A 17-gene expression signature to distinguish patients who are likely to achieve long-term remissions following front-line FCR chemoimmunotherapy from…

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In this paper, Carmen D Herling, Department I of Internal Medicine, Center for Integrated Oncology, Aachen-Bonn-Cologne-Duesseldorf, Cologne, Germany, and colleagues hypothesized that the duration of response to FCR chemoimmunotherapy depends on differences in the expression of protein-coding genes. Therefore, they developed and validated a 17-gene expression signature to identify patients that might achieve durable remissions following front-line FCR chemoimmunotherapy.

Study design and patients1

Results1

After the gene expression data analysis for the MDACC cohort, the authors identified 1,136 probes associated with time to progression. Using these probes, patients with similar gene expression patterns were divided into favorable, intermediate, and unfavorable prognosis subsets. The intermediate prognosis and unfavorable prognosis subset had a shorter time to progression compared with patients in the favorable subset.

Genes highly expressed in unfavorable cases (n= 424) were associated with metabolic pathways, including oxidative phosphorylation and ribonucleoside metabolism. Genes highly expressed in favorable or intermediate cases (n= 401) encoded products involved in ATP binding, purine ribonucleoside triphosphate binding, nucleic acid binding, and DNA-template transcription.

The authors developed a prognostic model with 17 genes to distinguish IGHV-unmutated patients that had an intermediate outcome from those with an unfavorable outcome after front-line FCR therapy. The development process included:

These 17 genes were validated in 109 patients with an IGHV-unmutated status from the CLL8 cohort. In this cohort, patients classified as high risk (unfavorable prognosis; median time to progression of 39 months [IQR 2269]) had a hazard ratio of 1.90 (95% CI 1.183.06; P = 0.008) compared with low-risk (intermediate prognosis; median time to progression of 59 months [IQR 2884]) patients. Of the 17 genes, 13 came from the cluster of genes highly expressed in unfavorable cases with shorter time to progression, and increased expression corresponds to increased risk of progression. Three of the 17 genes came from the cluster of genes highly expressed in favorable or intermediate cases with longer time to progression and increased expression corresponds to decreased risk.

Conclusions

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A 17-gene expression signature to distinguish patients who are likely to achieve long-term remissions following front-line FCR chemoimmunotherapy from...

Sickle Cell Therapy With CRISPR Gene Editing Shows Promise : Shots – Health News – NPR

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Victoria Gray, who has sickle cell disease, volunteered for one of the most anticipated medical experiments in decades: the first attempt to use the gene-editing technique CRISPR to treat a genetic disorder in the United States. Meredith Rizzo/NPR hide caption

Victoria Gray, who has sickle cell disease, volunteered for one of the most anticipated medical experiments in decades: the first attempt to use the gene-editing technique CRISPR to treat a genetic disorder in the United States.

When Victoria Gray was just 3 months old, her family discovered something was terribly wrong.

"My grandma was giving me a bath, and I was crying. So they took me to the emergency room to get me checked out," Gray says. "That's when they found out that I was having my first crisis."

It was Gray's first sickle cell crisis. These episodes are one of the worst things about sickle cell disease, a common and often devastating genetic blood disorder. People with the condition regularly suffer sudden, excruciating bouts of pain.

"Sometimes it feels like lightning strikes in my chest and real sharp pains all over. And it's a deep pain. I can't touch it and make it better," says Gray. "Sometimes, I will be just balled up and crying, not able to do anything for myself.

Gray is now 34 and lives in Forest, Miss. She volunteered to become the first patient in the United States with a genetic disease to get treated with the revolutionary gene-editing technique known as CRISPR.

NPR got exclusive access to chronicle Gray's journey through this medical experiment, which is being watched closely for some of the first hints that changing a person's genes with CRISPR could provide a powerful new way to treat many diseases.

"This is both enormously exciting for sickle cell disease and for all those other conditions that are next in line," says Dr. Francis Collins, director of the National Institutes of Health.

"To be able to take this new technology and give people a chance for a new life is a dream come true," Collins says. "And here we are."

Doctors removed bone marrow cells from Gray's body, edited a gene inside them with CRISPR and infused the modified cells back into her system this summer. And it appears the cells are doing what scientists hoped producing a protein that could alleviate the worst complications of sickle cell.

"We are very, very excited," says Dr. Haydar Frangoul of the Sarah Cannon Research Institute in Nashville, Tenn., who is treating Gray.

Frangoul and others stress that it's far too soon to reach any definitive conclusions. Gray and many other patients will have to be treated and followed for much longer to know whether the gene-edited cells are helping.

"We have to be cautious. It's too early to celebrate," Frangoul says. "But we are very encouraged so far."

Collins agrees.

"That first person is an absolute groundbreaker. She's out on the frontier," Collins says. "Victoria deserves a lot of credit for her courage in being that person. All of us are watching with great anticipation."

This is the story of Gray's journey through the landmark attempt to use the most sophisticated genetic technology in what could be the dawn of a new era in medicine.

The study took place at HCA Healthcare's Sarah Cannon Research Institute and TriStar Centennial Medical Center, in Nashville, Tenn., one of 11 sites recruiting patients for the research in the U.S., Canada and Europe. Meredith Rizzo/NPR hide caption

The study took place at HCA Healthcare's Sarah Cannon Research Institute and TriStar Centennial Medical Center, in Nashville, Tenn., one of 11 sites recruiting patients for the research in the U.S., Canada and Europe.

Life filled with pain

When I first meet her, Gray is in a bed at the TriStar Centennial Medical Center in Nashville wearing a hospital gown, big gold hoop hearings and her signature glittery eye shadow.

It's July 22, 2019, and Gray has been in the hospital for almost two months. She is still recovering from the procedure, parts of which were grueling.

Nevertheless, Gray sits up as visitors enter her room.

"Nice to meet y'all," she says.

Gray is just days away from her birthday, which she'll be celebrating far from her husband, her four children and the rest of her family. Only her father is with her in Nashville.

"It's the right time to get healed," says Gray.

Gray describes what life has been like with sickle cell, which afflicts millions of people around the world, including about 100,000 in the United States. Many are African American.

In July, Gray was recovering after a medical procedure that infused billions of her own bone marrow cells back into her body after they had been modified using the gene-editing technique CRISPR. Her father, Timothy Wright (right), traveled from Mississippi to keep her company. Meredith Rizzo/NPR hide caption

In July, Gray was recovering after a medical procedure that infused billions of her own bone marrow cells back into her body after they had been modified using the gene-editing technique CRISPR. Her father, Timothy Wright (right), traveled from Mississippi to keep her company.

"It's horrible," Gray says. "When you can't walk or, you know, lift up a spoon to feed yourself, it gets real hard."

The disease is caused by a genetic defect that turns healthy, plump and pliable red blood cells into deformed, sickle-shaped cells. The defective cells don't carry oxygen well, are hard and sticky and tend to clog up the bloodstream. The blockages and lack of oxygen wreak havoc in the body, damaging vital organs and other parts of the body.

Growing up, Victoria never got to play like other kids. Her sickle cells made her weak and prone to infections. She spent a lot of time in the hospital, recovering, getting blood transfusions all the while trying to keep up with school.

"I didn't feel normal. I couldn't do the regular things that every other kid could do. So I had to be labeled as the sick one."

Gray made it to college. But she eventually had to drop out and give up her dream of becoming a nurse. She got a job selling makeup instead but had to quit that too.

The sickle-shaped cells eventually damaged Gray's heart and other parts of her body. Gray knows that many patients with sickle cell don't live beyond middle age.

"It's horrible knowing that I could have a stroke or a heart attack at any time because I have these cells in me that are misshapen," she says. "Who wouldn't worry?"

Gray says she understands the risks involved in the treatment. "This gives me hope if it gives me nothing else," she says. Meredith Rizzo/NPR hide caption

Gray says she understands the risks involved in the treatment. "This gives me hope if it gives me nothing else," she says.

Gray married and had children. But she hasn't been able to do a lot of things most parents can, like jump on a trampoline or take her kids to sporting events. She has often had to leave them in the middle of the night to rush to the hospital for help.

"It's scary. And it affected my oldest son, you know, because he's older. So he understands. He started acting out in school. And his teacher told me, 'I believe Jemarius is acting out because he really believes you're going to die,' " Gray says, choking back tears.

Some patients can get help from drugs, and some undergo bone marrow transplants. But that procedure is risky; there's no cure for most patients.

"It was just my religion that kind of kept me going," Gray says.

An eager volunteer

Gray had been exploring the possibility of getting a bone marrow transplant when Frangoul told her about a plan to study gene editing with CRISPR to try to treat sickle cell for the first time. She jumped at the chance to volunteer.

"I was excited," Gray says.

CRISPR enables scientists to edit genes much more easily than ever before. Doctors hope it will give them a powerful new way to fight cancer, AIDS, heart disease and a long list of genetic afflictions.

"CRISPR technology has a lot of potential use in the future," Frangoul says.

To try to treat Gray's sickle cell, doctors started by removing bone marrow cells from her blood last spring.

Next, scientists used CRISPR to edit a gene in the cells to turn on the production of fetal hemoglobin. It's a protein that fetuses make in the womb to get oxygen from their mothers' blood.

"Once a baby is born, a switch will flip on. It's a gene that tells the ... bone marrow cells that produce red cells to stop making fetal hemoglobin," says Frangoul, medical director of pediatric hematology/oncology at HCA Healthcare's TriStar Centennial Medical Center.

The hope is that restoring production of fetal hemoglobin will compensate for the defective adult-hemoglobin sickle cells that patients produce.

Patients with sickle cell disease have blood cells that are stiff and misshapen. The cells don't carry oxygen as well and clog up the bloodstream, resulting in periodic bouts of excruciating pain. Ed Reschke/Getty Images hide caption

Patients with sickle cell disease have blood cells that are stiff and misshapen. The cells don't carry oxygen as well and clog up the bloodstream, resulting in periodic bouts of excruciating pain.

"We are trying to introduce enough ... fetal hemoglobin into the red blood cell to make the red blood cell go back to being happy and squishy and not sticky and hard, so it can go deliver oxygen where it's supposed to," Frangoul says.

Then on July 2, after extracting Gray's cells and sending them to a lab to get edited, Frangoul infused more than 2 billion of the edited cells into her body.

"They had the cells in a big syringe. And when it went in, my heart rate shot up real high. And it kind of made it hard to breath," Gray says. "So that was a little scary, tough moment for me."

