Tagged: Genetics Toggle Comment Threads | Keyboard Shortcuts

  • richardmitnick 7:26 am on September 4, 2018 Permalink | Reply
    Tags: , Biobank, Biostatistics, Genetics, GenV, Integrated healthcare data, Karen Lamb,   

    From COSMOS Magazine: Women in STEM- “Superstars of STEM: Finding the trends in newborn lives” Karen Lamb. 

    Cosmos Magazine bloc

    From COSMOS Magazine

    04 September 2018
    Dion Pretorius

    Biostatistician Karen Lamb. Credit STA

    The world is on the cusp of a digital health transformation, and integrated healthcare data is already enhancing the way people access care, tackle disease and respond to treatments.

    New technology is allowing healthcare professionals to begin personalising medicines, as well as informing much more sophisticated research. As a result, we are beginning to better understand how and why people respond differently to the same treatment or drug.

    But there is the potential to do so much more.

    Karen Lamb is a senior team member at GenV (Generation Victoria), a project led by the Murdoch Children’s Research Institute (MCRI) in the Australian city of Melbourne.

    GenV plans to approach all babies born in the state of Victoria in 2020, and follow them for two years, asking their parents’ consent to take part throughout the baby’s childhood. It will put the state’s medical research at the forefront of this data revolution.

    Lamb is a biostatistician, brought in to make sure the data from this world-first project is as accessible and useful for researchers as possible.

    She says that the project is unique in the way it focusses on an entire population of newborns within a state or territory, rather than just a sample – which makes it one of the most ambitious children’s projects ever attempted.

    The team is looking to amalgamate data that is already collected and stored separately during routine check-ups, to inform future research. For interested families, they also plan to collect additional genetic information from the children and their parents.

    “Each person’s information is unique, but combine data from a large population and you can unravel valuable trends and patterns,” Lamb explains.

    “By improving, combining and unifying the data, researchers will be able to do things like identify markers for disease; trends in obesity and cardiovascular disease; devise ways to diagnose and treat allergies; and provide a foundation for better integrated health data across Victoria.”

    Melissa Wake, director of GenV, says that by 2035 the project’s mission is to have solved complex health, development and wellbeing issues for children now, and the adults they will become.

    Wake says to create a study of this scale, the team looked at examples from overseas, such as the UK Biobank, the Norwegian Mother and Child Cohort Study, and the Japan Environment and Children’s Study.

    “In the UK, their Biobank work has uncovered genes associated with Alzheimer’s disease and helped researchers to map genetic variants that increase the risk of depression,” Wake says.

    Lamb says that expertise in biostatistics has been shown to be critical in assisting in the design of studies and in developing methodologies to tackle complex health questions.

    “I can ensure that the data is protected, de-identified, and stored in a way that is easily accessible and relevant for researchers,” she says.

    “This means scientists will be spending less time collecting, cleaning and refining data sets, and more time working on treatments for some of the world’s most challenging diseases. In addition, families will know that their data are not only safe and private, but helping other children in the future.”

    See the full article here .

    Please help promote STEM in your local schools.

    Stem Education Coalition

  • richardmitnick 12:24 am on July 2, 2018 Permalink | Reply
    Tags: , C6orf106 or "C6", , , , Gene discovery unlocks mysteries of our immunity, Genetics, Our immune system   

    From Commonwealth Scientific and Industrial Research Organisation CSIRO: “Gene discovery unlocks mysteries of our immunity” 

    CSIRO bloc

    From Commonwealth Scientific and Industrial Research Organisation CSIRO


    Ofa Fitzgibbons
    Communication Advisor
    +61 2 4960 6188

    Australia’s national science agency CSIRO has identified a new gene that plays a critical role in regulating the body’s immune response to infection and disease.

    The C6orf106 or “C6” gene. No image credit.

    The discovery could lead to the development of new treatments for influenza, arthritis and even cancer.

    The gene, called C6orf106 or “C6”, controls the production of proteins involved in infectious diseases, cancer and diabetes. The gene has existed for 500 million years, but its potential is only now understood.

    “Our immune system produces proteins called cytokines that help fortify the immune system and work to prevent viruses and other pathogens from replicating and causing disease,” CSIRO researcher Dr Cameron Stewart said.

    “C6 regulates this process by switching off the production of certain cytokines to stop our immune response from spiralling out of control.

    “The cytokines regulated by C6 are implicated in a variety of diseases including cancer, diabetes and inflammatory disorders such as rheumatoid arthritis.”

    The discovery helps improve our understanding of our immune system, and it is hoped that this understanding will enable scientists to develop new, more targeted therapies.

    Dr Rebecca Ambrose was part of the CSIRO team that discovered the gene, and co-authored the recent paper announcing the discovery in the Journal of Biological Chemistry.

    “Even though the human genome was first fully sequenced in 2003, there are still thousands of genes that we know very little about,” Dr Rebecca Ambrose, a former CSIRO researcher, now based at the Hudson Institute of Medical Research said.

    “It’s exciting to consider that C6 has existed for more than 500 million years, preserved and passed down from simple organisms all the way to humans. But only now are we gaining insights into its importance.”

    Having discovered the function of C6, the researchers are awarded the privilege of naming it, and are enlisting the help of the community to do so.

    “The current name, C6orf106, reflects the gene’s location within the human genome, rather than relating to any particular function,” Dr Stewart said.

    “We think we can do better than that, and are inviting suggestions from the public.”

    A shortlist of names will be made available for final approval by a governing third party.

    The breakthrough builds on decades of work in infectious diseases, by researchers from CSIRO, Australia’s national science agency.

