Department of Biochemistry

Atherosclerosis: Research reveals new mechanism and therapeutic target
1. New research offers fresh insights into how a type of immune cell can destabilize the fatty deposits, or plaques, that form in arteries during atherosclerosis.
2. Healthy arteries keep the heart healthy. A new study may help prevent atherosclerosis — a disease that affects our blood vessels.
3. Atherosclerosis is a persistent, inflammatory condition in which plaques build up inside arteries, causing them to narrow and restrict blood flow.
4. When an atherosclerotic plaque bursts or breaks, it can trigger a heart attack or stroke.
5. Neutrophils are an abundant type of leukocyte (white blood cell) that defend against infection by attacking microbes. They also serve "many roles in inflammation."
6. The new international study reveals that neutrophils can aggravate atherosclerosis by triggering a previously unknown type of cell death that destabilizes arterial plaques.
7. A recent Nature paper describes how neutrophils can induce a series of molecular events that also kills the smooth muscle cells that help to retain the plaques in the artery wall.
8. "Every inflammatory reaction," says co-corresponding study author Prof. Oliver Söhnlein, from the Institute for Cardiovascular Prevention at the Ludwig Maximilian University (LMU) of Munich in Germany, "results in some collateral damage, because neutrophils also attack healthy cells."
9. He and his colleagues have also designed and made a "tailored peptide" that could potentially target and block the cell-death process.
10. Embryo stem cells created from skin cells
11. Researchers at the Hebrew University of Jerusalem (HU) have found a way to transform skin cells into the three major stem cell types that comprise early-stage embryos. The work (in mouse cells) has significant implications for modelling embryonic disease and placental dysfunctions, as well as paving the way to create whole embryos from skin cells.
12. As published in Cell Stem Cell, Dr. Yossi Buganim of HU's Department of Developmental Biology and Cancer Research and his team discovered a set of genes capable of transforming murine skin cells into all three of the cell types that comprise the early embryo: the embryo itself, the placenta and the extra-embryonic tissues, such as the umbilical cord. In the future, it may be possible to create entire human embryos out of human skin cells, without the need for sperm or eggs. This discovery also has vast implications for modelling embryonic defects and shedding light on placental dysfunctions, as well as solving certain infertility problems by creating human embryos in a petri dish.
13. Back in 2006, Japanese researchers discovered the capacity of skin cells to be "reprogrammed" into early embryonic cells that can generate an entire fetus, by expressing four central embryonic genes. These reprogrammed skin cells, termed "Induced Plutipotent Stem Cells" (iPSCs), are similar to cells that develop in the early days after fertilization and are essentially identical to their natural counterparts. These cells can develop into all fetal cell types, but not into extra-embryonic tissues, such as the placenta.
14. Now, the Hebrew University research team, headed by Dr. Yossi Buganim, Dr. Oren Ram from the HU's Institute of Life Science and Professor Tommy Kaplan from HU's School of Computer Science and Engineering, as well as doctoral students Hani Benchetrit and Mohammad Jaber, found a new combination of five genes that, when inserted into skin cells, reprogram the cells into each of three early embryonic cell types -- iPS cells which create fetuses, placental stem cells, and stem cells that develop into other extra-embryonic tissues, such as the umbilical cord. These transformations take about one month.
15. The HU team used new technology to scrutinize the molecular forces that govern cell fate decisions for skin cell reprogramming and the natural process of embryonic development. For example, the researchers discovered that the gene "Eomes" pushes the cell towards placental stem cell identity and placental development, while the "Esrrb" gene orchestrates fetus stem cells development through the temporary acquisition of an extrae-mbryonic stem cell identity.
16. To uncover the molecular mechanisms that are activated during the formation of these various cell types, the researchers analyzed changes to the genome structure and function inside the cells when the five genes are introduced into the cell. They discovered that during the first stage, skin cells lose their cellular identity and then slowly acquire a new identity of one of the three early embryonic cell types, and that this process is governed by the levels of two of the five genes.
17. Recently, attempts have been made to develop an entire mouse embryo without using sperm or egg cells. These attempts used the three early cell types isolated directly from a live, developing embryo. However, HU's study is the first attempt to create all three main cell lineages at once from skin cells. Further, these findings mean there may be no need to "sacrifice" a live embryo to create a test tube embryo.
18. End to Aids in sight as huge study finds drugs stop HIV transmission
19. An end to the Aids epidemic could be in sight after a landmark study found men whose HIV infection was fully suppressed by antiretroviral drugs had no chance of infecting their partner.
20. The success of the medicine means that if everyone with HIV were fully treated, there would be no further infections.
21. Among nearly 1,000 male couples across Europe where one partner with HIV was receiving treatment to suppress the virus, there were no cases of transmission of the infection to the HIV-negative partner during sex without a condom. Although 15 men were infected with HIV during the eight-year study, DNA testing proved that was through sex with someone other than their partner who was not on treatment.
22. “It’s brilliant – fantastic. This very much puts this issue to bed,” said Prof Alison Rodger from University College London, the co-leader of the paperpublished in the Lancet medical journal. Earlier studies have also shown the treatment protects heterosexual couples where one partner has HIV.
