chain, yielding sequence information. 

The result, as with the original Sequel, is long-read DNA or RNA sequences, now delivered more quickly and at lower cost, says Marty Badgett, PacBio’s senior director of product management. Long reads allow researchers to identify structural variants in the genome, “which is quite complementary to [information gleaned from] short reads,” such as single nucleotide polymorphisms (SNPs), he says. That structural information includes translocations in the genome, copy number variants, insertions, and deletions. 

Because of its long read lengths and flexible run conditions, the Sequel II is adept at de novo genome sequencing in species for which no reference genome is yet available, says Shawn Levy, a geneticist at the nonprofit HudsonAlpha Institute for Biotechnology, which was given early access to the instrument. And, he adds, the instrument’s long-read sequencing is also good for analyzing highly repetitive or homologous regions of the genome. Levy says that he and other researchers at Huntsville, Alabama–based HudsonAlpha are exploring the use of the Sequel II to search for genetic causes of rare diseases for which no SNPs can be found, and to analyze RNA in cancer cells, among other applications.

Wiley: “Does longer reads with greater accuracy, at greater throughput, and at significantly lower cost. PacBio sets the standard for long-read sequencing and this upgrade of their instrument should have high impact on genomics sciences.”

NanoliveCX-A

A live-cell imaging microscope released in July 2019, CX-A promises to answer important questions about cellular interactions “in a much more elegant and powerful way” than ever before, quantitative biologist Mathieu Fréchin tells The Scientist. Fréchin works at Nanolive, the company that developed the microscope, and has used the instrument to observe mitochondrial fission and fusion, the way groups of cells interact and react to one another, and other cellular phenomena. 

To capture such dynamics, CX-A doesn’t use stains or labels. Instead, it reconstructs a three-dimensional hologram based on how the sample refracts light. To understand how it works, “think of straw in a clear glass of lemonade,” says Alexander Jones, Nanolive’s chief commercial officer. In the air, the straw appears normal, but in the lemonade, it appears bent, or refracted. In a cell, each organelle refracts light differently, as if each organelle were a different lemonade. CX-A accounts for the variations in refraction and reconstructs the three-dimensional image formed by the interference of the refraction of the cellular components in its field of view. 

This holographic technique was the backbone of Nanolive 3D Cell Explorer, which won a spot in our 2015 Top 10 Innovations. The company’s new technology builds on the 3D Cell Explorer design and is automated so scientists can program the various fields of view they would like to observe in a single slide or in 96-well plates, then walk away and let the machine do the work. “It’s the difference between the Wright brothers’ airplane and the Concorde,” Jones says. Although Nanolive declined to give a precise cost for CX-A, Jones says that the tool is a tenth of the price of a super-resolution confocal microscope, which typically runs between $300,000 and $500,000.

Kamdar: “Nanolive imaging is a great discovery tool that allows the measurement of cellular processes and kinetics in real-time, enabling multi-parameter analysis at single-cell and subcellular scale.”

Abbott FreeStyle Libre 2

With a swipe of a cellphone across a sensor attached to the back of his arm, Michael Krauser can instantaneously check his glucose levels. For Krauser, a diabetes patient living in Germany, there are no painful finger pricks, and no hassle trying get enough blood on test strips to measure his glucose. Abbott’s FreeStyle Libre 2 is an “elegant” solution to checking his glucose that “adds a certain security to my life,” he says.

The FreeStyle Libre 2 system was approved for use in Europe in 2018 and is not yet available in the US. When the glucose monitoring system does hit the US market, each sensor, which is temporary and lasts two weeks, will cost about $55. The size of two stacked quarters, a sensor measures glucose through what looks like a pin inserted into the interstitial fluid, a liquid that surrounds the cells just below the skin. Patients can check their glucose by swiping a smartphone loaded with the FreeStyle LibreLink app across the sensor, or they can buy the FreeStyle Libre reader for a one-time cost of $70.

The Bluetooth-enabled sensor allows users to set sound or vibration alarms on their phones or readers to alert them when their blood sugar is too low or too high, so they can bring it back to baseline by eating carbs or injecting insulin. The alerts are extremely helpful to children and other patients who might not other-wise know of extreme changes in their glucose levels, especially during sleep, says Marc Taub, the divisional vice president of product development for diabetes care at Abbott.

“Innovations like the FreeStyle Libre 2 technology give me courage to live a good life with my type 1 diabetes,” Krauser says.

Cruickshank-Quinn: “This offers a great solution for diabetics so that they no longer need constant finger sticks, and the option to use either the reader or smartphone gives patients flexibility of choices, especially in these technologically advanced times.”

Akoya Biosciences CODEX

Until a few years ago, tumor profiling either lacked spatial context, or was limited to just two or three markers at a time, says Julia Kennedy-Darling, director of research and development at Akoya Biosciences. Increasing the amount of spatial information that can be mined from tumors is important, she says, because “we’re understanding that it’s not sufficient just to be able to catalog what cells might be present in a sample, but where they are and which cells are next to each other.” To that end, as a postdoc in Garry Nolan’s lab at Stanford University, Kennedy-Darling codeveloped a technique to detect up to 40 different markers—and indicate their locations—in a single sample.

