Category Archives: Gene Medicine

A new study led by researchers at Baylor College of Medicine revealed how in utero Zika virus infection can lead to microcephaly in newborns. The team discovered that the Zika virus protein NS4A disrupts brain growth by hijacking a pathway that regulates the generation of new neurons. The findings point at the possibility of developing therapeutic strategies to prevent microcephaly linked to Zika virus infection. The study appeared Thursday in the journal Developmental Cell.

Patients with rare genetic mutations shed light on how Zika virus causes microcephaly

The current study was initiated when a patient presented with a small brain size at birth and severe abnormalities in brain structures at the Baylor Hopkins Center for Mendelian Genomics (CMG), a center directed by Dr. Jim Lupski, professor of pediatrics, molecular and human genetics at Baylor College of Medicine and attending physician at Texas Childrens Hospital, said Dr. Hugo J. Bellen, professor at Baylor, investigator at the Howard Hughes Medical Institute and Jan and Dan Duncan Neurological Research Institute at Texas Childrens Hospital.

This patient and others in a cohort at CMG had not been infected by Zika virus in utero. They had a genetic defect that caused microcephaly. CMG scientists determined that the ANKLE2 gene was associated with the condition. Interestingly, a few years back the Bellen lab had discovered in the fruit fly model that ANKLE2 gene was associated with neurodevelopmental disorders. Knowing that Zika virus infection in utero can cause microcephaly in newborns, the team explored the possibility that Zika virus was mediating its effects in the brain via ANKLE2.

In a subsequent fruit fly study, the researchers demonstrated that overexpression of Zika protein NS4A causes microcephaly in the flies by inhibiting the function of ANKLE2, a cell cycle regulator that acts by suppressing the activity of VRK1 protein.

Since very little is known about the role of ANKLE2 or VRK1 in brain development, Bellen and his colleagues applied a multidisciplinary approach to tease apart the exact mechanism underlying ANKLE2-associated microcephaly.

The fruit fly helps clarify the mystery

The team found that fruit fly larvae with mutations in ANKLE2 gene had small brains with dramatically fewer neuroblasts brain cell precursors and could not survive into adulthood. Experimental expression of the normal human version of ANKLE2 gene in mutant larvae restored all the defects, establishing the loss of Ankle2 function as the underlying cause.

To understand why ANKLE2 mutants have fewer neuroblasts and significantly smaller brains, we probed deeper into asymmetric cell divisions, a fundamental process that produces and maintains neuroblasts, also called neural stem cells, in the developing brains of flies and humans, said first author Dr. Nichole Link, postdoctoral associate in the Bellen lab.

Asymmetric cell division is an exquisitely regulated process by which neuroblasts produce two different cell types. One is a copy of the neuroblast and the other is a cell programmed to become a different type of cell, such as a neuron or glia.

Proper asymmetric distribution and division of these cells is crucial to normal brain development, as they need to generate a correct number of neurons, produce diverse neuronal lineages and replenish the pool of neuroblasts for further rounds of division.

When flies had reduced levels of Ankle2, key proteins, such as Par complex proteins and Miranda, were misplaced in the neuroblasts of Ankle2 larvae. Moreover, live imaging analysis of these neuroblasts showed many obvious signs of defective or incomplete cell divisions. These observations indicated that Ankle2 is a critical regulator of asymmetric cell divisions, said Link.

Further analyses revealed more details about how Ankle2 regulates asymmetric neuroblast division. They found that Ankle2 protein interacts with VRK1 kinases, and that Ankle2 mutants alter this interaction in ways that disrupt asymmetric cell division.

The Zika connection

Linking our findings to Zika virus-associated microcephaly, we found that expressing Zika virus protein NS4A in flies caused microcephaly by hijacking the Ankle2/VRK1 regulation of asymmetric neuroblast divisions. This offers an explanation to why the severe microcephaly observed in patients with defects in the ANKLE2 and VRK1 genes is strikingly similar to that of infants with in utero Zika virus infection, Link said.