23. She added: “Our findings provide conclusive evidence for gay men that the risk of HIV transmission with suppressive ART [antiretroviral therapy] is zero. Our findings support the message of the international U=U campaignthat an undetectable viral load makes HIV untransmittable.
24. “This powerful message can help end the HIV pandemic by preventing HIV transmission, and tackling the stigma and discrimination that many people with HIV face.
25. “Increased efforts must now focus on wider dissemination of this powerful message and ensuring that all HIV-positive people have access to testing, effective treatment, adherence support and linkage to care to help maintain an undetectable viral load.”
26. In 2017, there were almost 40 million people worldwide living with HIV, of whom
27. 7 million were on antiretroviral treatment. An estimated 101,600 people are living with HIV in the UK, and of these, about 7,800 are undiagnosed, so do not know they are HIV positive.
28. Myron S Cohen of the UNC Institute for Global Health and Infectious Diseases at Chapel Hill in North Carolina, said in a commentary in the Lancet on the study that it should push the world forward on a strategy to test and treat everyone who has HIV. But, he added, maximising the benefits of treatment, particularly for men who have sex with men, has proved difficult.
29. “It is not always easy for people to get tested for HIV or find access to care; in addition, fear, stigma, homophobia and other adverse social forces continue to compromise HIV treatment,” he said.
30. “Diagnosis of HIV infection is difficult in the early stages of infection when transmission is very efficient, and this limitation also compromises the treatment as prevention strategy.”
31. According to the National Aids Trust, 97% of people on HIV treatment in the UK have an undetectable level of the virus, meaning they cannot pass it on. “Hearing this can be enormously empowering and reassuring to people living with HIV,” said Deborah Gold, the trust’s chief executive.
32. The latest findings reinforce the importance of people taking HIV tests frequently, which could ultimately end the transmission of the virus altogether in the future. New diagnoses have been declining since their peak in 2005, with figures from 2017 showing a 17% drop on 2016 and a 28% fall compared with 2015.
33. Late diagnosis remains a major challenge, still accounting for about 43% of new HIV diagnoses. This disproportionately affects certain groups, including black African heterosexual men and people aged 65 and older.
34. “If we don’t reduce late diagnosis, there will always be those who are not aware of their HIV status and who therefore cannot access treatment,” said Gold. “We think that the findings from this study could be incredibly powerful in breaking down some of the barriers to testing in communities where there is still a lot of stigma around HIV.”
35. However, she added that government funding cuts to specialist health services would make it more difficult to achieve a goal of eliminating transmission by 2030.
36. Jens Lundgren, a professor of infectious diseases at Rigshospitalet, University of Copenhagen, and joint-lead for the study, called Partner, said: “We have now provided the conclusive scientific evidence for how treatment effectively prevents further sexual transmission of HIV.”
37. Dr Michael Brady, the medical director at the Terrence Higgins Trust, said: “It is impossible to overstate the importance of these findings.
38. “The Partner study has given us the confidence to say, without doubt, that people living with HIV who are on effective treatment cannot pass the virus on to their sexual partners. This has incredible impact on the lives of people living with HIV and is a powerful message to address HIV-related stigma.”
39. Bruce Richman, the founding executive director of the Prevention Access Campaign, which launched U=U, said Pac was tremendously grateful to the researchers and participants. He said the study “has for ever changed what it means to live and love with HIV around the world”.
40. In a linked comment in the journal, Cohen expressed optimism for future treatment of Aids. “During the course of these studies, antiretroviral drugs have become more effective, reliable, durable, easier to take, well tolerated and much less expensive,” he said.
41. “The results … provide yet one more catalyst for a universal test-and-treat strategy to provide the full benefits of antiretroviral drugs. This and other strategies continue to push us toward the end of Aids.”
42. Case study
43. Alex Sparrowhawk, 34, has been living with HIV for almost 10 years. When he was diagnosed in November 2009, he had two major concerns: how being HIV positive would impact his work as a financial analyst, and what it meant for future relationships.
44. “I was single at the time,” he said. “Just navigating what to do – when to tell people and how to talk to people was really difficult.”
45. Alex immediately began antiretroviral treatment, initially taking four pills a day, which was reduced to one pill once his viral load came down to undetectable levels several months later. The latest results confirm that for the past nine years, he has not been able to transmit the virus to anyone, although at the time, medical advice was less definitive.
46. Between his diagnosis and now, Alex spent six-and-a-half years in a relationship, and said the possibility – however tiny – of transmitting HIV to his partner was a source of anxiety. “You’d be told it was very unlikely, or that it was only possible under certain circumstances like having an STI,” he said. “But you’re constantly worried about these caveats and you go through this worry together.
47. “Now we can say zero risk, which is just so much more empowering for people. It’s a huge weight off your shoulders.”
48. Alex hopes the findings will help transform public attitudes about HIV, bringing them in line with medical evidence. “A lot of stigma is driven by fear of being exposed to HIV,” he said. “People still think you can get it from kissing and casual contact. If more people knew about this study, this would change.”