That technique, called CODEX, overcomes the problem of spectral overlap—that is, when too many antibodies fluorescing different colors are added to a sample, researchers can’t reliably distinguish among them using conventional detection methods. The key with CODEX, Kennedy-Darling explains, is that dyes aren’t covalently bonded to particular antibodies, but are induced to associate with different antibodies over multiple cycles of analysis, with three dyes revealed and imaged in each cycle. Akoya declined to reveal CODEX’s price. 

The instrument’s capacity to collect data on multiple markers per sample was a selling point for Andras Heczey, an oncology researcher at Baylor College of Medicine who has used CODEX for antibody validation and plans to deploy it to analyze how immunotherapy treatments interact with cancers. “Postinfusion biopsies are extremely precious” because they’re hard to come by, he explains, and they tend to be small. His aim with CODEX is to “get the most data from small samples of tissues to understand as much of the tumor micro-environment as possible.”

Wiley: “Although multiplexed antibody detection systems have been described before, the simplicity . . . of this system should make this powerful approach more generally available.”

Owlstone Medical EVOC Probes

Launched in June, EVOC probes from Owlstone Medical are a new way to measure exogenous volatile organic compounds in the breath. The probes expand upon the company’s Breath Biopsy platform, launched in 2017, in which researchers collect breath samples from patients that are then analyzed in Owlstone Medical’s lab for biomarkers of cancer or other diseases. Prior to the launch of EVOC probes, the company’s breath research was focused on endogenous, or internally generated, biomarkers. EVOC probes, on the other hand, allow scientists to administer small doses of safe volatile organic compounds, such as terpenes, as probes and then measure the concentration of the products of reactions involving those compounds to assess liver function or drug metabolism. “The big advantage is that you know what you’re looking for,” says Billy Boyle, cofounder and CEO of Owlstone Medical. “Rather than having to try and find the tiny needle in the haystack, you’re able to introduce a much larger signal into the system.”

The product’s price tag, about $400 per experiment, includes the cost of the probes and the breath collection device and data analysis. The company is currently working with cancer researchers such as Rebecca Fitzgerald at the University of Cambridge to develop tests for clinical settings, where the cost of running breath-based tests would be far cheaper than the current cost in the research sector—on the scale of “tens of dollars,” says Boyle. “The technology is easy to use and generally well tolerated by patients,” Fitzgerald writes in an email to The Scientist. “[Patients] find the process noninvasive compared to other ways of taking samples, such as taking blood samples or tissue biopsies,” adds Irene Debiram-
Beecham
, a principal research nurse at the University of Cambridge who helped coordinate recent studies in Fitzgerald’s lab.

Cruickshank-Quinn: “This technology . . . has potential to provide a quick screening tool in the health-care field but to also allow scientists to perform noninvasive studies in a number of research areas, including lung health and disease.”

10X Genomics Chromium Single Cell ATAC Solution

In 2013, researchers at Stanford University reported a new chromatin interrogation method called ATAC-seq (Assay for Transposase Accessible Chromatin). It treats cells with a transposase, an enzyme that cuts open stretches of DNA and adds adapters to those nucleic acids, allowing scientists to then amplify and sequence the fragments (Nat Meth, 10:1213–18, 2013). The group launched a company, Epinomics, to commercialize the technology. Around the same time, 10x Genomics was developing single-cell RNA sequencing using a droplet-based approach, notes Stanford’s Howard Chang, codeveloper of ATAC-seq. “Marrying these two technologies together seemed like a very attractive proposition” that could lead to a high-throughput single-cell ATAC-seq system.

10X acquired Epinomics in late August of last year, and a little more than a month later, launched the Chromium Single Cell ATAC Solution, at a cost of $1,500 per sample. The product partitions individual cell nuclei into droplets and uses genetic barcodes to tag relevant sequences—in this case, those in the open chromatin position. The DNA can then be sequenced en masse and sorted bioinformatically to determine which fragments came from which cells. 10X’s droplet-based approach scaled the throughput of single-cell ATAC sequencing from a few hundred that could be done manually to thousands or tens of thousands of cells per run, says Fergus Chan, cofounder of Epinomics and now director of product management at 10X.

Immunologist Ansuman Satpathy, a former postdoc in Chang’s group, now uses the Chromium Single Cell ATAC Solution in his own lab at Stanford to study immune cell biology in the context of cancer. Satpathy notes that the technology yields data on many different levels—from individual enhancers to the genes that they regulate to genome-wide transcription factor activity. “It gives you [insights into] many more features of a cell than you could get from other assays,” Satpathy says.

Kamdar: “Discover cellular heterogeneity stemming from epigenetic variability. Accelerates the understanding of the regulatory landscape of the genome, thereby providing insights into cell variability.”