    See the full article here .


    Please help promote STEM in your local schools.

    Stem Education Coalition

    CSIRO campus

    CSIRO, the Commonwealth Scientific and Industrial Research Organisation, is Australia’s national science agency and one of the largest and most diverse research agencies in the world.

  • richardmitnick 1:49 pm on June 29, 2018 Permalink | Reply
    Tags: ADA-SCID or bubble baby disease, Family travels 7500 miles to save son’s life with treatment developed at UCLA, Genetics, ,   

    From UCLA Newsroom: “Family travels 7,500 miles to save son’s life with treatment developed at UCLA” 

    From UCLA Newsroom

    June 28, 2018
    Mirabai Vogt-James

    Stem cell gene therapy cures baby with life-threatening immune disorder.

    Hussein El Kerdi before and after his successful treatment for ADA-SCID, also known as bubble baby disease. Courtesy of the El Kerdi family.

    When he was born in September 2015, Hussein El Kerdi looked like a healthy baby boy. No one knew that his immune cells lacked an important enzyme. But the absence of that enzyme would profoundly change the El Kerdi family’s life, sending them on a journey from their small hometown in Lebanon to UCLA. Their one goal: to save Hussein’s life.

    When Hussein was three months old, a physician in Beirut diagnosed Hussein with a life-threatening immune disorder called adenosine deaminase-deficient severe combined immunodeficiency, also known as ADA-SCID or bubble baby disease.

    The disorder is caused by a genetic mutation that results in lack of the adenosine deaminase enzyme, without which immune cells cannot fight infections. Babies with the disease must remain isolated in germ-free environments to avoid exposure to viruses and bacteria. If the disease is not treated, even a minor cold could be fatal, and babies with the condition typically do not survive past their second birthday.

    Dr. Donald Kohn, a physician-scientist at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, has been perfecting a stem cell gene therapy for bubble baby disease for more than three decades. The treatment uses blood-forming stem cells, which have two important properties: They can make exact copies of themselves and they can produce all of the cells that make up the blood system, including immune cells such as T cells.

    Kohn’s treatment involves removing those blood-forming stem cells from the patient’s bone marrow and correcting the genetic mutation by inserting the gene responsible for making adenosine deaminase. The corrected stem cells are then infused back into the patient, where they begin producing a continual supply of healthy immune cells that are capable of fighting infection.

    Kohn, whose work focuses on genetic blood disorders, received approval from the U.S. Food and Drug Administration in 1993 to test the treatment in clinical trials. Since then, 30 out of 30 babies with the condition have been cured in six trials run by Kohn; data from a seventh trial is currently being analyzed.

    2017 study analyzes therapy for bubble baby disease

    In Lebanon, Hussein’s father, Ali, and mother, Zahraa, had heard nothing about the treatment. They were told that there had been no other cases of bubble baby disease in the Middle East, and that Great Britain and the U.S. were the only places where this experimental treatment was available.

    With help from family and friends, the El Kerdis created a plan that would eventually bring them to UCLA. A relative who is a doctor in Michigan emailed Kohn to tell him about Hussein, and Kohn — along with colleagues from the UCLA Broad Stem Cell Research Center, the David Geffen School of Medicine at UCLA and UCLA Mattel Children’s Hospital — began to make arrangements for the El Kerdis’ arrival and Hussein’s treatment.

    In April 2016, the family arrived in Los Angeles; Hussein was six months old and desperately ill.

    “I hadn’t seen a patient like Hussein in 15 or 20 years,” Kohn said. “About three to four weeks in, I thought he wasn’t going to make it through. But he did.”

    Each day leading up to his stem cell gene therapy treatment, Hussein became stronger thanks to the expert care provided by the pediatric intensive care unit at the children’s hospital.

    On July 12, 2016, some of Hussein’s bone marrow was removed and blood-forming stem cells were extracted from it. Two days later, after the cells were genetically modified, they were infused back into Hussein. Over the next couple of months, the stem cells began to create immune cells that produce adenosine deaminase. By the beginning of that September, just a few weeks before his first birthday, Hussein was healthy enough to go home.

    Evangelina’s story: Another baby with the condition is cured

    Before leaving UCLA, the El Kerdis celebrated Hussein’s birthday with Kohn and several of the nurses who cared for him. During the celebration, Ali and Zahraa expressed their gratitude.

    Hussein El Kerdi during his 2016 procedure at UCLA. His father, Ali El Kerdi (with cell phone) looks on. UCLA Broad Stem Cell Research Center.

    “I hope that when Hussein grows up, he comes to the States and gets educated to be a doctor at UCLA,” Ali El Kerdi said. “On behalf of myself and my wife and child, I want to say thank you to Dr. Kohn and to UCLA and to all the people who helped bring this miracle to life.”

    Zahraa El Kerdi said, “I cannot describe my happiness; I’m going back to my family with my child in good health. It’s so exciting, I cannot describe it.”

    Now, nearly two years after the procedure, Hussein is healthy and thriving at home with his family.

    Orchard Therapeutics, a biotechnology company that was launched in 2016, is working to bring the therapy that Hussein received to more patients.

    $20 million grant funds new clinical trial on ADA-SCID

    The company has a research partnership with UCLA to develop the treatment that Kohn created as a frozen product, which would allow it to be used at other medical centers. Kohn is hopeful that the treatment, called OTL-101, will be approved by the FDA in due course so that it can be made available to hospitals across the U.S.

    Kohn is currently conducting clinical trials that test similar stem cell gene therapy techniques for other blood diseases, including sickle cell disease, which is the most common inherited blood disorder in the U.S.

