caroplasma – BioQuakes

Author: caroplasma

A Life Saving Treatment: CRISPR Gene Editing

On March 20, 2022

A proud, hard-working father is what Paddy Doherty looked up to all of his life until a sudden heart attack that took the life of his dad. What would you do if someone you love is unexpectedly gone without a goodbye?

His father had a career in construction and various home improvement projects which kept him active until his 60s until Doherty first caught glimpses of a worrying decline in his dad’s health. “I noticed him getting breathless on walks. He’d stop for a while and maybe make an excuse for stopping, saying, ‘Oh, isn’t that a lovely tree’ or whatever,” said Doherty, who lives in Ireland. Doctors chalked it up to angina, or chest pain caused by reduced blood flow to the heart, symptomatic of an underlying heart problem.

After his dad died, the true cause was discovered: a rare disease called transthyretin (ATTR) amyloidosis, characterized by a misfolded protein that builds up in the heart and interferes with normal function. As learned in AP Biology, misfolded proteins are caused by the lack of chaperonins that are present in cells to provide a secure hydrophilic environment. The misfolded proteins cannot achieve their native state and are contorted into shapes that are unfavorable to the environment it’s in. The formation of oligomers and aggregates occurs in the cell when a critical concentration of misfolded protein is reached. Aggregated proteins inside the cell often lead to the formation of an amyloid-like structure, which eventually causes different types of degenerative disorders and ultimately cell death.

“Patients left untreated with this type of amyloidosis develop heart failure, low blood pressure, horrible bowel disturbance, and eventually become incontinent of urine and feces,” said Julian Gillmore, nephrologist and head of the National Amyloidosis Centre at University College London. “It’s a truly awful, gradually progressive disease that is ultimately fatal.”

In February last year, Doherty began to experience the same early breathing symptoms his father had had. As an avid hiker who had trekked the Himalayas, he was surprised to find himself getting winded on local hill walks. Testing confirmed that Doherty had a hereditary form of ATTR amyloidosis.

But there was one bit of good news: If Doherty had been diagnosed even a year earlier, no treatment options would have been available to him — an all-too-common situation for over 30 million U.S. patients with rare diseases. But Gillmore, Doherty’s doctor, offered him the chance to participate in an early-stage clinical trial using CRISPR, a groundbreaking genome editing therapy with the potential to cure his ATTR amyloidosis in a single dose.

“I had no side effects and left the facility after two days,” Doherty said. “The walk that I felt breathless on, which is a steep kind of mountain walk through a forest, I’m doing that every Sunday now.” CRISPR-Cas9 allows researchers to alter the DNA of living things at will. It works like genetic scissors that can insert, repair or edit individual genes to rewrite the code of life. The system itself consists of two molecules — a protein known as Cas9 that works like scissors and a guide RNA that takes Cas9 to the right place in the genome — that can be inserted into cells or the bloodstream.

In the case of the clinical trial on patients with ATTR amyloidosis, Gillmore and his colleagues aimed to edit the malfunctioning gene itself and demonstrate for the first time that direct infusion of CRISPR molecules into the bloodstream is safe effective.

The hereditary form of ATTR amyloidosis affects roughly 50,000 people worldwide with a large cluster of patients like Doherty with roots in Donegal County, Ireland. Because circulating transthyretin is made almost entirely in the liver — and everything that enters the bloodstream is carried to the liver to metabolize — the researchers realized they could simply inject patients with the CRISPR-based therapy.

The therapy, called NTLA-2001, appeared to knock out the mutated gene as intended. Only six patients were tested in total, but the three who received the higher of two doses — including Doherty — saw their transthyretin levels drop by an average of 87 percent after 28 days. The results remain preliminary, and several more patients will need to be tested before the trial is complete.

Doherty said he hopes his family members and fellow Donegal residents will be able to benefit from CRISPR as much as he has. Fortunately, testing shows his two daughters did not inherit ATTR amyloidosis. And along with his father, Paddy’s uncle and cousin both died of the disease.