After that moment passed, Gray says, she cried. But her tears were "happy tears," she adds.

"It was amazing and just kind of overwhelming," she says, "after all that I had went through, to finally get what I came for."

The cells won't cure sickle cell. But the hope is that the fetal hemoglobin will prevent many of the disease's complications.

"This opens the door for many patients to potentially be treated and to have their disease modified to become mild," Frangoul says.

The procedure was not easy. It involved going through many of the same steps as a standard bone marrow transplant, including getting chemotherapy to make room in the bone marrow for the gene-edited cells. The chemotherapy left Gray weak and struggling with complications, including painful mouth sores that made it difficult to eat and drink.

But Gray says the ordeal will have been worth it if the treatment works.

She calls her new gene-edited cells her "supercells."

"They gotta be super to do great things in my body and to help me be better and help me have more time with my kids and my family," she says.

Gray was diagnosed with sickle cell disease as an infant. She was considering a bone marrow transplant when she heard about the CRISPR study and jumped at the chance to volunteer. Meredith Rizzo/NPR hide caption

Gray was diagnosed with sickle cell disease as an infant. She was considering a bone marrow transplant when she heard about the CRISPR study and jumped at the chance to volunteer.

Concerns about risk

Other doctors and scientists are excited about the research. But they're cautious too.

"This is an exciting moment in medicine," says Laurie Zoloth, a bioethicist at the University of Chicago. "Everyone agrees with that. CRISPR promises the capacity to alter the human genome and to begin to directly address genetic diseases."

Still, Zoloth worries that the latest wave of genetic studies, including the CRISPR sickle cell study, may not have gotten enough scrutiny by objective experts.

"This a brand-new technology. It seems to work really well in animals and really well in culture dishes," she says. "It's completely unknown how it works in actual human beings. So there are a lot of unknowns. It might make you sicker."

Zoloth is especially concerned because the research involves African Americans, who have been mistreated in past medical studies.

Frangoul acknowledges that there are risks with experimental treatments. But he says the research is going very slowly with close oversight by the Food and Drug Administration and others.

"We are very cautious about how we do this trial in a very systematic way to monitor the patients carefully for any complications related to the therapy," Frangoul says.

Gray says she understands the risks of being the first patient and that the study could be just a first step that benefits only other patients, years from now. But she can't help but hope it works for her.

Dr. Haydar Frangoul, medical director of pediatric hematology/oncology at HCA Healthcare's Sarah Cannon Research Institute and TriStar Centennial Medical Center, is leading the study in Nashville. Meredith Rizzo/NPR hide caption

Dr. Haydar Frangoul, medical director of pediatric hematology/oncology at HCA Healthcare's Sarah Cannon Research Institute and TriStar Centennial Medical Center, is leading the study in Nashville.

She imagines a day when she may "wake up and not be in pain" and "be tired because I've done something not just tired for no reason." Perhaps she could play more with her kids, she says, and look forward to watching them grow up.

"That means the world to me," Gray says.

It could be many weeks or even months before the first clues emerge about whether the edited cells are safe and might be working.

"This gives me hope if it gives me nothing else," she says in July.

Heading home at last

About two months later, Gray has recovered enough to leave the hospital. She has been living in a nearby apartment for several weeks.

Enough time has passed since Gray received the cells for any concerns about immediate side effects from the cells to have largely passed. And her gene-edited cells have started working well enough for her immune system to have resumed functioning.

So Gray is packing. She will finally go home to see her children in Mississippi for the first time in months. Gray's husband is there to drive her home.

"I'm excited," she says. "I know it's going to be emotional for me. I miss the hugs and the kisses and just everything."

After living for months in Nashville, where the study was taking place, Gray packs her bags to finally go home to her kids and family in Forest, Miss. Meredith Rizzo/NPR hide caption

After living for months in Nashville, where the study was taking place, Gray packs her bags to finally go home to her kids and family in Forest, Miss.

Gray is wearing bright red glittery eye shadow. It matches her red tank top, which repeats "I am important" across the front.

She unzips a suitcase and starts pulling clothes from the closet.

"My goodness. Did I really bring all this?" she says with a laugh.

Before Gray can finish packing and depart, she has to stop by the hospital again.

"Are you excited about seeing the kids?" Frangoul says as he greets her. "Are they going to have a big welcome sign for you in Mississippi?"

Turns out that Gray has decided to make her homecoming a surprise.

"I'm just going to show up tomorrow. Like, 'Mama's home,' " she says, and laughs.

After examining Gray, Frangoul tells her that she will need to come back to Nashville once a month for checkups and blood tests to see if her genetically modified cells are producing fetal hemoglobin and giving her healthier red blood cells.

"We are very hopeful that this will work for Victoria, but we don't know that yet," Frangoul says.

Gray will also keep detailed diaries about her health, including how much pain she's experiencing, how much pain medication she needs and whether she needs any blood transfusions.

"Victoria is a pioneer in this. And we are very excited. This is a big moment for Victoria and for this pivotal trial," Frangoul says. "If we can show that this therapy is safe and effective, it can potentially change the lives of many patients."

Gray hopes so too.

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Fundraising Started for Another Baby with SMA to Receive World’s Most Expensive Medicine – Hungary Today

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Following the successful fundraising for Zente and Levente, two Hungarian toddlers suffering from SMA (spinal muscular atrophy) for their 700 million HUF treatment, themost expensive medicine in the world, Hungary has come together again for a third boy suffering from SMA Noel, who lives in rkrtvlyes in Bihar county, Romania.

Noels mother reported on a Facebook page created for the baby, who is only a few months old, is suffering from the same illness as the two other boys who recently received the support of a whole country, which made it possible for them to receive treatment. The family has created a foundation, but people can donate to multiple bank accounts as well.

Fundraiser Set up for Another Toddler to Receive Worlds Most Expensive Medicine

The mother emphasized that she would like to point out that I not only ask Hungarian people and those living in Hungary to help. We created the site in Hungarian because it is our mother tongue and because there are many helpful Hungarian people living here in Romania as well. Of course, translations are being made.

They have already taken the necessary steps and are waiting for an approval for Noel to receive another medicine, Spinraza, which will help him to develop, and for his condition to not further deteriorate. The Spinraza injection is financed completely by the National Health Insurance Fund (NEAK). The vaccine was patented just last year. This treatment is not cheap either, as an injection costs 23 million HUF, but the cost is entirely borne by NEAK. However, this medicine is needed by patients for the rest of their lives.

Fundraising for Toddlers Expensive Treatment Moves Hungary

This is why they have also set up fundraising to receive a medicine which is only needed once to improve the babys condition. However, this expensive medicine, called Zolgensma, is currently the most expensive medicine in the world and it has only been on the market since May.

SMA-1 is an extremely rare genetic disorder which affects only one in eight to ten thousand people. Because of a defective gene, their body does not produce the protein that protects muscle cells, so their muscles slowly deteriorate. Symptoms of SMA-1 usually occur during the first months of the patients life. In most cases, due to respiratory paralysis, children do not reach age two. There are approximately 120 SMA patients officially registered in Hungary (this applies to all types of SMA, not just SMA-1) but due to the outdated registration system, professionals say that the actual number is around 300.

The essence of the treatment is that the patients are given a virus by gene therapy that infects and replaces the gene pool of defective or missing motor neurons, thus preventing muscular atrophy.In Hungary, another treatment may have given hope to SMA patients as of last year, but for the time being, it is only funded on a case-by-case basis, exclusively for children.

featured photo: Noel and his family. (photo:Kicsi Noel SMA 1 Facebook)

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Weining Lu, Kidney Researcher, Named BU Innovator of the Year – BU Today

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Serendipity, love, change. These are just some of the forces that brought Weining Lu first to Boston, and then to Boston University, where he and members of his lab collaborated with Pfizer to develop a potential new drug that could offer new hope to the hundreds of millions of people around the world struggling with chronic kidney disease.

Academia and industry scientists working togetherthats a completely different research model than being funded by the National Institutes of Health or a foundation grant, says Lu, BU School of Medicine associate professor of medicine.

Lus hypothesis that a gene called ROBO2 could play a key role in moderating kidney function earned him an opportunity to collaborate with and receive funding from Pfizers Centers for Therapeutic Innovation (CTI) in November 2012, the first BU faculty member to do so. Now, with a promising new compound borne from the research collaboration in phase 2 clinical trials, Lu has been named BUs Innovator of the Year, an award bestowed annually on a faculty member who translates his/her world-class research into inventions and innovations that benefit humankind.

Translating basic research into real-world products, especially in the medical domain, is exceptionally difficult and not an area that many of our faculty are engaged in, says Gloria Waters, BU vice president and associate provost for research. It is very exciting to see one of our faculty members working to translate their basic research into a potential therapeutic that could have a tremendous impact on patients.

The novel drug candidate has made it through a phase 1 clinical trial and is currently in a phase 2 clinical trial.

Dr. Lus creativity and drive has made a [successful collaboration] with Pfizer that could serve as a blueprint for future [joint research programs] with biopharma, David Salant, BU School of Medicine vice-chair of research and professor of medicine, said in his letter nominating Lu for the award.

Lus path toward becoming a BU faculty member and developing a promising new kidney disease drug was full of obstacles. Born in China, Lu says hes fortunate that Chinas Cultural Revolution ended by the time he was 10 years old. Otherwise, [I] likely would have become a member of Chinas lost generationpeople who forewent the opportunity to attend university as most of Chinas institutions of higher education were closed during the [revolution].

At Zhejiang University, Lu earned a medical degree and then went on to complete his residency. I had a good life over there, he says. Lu was working as a hospital clinician until he discovered that a Chinese regulation called Hukou would prevent him from living with his future wife, whom he had met at medical school. Today its better, people in China have much more freedom. But then, this household registration system was in place, Lu says. It was difficult to move freely from one city to another.

Lu found himself at a crossroad. His brother, who had decided to move to the United States to pursue a new life, had immigrated to Boston, where hes the chief acupuncturist at Dana Farber Cancer Institute. Similarly, Lu and his wife thought, why not just go to Boston to start a new life, too?

And so they did. After moving to Boston, Lu was pursuing a PhD at Northeastern University when he was surprised one day to be invited to interview for a research position in the division of nephrology at Brigham and Womens Hospital. Id never applied for any position, though, Lu says. My wife, who was planning to have our first child, had submitted the application for me. And thats how I got into kidney research.