    Kohn is a paid member of the Orchard Therapeutics scientific advisory board; on behalf of the Regents of the University of California, the UCLA Technology Development Group has licensed intellectual property related to the ADA-SCID treatment developed by Kohn to the company.

    See the full article here .

    Please help promote STEM in your local schools.

    Stem Education Coalition

    UC LA Campus

    For nearly 100 years, UCLA has been a pioneer, persevering through impossibility, turning the futile into the attainable.

    We doubt the critics, reject the status quo and see opportunity in dissatisfaction. Our campus, faculty and students are driven by optimism. It is not naïve; it is essential. And it has fueled every accomplishment, allowing us to redefine what’s possible, time after time.

    This can-do perspective has brought us 12 Nobel Prizes, 12 Rhodes Scholarships, more NCAA titles than any university and more Olympic medals than most nations. Our faculty and alumni helped create the Internet and pioneered reverse osmosis. And more than 100 companies have been created based on technology developed at UCLA.

  • richardmitnick 1:13 pm on June 18, 2018 Permalink | Reply
    Tags: , Genetics, , ,   

    From Lawrence Berkeley National Lab: “Faster, Cheaper, Better: A New Way to Synthesize DNA” 

    Berkeley Logo

    From Lawrence Berkeley National Lab

    June 18, 2018
    Julie Chao
    (510) 486-6491

    Sebastian Palluk (left) and Daniel Arlow of the Joint BioEnergy Institute (JBEI) have pioneered a new way to synthesize DNA sequences. (Credit: Marilyn Chung/Berkeley Lab)

    In the rapidly growing field of synthetic biology, in which organisms can be engineered to do things like decompose plastic and manufacture biofuels and medicines, production of custom DNA sequences is a fundamental tool for scientific discovery. Yet the process of DNA synthesis, which has remained virtually unchanged for more than 40 years, can be slow and unreliable.

    Now in what could address a critical bottleneck in biology research, researchers at the Department of Energy’s Joint BioEnergy Institute (JBEI), based at Lawrence Berkeley National Laboratory (Berkeley Lab), announced they have pioneered a new way to synthesize DNA sequences through a creative use of enzymes that promises to be faster, cheaper, and more accurate. The discovery, led by JBEI graduate students Sebastian Palluk and Daniel Arlow, was published in Nature Biotechnology in a paper titled De novo DNA Synthesis Using Polymerase-Nucleotide Conjugates.

    “DNA synthesis is at the core of everything we try to do when we build biology,” said JBEI CEO Jay Keasling, the corresponding author on the paper and also a Berkeley Lab senior faculty scientist. “Sebastian and Dan have created what I think will be the best way to synthesize DNA since [Marvin] Caruthers invented solid-phase DNA synthesis almost 40 years ago. What this means for science is that we can engineer biology much less expensively – and in new ways – than we would have been able to do in the past.”

    The Caruthers process uses the tools of organic chemistry to attach DNA building blocks one at a time and has become the standard method used by DNA synthesis companies and labs around the world. However, it has drawbacks, the main ones being that it reaches its limit at about 200 bases, partly due to side reactions than can occur during the synthesis procedure, and that it produces hazardous waste. For researchers, even 1,000 bases is considered a small gene, so to make longer sequences, the shorter ones are stitched together using a process that is failure-prone and can’t make certain sequences.

    Buying your genes online

    A DNA sequence is made up of a combination of four chemical bases, represented by the letters A, C, T, and G. Researchers regularly work with genes of several thousand bases in length. To obtain them, they either need to isolate the genes from an existing organism, or they can order the genes from a company.

    “You literally paste the sequence into a website, then wait two weeks,” Arlow said. “Let’s say you buy 10 genes. Maybe nine of them will be delivered to you on time. In addition, if you want to test a thousand genes, at $300 per gene, the costs add up very quickly.”

    Palluk and Arlow were motivated to work on this problem because, as students, they were spending many long, tedious hours making DNA sequences for their experiments when they would much rather have been doing the actual experiment.

    “DNA is a huge biomolecule,” Palluk said. “Nature makes biomolecules using enzymes, and those enzymes are amazingly good at handling DNA and copying DNA. Typically our organic chemistry processes are not anywhere close to the precision that natural enzymes offer.”

    Faster, Cheaper, Better Way to Make DNA

    Thinking outside the box

    The idea of using an enzyme to make DNA is not new – scientists have been trying for decades to find a way to do it, without success. The enzyme of choice is called TdT (terminal deoxynucleotidyl transferase), which is found in the immune system of vertebrates and is one of the few enzymes in nature that writes new DNA from scratch rather than copying DNA. What’s more, it’s fast, able to add 200 bases per minute.

    In order to harness TdT to synthesize a desired sequence, the key requirement is to make it add just one nucleotide, or DNA building block, and then stop before it keeps adding the same nucleotide repeatedly. All of the previous proposals envisioned using nucleotides modified with special blocking groups to prevent multiple additions. However, the problem is that the catalytic site of the enzyme is not large enough to accept the nucleotide with a blocking group attached. “People have basically tried to ‘dig a hole’ in the enzyme by mutating it to make room for this blocking group,” Arlow said. “It’s tricky because you need to make space for it but also not screw up the activity of the enzyme.”

    Palluk and Arlow came up with a different approach. “Instead of trying to dig a hole in the enzyme, what we do is tether one nucleotide to each TdT enzyme via a cleavable linker,” Arlow said. “That way, after extending a DNA molecule using its tethered nucleotide, the enzyme has no other nucleotides available to add, so it stops. A key advantage of this approach is that the backbone of the DNA – the part that actually does the chemical reaction – is just like natural DNA, so we can try to get the full speed out of the enzyme.”