“When the trial is over, I hope that CRISPR is available and affordable for all amyloidosis patients,” Doherty said. “If a pharmaceutical company can mass-produce something like that and sell it at a good price, it would be a godsend.”

Pregnancy vs The Vaccine

By caroplasma

On February 15, 2022

In Student Post

Getting COVID as one person is already a risky and life-threatening experience, but imagine obtaining COVID while carrying another human inside of you! Though there are risks of getting the vaccine shots while pregnant, there are far more risks for the baby to be born unhealthy if the mother is unvaccinated. Why risk your baby’s life when there is an easily preventable way of avoiding the possibility of losing your child?

The risks from developing COVID-19 when pregnant and unvaccinated were demonstrated in a recent study from Scotland. From December 2020 until the end of October 2021, a period when vaccines were available, there were 4,950 confirmed coronavirus infections among pregnant women. 77% percent occurred in those unvaccinated, along with 91 percent of the 823 hospital stays and all but two of the 104 intensive care admissions, researchers report January 13 in Nature Medicine.

Babies suffered too. The death rate for babies born within 28 days of their mother’s COVID-19 diagnosis was 22.6 deaths per 1,000 births, much higher than the rate for all newborns during the pandemic, 5.6 per 1,000. All of the babies who died over the course of the study were born to women who weren’t vaccinated when they got COVID-19, the researchers found. Scientists are still unraveling what’s happening behind the scenes during a SARS-CoV-2 infection in pregnancy, and why the delta variant was especially deadly for those expecting. The highest numbers of U.S. deaths for pregnant individuals, 40 in August and 35 in September, occurred during the delta surge. There aren’t details yet on how pregnant people fare after becoming ill with the now-dominant omicron variant. But experts don’t advise a wait-and-see approach. And the vaccines continue to offer protection against severe disease and death.

Pregnancy can be a risky time to get an infection in general. Influenza and malaria, for example, can be more severe in people who are pregnant than in those who aren’t. That risk is tied to changes in the immune system. “Pregnancy is a very complicated immune state,” says Andrea Edlow, a maternal-fetal medicine specialist at Massachusetts General Hospital and Harvard Medical School in Boston. The immune system needs to defend pregnant individuals and their fetuses against pathogens. If COVID is contracted by the mother while pregnant, then the baby in the womb will have to fight off COVID just as the mother has to. Learned in AP Biology, the mother has an advantage over the baby because the mother’s immune system has been exposed to more pathogens including bacteria, viruses, toxins, or other foreign substances that the baby hasn’t. In other words, the mother has adaptive immunity or acquired immunity, so after the first line of defense, known as innate immunity, is insufficient to control the infection, the adaptive response kicks into gear to try and fight off COVID. This puts the baby at severe risk of dying because its immune system is not fully developed yet, and hasn’t been exposed to any other pathogen before.

There have been 169,407 cases of COVID-19 among pregnant individuals in the United States since the pandemic’s start, with a spike in late December of 2021 due to omicron. The counts for January 2022 are not yet complete. When the delta variant took over in the summer and fall of 2021, the risk of stillbirth grew, the study found. From March 2020 to June 2021, before delta, the risk was 1.5 times higher for pregnant women with COVID-19. From July to September of 2021, when delta reigned, there were 3,559 deliveries among women with COVID-19, of which 96, or 2.7 percent, were stillbirths. Of the 169,330 deliveries among those without the disease, 1,075, or 0.6 percent, were stillbirths. That’s four times the risk.

The first inklings that COVID-19 was especially dangerous for pregnant people came in the first year of the pandemic. Year two brought vaccines and plenty of research found COVID-19 vaccination was safe during pregnancy. More than 194,000 pregnant people in the United States have gotten COVID-19 vaccines as of January 31, according to the CDC. There have been no reported safety concerns. A study of close to 2,500 participants in a CDC COVID-19 pregnancy registry found no increased risk of miscarriage after vaccination, researchers reported in October of 2021 in the New England Journal of Medicine. Nor is there a risk of the baby coming too soon or too small, researchers report January 7 in Morbidity and Mortality Weekly Report. The U.S. study of over 40,000 pregnant women found no link between COVID-19 vaccination and preterm birth.