Horizon DiscoveryEdit-R all-in-one lentiviral sgRNA

Horizon Discovery is back among the Top 10 Innovations this year with another CRISPR product—the Edit-R all-in-one lentiviral sgRNA. The company won a spot in last year’s Top 10 with an mRNA that codes for the DNA-cutting nuclease Cas9, while this year’s winning invention combines the sequences for Cas9 and the single guide RNA (sgRNA) that leads the enzyme to the appropriate spot in the genome, all packaged into a viral vector.

Horizon offers predesigned guide RNAs to knock out any gene in the human, mouse, or rat genomes. If users work on any one of 40 other species, they can get custom-made reagents. “Enter in the species, the gene of interest, where you want the guide to edit, and we package it into the all-in-one vector,” says Ryan Donnelly, the product manager for the gene editing portfolio at Horizon. He says the company designed the algorithm that builds the guide RNAs not just to make cuts efficiently, but to reliably knock out specific genes in doing so.

Since the product came out in November 2018, Donnelly says, customers have primarily used it to validate a few genes of interest from larger functional screens or for quick proof-of-principle tests to check if a gene is involved in a particular phenotype they’re studying. (The company did not provide a user to comment by deadline.) Prices range from $500 to $1,000, depending on whether scientists select plasmids or ready-to-use viral particles and off-the-shelf or bespoke guide RNAs.

Wiley: “You pick the gene of interest, and they supply the virus particles that will knock it out at a very reasonable price. Only a single selection step is required. Definitely could greatly accelerate research in understanding gene function in cells.”


THE JUDGES

Charmion Cruickshank-Quinn

Application Scientist at Agilent Technologies. Cruickshank-Quinn was a research fellow at National Jewish Health in Denver before becoming a postdoc and then instructor at the University of Colorado Anschutz Medical Campus. Her background is in mass spectrometry, transcriptomics, and metabolomics as it relates to lung disease research.


Kim Kamdar

Managing Partner at Domain Associates, a health care–focused venture fund that creates and invests in biopharm, device, and diagnostic companies. Kamdar began her career as a scientist and pursued drug-discovery research at Novartis/Syngenta for nine years.


H. Steven Wiley

Senior Research Scientist and Laboratory Fellow at Pacific Northwest National Laboratory. Wiley published some of the earliest computer models of receptor regulation and is known for developing a variety of quantitative biochemical and optical assays as a basis for validating computational models of cell processes.


Editor’s Note: The judges considered dozens of entries submitted for a variety of life-science products by companies and users. The judging panel evaluated submissions with only basic instructions from The Scientist, and its members were invited to participate based on their familiarity with life-science tools and technologies. They have no financial ties to the products or companies involved in the competition. In this issue of The Scientist, any advertisements placed by winners named in this article were purchased after our independent judges selected the winning products and had no bearing on the outcome of the competition.

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AgeX and Lineage granted pluripotent patent

AgeX Therapeutics and Lineage Cell Therapeutics awarded US patent for ‘Method of Generating Induced Pluripotent Stem Cells’.

AgeX Therapeutics, Inc. and Lineage Cell Therapeutics, Inc. today announced that the United States Patent and Trademark Office (USPTO) has issued US Patent No. 10,501,723, entitled “Methods of Reprogramming Animal Somatic Cells” covering what is commonly designated “induced Pluripotent Stem” (iPS) cells. The issued claims include methods to manufacture pluripotent cells capable of becoming any cell in the body. The patent has an early priority date, having been filed before the first scientific publication of Shinya Yamanaka, for which he won the Nobel Prize for Physiology or Medicine in 2012.

“This patent broadly describes multiple techniques for reprogramming cells of the body back to the all-powerful stem cell state,” said Dr Michael D West, CEO of AgeX and first inventor on the patent. “Perhaps more significantly, it includes certain factors that address some of the difficulties currently encountered with iPS cells. It also reflects the foundational work our scientists have undertaken to apply reprogramming technology to age-reversal, specifically, induced Tissue Regeneration (iTR) which is currently a focus of AgeX product development.” This video describes the significance of the patent in AgeX’s product development:

Induced Pluripotent Stem Cells (iPS) are typically derived from adult skin or blood cells which have been “reprogrammed” or “induced” to retrace their developmental age and regain the potential to form all of the young cell and tissue types of the body. In 2010 inventors of the -723 patent issued today demonstrated that this reversal of developmental aging even extended to the telomere clock of cell aging.

This reprogramming technology provides an alternate source of starting material for the manufacture of potentially any type of human cell needed for therapeutic purposes. Because iPSCs can be derived directly from adult tissues, they can be used to generate pluripotent cells from patients with known genetic abnormalities for drug discovery or as an alternative source of cell types for regenerative therapies.