    Once the nucleotide is added to the DNA molecule, the enzyme is cleaved off. Then the cycle can begin again with the next nucleotide tethered to another TdT enzyme.

    Keasling finds the approach clever and counterintuitive. “Rather than reusing an enzyme as a catalyst, they said, ‘Hey, we can make enzymes really inexpensively. Let’s just throw it away.’ So the enzyme becomes a reagent rather than a catalyst,” he said. “That kind of thinking then allowed them to do something very different from what’s been proposed in the literature and – I think – accomplish something really important.”

    They demonstrated their method by manually making a DNA sequence of 10 bases. Not surprisingly, the two students were initially met with skepticism. “Even when we had first results, people would say, ‘It doesn’t make sense; it doesn’t seem right. That’s not how you use an enzyme,’” Palluk recalled.

    The two still have much work to do to optimize their method, but they are reasonably confident that they will be able to eventually make a gene with 1,000 bases in one go at many times the speed of the chemical method.

    Berkeley Lab has world-renowned capabilities in synthetic biology, technology development for biology, and engineering for biological process development. A number of technologies developed at JBEI and by the Lab’s Biosciences Area researchers have been spun into startups, including Lygos, Afingen, TeselaGen, and CinderBio.

    “After decades of optimization and fine-tuning, the conventional method now typically achieves a yield of about 99.5 percent per step. Our proof-of-concept synthesis had a yield of 98 percent per step, so it’s not quite on par yet, but it’s a promising starting point,” Palluk said. “We think that we’ll catch up soon and believe that we can push the system far beyond the current limitations of chemical synthesis.”

    “Our dream is to make a gene overnight,” Arlow said. “For companies trying to sustainably biomanufacture useful products, new pharmaceuticals, or tools for more environmentally friendly agriculture, and for JBEI and DOE, where we’re trying to produce fuels and chemicals from biomass, DNA synthesis is a key step. If you speed that up, it could drastically accelerate the whole process of discovery.”

    JBEI is a DOE Bioenergy Research Center funded by DOE’s Office of Science, and is dedicated to developing advanced biofuels. Other co-authors on the paper are: Tristan de Rond, Sebastian Barthel, Justine Kang, Rathin Bector, Hratch Baghdassarian, Alisa Truong, Peter Kim, Anup Singh, and Nathan Hillson.

    See the full article here .

    Please help promote STEM in your local schools.

    Stem Education Coalition

    A U.S. Department of Energy National Laboratory Operated by the University of California

    University of California Seal

    DOE Seal

  • richardmitnick 12:38 pm on May 20, 2018 Permalink | Reply
    Tags: , , , Genetics,   

    From Astrobiology Magazine: “How primordial life on Earth might have replicated itself” 

    Astrobiology Magazine

    From Astrobiology Magazine

    May 20, 2018

    Liquid brine containing replicating RNA molecules is concentrated in the cracks between ice crystals, as seen with an electron microscope. Credit: Philipp Holliger, MRC LMB

    Scientists have created a new type of genetic replication system which demonstrates how the first life on Earth – in the form of RNA – could have replicated itself. The scientists from the Medical Research Council (MRC) Laboratory of Molecular Biology say the new RNA utilises a system of genetic replication unlike any known to naturally occur on Earth today.

    A popular theory for the earliest stages of life on Earth is that it was founded on strands of RNA, a chemical cousin of DNA. Like DNA, RNA strands can carry genetic information using a code of four molecular letters (bases), but RNA can be more than a simple ‘string’ of information. Some RNA strands can also fold up into three-dimensional shapes that can form enzymes, called ribozymes, and carry out chemical reactions.

    If a ribozyme could replicate folded RNA, it might be able to copy itself and support a simple living system.

    Previously, scientists had developed ribozymes that could replicate straight strands of RNA, but if the RNA was folded it blocked the ribozyme from copying it. Since ribozymes themselves are folded RNAs, their own replication is blocked.

    Now, in a paper published today in the journal eLife, the scientists have resolved this paradox by engineering the first ribozyme that is able to replicate folded RNAs, including itself.

    Normally when copying RNA, an enzyme would add single bases (C, G, A or U) one at a time, but the new ribozyme uses three bases joined together, as a ‘triplet’ (e.g. GAU). These triplet building blocks enable the ribozyme to copy folded RNA, because the triplets bind to the RNA much more strongly and cause it to unravel – so the new ribozyme can copy its own folded RNA strands.

    The scientists say that the ‘primordial soup’ could have contained a mixture of bases in many lengths – one, two, three, four or more bases joined together – but they found that using strings of bases longer than a triplet made copying the RNA less accurate.

    Dr Philipp Holliger, from the MRC Laboratory of Molecular Biology and senior author on the paper, said: “We found a solution to the RNA replication paradox by re-thinking how to approach the problem – we stopped trying to mimic existing biology and designed a completely new synthetic strategy. It is exciting that our RNA can now synthesise itself.

    “These triplets of bases seem to represent a sweet spot, where we get a nice opening up of the folded RNA structures, but accuracy is still high. Notably, although triplets are not used in present-day biology for replication, protein synthesis by the ribosome – an ancient RNA machine thought to be a relic of early RNA-based life – proceeds using a triplet code.

    “However, this is only a first step because our ribozyme still needs a lot of help from us to do replication. We provided a pure system, so the next step is to integrate this into the more complex substrate mixtures mimicking the primordial soup – this likely was a diverse chemical environment also containing a range of simple peptides and lipids that could have interacted with the RNA.”