The job change turned out to be a catalyst for his path to BU. Serendipity is a fundamental part of scientific discovery, Lu says. After 10 years doing kidney and genetics-related research at Brigham, BU invited Lu to establish his own lab on the Boston University Medical Campus.

In my lab, we study patients with genetic defects related to their kidney and urinary tracts, Lu says. In his research, he noticed something special about the gene ROBO2 as it relates to a kidneys filtering ability. The observation led to a research collaboration with Pfizer, focused on ROBO2 as a potential drug target. ROBO2 is highly expressed in the developing kidney and urinary tract. We thought that lacking this protein or gene would cause kidney and urinary defects at birth and also adult kidney disease, so we studied this for several years. But our initial hypothesis was wrong, which was okay. Instead, we found that if you block or delete ROBO2 after birth, it could potentially help kidney function.

Although he wanted to publish the results of his findings, Lu took a gamble and held off in order to protect any potential patent rights that could be jeopardized by public disclosure. Over the course of seven years working in collaboration with Pfizer, Lu says hes experienced many challenges. Theres a different culture between academia and industry. The reward systems are completely different, and the habits and behaviors we have are different. In academia, to be promoted you need to stay funded and produce high-impact publications and grant funding.

In contrast, Pfizer says its focused on developing a molecule that can ultimately be translated into a potential therapy.

Deciding to take a chance on a non-traditional research route in collaboration with industry, which works at a different pace, plays by a different set of rules, and communicates progress in a different waythats a really hard choice for an academic researcher to make, says Michael Pratt, BU managing director of technology development. But it really accelerated the project. Lu took a risk and it paid off with the science.

Weining was focused on birth defects of urinary tract and kidney, but he followed the data he was getting [in the lab]. He said, I think I have a potential drug target for adults with kidney disease. So he changed his way of thinking, which is what being innovative is all about, says Steve Berasi, a senior director at Pfizer CTI whos been working with Lu since he first proposed collaborating on ROBO2.

Lu says it helps to keep the end goal in mind. In the case of ROBO2, it could be a significant game changer for the 37 million people in the US and 850 million people worldwide with chronic kidney disease.

Says Lu: I would say to persist and believe in your science.

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

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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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What If (Almost) Every Gene Affects (Almost) Everything? – The Atlantic

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In 1999, a group of scientists scoured the genomes of around 150 pairs of siblings in an attempt to find genes that are involved in autism. They came up empty. They reasoned that this was because the risk of autism is not governed by a small number of powerful genes, which their study would have uncovered. Instead, its likely affected by a large number of genes that each have a small effect. Perhaps, they wrote, there might be 15 such genes or more.

Two decades later, that figure seems absurdly and naively low. If you told a modern geneticist that a complex traitwhether a physical characteristic like height or weight, or the risk of a disease like cancer or schizophreniawas the work of just 15 genes, theyd probably laugh. Its now thought that such traits are the work of thousands of genetic variants, working in concert. The vast majority of them have only tiny effects, but together, they can dramatically shape our bodies and our health. Theyre weak individually, but powerful en masse.

But Evan Boyle, Yang Li, and Jonathan Pritchard from Stanford University think that this framework doesnt go far enough.

They note that researchers often assume that those thousands of weakly-acting genetic variants will all cluster together in relevant genes. For example, you might expect that height-associated variants will affect genes that control the growth of bones. Similarly, schizophrenia-associated variants might affect genes that are involved in the nervous system. Theres been this notion that for every gene thats involved in a trait, thered be a story connecting that gene to the trait, says Pritchard. And he thinks thats only partly true.

Yes, he says, there will be core genes that follow this pattern. They will affect traits in ways that make biological sense. But genes dont work in isolation. They influence each other in large networks, so that if a variant changes any one gene, it could change an entire gene network, says Boyle. He believes that these networks are so thoroughly interconnected that every gene is just a few degrees of separation away from every other. Which means that changes in basically any gene will ripple inwards to affect the core genes for a particular trait.

The Stanford trio call this the omnigenic model. In the simplest terms, theyre saying that most genes matter for most things.

More specifically, it means that all the genes that are switched on in a particular type of cellsay, a neuron or a heart muscle cellare probably involved in almost every complex trait that involves those cells. So, for example, nearly every gene thats switched on in neurons would play some role in defining a persons intelligence, or risk of dementia, or propensity to learn. Some of these roles may be starring parts. Others might be mere cameos. But few genes would be left out of the production altogether.

This might explain why the search for genetic variants behind complex traits has been so arduous. For example, a giant study called er GIANT looked at the genomes of 250,000 people and identified 700 variants that affect our height. As predicted, each has a tiny effect, raising a persons stature by just a millimeter. And collectively, they explain just 16 percent of the variation in heights that you see in people of European ancestry. Thats not very much, especially when scientists estimate that some 80 percent of all human height variation can be explained by genetic factors. Wheres that missing fraction?

Pritchards team re-analyzed the GIANT data and calculated that there are probably more than 100,000 variants that affect our height, and most of these shift it by just a seventh of a millimeter. Theyre so minuscule in their effects that its hard to tell them apart from statistical noise, which is why geneticists typically ignore them. And yet, Pritchards team noted that many of these weak signals cropped up consistently across different studies, which suggests that they are real results. And since these variants are spread evenly across the entire genome, they implicate a substantial fraction of all genes, Pritchard says.

The team found more evidence for their omnigenic model by analyzing other large genetic studies of rheumatoid arthritis, schizophrenia, and Crohns disease. Many of the variants identified by these studies seem relevant to the disease in question. For example, some of the schizophrenia variants affect genes involved in the nervous system. But mostly, the variants affect genes that dont make for compelling stories, and that do pretty generic things. According to the omnigenic model, theyre only contributing to the risk of disease in incidental ways, by rippling across to the more relevant core genes. Its the only model I can come up with that make all the data fit, Pritchard says.

Pritchards a very perceptive investigator, who looks beyond what most people do, says Aravinda Chakravarti, a geneticist at John Hopkins Medicine. Do I believe this all correct? No, but its very compelling. Its a serious hypothesis that weve got to prove or disprove.

If Pritchard is right, it has big implications for genetics as a field. Geneticists are running ever-bigger and more expensive searches to identify the variants behind all kinds of traits and diseases, in the specific hope that their results will tell them something biologically interesting. They could show us more about how our bodies develop, for example, or point to new approaches for treating disease. But if Pritchard is right, then most variants will not provide such leads because they exert their influence in incidental ways.

Put it this way: The Atlantic is produced by all of us who work here, but our lives are also affected by all the people we encounterfriends, roommates, partners, taxi drivers, passers-by etc. If you listed everyone who influences what happens at The Atlantic, even in small ways, all of those peripheral people would show up on the list. But almost none of them would tell you much about how we do journalism. They're important, but also not actually that relevant. Pritchard thinks the same is true for our genes. And if thats the case, he says, its not clear to me that increasing your study size is going to help very much.

The alternative, he says, is to map the networks of genes that operate within different cells. Once we know those, well be better placed to understand the results from the forthcoming mega-studies. It is a really hard problem, says Boyle. Historically, even understanding the role of one gene in one disease has been considered a major success. Now we have to somehow understand how combinations of seemingly hundreds or thousands of genes work together in very complicated ways. Its beyond our current ability.

There are, however, projects that are trying to do exactly that. Im very excited about trying to understand whether these network ideas are correct, says Pritchard. I think its telling us something profound about how our cells work.

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What If (Almost) Every Gene Affects (Almost) Everything? - The Atlantic