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For decades, researchers have been unsuccessful in finding experimental evidence between defects in asymmetric cell divisions and microcephaly in vertebrate models. The current work makes a giant leap in that direction and provides strong evidence that links a single evolutionarily conserved Ankle2/VRK1 pathway as a regulator of asymmetric division of neuroblasts and microcephaly, Bellen said.

Moreover, it shows that irrespective of the nature of the initial triggering event, whether it is a Zika virus infection or congenital mutations, the microcephaly converges on the disruption of Ankle2 and VRK1, making them promising drug targets.

Another important takeaway from this work is that studying a rare disorder (which refers to those resulting from rare disease-causing variations in ANKLE2 or VRK1 genes) originally observed in a single patient can lead to valuable mechanistic insights and open up exciting therapeutic possibilities to solve common human genetic disorders and viral infections.

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How in utero Zika virus infection can lead to microcephaly in newborns: Baylor research - Outbreak News Today

Groundbreaking research has found that the majority of people with cystic fibrosis can be treated successfully.

Researchers at Queens University in Belfast and at the Cystic Fibrosis Unit at St Vincents Hospital Dublin, have identified how a combination of three drugs, known as triple therapy, can tackle the underlying cause of the incurable disease.

The drug, Trikaftatm, targets the root cause of cystic fibrosis (CF), a genetic condition that clogs up the lungs and digestive system, making breathing difficult and often resulting in an early death for those affected.

CF is an inherited chronic disease that primarily affects the lungs and digestive system of about 1,300 children and adults in Ireland and 70,000 worldwide.

That figure, according to Philip Watt of Cystic Fibrosis Ireland, is set to increase by 75% in adults and 25% in children in this country according to ongoing studies by 2025.

This new drug Trikaftatm will benefit 90% of sufferers worldwide, lung function is expected to increase dramatically and will result in a 60% decrease in hospitalisation. This is a hugely welcome advancement. Many of the trials by the Queens University researchers were carried out at several centres in Ireland including St Vincents Hospital Dublin.

Dr Francis Collins, an American researcher who discovered the CF gene in 1989 has already said this is the breakthrough in research he has been waiting for. Many of the trials prior to this did not achieve as much as this study has.

Dr Collins who is the director of the National Institutes of Health writing in The New England Journal of Medicine and the highly respected Lancet medical magazine over the weekend, said these findings indicate that it may soon be possible to offer safe and effective molecularly targeted therapies to 90% of persons with cystic fibrosis.

He said that this should be a cause for major celebration and the best day ever for all of us traveling down this long road together will be the day when the more than 70,000 persons with cystic fibrosis worldwide do not need to take drug therapy at all and there finally is a permanent cure for cystic fibrosis that works for everyone.

Mr Watt added: The Food and Drugs Administration in the US has approved this drug five months ahead of time and now the European Medicines Agency is reviewing it. As a result we would expect this drug to be on the market here by the Summer of next year to those over 12-years-of-age. We would be hopeful that will include children aged as young as two in the future.

The numbers of adults and children increasing in Western Europe is down to advancements in related drugs and quality of services.

Talks and negotiations with the Health Service Executive on this new announcement will, Im sure, commence as a pipeline deal on future drug advancements was agreed with them in 2017 when Orkambi was finally approved. So far we are not privy to the potential costs of this new drug.

However, it is estimated that the drug may cost around $311,000 or 279,000 annually by Vertex, a pharmaceutical company that produces other CF drugs.

Ireland has the highest incidence of CF in the world with one in 19 Irish people being said to carry one copy of the altered gene, with three times the rate of the United States and the rest of the EU.

The organisation has pointed out that it is important to have a network of centres of expertise in dealing with disease.

A defective gene and its protein product cause the body to produce unusually thick, sticky mucus that clogs the lungs and leads to life-threatening lung infections; and obstructs the pancreas and stops natural enzymes from helping the body break down and absorb food.