    The experiments were conducted in ice at -7°C, because the researchers had previously discovered that freezing concentrates the RNA molecules in a liquid brine in tiny gaps between the ice crystals. This also is beneficial for the RNA enzymes, which are more stable and function better at cold temperatures.

    Dr Holliger added: “This is completely new synthetic biology and there are many aspects of the system that we have not yet explored. We hope in future, it will also have some biotechnology applications, such as adding chemical modifications at specific positions to RNA polymers to study RNA epigenetics or augment the function of RNA.”

    Dr Nathan Richardson, Head of Molecular and Cellular Medicine at the MRC, said: “This is a really exciting example of blue skies research that has revealed important insights into how the very beginnings of life may have emerged from the ‘primordial soup’ some 3.7 billion years ago. Not only is this fascinating science, but understanding the minimal requirements for RNA replication and how these systems can be manipulated could offer exciting new strategies for treating human disease.”

    See the full article here .

    Please help promote STEM in your local schools.


    Stem Education Coalition

  • richardmitnick 11:21 am on April 25, 2018 Permalink | Reply
    Tags: , FOXG1, Genetics, , Soo-Kyung a specialist in genetics, Yuna Lee   

    From The New York Times: “Infinitesimal Odds: A Scientist Finds Her Child’s Rare Illness Stems From the Gene She Studies” 

    New York Times

    The New York Times

    April 23, 2018
    Pam Belluck

    By the time her mother received the doctor’s email, Yuna Lee was already 2 years old, a child with a frightening medical mystery. Plagued with body-rattling seizures and inconsolable crying, she could not speak, walk or stand.

    “Why is she suffering so much?” her mother, Soo-Kyung Lee, anguished. Brain scans, genetic tests and neurological exams yielded no answers. But when an email popped up suggesting that Yuna might have a mutation on a gene called FOXG1, Soo-Kyung froze.

    “I knew,” she said, “what that gene was.”

    Almost no one else in the world would have had any idea. But Soo-Kyung is a specialist in the genetics of the brain—“a star,” said Robert Riddle, a program director in neurogenetics at the National Institute of Neurological Disorders and Stroke. For years, Soo-Kyung, a developmental biologist at Oregon Health and Science University, had worked with the FOX family of genes.

    “I knew how critical FOXG1 is for brain development,” she said.

    She also knew harmful FOXG1 mutations are exceedingly rare and usually not inherited — the gene mutates spontaneously during pregnancy. Only about 300 people worldwide are known to have FOXG1 syndrome, a condition designated a separate disorder relatively recently. The odds her own daughter would have it were infinitesimal.

    “It is an astounding story,” Dr. Riddle said. “A basic researcher working on something that might help humanity, and it turns out it directly affects her child.”

    Suddenly, Soo-Kyung, 42, and her husband Jae Lee, 57, another genetics specialist at O.H.S.U., had to transform from dispassionate scientists into parents of a patient, desperate for answers.

    Soo-Kyung and Yuna on a FaceTime call with Soo-Kyung’s parents in Korea.CreditRuth Fremson/The New York Times.

    Yuna during free playtime in the schoolyard at Bridlemile Elementary School in Portland, Ore. Yuna cannot walk, but she spends time daily in a gait trainer to help her learn to propel herself with her feet.CreditRuth Fremson/The New York Times.

    They were plunged into a fast-moving ocean of newly identified gene mutations, newly named diagnoses, and answers that raise new questions.The newfound capacity to sequence genomes is spurring a genetic gold rush, linking mystifying diseases to specific mutations — often random mutations not passed down from parents.

    New research shows that each year, about 400,000 babies born worldwide have neurological disorders caused by random mutations, said Matthew Hurles, head of human genetics at Wellcome Trust Sanger Institute. As sequencing becomes cheaper, more children will receive specific diagnoses like FOXG1 syndrome, doctors say.

    This burst of discovery might eventually help doctors treat or prevent some brain damage. “We used to lump them all together under autism or another category,” said Dr. Joseph Gleeson, a neurogeneticist at University of California San Diego. “It’s really changing the way doctors are thinking about disease.”

    Balancing the missions of science and motherhood, Soo-Kyung has begun doing what she is uniquely positioned to do: aiming her research squarely at her daughter’s disorder. With Jae’s help, she is studying how the FOXG1 gene works and why mutations like Yuna’s are so devastating.

    “Our ultimate goal is to find a better treatment for FOXG1 syndrome patients,” she said. Her day-to-day goal is helping Yuna make slivers of developmental progress.

    Yuna is now a sweet-natured 8-year-old still wearing a toddler’s onesie over a diaper. “Cognitively she’s about 18 months,” Jae, her father, said.

    A major achievement would be getting Yuna to indicate when her diaper is wet. Or to stand when they prop her against a kitchen corner and remove their hands for a split second. “If Yuna doesn’t fall down right away,” Soo-Kyung said, “we consider that a success.”

    “My daughter’s brain is so damaged,” Soo-Kyung said, eyes brimming with tears. “Can we rescue any of her skills?”

    Soo-Kyung, left, and Jae, right, work next door to each other; together they are researching FOXG1 syndrome, the rare disorder Yuna has.CreditRuth Fremson/The New York Times

    When their daughter was born in Houston in January 2010, southeast Texas experienced a rare snowfall. It inspired the Lees, then professors at Baylor College of Medicine, to name her “Yuna,” meaning “snow girl” in a Korean dialect, with the middle name “Heidi” for its allusion to snowy peaks.