Even with the reassuring data on COVID-19 vaccination during pregnancy, it’s been hard to stamp out the uncertainty some feel about the shots. Other vaccines are routinely recommended in pregnancy, such as the influenza shot. But the COVID-19 vaccines were new, and pregnant people, as is standard practice, were excluded from the clinical trials that assessed the shots’ safety and efficacy. Excluding pregnant women from the trials can make it seem like “something must be wrong, this must be dangerous,” Edlow says. There were no safety issues among individuals who became pregnant during the trials, nor were there safety concerns in animal studies. Medical organizations said that COVID-19 vaccines shouldn’t be withheld due to pregnancy, but a forceful recommendation for vaccination didn’t come until July 2021.

Though there has been hesitation from amounts of pregnant women about receiving the vaccine, at the end of the day they are just trying to protect their children from this very harmful and deadly virus, and the more knowledge they get from their doctors the more they understand that the best way for their child to be protected and healthy is if they get the vaccine.

2021: The Year Of The Coronavirus Variants

By caroplasma

On January 17, 2022

In Student Post

Alpha and beta kicked off the 2021 year, and several worrisome variants later, omicron closed it out. How omicron may come to define the pandemic’s future remains uncertain. But even as omicron comes on strong, one variant, which rose to global dominance midyear in a way variants like alpha and beta never did, continues to largely define the pandemic right now: delta.

Things had actually seemed to be looking up in some parts of the world in the late spring and early summer of 2021, a year and a half into the COVID-19 pandemic. In the United States, for instance, millions of people were vaccinated, cases of the disease were falling, and people were beginning to socialize and resume normal activities.

But then delta hit hard. First spotted in India in October 2020, this variant of SARS-CoV-2, the coronavirus known as COVID-19, quickly swept around the world, supplanting other versions of the virus in 2021. Delta overwhelmed health care systems, tore through unvaccinated populations and showed that even the vaccinated were vulnerable, causing some breakthrough cases.

It soon became clear why delta wreaks so much havoc. People infected with delta make more of the virus and spread it for longer than people infected with other variants, researchers reported in Clinical Infectious Diseases in August. As a result, delta infections are more contagious. Consider two scenarios in a community where no one has immunity to the coronavirus: A person infected with an earlier version of the virus — the one first identified in Wuhan, China, that set off the pandemic — might spread it to two or three others. But a person infected with delta may transmit it to five or six people.

Mutations similar to delta’s have appeared here and there in other variants that proved themselves capable of spreading more easily or better evading the body’s immune defenses than the original virus. That includes alpha, first spotted in the United Kingdom; beta, first characterized in South Africa; and gamma, first noted in Brazil. The recently discovered omicron variant, first described in South Africa and Botswana, also shares some of the same mutations.

Some of delta’s grab bag of mutations are identical to those found in other variants, while others change the same protein building block, or amino acid, in a different way or pop up in the same part of the virus. For instance, alpha and omicron also have the same mutation of the 203rd amino acid in the N protein, but it is a different amino acid change than seen in delta. And some mutations are entirely new to delta.

These mutations on the coronavirus’ spike protein are what define delta as delta. The spike protein helps the coronavirus attach to and enter human cells penetrating host cells and cause infection. Spike proteins as learned in AP Biology while talking about COVID-19, a spike protein is a protein that forms a large structure known as a spike or peplomer projecting from the surface of an enveloped virus. The delta variant’s version carries a unique collection of mutations, marked by yellow dots in this 3-D rendering. Some of these mutations may help the virus more easily infect cells or hide from antibodies.

Though more recently in 2022 most of the population is getting the omicron variant, we must not forget the dominant variant that took control of the world and harmed a lot of people within a very short frame of time. Just when we thought we were out of the woods of COVID-19 during the summer of 2021, the delta variant proved us wrong.

The COVID-19 Treatment Pill: Destroying or Amplifying The Virus?

By caroplasma

On December 14, 2021

In Student Post

After seeing millions of people die from COVID-19, a new discovery has been found that could be the first long term treatment option to give patients suffering from COVID-19 a chance to fight it off, but how sure can we be that the treatment pill will work?