Path breaking – Gulf Times

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Using a powerful gene-editing technique, scientists have rid human embryos of a mutation that causes an inherited form of heart disease often deadly to healthy young athletes and adults in their prime.The experiment marks the first time that scientists have altered the human genome to ensure a disease-causing mutation would disappear not only from the DNA of the subject on which its performed, but from the genes of his or her progeny as well.The controversial procedure, known as germ-line editing, was conducted at Oregon Health & Science University using human embryos expressly created for the purpose. It was reported in the journal Nature.The new research comes less than six months after the National Academies of Science, Engineering and Medicine recommended that scientists limit their trials of human germ-line editing to diseases that could not be treated with reasonable alternatives at least for now.In a bid to make the experiment relevant to real-life dilemmas faced by parents who carry genes for inherited diseases, the researchers focused their editing efforts on a mutation that causes inherited hypertrophic cardiomyopathy.In this genetic condition, a parent who carries one normal and one faulty copy of a the MYBPC3 gene has a 50-50 chance of passing that mutation on to his or her offspring. If the child inherits the mutation, his or her heart muscle is likely to grow prematurely weak and stiff, causing heart failure and often early death.In diseases where one parent carries such an autosomal dominant mutation, a couple will often seek the assistance of fertility doctors to minimise the risk of passing such a mutation on to a child. A womans egg production is medically stimulated, and eggs and sperm meet in a lab a process called in vitro fertilisation. Then embryologists inspect the resulting embryos, cull the ones that have inherited an unwanted mutation, and transfer only unaffected embryos into a womans uterus to be carried to term.In the new research, researchers set out to test whether germ-line gene editing could make the process of choosing healthy embryos more effective and efficient by creating more of them.In the end, their experiment showed it could. The targeted correction of a disease-causing gene carried by a single parent can potentially rescue a substantial portion of mutant human embryos, thus increasing the number of embryos available for transfer, the authors wrote in Nature. Co-author Dr Paula Amato, an Oregon Health & Science University (OHSU) professor of obstetrics and gynaecology, said the technique could potentially decrease the number of cycles needed for people trying to have children free of genetic disease if its found safe for use in fertility clinics.Along the way, though, many of the researchers findings were scientifically surprising. Long-feared effects of germ-line editing, including collateral damage to off-target genetic sequences, scarcely materialised. And mosaicism, a phenomenon in which edited DNA appears in some but not all cells, was found to be minimal.The studys lead author, OHSU biologist Shoukhrat Mitalipov, called these exciting and surprising moments. But he cautioned that there is room to improve the techniques demonstrated to produce mutation-free embryos. As for conducting human clinical trials of the germ-line correction, he said those would have to wait until results showed a near-perfect level of efficiency and accuracy, and could be limited by state and federal regulations.Eventually, Mitalipov said, such germ-line gene editing might also make it easier for parents who carry other gene mutations that follow a similar pattern of inheritance including some that cause breast and ovarian cancers, cystic fibrosis and muscular dystrophy to have healthy children who would not pass those genes to their own offspring.There is still a long road ahead, predicted Mitalipov, who heads the Center for Embryonic Cell and Gene Therapy at the Portland university.The research drew a mix of praise and concern from experts in genetic medicine.Dr Richard O. Hynes, who co-chaired the National Academies report issued in February, called the new study very good science that advances understanding of genetic repair on many fronts. Hynes, who was not involved with the latest research effort, said he was pleasantly surprised by researchers clever modifications and their outcomes.Its likely to become feasible, technically not tomorrow, not next year, but in some foreseeable time. Less than a decade, Id say, said Haynes, a biologist and cancer researcher at MIT and the Howard Hughes Medical Institute.University of California, Berkeley molecular and cell biologist Jennifer Doudna, one of pioneers of the CRISPR-Cas9 gene-editing technique, acknowledged the new research highlights a prospective use of gene editing for one inherited disease and offers some insights into the process.But Doudna questioned how broadly the experiments promising results would apply to other inherited diseases. She said she does not believe the use of germ-line editing as a means to improve efficiency at infertility clinics meets the criteria laid out by the National Academies of Science, which urged that the techniques only be explored as treatment for diseases with no reasonable alternative.Already, 50 percent of embryos would be normal, said Doudna. Why not just implant those?Doudna said she worried that the new findings will encourage people to proceed down this road before the scientific and ethical implications of germ-line editing have been fully considered.A large group of experts concluded that clinical use should not proceed until and unless theres broad societal consensus, and that just hasnt happened, Doudna said. This study underscores the urgency of having those debates. Because its coming.What is clear is that the researchers a multinational team of geneticists, cardiologists, fertility experts and embryologists from OHSU and from labs in South Korea and China tried a number of innovations in an effort to improve the safety, efficiency and fidelity of gene editing. And most yielded promising results.After retrieving eggs from 12 healthy female volunteers, researchers simultaneously performed two steps that had never been combined in a lab: At the same moment that they fertilised the eggs with the sperm of a man who carried a single copy of the mutated gene, they introduced the CRISPR-Cas9 repair machinery.The resulting embryos took up the genetic-editing programme so efficiently and uniformly that, after five days of incubation, 72.4 percent of the embryos (42 of 58) created and tested were free of the MYBPC3 mutation. By comparison, when sperm carrying the single mutation was used to fertilise eggs without any genetic manipulation, just 47.4 percent of embryos were free of the mutation linked to the deadly heart condition.The researchers believe the timing and the techniques they used prompted the embryos to rely on the healthy maternal copy of the gene as a model for fixing the MYBPC3 mutation, and not a repair template they introduced alongside the editing machinery when the eggs were fertilised. Only one of the 42 embryos used the introduced template for repair. The scientists contrasted this process to the DNA-repair mechanism operating in stem cells, which do use repair templates.As the embryos cells divided and they matured to the blastocyst stage the point at which they would usually be ready for transfer to a womans uterus they did so normally. After extensive testing, the embryos were used to make embryonic stem-cell lines, which are stored in liquid nitrogen and can be used in future research.Researchers also noted that genetic mosaicism a concern raised by earlier experimental efforts at gene editing was virtually absent from the 42 embryos that were free of the disease-causing mutation. Only one of the 42 embryos exhibited mosaicism, a condition in which cells did not all carry the same mutation-free genetic code.MITs Hynes said such findings offer important insights into how human embryos grow, develop and respond to anomalies, and will help families facing infertility and inherited illnesses.Human embryogenesis is clearly different from that of a mouse, which we know a lot about, said Hynes. That needs to be studied in human embryos, and theres no other way to do it.The results of the current study are not low enough yet for most applications certainly not for clinical applications, but its a big step forward, he added.While calling the new research very nice science, Hynes downplayed fears that germ-line editing would soon lead to tinkering with such attributes as looks, personality traits and intelligence in human children. Were not looking at designed babies around the corner not for a long time, he said.But we need to take advantage of the time and space we now have, he said, to make decisions about which uses of the technique are legitimate and which are not. Los Angeles Times/TNS

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Path breaking - Gulf Times

TP53 gene – Genetics Home Reference

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Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014 Jul 31;511(7511):543-50. doi: 10.1038/nature13385. Epub 2014 Jul 9. Erratum in: Nature. 2014 Oct 9;514(7521):262. Rogers, K [corrected to Rodgers, K].

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Loyo M, Li RJ, Bettegowda C, Pickering CR, Frederick MJ, Myers JN, Agrawal N. Lessons learned from next-generation sequencing in head and neck cancer. Head Neck. 2013 Mar;35(3):454-63. doi: 10.1002/hed.23100. Epub 2012 Aug 21. Review.

Masciari S, Dillon DA, Rath M, Robson M, Weitzel JN, Balmana J, Gruber SB, Ford JM, Euhus D, Lebensohn A, Telli M, Pochebit SM, Lypas G, Garber JE. Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort. Breast Cancer Res Treat. 2012 Jun;133(3):1125-30. doi: 10.1007/s10549-012-1993-9. Epub 2012 Mar 4.

Masica DL, Li S, Douville C, Manola J, Ferris RL, Burtness B, Forastiere AA, Koch WM, Chung CH, Karchin R. Predicting survival in head and neck squamous cell carcinoma from TP53 mutation. Hum Genet. 2015 May;134(5):497-507. doi: 10.1007/s00439-014-1470-0. Epub 2014 Aug 10.

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Schneider K, Zelley K, Nichols KE, Garber J. Li-Fraumeni Syndrome. 1999 Jan 19 [updated 2013 Apr 11]. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from http://www.ncbi.nlm.nih.gov/books/NBK1311/

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TP53 gene - Genetics Home Reference

Crispr inventor worries about the unintended consequences of gene editing – Marketplace.org

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ByMolly Wood and Paulina Velasco

June 16, 2017 | 3:00 PM

In 2012, Jennifer Doudna, along with a small group of scientists, invented a ground-breaking technology to edit DNA known as Crispr. Scientists are still experimenting with it.

Crispr has been in the news recently because a group of scientists released a much-debated study arguing that editing genes can lead to many unintended, unpredictable consequences. In the controversial case, the scientists edited genetic blindness out of a group of mice and said they found two thousand unintended consequences. The scientific community is split on the results, and Doudna said it's hard to conclude anything from the study. But she knows the possible dangers of gene editing, and she warned about them in aWired article in May.

Marketplace's senior tech correspondent Molly Wood spoke withDoudna at the Wired Business Conference in New York earlier this month and asked Doudna whatconcerns her the most about her revolutionary new technology?

The following is an edited transcript of their conversation.

Jennifer Doudna: I guess I worry about a couple of things. I think there's sort of the potential for unintended consequences of gene editing in people for clinical use. How would you ever do the kinds of experiments that you might want to do to ensure safety? And then there's another application of gene editing called gene drive that involves moving a genetic trait very quickly through a population. And there's been discussion about this in the media around the use of gene drives in insects like mosquitoes to control the spread of disease. On one hand, that sounds like a desirable thing, and on the other hand, I think one, again, has to think about potential for unintended consequences of releasing a system like that into an environmental setting where you can't predict what might happen.

Molly Wood: How important is the accessibility? You know, you could buy a Crispr kit online for $150. What does that kind of accessibility lead to, either in terms of opportunity or problems?

Doudna: I think it's mostly a really good thing in the sense that it makes the science more tangible. I honestly feel that things that break down the barriers between scientists and technologists and everybody else, in a way, is a good thing. Although it's easy to use this technology for those that have some training in molecular biology, its actually not going to be very easy to do anything that would be particularly dangerous in my opinion.

Wood: How do you think this technology could change the way we practice medicine? I mean, if we're really talking about potentially curing genetic diseases, it seems like a whole industry will be affected by that.

Doudna: I think it's a fascinating question, and I've been thinking about this a lot and having a number of discussions with folks that work in the pharmaceutical industry to think about really changing the paradigm for how we do human therapeutics, at least for certain types of disease. Imagine that you had a technology or a treatment that allowed, rather than having someone take a pill every day for the rest of their life, that you had a treatment that you could do once and cure them. It also brings along a lot of other issues. Who pays for that? How do you price such a thing? How do you get insurance companies to cover it? Even if there won't be easy answers, I think the first step is really just to realize that that's the moment that we're in right now.

Wood: One of the things I find fascinating is the intellectual property part of the conversation to what extent people might try to patent genetically modified versions of organisms or plants or even human genes?

Doudna: It's very difficult to patent genes. But I think youre touching on an important point. I think the real value of a technology like this that really allows research to move at a much faster pace than it has in the past, is that it opens up opportunities for applications that I think will lead to incredible commercial opportunities and creative things to make products that couldn't have been generated in the past. And along with that, of course, goes all of the issues regarding regulation and pricing and things like that.

Wood: Jennifer, on that question of regulation and pricing, do you have a sense of what body might end up being in charge of that? Because it's really a global issue on some level, right?

Doudna: It is. But I think a lot of it will come down to initial regulatory approval. If we're talking about agricultural products in the U.S. we're talking about the U.S. Department of Agriculture. We might be talking about the Food and Drug Administration, certainly for therapeutics. Of course that affects pricing and valuations, because if there is an onerous regulatory pathway for things, then that adds to the cost of developing them. So this is why I think it's actually very important that scientists be engaging right now with these agencies to set up appropriate regulations, but also not ones that are so onerous that it really prevents development of important products.

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Newly identified method of gene regulation challenges accepted … – Phys.Org

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June 15, 2017

Researchers at the Stanford University School of Medicine have discovered an unexpected layer of the regulation of gene expression. The finding will likely disrupt scientists' understanding of how cells regulate their genes to develop, communicate and carry out specific tasks throughout the body.

The researchers found that cellular workhorses called ribosomes, which are responsible for transforming genes encoded in RNA into proteins, display a never-before-imagined variety in their composition that significantly affects their function. In particular, the protein components of a ribosome serve to tune the tiny machine so that it specializes in the translation of genes in related cellular pathways. One type of ribosome, for example, prefers to translate genes involved in cellular differentiation, while another specializes in genes that carry out essential metabolic duties.