    “She was perfectly normal,” Jae said. “We were joking, ‘What will come later?’ Yuna’s mom is a very smart person, so we thought, ‘Well, she will make the world better.’”

    But soon, things seemed off. Yuna often failed to respond to sounds. She struggled to swallow milk from breast or bottle. What she did swallow she vomited. “She looked like someone with malnutrition,” Soo-Kyung said.

    A doctor said her head circumference was not growing enough. Then Yuna began having seizures , often sending the Lees to the emergency room. She cried so persistently that Soo-Kyung had to assure neighbors Yuna was not being abused.

    “What did I do wrong?” Soo-Kyung grilled herself. Had she eaten something while pregnant that infected Yuna? “I was traveling a lot during the pregnancy to attend seminars — was I too stressed?”

    Yuna and her mother in a family photo. Born in Texas during a rare snowfall, her name, Yuna, means “snow girl” in a Korean dialect. No image credit.

    Shortly after Yuna’s second birthday, Soo-Kyung traveled to Washington, D.C. to serve on a National Institutes of Health panel reviewing grant proposals from brain development researchers. At dinner, she found herself next to Dr. David Rowitch, a respected neonatologist and neuroscientist she knew only by reputation.

    “She started to tell me what’s going on with her daughter,” recalled Dr. Rowitch, professor and head of pediatrics at the University of Cambridge who was then at the University of California San Francisco. He was stumped but offered to send Yuna’s brain scans to “the world’s expert” in neuroradiology: Dr. Jim Barkovich at U.C.S.F.

    Dr. Barkovich said Yuna’s scans revealed “a very unusual pattern,” one he had not seen in decades of evaluating brain images sent to him from around the world. Yuna’s cerebral cortex had abnormal white matter, meaning “there were probably cells dying,” he said, and the corpus callosum, the corridor across which cells in the left and right hemispheres communicate, was “way too thin.”

    Searching scientific literature, he said, “I found a gene that seemed to be expressed in that area and found that when it was mutated it caused a very similar pattern.” That gene was FOXG1.

    Left, Soo-Kyung watching a postdoctoral student with mouse brains in her lab at OHSU. Right, examining mouse brain cells. She has begun aiming her research at understanding Yuna’s brain disorder.CreditRuth Fremson/The New York Times.

    Yuna exploring her mother’s closet after her bath. Her mother, Soo-Kyung, began sleeping on the mattress after she collapsed from the stress of caring for Yuna; sleeping in the closet helps Soo-Kyung rest without noise or distraction.CreditRuth Fremson/The New York Times.

    FOXG1 is so crucial that its original name was “Brain Factor 1,” said Dr. William Dobyns, a professor of pediatrics and neurology at University of Washington, who published a 2011 study recommending a separate diagnosis: FOXG1 syndrome. “It’s one of the most important genes in brain development.”

    FOXG1 provides blueprints for a protein that helps other genes switch on or off. It helps with three vital fetal brain stages: delineating the top and bottom regions, adjusting the number of nerve cells produced and “setting up the organization of the entire cortex,” Dr. Dobyns said.

    So, when Dr. Barkovich’s email said he “would not be surprised if this is a FOXG1 mutation,” Soo-Kyung’s heart shuddered. “That’s unthinkable,” she despaired.

    Yuna’s neurologist declined to authorize FOXG1 gene analysis, considering the possibility improbable — and irrelevant because it would not change Yuna’s treatment, Soo-Kyung said. So she decided to sequence the gene herself, preparing to seek university permission since her lab only worked with animals. Then, she became pregnant again. That provided justification for professional analysis of Yuna’s gene to determine if there was a heritable mutation the Lees could have also transmitted to their second child.

    When results showed a FOXG1 mutation, Soo-Kyung requested the raw data, hoping the lab had messed up. But scanning the data, Soo-Kyung spotted the problem instantly: Yuna was missing one nucleotide, Number 256 in the 86th amino acid of one copy of FOXG1, which has 489 amino acids.

    It was a random mutation, so she felt relief her second child was at little risk. But its location in the DNA sequence had given Yuna a smaller, incompletely functioning brain. A single mutation had disabled the entire gene.

    Music seems to calm Yuna, so her father Jae often plays guitar in the evenings. Yuna’s brother, Joon, 5, helps as he can.CreditRuth Fremson/The New York Times.

    Bridlemile Elementary School’s long hallway is both minefield and laboratory for Yuna. In a wheelchair or special walker, she is guided by a paraprofessional, Audrey Lungershausen, who tries to keep her from grabbing student artwork and coats, while encouraging her to identify balls and faces on a mural.

    Soo-Kyung must also navigate a daunting hallway. In June 2016, overcome by stress, she collapsed. Diagnosed with vestibular neuritis, an infection involving nerves linking the ear and brain, she was bedridden for weeks and struggled to stand. She still experiences vertigo and nausea walking the hall to her lab, “like I’m on a ship that’s constantly moving.”

    Her disability, glancingly parallel to her daughter’s, helps her understand that “the world that Yuna has to face with her limited ability to control her body — that must be really scary to her,” she said.

    While Yuna’s condition gives Soo-Kyung’s work personal importance, her own condition makes it harder. She cannot look at her computer more than 25 minutes straight, reads with a yellow filter often used by children with autism, and does visual exercises using paper images taped to her office wall..

    Like Yuna, Soo-Kyung needed physical, occupational and speech therapy. A psychiatrist prescribed an antidepressant. Instead of sleeping in Yuna’s room, Soo-Kyung began blocking out light and sound by sleeping on a mattress on the floor of the master bedroom closet. “They say I may not recover to a normal level.”