Researchers believe it is possible to help control the symptoms and delay complications to make the condition easier to live with.

Dr Damian Downey, is a Clinical Senior Lecturer at the Wellcome-Wolfson Institute for Experimental Medicine, Queens University Belfast and co-author on the worldwide trial, set-up to assess the safety and efficacy of a new triple-drug combination called Trikaftatm in patients with CF aged 12 years and older.

The study involved a four-week, randomised, active-controlled trial in 107 patients who had two copies of the (F508del) most common gene mutation.

Dr Downey said: The trial was a success in demonstrating that this drug combination can potentially treat up to 90% of people with CF by addressing the underlying cause of their disease.

This new triple therapy has the potential to transform the lives of people with CF. It results in a significant improvement in lung function and quality of life and also reduces the frequency of chest infections. This treatment will likely alter the future of CF care.

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Research finds majority of people with cystic fibrosis can be treated successfully with three-drug combo - BreakingNews.ie

Super-tasters are extremely sensitive to bitterness, a common characteristic of many dark green, leafy veggies such as broccoli, cauliflower, cabbage and Brussels sprouts, to name a few. Super-tasters are extremely sensitive to bitterness, a common characteristic of many dark green, leafy veggies such as broccoli, cauliflower, cabbage and Brussels sprouts, to name a few. Related stories

ATLANTA - If certain vegetables have always made you gag, you may be more than a picky eater. Instead, you might be what scientists call a "super-taster:" a person with a genetic predisposition to taste food differently.

Unfortunately, being a super-taster doesn't make everything taste better. In fact, it can do the opposite.

Super-tasters are extremely sensitive to bitterness, a common characteristic of many dark green, leafy veggies such as broccoli, cauliflower, cabbage and Brussels sprouts, to name a few.

"The person who has that genetic propensity gets more of the sulfur flavor of, say, Brussels sprouts, especially if they've been overcooked," said University of Connecticut professor Valerie Duffy, an expert in the study of food taste, preference and consumption.

"So that [bitter] vegetable is disliked, and because people generalize, soon all vegetables are disliked," Duffy said. "If you ask people, 'Do you like vegetables?' They don't usually say, 'Oh yeah, I don't like this, but I like these others.' People tend to either like vegetables or not."

In fact, people with the "bitter gene" are 2.6 times more likely to eat fewer vegetables than people who do not have that gene, according to a new study presented Monday at the annual meeting of the American Heart Association.

"We wanted to know if genetics affected the ability of people who need to eat heart-healthy foods from eating them," said study author Jennifer Smith, a registered nurse who is a postdoc in cardiovascular science at the University of Kentucky School of Medicine.

"While we didn't see results in gene type for sodium, sugar or saturated fat, we did see a difference in vegetables," Smith said, adding that people with the gene tasted "a 'ruin-your-day' level of bitterness."

Our sense of taste relies on much more than a gene or two. Receptors on our taste buds are primed to respond to five basic flavors: salty, sweet, sour, bitter and umami, which is a savory flavor created by an amino acid called glutamate (think of mushrooms, soy sauce, broth and aged cheeses).

"But it's also smelling through the mouth and the touch, texture and temperature of the food," Duffy said. "It's very difficult to separate out taste from the rest. So when any of us say the food tastes good, it's a composite sensation that we're reacting to."

Even our saliva can enter the mix, creating unique ways to experience food.

"When we come to the table, we don't perceive the food flavor or the taste of food equally," Duffy said. "Some people live in a pastel food world versus others who might live in a more vibrant, neon food world. It could explain some of the differences in our food preference."

While there are more than 25 different taste receptors in our mouth, one in particular has been highly researched: the TAS2R38, which has two variants called AVI and PAV.

About 50% of us inherent one of each, and while we can taste bitter and sweet, we are not especially sensitive to bitter foods.