The discovery is shocking because researchers have believed for decades that ribosomes functioned like tiny automatons, showing no preference as they translated any and all nearby RNA molecules into proteins. Now it appears that broad variation in protein production could be sparked not by changes in the expression levels of thousands of individual genes, but instead by small tweaks to ribosomal proteins.

'Broad implications'

"This discovery was completely unexpected," said Maria Barna, PhD, assistant professor of developmental biology and of genetics. "These findings will likely change the dogma for how the genetic code is translated. Until now, each of the 1 to10 million ribosomes within a cell has been thought to be identical and interchangeable. Now we're uncovering a new layer of control to gene expression that will have broad implications for basic science and human disease."

Barna is the senior author of the study, which will be published online June 15 in Molecular Cell. Postdoctoral scholars Zhen Shi, PhD, and Kotaro Fujii, PhD, share lead authorship. Barna is a New York Stem Cell Robertson Investigator and is also a member of Stanford's Bio-X and Child Health Research Institute.

The work builds upon a previous study from Barna's laboratory that was published June 1 in Cell. The lead author of that study was postdoctoral scholar Deniz Simsek, PhD. It showed that ribosomes also differ in the types of proteins they accumulate on their outer shells. It also identified more than 400 ribosome-associated proteins, called RAPs, and showed that they can affect ribosomal function.

Every biology student learns the basics of how the genetic code is used to govern cellular life. In broad strokes, the DNA in the nucleus carries the building instructions for about 20,000 genes. Genes are chosen for expression by proteins that land on the DNA and "transcribe" the DNA sequence into short pieces of mobile, or messenger, RNA that can leave the nucleus. Once in the cell's cytoplasm, the RNA binds to ribosomes to be translated into strings of amino acids known as proteins.

Every living cell has up to 10 million ribosomes floating in its cellular soup. These tiny engines are themselves complex structures that contain up to 80 individual core proteins and four RNA molecules. Each ribosome has two main subunits: one that binds to and "reads" the RNA molecule to be translated, and another that assembles the protein based on the RNA blueprint. As shown for the first time in the Cell study, ribosomes also collect associated proteins called RAPs that decorate their outer shell like Christmas tree ornaments.

'Hints of a more complex scenario'

"Until recently, ribosomes have been thought to take an important but backstage role in the cell, just taking in and blindly translating the genetic code," said Barna. "But in the past couple of years there have been some intriguing hints of a more complex scenario. Some human genetic diseases caused by mutations in ribosomal proteins affect only specific organs or tissues, for example. This has been very perplexing. We wanted to revisit the textbook notion that all ribosomes are the same."

In 2011, members of Barna's lab showed that one core ribosomal protein called RPL38/eL38 is necessary for the appropriate patterning of the mammalian body plan during development; mice with a mutation in this protein developed skeletal defects such as extra ribs, facial clefts and abnormally short, malformed tails.

Shi and Fujii used a quantitative proteomics technology called selected reaction monitoring to precisely calculate the quantities, or stoichiometry, of each of several ribosomal proteins isolated from ribosomes within mouse embryonic stem cells. Their calculations showed that not all the ribosomal proteins were always present in the same amount. In other words, the ribosomes differed from one another in their compositions.

"We realized for the first time that, in terms of the exact stoichiometry of these proteins, there are significant differences among individual ribosomes," said Barna. "But what does this mean when it comes to thinking about fundamental aspects of a cell, how it functions?"

To find out, the researchers tagged the different ribosomal proteins and used them to isolate RNA molecules in the act of being translated by the ribosome. The results were unlike what they could have ever imagined.

"We found that, if you compare two populations of ribosomes, they exhibit a preference for translating certain types of genes," said Shi. "One prefers to translate genes associated with cell metabolism; another is more likely to be translating genes that make proteins necessary for embryonic development. We found entire biological pathways represented by the translational preferences of specific ribosomes. It's like the ribosomes have some kind of ingrained knowledge as to what genes they prefer to translate into proteins."

The findings dovetail with those of the Cell paper. That paper "showed that there is more to ribosomes than the 80 core proteins," said Simsek. "We identified hundreds of RAPs as components of the cell cycle, energy metabolism, and cell signaling. We believe these RAPs may allow the ribosomes to participate more dynamically in these intricate cellular functions."

"Barna and her team have taken a big step toward understanding how ribosomes control protein synthesis by looking at unperturbed stem cells form mammals," said Jamie Cate, PhD, professor of molecular and cell biology and of chemistry at the University of California-Berkeley. "They found 'built-in' regulators of translation for a subset of important mRNAs and are sure to find more in other cells. It is an important advance in the field." Cate was not involved in the research.

Freeing cells from micromanaging gene expression

The fact that ribosomes can differ among their core protein components as well as among their associated proteins, the RAPs, and that these differences can significantly affect ribosomal function, highlights a way that a cell could transform its protein landscape by simply modifying ribosomes so that they prefer to translate one type of genesay, those involved in metabolismover others. This possibility would free the cell from having to micromanage the expression levels of hundreds or thousands of genes involved in individual pathways. In this scenario, many more messenger RNAs could be available than get translated into proteins, simply based on what the majority of ribosomes prefer, and this preference could be tuned by a change in expression of just a few ribosomal proteins.

Barna and her colleagues are now planning to test whether the prevalence of certain types of ribosomes shift during major cellular changes, such as when a cell enters the cell cycle after resting, or when a stem cell begins to differentiate into a more specialized type of cell. They'd also like to learn more about how the ribosomes are able to discriminate between classes of genes.

Although the findings of the two papers introduce a new concept of genetic regulation within the cell, they make a kind of sense, the researchers said.

"About 60 percent of a cell's energy is spent making and maintaining ribosomes," said Barna. "The idea that they play no role in the regulation of genetic expression is, in retrospect, a bit silly."

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Again we're shocked to discover that the higher energy environment our solar system experiences, the greater the tightening and finite organizing we see at the cellular level. What will we find only to lose it as our system passes out of higher energy is astonishing. Looking thru this lens of higher energy in past cycles reforms myths into potential truths.

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How population health will benefit from the journey to precision medicine – MedCity News

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Population health and precision medicine seem like such polar opposites standing 180 degrees apart. But the path to fully realizing the benefits of precision medicine stands to reap rewards for population health along the way. That was the takeaway from an interview with India Hook-Barnard, the director of research strategy and associate director of Precision Medicine at the University of California San Francisco. She talked about the balance between the two areas of healthcare in an interview in Boston after she spoke at HIMSS Precision Medicine Summit this week.

Hook-Barnard called attention to a list of projects related to precision medicine. They included the Cell Cancer Map Initiative to discover molecular networks of cancer, the University of California Data Warehouse to connect 15 million electronic health records across the University of California health system, a Biobank that seeks to simplify the informed consent process and the Scalable Precision Open Knowledge Engine.

All of these projects are helping to advance precision medicine in different ways. They will enable us to more quickly make discoveries, provide better care, but also make better decisions in public health.

She called attention to some of the work of her colleagues. Atul Butte is the first director for the Institute of Computational Health Sciences. Among his many roles, he is one of the leaders of the University of California Data Warehouse. Among their tasks are to address privacy and security issues for making data from those records accessible across health systems plugged into the University of California network.

Theyre looking at being able to repurpose drugs, what will really provide better outcomes. It will be really huge being able to connect that kind of data and use it in a healthcare space and research space.

The San Francisco Cancer Initiative, is about sharing information for what works and what doesnt work for five types of cancer with the highest cost burden: prostate, breast, liver, colorectal and tobacco-related cancers. Each will be assigned a taskforce, Hook-Barnard said. The public-private partnership launched last year with a $3 million investment from a donor to the UCSF Helen Diller Family Comprehensive Cancer Center. The initiative is led by Dr. Robert Hiatt, the chair of the Department of Epidemiology and Biostatistics at UCSF. He authored a report on health disparities for cancer treatment outcomes.

Hook-Barnard described what the program seeks to accomplish using tobacco-related cancer as an example, and highlighted some of the questions the initiative seeks to address in this area. Social determinants of health will also come into play.

We know the dangers of smoking and the impact of it, yet there are certain communitiesthat are still developing lung cancer at much higher rate than others. Why is that? Is the messaging on prevention not resonating? Are cessation efforts not tailored enough to be effective? Is access to early screening for detection in certain neighborhoods [the problem]? Being able to tailor those kinds of preventive messaging, early screenings, diagnostics and access, could improve earlier access to treatment.

The Molecular Oncology initiative led by Michael Korn of UCSF is yet another initiative. The website offers this description of the UCSF500 gene panel assay the laboratory conducts.

a cutting-edge sequencing test that, in contrast with commercial cancer gene panel tests, sequences tumor DNA and the patients germline (inherited) DNA. This unique component of the UCSF500 molecular diagnostic test enables identification of genetic changes (mutations) in the DNA of a patients cancer, which helps oncologists improve treatment by identifying targeted therapies, or appropriate clinical trials, or in some cases clarify the exact type of cancer a patient has.

Although it is about using genomics in the clinic to get a more precise diagnosis, the goal of the initiative is to solve some of the wider questions that often go unanswered and to make sure that data isnt locked in a silo somewhere. What treatment(s) worked and why?

How do we capture that information to make sure that is shared and duplicated? We want to make sure those lessons, those findingsonce you have that piece of knowledge, how do you make sure it is shared with other medical centers? For precision medicine to work, it is about these different kinds of data and acquiring knowledge we need to enable data sharing.

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How population health will benefit from the journey to precision medicine - MedCity News

Analyses of liver cancer reveals unexpected genetic players – Baylor College of Medicine News (press release)

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Liver cancer has the second-highest worldwide cancer mortality, and yet there are limited therapeutic options to manage the disease. To learn more about the genetic causes of this cancer, and to identify potential new therapeutic targets for HCC, a nation-wide team of genomics researchers co-led by David Wheeler, Director of Cancer Genomics and Professor in the Human Genome Sequencing Center (HGSC) at Baylor College of Medicine, and Lewis Roberts, Professor of Medicine at the Mayo Clinic, analyzed 363 liver cancer cases from all over the world gathering genome mutations, epigenetic alteration through DNA methylation, RNA expression and protein expression. The research appears in Cell.

Part of the larger Cancer Genome Atlas project (TCGA), this work represents the first large scale, multi-platform analysis of HCC looking at numerous dimensions of the tumor. There have been large-cohort studies in liver cancer in the past, but they have been limited mainly to one aspect of the tumor, genome mutation. By looking at a wide variety of the tumors molecular characteristics we get substantially deeper insights into the operation of the cancer cell at the molecular level, Wheeler said.