    Soo-Kyung’s peripheral vision being tested at an occupational therapy session. She suffered a collapse in 2016 from the stress of juggling her scientific career while caring for Yuna, and dealt with the after-effects of vertigo.CreditRuth Fremson/The New York Times.

    Long before Yuna was born, Soo-Kyung stumbled upon research she found fascinating, showing that mice missing both FOXG1 genes did not form brains. That would apply to humans, too. “There’s nobody who is missing two copies of the gene,” said Dr. Riddle of the National Institute of Neurological Disorders and Stroke. “They don’t survive.”

    Soo-Kyung told Jae she wanted to someday study how FOXG1 drives brain development. “Then Yuna arrived,” Jae said.

    Now, studying mouse brains, the Lees have identified genes that interact with FOXG1, helping explain why one crippled copy of FOXG1 damages the corpus callosum’s ability to transmit signals between hemispheres.

    “We now understand how this gene works and why,” Soo-Kyung said.

    Many mysteries remain. Individual FOXG1 mutations affect gene function differently, so one FOXG1 patient’s symptoms can vary from another’s. For example, Charles A. Nelson III, an expert in child development and neurodevelopmental disorders at Boston Children’s Hospital and Harvard Medical School, evaluated two 10-year-old patients with mutations in different locations and markedly distinct levels of impairment.

    Since patients like Yuna, with one dysfunctional and one functional FOXG1 gene, produce half the necessary FOXG1 protein, Soo-Kyung wonders if gene therapy could restore some protein or boost protein activity in the good gene.

    But because FOXG1 is crucial so early in development, Dr. Rowitch said, “I don’t think you can just go back when the baby’s born and build the brain back up.”

    Still, Dr. Dobyns said, “are there parts of FOXG1 syndrome that we might be able to fix once we understand it better? Sure, parts of it.”

    Yuna Lee with her speech therapist, Diana Deaibes at Shriners Hospital for Children in Portland, Ore. nearly a year ago. A computer program was used to teach her to communicate with her eyes by staring at something she likes onscreen. The hope is for her to eventually direct her gaze to show that she wants food or a toy.CreditRuth Fremson/The New York Times

    When Yuna was 6, Soo-Kyung, half-asleep in bed with her, noticed something extraordinary: Yuna was sitting up. “Am I dreaming?” Soo-Kyung wondered. For years, Yuna failed to learn this skill, usually mastered by six-month-old babies.

    Physical therapists had stopped Yuna’s sessions, saying “ ‘What’s the point of doing it when she’s not making any progress?’” Soo-Kyung recalled. She began painstakingly urging Yuna to push up using her elbow, never sure Yuna understood. Then, “suddenly Yuna was sitting up and I didn’t know how it happened.” Probably a fluke, Soo-Kyung thought—but soon Yuna began sitting up regularly.

    Experts say too little is understood about newly recognized neurological disorders to know children’s developmental limits. But the Lees believe the sitting-up success shows that if they persevere, Yuna can make incremental progress. Their next goal is for Yuna to communicate when she is hungry, uncomfortable or wants something.

    Speech therapists could not get Yuna to intentionally press a button activating a recorded voice saying things like “more.” “I don’t know if she understands what I am telling her,” said Diana Deaibes, a speech-language pathologist at Shriners Hospital for Children.

    But the Lees refused to let Shriners pause speech therapy, urging therapists to try teaching Yuna to stare at something she wants. “We insisted,” said Jae, optimistic even though they attempted visual communication before “and it was a complete mess — she wasn’t able to do it at all.”

    Ms. Deaibes tried pictures and then computer eye-gaze programs that track Yuna’s eye movements. After months of Ms. Deaibes darkening the room to minimize distractions, buckling Yuna to control her jerky movements, Yuna can now stare for about three seconds, causing barn doors to open in computerized farmyards and other onscreen responses. The Lees hope to train Yuna to choose toys or books with her eyes.

    At school, Yuna spends time in a regular second-grade classroom where social exposure helps her and enlightens other students, said Bridlemile’s principal, Brad Pearson. These days, she increasingly responds to her name with eye contact or sound and rarely puts school materials in her mouth anymore, said Jim Steranko, who teaches Yuna in Bridlemile’s learning resource center.

    Listening to a teacher read.CreditRuth Fremson/The New York Times.

    Therapists working with Yuna are uncertain whether she is cognitively able to understand that the label contains her name.CreditRuth Fremson/The New York Times.

    Ms. Lungershausen assists Yuna with everything, including feeding her and, with another aide’s help, changing her diapers. She recently made colorful shapes for Yuna to grab while the second-graders studied fractions. “We have our bad days,” Ms. Lungershausen said. But she said Yuna increasingly recognizes phrases like “Let’s find the library door,” recently “brought a Kleenex to her nose after being prompted” and “brought my hand to her mouth and ‘kissed’ it, deliberately, first time since I’ve known her.”

    At 41 pounds, Yuna weighs 10 pounds less than her little brother, Joon, 5, who has begun helping care for his older sister. One day, after Yuna’s state-funded caregiver, Anne Marie Nguyen, bathed her and propped her in a baby play center to dry her, Joon, announcing he had finished “going potty,” brushed Yuna’s hair. Seeing her rip the bathroom thermostat’s cover off, Joon pulled Yuna’s hands from the wall, saying, “Don’t touch that.”