Another 25% of us are called "non-tasters" because we received two copies of AVI. Non-tasters aren't at all sensitive to bitterness; in fact food might actually be perceived as a bit sweeter.

The last 25% of us have two copies of PAV, which creates the extreme sensitivity to the bitterness some plants develop to keep animals from eating them.

When it comes to bitterness in the veggie family, the worst offenders tend to be cruciferous vegetables, such as broccoli, kale, bok choy, arugula, watercress, collards and cauliflower.

That's too bad, because they are also full of fiber, low in calories and are nutrient powerhouses. They're packed with vitamins A and C and what's called phytonutrients, which are compounds that may help to lower inflammation.

Rejecting cruciferous or any type of vegetable is a problem for the growing waistline and health of America.

"As we age as a population, vegetables are very important for helping us maintain our weight, providing all those wonderful nutrients to help us maintain our immune system and lower inflammation to prevent cancer, heart disease and more," Duffy said.

Food scientists are trying to develop ways to reduce the bitterness in veggies, in the hopes we can keep another generation of super-tasters from rejecting vegetables.

There's been some success. In fact, the Brussels sprouts we eat today are much sweeter than those our parents or grandparents ate. Dutch growers in the 90s searched their seed archives for older, less bitter varieties, then cross-pollinated them with today's higher yielding varieties.

People who already reject vegetables might try to use various cooking methods that can mask the bitter taste.

"Just because somebody carries the two copies of the bitter gene doesn't mean that they can't enjoy vegetables," Duffy said. "Cooking techniques such as adding a little fat, a little bit of sweetness, strong flavors like garlic or roasting them in the oven, which brings out natural sweetness, can all enhance the overall flavor or taste of the vegetable and block the bitterness."

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Your hatred of heart-healthy veggies could be genetic - LocalNews8.com

If certain vegetables have always made you choke, you may be more than a picky eater. Instead, you may be what scientists call a super-taster, an individual with a genetic predisposition to taste food differently. Unfortunately, being a super-taster does not make everything taste good. It can do exactly the opposite. Super-tasters are exceptionally sensitive to bitterness, a common feature of many dark green, leafy veggies such as cauliflower, broccoli, Brussels sprouts, and cabbage, to name a few.

The individual who has that genetic propensity gets more of the sulfur flavor of, say, Brussels sprouts, especially if theyve been overcooked, as stated by Professor Valerie Duffy of the University of Connecticut, an expert in the study of food taste, consumption and preference. So that bitter vegetable is disliked, and because people oversimplify, soon all vegetables are disliked, Duffy further added. If you ask people, do you like vegetables? They dont usually say, Oh yes, I dont like this, but I like these others. People tend to either like vegetables, or they dont like it completely. People with the bitter gene are 2.5 times more prone to eating fewer vegetables than people who do not have that gene, as per recent research presented recently at the annual meeting of the American Heart Association. We wanted to know if genetics affected the capability of people who require to eat heart-healthy foods from eating them, as stated by study author Jennifer Smith, a registered nurse who is a postdoc in cardiovascular science at the University of Kentucky School of Medicine. While we didnt see any results in gene type for sodium, saturated fat or sugar, we did see a difference in vegetables, Smith said, adding that individuals with the gene tasted a ruin-your-day level of bitterness.

Food scientists are trying to develop ways to decrease the bitterness in veggies, in the hopes that we can keep another generation of super-tasters from rejecting vegetables. Theres been some level of success. In fact, the Brussels sprouts we eat today are much sweeter as compared to those our parents or grandparents ate. Dutch growers in the 90s searched their seed archives for older, less bitter varieties, and then cross-pollinated them with todays high-yielding varieties.

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Your hatred for heart-healthy veggies might be genetic - SellRegular

For most patients,sudden cardiac death iscompletely unexpected, according toDr. Amit Khera, a cardiologist at Massachusetts General Hospital.