The research team made a number of interesting associations, including uncovering a major role of the sonic hedgehog pathway. Through a combination of p53 mutation, DNA methylation and viral integrations, this pathway becomes aberrantly activated. The sonic hedgehog pathway, the role of which had not been full appreciated in liver cancer previously, is activated in nearly half of the samples analyzed in this study.

We have a very active liver cancer community here at Baylor, so we had a great opportunity to work with them and benefit from their insights into liver cancer, Wheeler said. Among the many critical functions of the liver, hepatocytes expend a lot of energy in the production of albumin and urea. It was fascinating to realize how the liver cancer cell shuts these functions off, to its own purpose of tumor growth and cell division.

Intriguingly, we found that the urea cycle enzyme carbamyl phosphate synthase is downregulated by hypermethylation, while cytoplasmic carbamyl phosphate synthase II is upregulated, said Karl-Dimiter Bissig, Assistant Professor of Molecular and Cellular Biology at Baylor and co-author of the study. This might be explained by the anabolic needs of liver cancer, reprogramming glutamine pathways to favor pyrimidine production potentially facilitating DNA replication, which is beneficial to the cancer cell.

Albumin and apolipoprotein B are unexpected members on the list of genes mutated in liver cancer. Although neither has any obvious connection to cancer, both are at the top of the list of products that the liver secretes into the blood as part of its ordinary functions, explained Dr. David Moore, professor of molecular and cellular biology at Baylor. For the cancer cell, this secretion is a significant loss of raw materials, amino acids and lipids that could be used for growth. We proposed that mutation of these genes would give the cancer cells a growth advantage by preventing this expensive loss.

Multiple data platforms coupled with clinical data allowed the researchers to correlate the molecular findings with clinical attributes of the tumor, leading to insights into the roles of its molecules and genes to help design new therapies and identify prognostic implications that have the potential to influence HCC clinical management and survivorship.

This is outstanding research analyzing a cancer thats increasing in frequency, especially in Texas. Notably, the observation of gene expression signatures that forecast patient outcome, which we validate in external cohorts, is a remarkable achievement of the study. The results have the potential to mark a turning point in the treatment of this cancer, said Dr. Richard Gibbs, director of the HGSC at Baylor. The HGSC was also the DNA sequence production Center for the project.

Wheeler says they expect the data produced by this TCGA study to lead to new avenues for therapy in this difficult cancer for years to come. There are inhibitors currently under development for the sonic hedgehog pathway, and our results suggest that those inhibitors, if they pass into phase one clinical trials, could be applied in liver cancer patients, since the pathway is frequently activated in these patients, added Wheeler.

This work was supported by the National Institutes of Health and represents the last major cancer to be analyzed in the TCGA program. See a full list of contributors.

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Analyses of liver cancer reveals unexpected genetic players - Baylor College of Medicine News (press release)

Laboratory IT systems grapple with genetic testing surge – Healthcare IT News

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BOSTON Precision medicine holds big promise, but it's also posing big challenges for hospital labs trying to manage a huge increase in requests for genetic tests.

At the HIMSS Precision Medicine Summit on Tuesday, Patrick Mathias, associate director of laboratory medicine informatics at University of Washington, spotlighted just how complex the genetic testing boom has become for clinical technology.

Hospital laboratories are "feeling the first wave of precision medicine," said Mathias, as they're "on the front lines of coordinating high-complexity testing."

[Also:How Penn Medicine primed its IT infrastructure for precision medicine]

Many hospitals rely on having to send out tests to reference laboratory when testing is unavailable at primary lab. But that leads to IT challenges for hospitals. Most distinct tests aren't integrated into EHRs and there's a big potential for order entry errors from tests not defined in clinical information systems.

As genetic testing has evolved in complexity beyond the single-gene paradigm, the genetic testing market has become similarly complex and dynamic, he said with more than 69,100 genetic testing products on the market and as many as 10 new ones every day.

[Also:EHRs and health IT infrastructure not ready for precision medicine]

To improve the management of tests and better integrate their genetic information into workflow, Seattle Childrens Hospital which spends more than $1,000,000 annually on genetic sendout testing helped launched the Pediatric Laboratory Utilization Guidance Services, or PLUGS, a nationwide network with more 60 other hospitals and health systems, with the aim of improving ordering, retrieval, interpretation and reimbursement for genetic tests.

Along the way, within its own walls, coordination between clinical and IT staff was key, said Mathias, and demanded a nuanced approach to process improvement from both sides of the equation.

The initiative required staff at Seattle Children's to embrace workflow standardization improve the efficiency of manual sendout processes through. The hospital had to bolster lab staff expertise to improve ordering process, streamlining test comparison and get better test result management.

It also made used lab genetic counselors to improve quality and reduce costs they help spot and correct errors that could impacting patient safety, said Mathias, leading to cost savings that in turn justify the addition of more resources.

Having achieved those successes, "the challenge was how can we do that so we can scale across all health systems," said Mathias.

PLUGS enables hospital labs across to decrease testing costs and errors. Seattle Children's says network members that have implemented smart utilization management have achieved savings of 10 percent or more on their sendout testing.

Within his hospital, Mathias said clinicians and IT staff are still grappling with certain aspects of precision medicine especially making better use of testing results in clinical workflow.

"There's this foundational question of, if you want data in the workflow, there has to be some EHR integration," he said. "I don't think we've really solved that question yet.

HL7 and FHIR standards are helping, he said, but "this is the tip of the iceberg we need to lower the barrier to move usable genetic data."

But while integrating genomic data remains "an ongoing challenge," said Mathias, "we are creating actionable results today."

Twitter:@MikeMiliardHITN Email the writer: mike.miliard@himssmedia.com

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Dynamic DNA helps ward off gene damage, study reveals – Phys.Org

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June 15, 2017 DNA double helix. Credit: public domain

Researchers have identified properties in DNA's protective structure that could transform the way scientists think about the human genome.

Molecules involved in DNA's supportive scaffoldingonce thought to be fixedgo through dynamic and responsive changes to shield against mutations, the research shows.

Experts say this finding is crucial to understanding DNA damage and genome organisation and could impact current thinking on DNA-linked diseases, including cancers.

In human cells, DNA is wrapped around proteins to form chromatin. Chromatin shields DNA from damage and regulates what genetic information can be reada process known as transcription.

Researchersled by the University of Edinburghshowed that a chemical called scaffold attachment factor A (SAF-A) binds to specific molecules known as caRNAs to form a protective chromatin mesh.

For the first time, this mesh was shown to be dynamic, assembling and disassembling and allowing the structure to be flexible and responsive to cell signals.

In addition, loss of SAF-A was found to lead to abnormal folding of DNA and to promote damage to the genome.

SAF-A has previously been shown in mouse studies to be essential to embryo development and mutations of the SAF-A gene have repeatedly been found in cancer gene screening studies.

Scientists say the findings shed light on how chromatin protects DNA from high numbers of harmful mutations, a condition known as genetic instability.

The studypublished in Cellwas carried out in collaboration with Heriot Watt University. It was funded by the Medical Research Council (MRC).

Nick Gilbert, Professor of Genetics at the University of Edinburgh's MRC Institute of Genetics and Molecular Medicine, said: "These findings are very exciting and have fundamental implications for how we understand our own DNA, showing that chromatin is the true guardian of the genome. The results open new possibilities for investigating how we might protect against DNA mutations that we see in diseases like cancer."

Cutting-edge techniques used in the study were developed by the Edinburgh Super-Resolution Imaging Consortium, which is supported by the MRC, the Biotechnology and Biological Sciences Research Council and the Engineering and Physical Sciences Research Council.

Professor Rory Duncan, Head of the Institute for Biological Chemistry, Biophysics and Bioengineering at Heriot-Watt University said: "The molecules involved in this study are as small to humans as Jupiter is large. The bespoke microscope techniques that we developed to understand these very tiny structures are important not only for this project but for all of biology."

Explore further: In fruit fly and human genetics, timing is everything

Journal reference: Cell

Provided by: University of Edinburgh

Every animal starts as a clump of cells, which over time multiply and mature into many different types of cells, tissues, and organs. This is fundamental biology. Yet, the details of this process remain largely mysterious. ...

A research group led by Hitoshi Kurumizaka, a professor of structural biology at Waseda University, unveiled the crystal structure of an overlapping dinucleosome, a newly discovered chromatin structural unit. This may explain ...

The three-dimensional arrangement of the chromosome within which genes reside can profoundly affect gene activity. These structural effects remain poorly understood, but Assistant Professor of Plant Science Moussa Benhamed ...

The DNA molecules in each one of the cells in a person's body, if laid end to end, would measure approximately two metres in length. Remarkably, however, cells are able to fold and compact their genetic material in the confined ...

Chromatin remodeling proteins (chromatin remodelers) are essential and powerful regulators for critical DNA-templated cellular processes, such as DNA replication, recombination, gene transcription/repression, and DNA damage ...

When scientists finished decoding the human genome in 2003, they thought the findings would help us better understand diseases, discover genetic mutations linked to cancer, and lead to the design of smarter medicine. Now ...

Scientists have developed a new technique for investigating the effects of gene deletion at later stages in the life cycle of a parasite that causes malaria in rodents, according to a new study in PLOS Pathogens. The novel ...

Scientists from Rutgers University-New Brunswick, the biotechnology company NAICONS Srl., and elsewhere have discovered a new antibiotic effective against drug-resistant bacteria: pseudouridimycin. The new antibiotic is produced ...

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Almost all life on Earth is based on DNA being copied, or replicated. Now for the first time scientists have been able to watch the replication of a single DNA molecule, with some surprising findings. For one thing, there's ...

Researchers have identified properties in DNA's protective structure that could transform the way scientists think about the human genome.

James Cook University scientists have found evidence that even distantly related Australian fish species have evolved to look and act like each other, which confirms a central tenet of evolutionary theory.

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Moving Closer to Producing Heparin In the Lab – Technology Networks

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In a recent study, University of California San Diego researchers moved one step closer to the ability to make heparin in cultured cells. Heparin is a potent anti-coagulant and the most prescribed drug in hospitals, yet cell-culture-based production of heparin is currently not possible.In particular, the researchers found a critical gene in heparin biosynthesis: ZNF263 (zinc-finger protein 263). The researchers believe this gene regulator is a key discovery on the way to industrial heparin production. The idea would be to control this regulator in industrial cell lines using genetic engineering, paving the way for safe industrial production of heparin in well-controlled cell culture.