“The issuance of this patent highlights Lineage’s dominant position in the field of cell therapy,” stated Brian M Culley, CEO of Lineage. “Our efforts to develop new treatments rely on well-characterized and NIH-approved human cell lines. These lines are not genetically manipulated, which avoids the safety concerns associated with genetic aberrations arising from the creation of iPS cells. We believe the Lineage cell lines provide the safest option for our current clinical-stage programs, particularly in immune-privileged anatomical sites such as the eye (OpRegen® for the treatment of dry AMD) and spinal cord (OPC1, for the treatment of spinal cord injury). However, the vast intellectual property estate which underlies our cell therapy platform has never been limited to these particular cell lines. As one example, this newly-issued patent provides us with proprietary methods for producing induced pluripotent stem cells, or, as it was practiced by us prior to Yamanaka, Analytical Reprogramming Technology (ART). In certain settings, an ART/iPS approach might offer important advantages, such as for an autologous treatment or when the selection of preferential attributes from a series of iPS lines is desirable. Questions as to which stem cell technology is preferred ultimately will be answered by clinical safety and efficacy and likely will be indication-specific, so we believe it is in the best interest of our shareholders to generate patented technology which enables us to pursue programs in either or both formats which we believe will ensure the highest probability of success.”

US Patent No. 10,501,723, entitled “Methods of Reprogramming Animal Somatic Cells” was assigned to Advanced Cell Technology of Marlborough, Massachusetts (now Astellas Institute for Regenerative Medicine) and licensed to Lineage and sublicensed to AgeX Therapeutics for defined fields of use. Inventors of the patent include Michael D West, CEO of AgeX and previous CEO of Advanced Cell Technology, Karen B Chapman, PhD, and Roy Geoffrey Sargent, PhD.

Phil NewmanEditor-in-ChiefPhil has over 25 years of C-level management, marketing and business development expertise in Europe and North America. His creative background has helped him shape unconventional strategies for commercial growth – garnering both awards and investor ROI.

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These 10 countries top the ranks in chemistry research

Where the best chemistry takes place.

12 December 2019

Gemma Conroy

ERIC CABANIS/AFP via Getty Image

Aurelien Bancaud, an award-winning chemist from the French National Centre for Scientific Research (CNRS). CNRS is one of the most prolific institutions in chemistry in the Nature Index.

For the first time, China has taken the Nature Index crown as the biggest producer of high-quality research in chemistry, knocking the United States down to second place.

China’s chemistry output has grown by 17.9% since 2017, to achieve an impressive Share of 6,183.75 in 2018. Its output is almost double the collective Share of its Asian neighbours in the top 10: Japan, South Korea, and India.

Share, formerly referred to in the Nature Index as Fractional Count (FC), is a measure of an institution’s contribution to articles in the 82 journals tracked by the index.

After taking the top spot in chemistry for three years in a row, the US fell behind China in 2018 with a Share of 5,371.32, representing a 6.2% drop from the previous year.

While the eight other nations in the top 10 have maintained their places since 2017, all except Spain have seen declines in their chemistry output.

Japan is the fourth most prolific country in high-quality chemistry publishing, with a Share of 1,388.14. But it had the largest decrease in output among the top 10 countries between 2017 and 2018, dropping by 12.6%.

The United Kingdom took the fifth spot, with a Share of 1,023.58 – a 10.8% decrease since 2017.

Holding its own in tenth place, Spain showed signs of growth in chemistry research publishing, with its Share rising by 1.3% between 2017 and 2018.

Below are the top 10 countries in chemistry in the Nature Index.

Mouse over to see full names, locations, and Shares:

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The top 10 institutions for chemistry in 2018Nature Index | 20 June 2019Chemistry is the fastest path to a Nobel prizeGemma Conroy | 9 April 2019The top 10 countries for scientific research in 2018Bec Crew | 1 July 2019These are the happiest countries in the worldGemma Conroy | 10 September 2019

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These are the happiest countries in the world

Wealth isn’t everything.

10 September 2019

Gemma Conroy

Benjamin Scott

Money does not equal happiness, but it certainly helps. This interactive visualization by Benjamin Scott, a bioinformatics researcher at the Natural History Museum in London, reveals the happiest countries in the world and the factors that contribute to the satisfaction of their people.

The visualization is based on data from the annual World Happiness Report, which ranks 156 countries according to perceptions of happiness among its people. Published in March, the report is produced by the United Nations Sustainable Development Solutions Network in partnership with the Ernesto Illy Foundation.

The report explores the relationship between happiness and specific metrics such GDP per capita, social support, healthy life expectancy and perceptions of corruption.

Clicking on the coloured boxes reveals where each country ranks in each measure, while selecting all the boxes shows the overall happiness rankings. Explore the full interactive visualization here.

happiest countries
alt

Scandinavian countries lead the way in the happiness ranks, with Finland topping the charts followed by Denmark and NorwayAustraliaNew Zealand and Canada are also among the top 10 happiest nations. (We note that Singapore, which ranks 34th in the World Happiness Report, does not appear in the visualization.)

African countries dominated the 10 least happy countries, with Burundi, which has particularly low GDP per capita, ranked behind all other the nations. The Central African Republic is not far behind, despite taking the top spot overall in generosity and second place in freedom to make life choices.

While GDP appears to play a significant role in life satisfaction, being cashed-up isn’t everything. Qatar and Saudi Arabia are the richest nations among the ranked countries, but don’t rank in the top 20 for overall happiness.