Researchers identify new insecticide resistance mechanism by mosquitoes

Reviewed by James Ives, M.Psych. (Editor)Dec 26 2019

Researchers at LSTM have identified a completely new mechanism by which mosquitoes that carry malaria are becoming resistant to insecticide.

After studying both Anopheles gambiae and Anopheles coluzzii, two major malaria vectors in West Africa, they found that a particular family of binding proteins situated in the insect's legs were highly expressed in resistant populations.

First author on a paper published today in the journal Nature, Dr Victoria Ingham, explains:

We have found a completely new insecticide resistance mechanism that we think is contributing to the lower than expected efficacy of bed nets. The protein, which is based in the legs, comes into direct contact with the insecticide as the insect lands on the net, making it an excellent potential target for future additives to nets to overcome this potent resistance mechanism."

Examining the Anopheline mosquitoes, the team demonstrated that the binding protein, SAP2, was found elevated in resistant populations and further elevated following contact with pyrethroids, the insecticide class used on all bed nets. They found that when levels of this protein were reduced, by partial silencing of the gene, susceptibility to pyrethroids were restored; conversely when the protein was expressed at elevated levels, previously susceptible mosquitoes became resistant to pyrethroids.

The increase in insecticide resistance across mosquito populations has led to the introduction of new insecticide treated bed nets containing the synergist piperonyl butoxide (PBO) as well as pyrethroid insecticides. The synergist targets one of the most widespread and previously most potent resistance mechanisms caused by the cytochrome P450s. However, mosquitoes are continually evolving new resistance mechanisms and the discovery of this new resistance mechanism provides an excellent opportunity to identify additional synergists that could be used to restore susceptibility

Professor Hilary Ranson is senior author on the paper. She said:

Long-lasting insecticide treated bed nets remain one of the key interventions in malaria control. It is vital that we understand and mitigate for resistance within mosquito populations in order to ensure that the dramatic reductions in disease rates in previous decades are not reversed. This newly discovered resistance mechanism could provide us with an important target for both the monitoring of insecticide resistance and the development of novel compounds able to block pyrethroid resistance and prevent the spread of malaria."

Year 2020

Some severe COVID-19 cases linked to genetic mutations or antibodies that attack the body

People infected by the novel coronavirus can have symptoms that range from mild to deadly. Now, two new analyses suggest that some life-threatening cases can be traced to weak spots in patients' immune systems.