Heparin is currently produced by extracting the drug from pig intestines, which is a concern for safety, sustainability, and security reasons. Millions of pigs are needed each year to meet our needs, and most manufacturing is done outside the USA. Furthermore, ten years ago, contaminants from the pig preparations led to dozens of deaths. Thus, there is a need to develop sustainable recombinant production. The work provides new insights on exactly how cells control synthesis of heparin.

Since regulators for heparin were not known, a research team led by UC San Diego professors Jeffrey Esko and Nathan Lewis used bioinformatic software to scan the genes encoding enzymes involved in heparin production and specifically look for sequence elements that could represent binding sites for transcription factors. The existence of such a binding site could indicate that the respective gene is regulated by a corresponding gene regulator protein, i.e. a transcription factor.

One DNA sequence that stood out the most is preferred by a transcription factor called ZNF263 (zinc-finger protein 263), explains UC San Diego professor Nathan E. Lewis, who holds appointments in the UC San Diego School of Medicines Department of Pediatrics and in the UC San Diego Jacobs School of Engineerings Department of Bioengineering. While some research has been done on this gene regulator, this is the first major regulator involved in heparin synthesis, said Lewis. He is also Co-Director of the CHO Systems Biology Center at the UC San Diego Jacobs School of Engineering.

Using the gene-editing technology, CRISPR/Cas9, the UC San Diego researchers mutated ZNF263 in a human cell line that normally does not produce heparin. They found that the heparan sulfate that this cell line would normally produce was now chemically altered and showed a reactivity that was closer to heparin.

Experiments further showed that ZNF263 represses key genes involved in heparin production. Interestingly, analysis of gene expression data from human white blood cells showed suppression of ZNF263 in mast cells (which produce heparin in vivo) and basophils, which are related to mast cells. The researchers report that ZNF263 appears to be an active repressor of heparin biosynthesis throughout most cell types, and mast cells are enabled to produce heparin because ZNF263 is suppressed in these cells.

This finding could have important relevance in biotechnology. Cell lines used in industry (such as CHO cells that normally are unable to produce heparin) could be genetically modified to inactivate ZNF263 which could enable them to produce heparin, like mast cells do.

Philipp Spahn, a project scientist in Nathan Lewis lab in the Departments of Pediatrics and Bioengineering at UC San Diego, described further directions the team is pursuing: Our bioinformatic analysis revealed several additional potential gene regulators which can also contribute to heparin production and are now exciting objects of further study.ReferenceWeiss et al. (2020) ZNF263 is a transcriptional regulator of heparin and heparan sulfate biosynthesis. PNAS. DOI: https://doi.org/10.1073/pnas.1920880117

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Moving Closer to Producing Heparin In the Lab - Technology Networks

3 Best Healthcare Stocks to Buy in May – The Motley Fool

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The COVID-19 pandemic has wrecked havoc on several major industries this year. However, the healthcare sector has been one of the few bright spots in this rather ugly market. A wide swath of the healthcare space, in fact, is in positive territory for the year right now.

Generally speaking, investors have flocked to these companies because of their somewhat unique ability to continue to operate during this ongoing pandemic. Not many businesses outside of healthcare and technology can make that claim.

Which healthcare stocks have the best chance of pushing even higher over the course of May?AbbVie (NYSE:ABBV),Adverum Biotechnologies (NASDAQ:ADVM), andHeron Therapeutics (NASDAQ:HRTX) are three names healthcare investors will definitely want to keep their eyes on this month. Here's why.

Image source: Getty Images.

AbbVie is a large-cap biopharma company. The company's shares are worth checking out this month for two core reasons. First and foremost, AbbVie is slated to close on its $63 billion acquisition of Allerganbefore the end of May. This mega-merger will greatly diversify AbbVie's product portfolio, lowering the risk associated with the eventual decline of the company's anti-inflammatory medicine, Humira.

Secondly, AbbVie's brand-new immunology medicines Skyrizi and Rinvoq, and its blood cancer franchise consisting of Imbruvica andVenclexta, are all exceeding expectations at the moment. These four key products, in fact, helped AbbVie to handily beat Wall Street's first-quarter revenue estimate earlier this month.

AbbVie's shares have yet to truly benefit from these positive tailwinds, though. As proof, the company's stock is presently trading at less than nine times forward-looking earnings. That's a dirt-cheap valuation for a blue-chip biopharma stock, especially for one that pays a sky-high annualized yield of 5.53% at current levels. So, if you're on the hunt for a grossly undervalued growth and income vehicle, AbbVie should definitely be at the top of your list this month.

Adverum is a clinical-stage gene therapy company. The biotech's shares have gained 71% so far this year due to an encouraging clinical update for itswet age-related macular degeneration (wet AMD) candidate ADVM-022. ADVM-022 is designed to be a one-and-done gene therapy for wet AMD. Currently, patients with this serious eye disorder have to receivefrequent anti-VEGF injections simply to slow the progression the disease. Adverum's therapy could thus prove to be a game-changer for this condition.

What's the opportunity? Theanti-VEGF injection market for wet AMD is a multibillion-dollar space. Adverum's experimental therapy thus has the real potential to morph into a megablockbuster product by the end of the decade. The drawback with this small-cap biotech stock is that ADVM-022 is still in the early stages of development, meaning it could take several more years before Adverum books any sales for this high-value product candidate.

That being said, Adverum might have a big target on its back on the heels of this data release. Gene therapies are highly sought-after products, and ADVM-022 is targeting an enormous market in wet AMD. Adverum, in turn, may already be fielding buyout or partnering offers. Regardless, this small-cap biotech stock comes across as woefully undervalued based on ADVM-022's commercial opportunity.

Heron is an early commercial stage biopharma. The company currently markets two drugs indicated for chemotherapy-induced nausea and vomiting. But the real star of the show is the experimental postoperative pain medication HTX-011. Wall Street's peak sales for this pain drug presently range from a low of $545 million to a high of $1 billion. To put these revenue projections into context, Heron's market cap presently stands at a mere $1.33 billion.

What's the lowdown? The FDA's target review date for HTX-011 is set forJune 26, 2020. The agency could still delay a final decision due to the COVID-19 pandemic, but Heron seems to think the FDA will ultimately stick by this goal date.

The big picture is that HTX-011 -- if approved in a timely manner -- should super-charge Heron's top line over the next 10 years. This small-cap biotech stock, in turn, could be on the cusp of a major growth spurt in the second half of 2020.

What's the risk? Regulatory decisions are impossible to handicap. So, while Heron's stock does sport a juicy upside potential, investors probably shouldn't go hog-wild with this name ahead of this risky binary event. A smallish position, though, may be worth the risk.

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3 Best Healthcare Stocks to Buy in May - The Motley Fool

Gene-delivery system prevents vision loss from inherited eye disease – Medical Xpress

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May 10, 2017 Modified ECO nanoparticles bind to interphotoreceptor retinoid-binding protein (IRBP), which transports them to the target cells in the retinal pigment epithelium (RPE.) The ECO is taken up by the cell through endocytosis but the nanoparticles escape endosomes and release the RPE 65 DNA into the nucleus. The RPE65 gene is then expressed by the RPE call, protecting the photoreceptor cells and preserving vision. Credit: Zheng-Rong Lu

Researchers at Case Western Reserve University have developed gene-carrying nanoparticles that home in on target cells and prevent vision loss in mice with a human form of Leber congenital amaurosis.

The condition is one of the most common causes of blindness in children, according to the National Institutes of Health, affecting two to three of every 100,000 newborns.

Though this research focused on the form of the disease called Leber congenital amaurosis 2, or LCA2, the scientists and engineers involved in the study believe the technology holds promise for other forms of LCA as well as other inherited diseases that lead to severe vision loss or blindness.

"We believe this technology can deliver almost any type of gene to tackle inherited visual disorders," said Zheng-Rong Lu, the M. Frank and Margaret Domiter Rudy Professor of Biomedical Engineering at Case Western Reserve and leader of the research.

The research team's study is published in the June 16 issue of Molecular Therapy - Nucleic Acids.

Those with LAC2 carry a mutated RPE65 gene and suffer from profound vision loss from birth. The mutated gene fails to produce RPE65 protein in the retinal pigment epithelium (RPE), a cell layer critical for protecting photoreceptors (rods and cones). The protein is an essential constituent of the visual cycle that converts light to electrical signals to the brain.

Reaching target cells

Lu and colleagues designed a lipid-based nanoparticle called ECO to deliver healthy RPE65 genes to RPE cells.

"The promise of this technology is it localizes the drug to the photoreceptor cells, sparing the liver and kidney from exposure," said Krzysztof Palczewski, chairman of the Department of Pharmacology at the Case Western Reserve School of Medicine. Palczewski, a vision scientist, and Lu, who studies drug delivery, have worked together on this research for six years.

"He had a clever idea," Palczewski said. "The nanoparticle uses a protein present in the eye to serve as an anchor, and the gene is delivered when bound."

While other researchers focus on using modified viruses to deliver genes for therapy, sometimes the genes are too large for viruses to carry, Lu said. The ECO can be tailored to fit the cargo.

The exterior of the nanoparticle is coated with nucleic acids that act as targeting agents, drawing the delivery system to the retina and facilitating uptake by RPE cells. To track activity, Lu's team included a fluorescent marker

Treating LCA and more

Following injection into the retina of mice, the researchers could see fluorescent green concentrating in RPE cells. Testing showed a significant increase in light-induced electrical activity from the eyes to the brain, indicating the rods and cones were operating as they should in the visual cycle.

The therapeutic effect lasted 120 days in treated mice. No improvements were observed in untreated mice.

"This work is important beyond one disease," Palczewski said. "The loss of photoreceptor cells affects virtually all of us."

As people age, they lose about 30 percent of their photoreceptors, he explained. Disease or an injury to the retina also can cause the loss of protective proteins in the cells, resulting in additional cell death. The technology potentially could be applied to protect these aged or damaged cells.

The researchers are now investigating whether the ECO system is effective against other visual disorders, including Stargardt disease, which is a form of inherited juvenile macular degeneration, primarily affecting the central portion of the visual field. They are also studying whether the nanoparticles can be used with the CRISPR/Cas9 gene-editing technique to treat genetic lesions related to retinal degenerative diseases.