New data about an antiviral pill made by Merck with its partner Ridgeback Pharmaceuticals show that the treatment pill is not as stellar as first believed. The drug has drawbacks that could outweigh its potential to fight the coronavirus and keep people out of the hospital.

The U.S. Food and Drug Administration is now deciding whether to grant emergency use authorization for the drug called molnupiravir, after the agency’s advisory panel narrowly voted to recommend it on November 30. The drug was authorized to be of use in the United Kingdom on November 4, and if the FDA follows suit, it could wind up being just a temporary treatment. Some advisers have already urged the agency to be ready to withdraw the authorization as soon as something better comes along.

Finding an early treatment for COVID-19 hasn’t been easy due to the constant trial and error that scientists keep facing, so when the development of molnupiravir came out a lot of experts hailed it as they thought it could be a potential game changer for the pandemic. It would be utilized as a pill that could be given to people early in the infection, keep health care systems from being overwhelmed, and spare people at high risk from the most severe complications.

In a clinical trial, the drug showed early signs of preventing hospitalization and death from COVID-19 in people who are at high risk. In fact, the results were so promising — a 48 percent reduction in the relative risk of hospitalization or death — that the trial was stopped so that the drug might potentially reach the public earlier.

But on November 26, Merck announced in a news release that when all the available data from the trial was in, the reduction in relative risk fell to 30 percent against hospitalization and death compared with a placebo. The shift stemmed from an unexplained decrease in severe disease among people in the placebo group in the last part of the trial.

Overall, among the 709 people in the molnupiravir group, there were 48 hospitalizations and one death compared with 68 hospitalizations and nine deaths among the 699 people who got a placebo, dropping the effectiveness from the initial 48 percent to 30 percent.

Taking that lower-than-expected efficacy into account, the FDA’s antimicrobial drugs advisory committee came to a split 13–10 decision about whether the antiviral drug should be granted emergency use authorization, with experts on each side of the vote often agreeing with points made by the opposing side. The debate and vote reflected a storm of uncertainty about the drug’s efficacy and who should use it — the list of people who would not be eligible is far longer than those most experts would give the drug to. The panel also looked into whether the drug could lead to even more dangerous versions of the coronavirus, whether it can cause growth delays in children or mutations in human DNA, and other unanswered questions.

The antiviral pill works by making mutations in viral RNA so that viruses are rendered noninfectious and eventually stop replicating. Such mutations happen throughout the virus’s genetic instruction book, or genome.

Some of those mutations could land in the spike protein, which helps the coronavirus break into cells, or other proteins and make the virus more transmissible or more evasive to vaccines. As learned in AP Biology, the spike proteins enable the host cell to be taken over by the virus and multiply and infect the surrounding cells. The vaccine that is being administered to people all around the world contains the antibodies that you would get if you were to be infected with the COVID-19 virus, so that if you were to get the virus, your body would go into its secondary immune response. This is when the memory cells facilitate a faster, stronger and longer response to the same COVID-19 antigen. Getting the vaccine would protect your body from having a life threatening reaction to the virus. If there is a mutation that lands on the spike protein, then the vaccine will be of no use to people since that is a completely different makeup of the virus. That’s especially a fear if people don’t finish the full five-day course of the drug needed to render the virus inoperable, leading potentially to highly mutated new forms of the virus that could infect others.

Merck representatives said that possibility is unlikely, because after five days of taking even a half dose of the drug, infectious viruses were no longer detectable among study participants tested. In one study, the company found seven patients who had changes in the coronavirus’s spike protein after taking molnupiravir, but there was no evidence that the viruses spread to other people or affected the patient’s health.

Molnupiravir might also create mutations in human DNA, researchers say. The drug is a nucleoside analog — an artificial RNA building block that can mimic the bases cytosine and uracil. Some enzymes in human cells might convert those RNA subunits to a DNA building block, which may lead to mutations in human DNA, especially in rapidly reproducing cells, such as blood cells. How likely that is is an open question.