At least 3.5 percent of study patients with severe COVID-19, the disease caused by the novel coronavirus, have mutations in genes involved in antiviral defense. And at least 10 percent of patients with severe disease create "auto-antibodies" that attack the immune system, instead of fighting the virus. The results, reported in two papers in the journal Science on September 24, 2020, identify some root causes of life-threatening COVID-19, says study leader Jean-Laurent Casanova, a Howard Hughes Medical Institute Investigator at The Rockefeller University.

Seeing these harmful antibodies in so many patients -- 101 out of 987 -- was "a stunning observation," he says. "These two papers provide the first explanation for why COVID-19 can be so severe in some people, while most others infected by the same virus are okay."

The work has immediate implications for diagnostics and treatment, Casanova says. If someone tests positive for the virus, they should "absolutely" be tested for the auto-antibodies, too, he adds, "with medical follow-up if those tests are positive." It's possible that removing such antibodies from the blood could ease symptoms of the disease.

A global effort

Casanova's team, in collaboration with clinicians around the world, first began enrolling COVID-19 patients in their study in February. At the time, they were seeking young people with severe forms of the disease to investigate whether these patients might have underlying weaknesses in their immune systems that made them especially vulnerable to the virus.

The plan was to scan patients' genomes -- in particular, a set of 13 genes involved in interferon immunity against influenza. In healthy people, interferon molecules act as the body's security system. They detect invading viruses and bacteria and sound the alarm, which brings other immune defenders to the scene.

Casanova's team has previously discovered genetic mutations that hinder interferon production and function. People with these mutations are more vulnerable to certain pathogens, including those that cause influenza. Finding similar mutations in people with COVID-19, the team thought, could help doctors identify patients at risk of developing severe forms of the disease. It could also point to new directions for treatment, he says.

In March, Casanova's team was aiming to enroll 500 patients with severe COVID-19 worldwide in their study. By August, they had more than 1,500, and they now have over 3,000. As the researchers began analyzing patient samples, they started to uncover harmful mutations, in people young and old. The team found that 23 out of 659 patients studied carried errors in genes involved in producing antiviral interferons.

Without a full complement of these antiviral defenders, COVID-19 patients wouldn't be able to fend off the virus, the researchers suspected. That thought sparked a new idea. Maybe other patients with severe COVID-19 also lacked interferons -- but for a different reason. Maybe some patients' bodies were harming these molecules themselves. As in autoimmune disorders such as type 1 diabetes and rheumatoid arthritis, some patients might be making antibodies that target the body. "That was the eureka moment for us," Casanova says.

The team's analysis of 987 patients with life-threatening COVID-19 revealed just that. At least 101 of the patients had auto-antibodies against an assortment of interferon proteins. "We said, 'bingo'!" Casanova remembers. These antibodies blocked interferon action and were not present in patients with mild COVID-19 cases, the researchers discovered.

"It's an unprecedented finding," says study co-author Isabelle Meyts, a pediatrician at the University Hospitals KU Leuven, in Belgium, who earlier this year helped enroll patients in the study, gather samples, and perform experiments. By testing for the presence of these antibodies, she says, "you can almost predict who will become severely ill."

The vast majority -- 94 percent -- of patients with the harmful antibodies were men, the team found. Men are more likely to develop severe forms of COVID-19, and this work offers one explanation for that gender variability, Meyts says.

Casanova's lab is now looking for the genetic driver behind those auto-antibodies. They could be linked to mutations on the X chromosome, he says. Such mutations might not affect women, because they have a second X chromosome to compensate for any defects in the first. But for men, who carry only a single X, even small genetic errors can be consequential.

Looking ahead Clinically, the team's new work could change how doctors and health officials think about vaccination distribution strategies, and even potential treatments. A clinical trial could examine, for instance, whether infected people who have the auto-antibodies benefit from treatment with one of the 17 interferons not neutralized by the auto-antibodies, or with plasmapheresis, a medical procedure that strips the antibodies from patients' blood. Either method could potentially counteract the effect of these harmful antibodies, Meyts says.

In addition to the current work, Meyts, Casanova, and hundreds of other scientists involved with an international consortium called the COVID Human Genetic Effort are working to understand a second piece of the coronavirus puzzle. Instead of hunting for factors that make patients especially vulnerable to COVID-19, they're looking for the opposite -- genetic factors that might be protective. They're now recruiting people from the households of patients with severe COVID-19 -- people who were exposed to the virus but did not develop the disease. "Our lab is currently running at full speed," Casanova says.