Another interactive visualization based on the World Happiness Report, created by Rebecca Barter from the Department of Statistics at the University of California, Berkeley, includes additional variables that are linked to happiness, including school years, sustainable economic development, health expenditure and employment rate.

alt

The number of years spent in school and tertiary education plays a role in overall happiness, with happy countries Australia, Iceland and Belgium spending an average of 20 years in the classroom, the highest of all nations included in the visualization.

And although Australia and New Zealand spend around half as much per person on healthcare as the United States (US$4,492, US$3,530 and US$9,536 respectively), they are ahead of the country in overall happiness.

Below you can see the US as a major outlier in healthcare spending:

alt

Explore Benjamin Scott’s and Rebecca Barter’s visualizations in full.

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The top 10 institutions for chemistry in 2018

These 10 institutions in the Nature Index were the largest contributors to chemistry papers published in 82 leading journals in 2018.

20 June 2019

Nature Index

Jean-Claude MOSCHETTI / AlgoSolis / CNRS Phototheque

Microalgae cultured in the Raceway Basin of the CNRS to advance the study of biofuels, cosmetics, health and nutrition.

This is the fourth consecutive year in which leading institutions of ChinaFrance and Germany have topped the field in high-quality chemistry research output.

The biggest movers in this category for 2018 include Tsingua University in China, which jumped from 17th place in 2015 to sixth place in 2018, and Nanjing University, which climbed six spots from last year to secure the fourth spot for 2018. Kyoto University in Japan dropped out of the top 10 after ranking fourth last year

See the Nature Index 2019 Annual Tables Top 100 institutions for chemistry.

alt

1. Chinese Academy of Sciences (CAS)

Fractional count: 881.87 (6.8%), Article count: 2,206

The Chinese Academy of Sciences (CAS) has retained the world’s top slot in chemistry for the past four years in the Nature Index, and in 2018 had almost four times the FC of the number 2 seed, the French National Centre for Scientific Research (CNRS).

A major point of difference for CAS is its enormous size, encompassing 105 institutes across China, which support more than 60,000 research staff. Of note among its many chemistry-focused institutes are the highly productive Institute of Chemistry (IOC), based in Beijing, and the Dalian Institute of Chemical Physics, which specializes in such areas as catalytic chemistry, chromatography, and pharmaceutical chemistry.

In 2018, in a high-impact paper published in the Journal of the American Chemical Society by IOC scientists described a new type of solar cell that can achieve unprecedented power conversion efficiency rates.

CAS president, Bai Chunli, is a physical chemist and nanoscientist, known for his pioneering work in scanning tunnelling microscopy and nanotechnology.

2. French National Centre for Scientific Research (CNRS)

Fractional count: 240.53 (−4.8%), Article count: 1,111

Based in Paris, the French National Center for Scientific Research (CNRS) is the only French organization for multidisciplinary research. It is also the largest governmental research organization in France, and the largest agency in Europe undertaking basic research.

With an annual budget of €25.5 million (approximately US$28 million), its Institute of Chemistry supports 12,000 staff, including researchers, teacher-researchers, engineers, technicians and administrators, across 133 labs.

Alejandro Franco, who was only 13 when he patented his first hydrogen fuel cell and is now developing advanced simulation systems to improve battery power, is one of its rising stars. So is Raphaël Rodriguez, who was the first French scientist to win the Tetrahedron Young Investigator Award, an international prize for exceptional chemists under the age of 40.

3. Max Planck Society

Fractional count: 223.91 (2%), Article count: 560

Chemistry is fundamental to the Max Planck Society’s history; its Institute of Chemistry was one of the first established within the German research organization. Its performance in the discipline continues to flourish, earning it third place among the top institutions in the field.

The Max Planck Society’s work ranges from investigating the chemical processes in Earth’s foundations, to understanding how cells communicate. The Max Planck Institute for Chemical Energy Conversion, re-established in 2012, focuses on the storage of energy, such as solar and wind power.

Last year, Max Planck Society researchers were part of an international team that discovered how tiny aerosol particles can fuel storms and alter weather patterns. Published in Science, the findings showed that even the smallest particles can generate large effects.

4. Nanjing University

Fractional count: 207.77 (25.6%), Article count: 379

With an incredible surge of 25.6% over the previous year, Nanjing University jumped from tenth position in 2017 to fourth place in 2018, according to its high-quality research output in chemistry, as tracked by the Nature Index.

The university owns China’s oldest chemistry department, launched in 1920 at the National Southeastern University, which later became the National Central University before being renamed again to Nanjing University in 1950.

Today, Nanjing University produces the country’s highest-profile chemistry research, owning two government-funded State Key Labs – the State Key Lab of Coordination Chemistry and the State Key Lab of Analytical Chemistry for Life Science – a very rare point of difference for a university in China.

Its School of Chemistry and Chemical Engineering boasts 101 full professors, including 5 members of the Chinese Academy of Sciences, and runs one of the oldest doctoral chemistry programs in China.