Explore further: Fish eyes to help understand human inherited blindness

Newborns babies can be at risk of congenital blindness, presenting sight defects due to lesions or to genetic mutations in their genome. Among the latter, Leber Congenital Amaurosisor LCAis one of the most widespread ...

Silencing a gene called Nrl in mice prevents the loss of cells from degenerative diseases of the retina, according to a new study. The findings could lead to novel therapies for preventing vision loss from human diseases ...

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have discovered how a protein called 24 establishes proper vision. Their research helps explain why mutations in the gene encoding 24 lead ...

A new gene therapy has restored some sight in people born with an inherited, progressive form of blindness. The technique replaces a defective gene in the eye with a normal working copy of the gene using a single injection.

A new research report published in The FASEB Journal will help ophthalmologists and scientists better understand a rare genetic disease that causes increased susceptibility to blue light, night blindness, and decreased vision ...

Research led by Minghao Jin, PhD, Assistant Professor of Ophthalmology and Neuroscience at the LSU Health Sciences Center New Orleans Neuroscience Center of Excellence, has found a protein that protects retinal photoreceptor ...

Researchers at Case Western Reserve University have developed gene-carrying nanoparticles that home in on target cells and prevent vision loss in mice with a human form of Leber congenital amaurosis.

Monthly eye injections of Avastin (bevacizumab) are as effective as the more expensive drug Eylea (aflibercept) for the treatment of central retinal vein occlusion (CRVO), according to a clinical trial funded by the National ...

Researchers comparing leading treatment approaches for patients with severe uveitis have discovered that systemic therapy with oral corticosteroids and immunosuppression can preserve or improve vision in the long term better ...

A synthetic, soft tissue retina developed by an Oxford University student could offer fresh hope to visually impaired people.

Glaucoma, a leading cause of blindness worldwide, most often is diagnosed during a routine eye exam. Over time, elevated pressure inside the eye damages the optic nerve, leading to vision loss. Unfortunately, there's no way ...

The tip of our optic nerve is typically the first place injured by glaucoma.

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Invitae Announces Program with BioMarin to Expand Access to Genetic Testing for Skeletal Dysplasias – Yahoo Finance

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-Genetic testing can identify causes of rare disorders that affect bone growth and development in children-

SAN FRANCISCO, Dec. 10, 2019 /PRNewswire/ --Invitae (NYSE: NVTA), a leading medical genetics company, today announced the launch of Discover Dysplasias, an initiative with BioMarin Pharmaceutical to offer genetic testing at no charge to patients who show signs or symptoms of having a skeletal dysplasia, a group of rare, mostly genetic disorders that affect bones and joints and impact growth and development in children.

Invitae's (NVTA) mission is to bring comprehensive genetic information into mainstream medical practice to improve the quality of healthcare for billions of people. http://www.invitae.com (PRNewsFoto/Invitae Corporation)

"There are hundreds of different types of skeletal dysplasia, many with similar clinical features. If left untreated, patients can experience a variety of serious consequences, such as developmental delay, as well as serious spinal and joint problems," said Robert Nussbaum, M.D., chief medical officer of Invitae. "By identifying the genetic cause of the disease earlier, clinicians can get children on a treatment plan specific to their precise condition sooner, which could help avoid or delay the most serious consequences of the disease. We are pleased to collaborate with BioMarin on this program to increase access to genetic testing for patients."

In some cases, signs are noticeable at birth, while more serious symptoms may not develop until later in childhood. Children with skeletal dysplasia may exhibit:

Skeletal dysplasias are typically diagnosed based on symptoms, clinician observation and diagnostic imaging. Genetic testing can provide a specific diagnosis and, in some cases, may help put patients on the path to disease-specific management sooner. BioMarin and Invitae are committed to helping shorten the diagnostic odyssey for patients and families living with skeletal dysplasias.

The Discover Dysplasias program is available to healthcare providers in the United States who can use the program to order testing for patients with signs or symptoms suggestive of or consistent with a diagnosis of skeletal dysplasia. Invitae is offering genetic testing for 109 genes associated with skeletal dysplasia, as well as no-charge genetic counseling to help clinicians, patients and their families understand the results. To be eligible, patients must have one of the following: skeletal abnormalities suggestive of skeletal dysplasia, short stature, disproportionate growth, dysmorphic facial features or other signs or symptoms suggestive of a skeletal dysplasia.

BioMarin provides financial support for this program to enable testing to be available at no charge to patients who elect to participate, subject to the terms and conditions of the program. Discover Dysplasias is BioMarin and Invitae's second program together. The companies also created Behind the Seizure, a program that expands access to genetic testing for children with epilepsy.

Additional details and terms and conditions of the program are available for healthcare providers at http://www.discoverdysplasias.com.

Invitae sponsored testing programs are designed to increase access to genetic testing, particularly in conditions where earlier testing can improve diagnosis and treatment yet testing remains underutilized. The company has programs for patients suspected of having a variety of rare and neurological disorders. Learn more at http://www.invitae.com/sponsored-testing.

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About BioMarin

BioMarin is a global biotechnology company that develops and commercializes innovative therapies for serious and life-threatening rare genetic diseases. The Company's portfolio consists of seven commercialized products and multiple clinical and pre-clinical product candidates. For additional information, please visit http://www.biomarin.com.

About InvitaeInvitae Corporation(NYSE: NVTA) is a leading medical genetics company, whose mission is to bring comprehensive genetic information into mainstream medicine to improve healthcare for billions of people. Invitae's goal is to aggregate the world's genetic tests into a single service with higher quality, faster turnaround time, and lower prices. For more information, visit the company's website atinvitae.com.

Safe Harbor StatementThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to the benefits of genetic testing and the Discover Dysplasias program. Forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially, and reported results should not be considered as an indication of future performance. These risks and uncertainties include, but are not limited to: the company's history of losses; the company's ability to compete; the company's failure to manage growth effectively; the company's need to scale its infrastructure in advance of demand for its tests and to increase demand for its tests; the company's ability to use rapidly changing genetic data to interpret test results accurately and consistently; security breaches, loss of data and other disruptions; laws and regulations applicable to the company's business; and the other risks set forth in the company's filings with the Securities and Exchange Commission, including the risks set forth in the company's Quarterly Report on Form 10-Q for the quarter ended September 30, 2019. These forward-looking statements speak only as of the date hereof, and Invitae Corporation disclaims any obligation to update these forward-looking statements.

Contact:Laura D'Angelopr@invitae.com(628) 213-3283

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AI Discovers Smell Genes Linked To Cancer Outcomes – Unite.AI

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The AI community must collaborate with geneticists, in finding a treatment for those deemed most at risk of coronavirus. A potential treatment could involve removing a persons cells, editing the DNA and then injecting the cells back in, now hopefully armed with a successful immune response. This is currently being worked on for some other vaccines.

The first step would be sequencing the entire human genome from a sizeable segment of the human population.

Sequencing Human Genomes

Sequencing the first human genome cost $2.7 billion and took nearly 15 years to complete. The current cost of sequencing an entire human has dropped dramatically. As recent as 2015 the cost was $4000, now the cost is less than $1000 per person. This cost could drop a few percentage points more when economies of scale are taken into consideration.

We need to sequence the genome of two different types of patients:

It is impossible to predict which data point will be most valuable, but each sequenced genome would provide a dataset. The more data the more options there are to locate DNA variations which increase a bodys resistance to the disease vector.

Nations are currently losing trillions of dollars to this outbreak, the cost of $1000 a human genome is minor in comparison. A minimum of 1,000 volunteers for both segments of the population would arm researchers with significant volumes of big data. Should the trial increase in size by one order of magnitude, the AI would have even more training data which would increase the odds of success by several orders of magnitude. The more data the better, which is why a target of 10,000 volunteers should be aimed for.

Machine Learning

While multiple functionalities of machine learning would be present, deep learning would be used to find patterns in the data. For instance, there might be an observation that certain DNA variables correspond to a high immunity, while others correspond to a high mortality. At a minimum we would learn which segments of the human population are more susceptible and should be quarantined.

To decipher this data an Artificial Neural Network (ANN) would be located on the cloud, and sequenced human genomes from around the world would be uploaded. With time being of the essence, parallel computing will reduce the time required for the ANN to work its magic.

We could even take it one step further and use the output data sorted by the ANN,and feed it into a separate system called a Recurrent Neural Network (RNN). The RNN uses reinforcement learning to identify which gene selected by the initial ANN is most successful in a simulated environment. The reinforcement learning agent would gamify the entire process of creating a simulated setting, to test which DNA changes are more effective.

A simulated environment is like a virtual game environment, something many AI companies are well positioned to take advantage of based on their previous success in designing AI algorithms to win at esports. This includes companies such DeepMind and OpenAI.

These companies can use their underlying architecture optimized at mastering video games, to create a stimulated environment, test gene edits, and learn which edits lead to specific desired changes.

Once a gene is identified, another technology is used to make the edits.

CRISPR

Recently, the first ever study using CRISPR to edit DNA inside the human body was approved. This was to treat a rare type of genetic disorder that effects one of every 100,000 newborns. The condition can be caused by mutations in as many as 14 genes that play a role in the growth and operation of the retina. In this case, CRISPR sets out to carefully target DNA and to cause slight temporary damage to the DNA strand, causing the cell to repair itself. It is this restorative healing process which has the potential to restore eyesight.

While we are still waiting for results on if this treatment will work, the precedent of having CRISPR approved for trials in the human body is transformational. Potential disorders which can be treated include improving a bodys immune response to specific disease vectors.

Potentially, we can manipulate the bodys natural genetic resistance to a specific disease. The diseases that could potentially be targeted are diverse, but the community should be focusing on the treatment of the new global epidemic coronavirus. A threat that if unchecked could lead to a death sentence to a large percentage of our population.

FINAL THOUGHTS

While there are many potential options to achieving success, it will require that geneticists, epidemiologists, and machine learning specialists unify. A potential treatment option may be as described above, or may be revealed to be unimaginably different, the opportunity lies in the genome sequencing of a large segment of the population.

Deep learning is the best analysis tool that humans have ever created; we need to at a minimum attempt to use it to create a vaccine.

When we take into consideration what is currently at risk with this current epidemic, these three scientific communities need to come together to work on a cure.

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AI Discovers Smell Genes Linked To Cancer Outcomes - Unite.AI