Its always particularly devastating because many dont have prior symptoms. Their first symptom is actually dropping dead, Khera said. The question is can we find these people before something really bad happens?

Many scientists, including Khera, theorizedthat one way to find people who might suffer these sudden cardiac deaths fatal events related to an abrupt cardiovascular failure could betheir genetics.

We always had a hunch that maybe there was something in their DNA that predisposed them to this tragedy, he said.

Now, he and his colleagues believe theyve found 14 different gene variants, spread across seven genes that may put their carriers at greater risk for sudden heart death.

The researchers made this discovery by sequencingthe genes of 600 people who died from sudden cardiac death and600 people of the same age whowere healthy. Khera said they focused on 49 genesalreadyknown to be important for cardiovascular disease.

These genes contribute to any of the four major causes [for sudden cardiac death], he said. Sometimes its a weak heart and the pumping function is not quite right. The second is a heart attack. The third is a problem with the hearts rhythm. The last is a tear in a major blood vessel.

After a geneticist on the team analyzed the genetic data, Khera said 14 different versions of 7 genes stood out.

These 14 variants were found in 15 people. Whats really striking is that all 15 people were sudden cardiac death cases and zero were [healthy], he explained.

The team reported their findings Saturday in the Journal of the American College of Cardiology.

After identifying the specific gene variants, theresearchers looked ata larger database of 4,000 individuals. They found that about 1% of the population without a history of heart disease carries them.

Its a really small percent of people, but an important percent," said Khera. "These people are predisposed to sudden cardiac death, and if we can find them then we have tools to prevent disease onset.

Carrying one of these gene variants doesn't mean a person is certain to suffer from sudden cardiac death. But over a period of 15 years, Kherasaid, peoplewho carry at least one of the 14 gene variantsare three times more likely to succumb tosudden cardiac death.

In most cases, doctors saysudden cardiac death arises from preventable causes.

Most of the gene variations underlying [sudden cardiac death] are related to the electrical rhythm of the heart going chaotic or haywire," said Dr. Eric Topol, vice president of Scripps Research and a cardiologist who did not work on the study.

"There are many ways you can prevent this occurrence if you know a person has a high risk mutation, Topol said. Medications or a device like a defibrillator or pacemaker can fix the underlying problem.

There are likely many more mutations that increase the risk for sudden cardiac death.

The more we find of these, the more confident we are that they are the real deal, the better we will, in the future, be at preventing these catastrophes, Topol said. So, I think this is really important work.

And not every sudden cardiac death strikes healthy individuals with no previous history of heart disease, Khera added.

Of course, important lifestyle factors play a role, like smoking over the course of a lifetime or not well controlled blood pressure, he said.

But often, families and friends of those who die from sudden cardiac death dont get a reason for why it happened.

The DNA can provide an explanation as to why this happened, Khera said. And even more importantly, this persons family members may also have the gene variant, and if they know about it then they can take preventative measures.

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Knowing If You Have One Of These 14 Genetic Mutations May Help Prevent Sudden Cardiac Death - WBUR

Scholars are divided on how to regulate heritable genome editing.

Heritable genome editing refers to changing human reproductive cells so that the resulting fetus has genetic changes that its future offspring may inherit.

Proponents of heritable gene-editing champion the possibility of editing out incurable heritable diseases, but others caution that gene editing may have unintended effects. For example, an edit to prevent a child from inheriting a disease might also reduce that childs immunity to other diseases, a concern that is amplified by the fact that any changes to immunity would be heritable.

The debate is no longer theoretical. Shortly after reports of the first live births of gene-edited babies surfaced in 2018, a number of prominent scientists called for a ban on any further experimentation that would result in live births, at least until regulatory schemes were put in place.

This weeks Saturday Seminar explores scholarly works on current and proposed regulatory approaches to heritable gene-editing, as well as the unique challenges to effective regulation given factors like the medical tourism industry.

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The Next Generation's Genes - The Regulatory Review