“In recent years, Nanjing University has spared no effort to attract young talents,” says Shi Zhuangzhi, a leading young chemist who joined the university in 2014 as a Young Thousand Talent – China’s top talent scheme to attract young scientists.

“Young faculty members here enjoy perfect funding, decent salary and housing subsidies, and priority in recruiting excellent doctoral students.”

5. Peking University

Fractional count: 189.09 (5.6%), Article count: 574

Peking University was China’s first public comprehensive university, set up in 1898. Since then, it’s been considered one of the country’s two best universities, with Tsinghua University.

In 2018, its positions in the chemistry, physical sciencesEarth and environmental sciences, and life sciences categories were 5th, 11th, 10th, and 39th, respectively.

Its budgets are more limited than Tsinghua’s: in 2018 and 2019, its overall budgets were 12.55 billion yuan (US$1.82 billion) and 19 billion yuan (US$2.75 billion) respectively.

Of Peking University’s 4,573 faculty members, 78 are Chinese Academy of Sciences members and 18 are Chinese Academy of Engineering members. High-profile alumni include pharmaceutical chemist, Tu Youyou, credited with discovering the malaria treatments artemisinin and dihydroartemisinin – a major breakthrough in tropical medicine.

6. Tsinghua University

Fractional count: 183.83 (5.7%), Article count: 471

As one of China’s most prominent universities, Tsinghua University has made impressive progress in chemistry in recent years. Its ranking climbed to sixth in 2018, up from 17th place in 2015.

Tsinghua’s chemistry research is conducted by the Department of ChemistryDepartment of Chemical Engineering and the School of Materials Science and Engineering, and has a strong industry connection. Boosted by significant research funding of the university (15.7 billion yuan in 2019, or US$2.27 billion), which is the highest among all Chinese universities, Tsinghua chemists have excelled in nanomaterial, industrial catalysis and low-carbon technologies.

Key studies in 2018 led by Tsinghua scientists include one describing how calcium-ion batteries could be used for energy storage (Nature Chemistry), and another on an electrocatalyst that could potentially reduce carbon dioxide emissions in industrial production (Journal of the American Chemical Society).

7. University of Science and Technology of China

Fractional count: 182.53 (4.1%), Article count: 430

Established by the Chinese Academy of Sciences (CAS) in 1958 in Beijing, the University of Science and Technology of China was launched to drive the higher education of the country’s top talent in interdisciplinary science and technology. In 1970, it moved to its current location in Hefei, the capital of the Anhui Province.

The institute’s achievements include establishing the first graduate school in China as well as the first class for gifted young people in China and the first ‘big science’ facility in China, the Hefei Synchrotron Radiation Facility. With CAS, it now also jointly operates the Experimental Advanced Superconducting Tokamak and the Steady High Magnetic Field of the High Magnetic Field Laboratory.

Key chemistry papers of recent years concern the electroreduction of carbon dioxide into ‘clean’ fuels (Nature, 2016) and more environmentally friendly plastic crystals for refrigeration (Nature 2019).

8. Massachusetts Institute of Technology (MIT)

Fractional count: 164.31 (2.5%), Article count: 350

The Massachusetts Institute of Technology (MIT) appears in several top 10s in the Nature Index 2019 Annual Tables, for chemistryphysical sciences, life sciencesacademic institutions, and the global top 10.

As one of the world’s most prestigious higher-education institutions, it’s been at the frontier of research for more than 150 years, fostering an emphasis on entrepreneurship and applied science through close ties with industry.

Its Department of Chemistry dates back to 1865, and is recognized as one of the best places in the world for chemistry research. Known for achievements in polymer synthesis and medical imaging, key focus areas include discovering new chemical syntheses, creating sustainable energy solutions, detecting and curing disease, and developing novel materials.

In late 2018, three of its researchers, Stephen Buchwald, Jeremiah Johnson, and Timothy Swager received American Chemical Society National Awards for 2019. Swager was awarded for “the design, synthesis and study of polymers with innovative molecular designs to create materials with superior sensory, electronic, optoelectronic and mechanical properties.”

9. Northwestern University

Fractional count: 158.11 (12.1%), Article count: 299

Founded as a private research university in 1851, Northwestern University, based in Evanston, Illinois, now also has campuses in Chicago and Doha, Qatar, and employs 3,300 full-time research staff. It has an annual budget of US$2 billion and attracts more than US$700 million for sponsored research each year.

Northwestern is the second-fastest rising institute among the top 10 in high-quality chemistry research output for 2018 (Nanjing University was the fastest).

One of the star researchers in its Department of Chemistry is Emily Weiss, winner of the 2018 American Chemical Society’s Early-Career Award for her pioneering work on nanocrystals and low-conductivity materials.

Another is Chad Mirkin, whose 1999 invention of dip-pen nanolithography – a new nanotechnology tool that allowed circuit boards to become smaller – was recognized in 2012 by National Geographic as one of the top 100 scientific discoveries that changed the world.