Still, there are no good remedies for people with mild to moderate COVID-19. As of November 30, more than 82,000 people in the United States are being diagnosed with COVID-19 each day and more than 800 die. Those numbers are expected to increase as case counts surge in some parts of the country. The new omicron variant might add fuel to that fire if it proves more contagious than the currently dominant delta variant.

So even with all of molnupiravir’s drawbacks, federal regulators might decide a 30 percent reduction in hospitalizations and deaths is worth giving the drug temporary authorization.

The drug might be helpful for “the right patient population, the right virus at the right time,” said Lindsey Baden, an infectious diseases doctor at Brigham and Women’s Hospital in Boston who chaired the FDA’s advisory committee. “To me that at least suggests there are populations where there may be benefit.”

But more studies need to be done to address concerns about the drug, he said. “It’s the absence of data that makes many of us uncomfortable.”

President Joe Biden said December 2 during remarks laying out a plan to combat the omicron variant that the government has secured a supply of the drugs and, if authorized, will distribute them similarly to vaccines.

Did You Inherit Stress From Your Mother?

By caroplasma

On October 27, 2021

In Student Post

Have you ever wondered why you are so stressed? Maybe because of school, sports, or homework, but have you ever thought you could have inherited from your mother? I bet not. Biologists at the University of Iowa found that roundworm mothers subjected to heat stress passed the stress exposure to their offspring and their offspring’s children.

In a study last year researchers looked at how mother roundworms react when she senses danger, such as a change in temperature. Their results were that the mother ringworms release serotonin when she senses dangers by traveling from her nervous system to warn her unfertilized eggs. The warning is there “stored”, and then passed to offspring. Genes have “memories” of past environmental conditions that affect their expression even after these conditions have changed. It is still unclear how this “memory” is established, how it persists past fertilization and after the embryo develops into adults because most organisms typically reset any changes that have been made to genes’ past activity.

The research team turned to the roundworm, a creature regularly studied by scientists, for clues. They exposed mother roundworms to unexpected stresses and found the stress memory was ingrained in the mother’s eggs through the actions of a protein called the heat shock transcription factor, or HSF1. The HSF1 protein is present in all plants and animals and is activated by changes in temperature, salinity, and other stressors. Although protein can be found in both Prokaryotic and Eukaryotic cells, this particular protein is only found in Eukaryotic cells which means that it interacts with numerous things found in these types of cells. HSF1 interacts with mRNA processing, chromatin modification, transcriptional coactivators and corepressors, and DNA and RNA metabolism which are all an array of proteins with diverse cellular functions. As we learned in biology, proteins nearly have every task of cellular life, including receiving signals from outside of the cell and mobilizing intracellular response which explains why the HSF1 protein has many functions.

The team found that HSF1 recruits another protein, an enzyme called a histone 3 lysine 9 (H3K9) methyltransferase. This normally acts during embryogenesis to silence genes and erase the memory of their prior activity. However, the research team observed something else entirely. They found that HSF1 collaborates with the mechanisms that normally act to ‘reset’ the memory of gene expression during embryogenesis to, instead, establish this stress memory. One of these newly silenced genes encodes the insulin receptor, which is central to metabolic changes with diabetes in humans, and which, when silenced, alters an animal’s physiology, metabolism, and stress resilience. Because these silencing marks were found in offspring, their stress-response strategy was switched from one that depended on the ability to be highly responsive to stress, to relying instead on mechanisms that decreased stress responsiveness but provided long-term protection from stressful environments.

What the team concluded was that if the mother was exposed to stress for a short period of time, only its offspring would be subjected to stress in utero, but the offspring’s children would not. If the mothers were exposed to stress for a longer period of time, then the offsprings children would retain this “memory” of stress.

BioQuakes

AP Biology class blog for discussing current research in Biology

Author: caroplasma

A Life Saving Treatment: CRISPR Gene Editing

Pregnancy vs The Vaccine

2021: The Year Of The Coronavirus Variants

The COVID-19 Treatment Pill: Destroying or Amplifying The Virus?

Did You Inherit Stress From Your Mother?

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