10. Stanford University

Fractional count: 158.02 (−7.4%), Article count: 340

Chemistry was one of the 25 founding departments at Stanford University when it opened in 1891. The department awarded its first undergraduate degree to Charlotte Wray in 1894, and its first PhD in 1907 to William Draper Harkins, who would go on to predict the existence of the neutron in 1920.

There are now 24 faculty members in the department. Among them is Nobel laureate, W.E. Moerner, who was awarded the 2014 Nobel Prize in Chemistry for his role in the invention of microscopy techniques that could reveal molecular processes in real time.

Other notable Stanford chemists include Frank Abild-Pedersen, who in 2018 was one of the world’s most highly-cited researchers – his 2004 paper on atomic-scale imaging of carbon nanofibres has attracted more than 1,000 citations so far – and Carolyn Bertozzi, regarded as one of the top chemists of her generation.

Correction 12 August 2019The original version of this article used incorrect fractional counts, percentage changes and article counts to derive the rankings, which meant that some institutions were ranked incorrectly. The data and rankings have now been corrected.

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The top 10 countries for scientific research in 2018

These countries were the year’s the largest contributors to papers published in the 82 leading journals tracked by the Nature Index.

1 July 2019

Bec Crew

Rick Friedman/rickfriedman.com/Corbis via Getty Images

John Kovac of the Harvard Smithsonian Center for Astrophysics at Harvard’s Clay Telescope. The US is the most prolific country in the Nature Index, and Harvard is its most prolific institution.

China, with a remarkable rise in high-quality research output in 2018, is gaining on the dominant United States. In the top 10, Australia has jostled Spain out of 10th spot.

View the 2019 Annual Tables Countries/Territories top 50.

1. United States of America

The United States is the most prolific publisher of high-quality science in the world, but China is closing the gap with astonishing rapidity.

Output from the US was down in 2018 compared with 2017, but it continues to be bolstered by its top-performing institutes: Harvard UniversityStanford UniversityMIT and the National Institutes of Health.

The life sciences accounts for almost 50% of the nation’s output in the natural sciences, followed by chemistry, physical sciences, and Earth and environmental sciences, respectively.

In 2018, its biggest collaborative partners were China, the United Kingdom and Germany, while smaller countries, Australia and Switzerland, also made it into its top 10 collaborators list.

In the 2019 Nature Index Biomedical Sciences supplement, the US dominated the Top 200 Institutions table, counting seven of the top 10 institutions, and 15 of the top 20.

2. China

China’s rise in the research rankings is a well-told story, but that doesn’t make it any less remarkable. Its increase in FC in 2018 has been meteoric, and it’s got the whole world’s attention.

While chemistry accounts for around 50% of China’s output in the Nature Index, the physical sciences are also a major strength. Its top five performing institutes are the Chinese Academy of SciencesPeking UniversityNanjing UniversityTsinghua University, and the University of Science and Technology of China.

In early 2018, the US National Science Foundation released a report showing that, as far back as 2016, China overtook the US as the top producer of science and engineering articles tracked by Scopus. But in terms of high-quality natural sciences research output tracked by the Nature Index, the US still reigns supreme.

3. Germany

With two institutions in the Nature Index Top 100 Global Institutions table, Germany is a force in high-quality research publishing.

Its top institutions, the Max Planck Society and Helmholtz Association of German Research Centres, are among the top 10 in the physical scienceschemistrylife sciencesEarth and environmental sciences, and global research institutes categories for 2018.

In recent years, the country has become known as a desired destination for researchers, boasting a relatively low cost of living, stable growth and high research and development (R&D) spending.

It also counts more than 270 collaborative research centres that are funded by the German Research Foundation for up to 12-year periods, which allow researchers to commit to complex, long-term, multidisciplinary projects across universities and institutes.

4. United Kingdom

As Nature reported in April, Brexit has already damaged research in the UK. That said, it remains one of the world’s best in producing high-quality research in the natural sciences, retaining its long-standing fourth rank in the Nature Index Top 50 Countries/Territories table.

The UK’s top institutions include the University of Cambridge, the University of OxfordImperial College London and University College London, and its top collaborators for 2018 were the US, Germany and France.

In recent months, the closure of key animal-research facilities in the UK has sparked outcry from affected scientists, raising questions around the UK’s contribution to global mouse genetics research. Now, as Brexit lurches uncertainly onwards, the world is taking a closer look at the important research that goes on around it.

5. Japan

With an impressive standing among the world’s best research publishers, Japan is working hard to retain its position. While its strategy of funding selected institutions to boost their overseas collaboration is starting to bear fruit, it continues to look outwards in an effort to arrest the alarming decline in its high-quality scientific research.

Its top-performing institute, the University of Tokyo, also ranked highly in the 2019 Nature Index Annual tables in the physical sciencesacademic institutions, and top 100 global institutions categories. Kyoto UniversityOsaka University and RIKEN round out the country’s top four.

Japan’s research performance was the focus of a recent Nature Index supplement, which revealed how its proportion of articles co-authored with international researchers has increased, but correcting the slide in overall output is proving difficult for the nation.

6. France

France’s strengths in the natural sciences are diverse, with chemistry, physical sciences, and life sciences accounting for roughly equal shares in its high-quality research output, followed by Earth and environmental sciences.

In 2018, its highest-performing institute, the French National Centre for Scientific Research (CNRS), had more than six times the fractional count (FC) of its second highest- performing institute, the Pierre and Marie Curie University.

The CNRS is not only France’s premier research institute, it also shines on the world stage, ranking highly in the physical sciencesEarth and environmental scienceschemistry, and top 100 global institutions categories for 2018.

In February, France announced plans for its national strategy for research, promising funding stability and better career prospects for young researchers. But, as Nature reported, scientists say significant new investment will be crucial.

7. Canada

Universities across Canada might have reported a deluge of applications in 2017, as students and researchers sought respite from the anti-science stance of the Trump administration in the US and the disruption of Brexit in Europe, but this has yet to impact on its high-quality research output. Canada is one of a number of high-ranking countries in 2018 that saw a downturn in FC, compared with 2017.

Canada’s best-performing institute, the University of Toronto, reportedly saw an 81% increase in acceptance numbers from American students in 2017 compared to 2016, and the University of Alberta, ranked fourth in Canada by FC, saw international graduate student applications rise by 80%.

More recently, the country’s budget decisions around research for 2019 have been controversial, with small spending bumps for genomics and physics presenting a stark contrast to the $4-billion (US$3-billion) boost for basic science and research in 2018.

8. Switzerland

For a nation of just 8.4 million, Switzerland punches well above its weight in high-quality research output.

In 2018, an analysis by the United States National Center for Science and Engineering Statistics (NCSES) found that it contributed nearly three times more articles to the 1% of highly cited papers indexed by the Scopus database in 2013 than would be expected given its total output, due to factors such as its comparatively large research investment and hosting of the Large Hadron Collider.

The Swiss Federal Institute of Technology Zurich (ETH Zurich), the institution with the highest output of high-quality research in the natural sciences in the country, had almost twice the output of the second most prolific institution, the Swiss Federal Institute of Technology Lausanne (EPFL).

In 2018, ETH Zurich’s total revenue rose to CHF 1.8 billion (US$1.8 billion), with the federal government contributing CHF 1.3 billion to its funds.

Switzerland is also home to F. Hoffmann-La Roche AG and Novartis International AG, two multinational heavyweights in the pharmaceutical sector, signifying the country’s strength in the biomedical sciences.

9. South Korea

Thanks in no small part to its high R&D spending, South Korea’s strengths lie in the physical sciences and chemistry, and, as a 2018 study by Canadian researcher Mikko Packalen showed, in developing novel biomedical concepts.

Its biggest collaborative partners in 2018 were the US, China and Japan, and Seoul National University and the Korea Advanced Institute of Science and Technology were its top performers.

In mid-2018Nature reported that, while the country’s research was flourishing in some ways, it was struggling in others.

Academic publishing has been booming, and national R&D spending by industry and government was 4.24% of gross domestic product (GDP) in 2016, which was the second-highest percentage for any country worldwide. But many scientists – particularly those in smaller research groups – have communicated their dissatisfaction with the country’s funding decisions.

10. Australia

Australia has the rare distinction of being the only country to shake up the top 10 in the 2019 Nature Index Top 50 Countries/Territories table, and the only country in the top 10 apart from China where FC increased in 2018. While the top nine has remained unchanged for three years, Australia jostled Spain out of the 10th slot, up from rank 11 in 2017.

The country’s output by subject is fairly evenly spread, with the life sciences contributing the largest share to its high-quality research output, as tracked by the Nature Index. The University of Queensland is the best performing Australian research institute, followed by UNSW Sydney and Monash University in Melbourne.

But it’s not all good news. In late 2018, Australian scientists expressed disappointment over a budget update that cuts $328.5 million (US$230 million) from research funding that had been expected over the next four years, setting government investment in R&D at its lowest in 40 years.

Read next:

The top 10 research institutions for 2018

The top 10 institutions for chemistry in 2018

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NatureIndex19_Annual TablesCanadaSwitzerlandAustraliaSouth KoreaFranceGermanyChinaUnited KingdomUniversity of OxfordUniversity of CambridgeUniversity of TorontoUniversity of AlbertaSpainJapanHarvard UniversityStanford UniversityMassachusetts Institute of TechnologyNational Institutes of HealthChinese Academy of SciencesPeking UniversityTsinghua UniversityNanjing UniversityUniversity of WaterlooImperial College LondonUniversity of Science and Technology of ChinaMax Planck SocietyHelmholtz Association of German Research CentresSeoul National UniversityKorea Advanced Institute of Science and TechnologyUNSW SydneyUniversity of QueenslandMonash UniversityOsaka UniversityKyoto UniversityRIKENPierre and Marie Curie UniversitySwiss Federal Institute of Technology ZurichSwiss Federal Institute of Technology LausanneF. Hoffmann-La Roche AGNatureIndex19_JapanNatureIndex19_Biomedical SciencesRankingsNovartisUnited States Sign up for our newsletter!

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