    When Soo-Kyung returned home after lab work involving gene manipulation in mouse and chicken brains, she crouched on the playroom carpet, watching Yuna commando crawl and elbow herself to a sitting position. She lifted Yuna into the special walker, called a gait trainer and, waving toys, coaxed her to propel the contraption with her feet.

    Then came Yuna’s nightly FaceTime visit with her grandparents in South Korea, who sing and show pictures as Yuna intermittently eyes the screen. Later, Jae played guitar, while Soo-Kyung held Yuna, keeping her rangy arms from tearing into the instrument. Yuna smiled and bobbed.

    Soo-Kyung rarely used to mention her daughter to fellow scientists, but recently began thanking Yuna during presentations. “I was afraid every day that she might not be with me the next day,” Soo-Kyung said, voice breaking. “But she’s done amazing things that we wouldn’t dare to dream. So, how can anyone say she will never be able to do this, she will never be able to do that?”

    They carried Yuna upstairs to her giant crib, her body arching elastically. Carting her up and down is getting harder, so the Lees expect to move from the three-level, cliff-side house they bought to be closer, for Yuna’s sake, to the hospital and their labs. With breathtaking views of Mount St. Helens, it is an optimist’s house, where it is possible to see beyond the horizon.

    As Yuna, in the arms of her caregiver, Anne Marie Nguyen, grows, it gets harder to carry her up and down the house’s several flights of stairs.CreditRuth Fremson/The New York Times

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

  • richardmitnick 8:43 pm on April 24, 2018 Permalink | Reply
    Tags: , , Genetics, , , Wolbachia,   

    From Vanderbilt: “Unraveling genetic mystery next step in Zika and dengue fight” 

    Vanderbilt U Bloc

    Vanderbilt University

    Apr. 23, 2018
    Heidi Hall
    (615) 322-NEWS

    A Vanderbilt team took the next leap forward in using a little-known bacteria to stop the spread of deadly mosquito-borne viruses such as Zika and dengue.

    Wolbachia are bacteria that occur widely in insects and, once they do, inhibit certain pathogenic viruses the insects carry. The problem with using Wolbachia broadly to protect humans is that the bacteria do not normally occur in mosquitoes that transmit Zika and dengue. So success in modifying mosquitoes relies on the bacteria’s cunning ability to spread like wildfire into mosquito populations.

    Wolbachia do so by hijacking the insect reproductive system in a process called cytoplasmic incompatibility, or CI. This makes the sperm of infected fathers lethal to eggs of uninfected mothers. However, if infected fathers mate with infected mothers, the eggs live, and the infected mothers carrying Wolbachia will also infect all her offspring with it. Then those offspring pass on Wolbachia to the next generation, and so on, until they eventually replace all of the resident mosquitoes. As Wolbachia spreads in the population, the risk of dengue and Zika virus transmission drops.

    How that sperm and egg hijacking worked in infected fathers and mothers remained a mystery for decades, until Associate Professor of Biological Sciences Seth Bordenstein and his team helped solve it. They set out to dissect the number and types of genes that Wolbachia use to spread with the long-term goal of harnessing that genetic ability for protecting humans against diseases transmission.

    “In this new study, we’ve dissected a simple set of Wolbachia genes that replicate how Wolbachia change sperm and egg” Bordenstein said. “There are two genes that cause the incompatibility, and one of those same genes rescues the incompatibility. Engineering mosquitoes or Wolbachia for expression of these two genes could enhance or cause the spread of Wolbachia through target mosquito populations.”

    Their achievement is based on inserting genes into the genome of fruit flies. It is described in a paper appearing today in the Proceedings of the National Academy of Sciences.

    Wolbachia spreads itself by hijacking the insect reproductive system in a process called cytoplasmic incompatibility, or CI. (J. Dylan Shropshire/Vanderbilt University)

    In a previous study last year Nature, the team identified the two genes in Wolbachia — named cytoplasmic incompatibility factors cifA and cifB — and learned that they modify the sperm to kill eggs. Now they solved the other half of the genetic mystery: cifA single-handedly can protect embryos from death.

    “It’s a microbial encryption and de-encryptyion system that ensures Wolbachia spread through insect populations so they can adequately block the transmission of viruses and ultimately save lives” Bordenstein said.

    Coauthors of the paper include Ph.D. student and National Science Foundation Graduate Research Fellow J. Dylan Shropshire and Vanderbilt undergraduates Emily Layton and Helen Zhou.

    Vanderbilt University has filed patent applications on this new finding and seeks industry partners for further development through its Center for Technology Transfer and Commercialization.

    This work was supported by National Institutes of Health (NIH) awards R01 AI132581 and R21 HD086833, National Science Foundation award IOS 1456778, a National Science Foundation Graduate Research Fellowship, and Vanderbilt University Medical Center Cell Imaging Shared Resources (supported by NIH grants CA68485, DK20593, DK58404, DK59637 and EY08126).

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Commodore Cornelius Vanderbilt was in his 79th year when he decided to make the gift that founded Vanderbilt University in the spring of 1873.

    The $1 million that he gave to endow and build the university was the commodore’s only major philanthropy. Methodist Bishop Holland N. McTyeire of Nashville, husband of Amelia Townsend who was a cousin of the commodore’s young second wife Frank Crawford, went to New York for medical treatment early in 1873 and spent time recovering in the Vanderbilt mansion. He won the commodore’s admiration and support for the project of building a university in the South that would “contribute to strengthening the ties which should exist between all sections of our common country.”

    McTyeire chose the site for the campus, supervised the construction of buildings and personally planted many of the trees that today make Vanderbilt a national arboretum. At the outset, the university consisted of one Main Building (now Kirkland Hall), an astronomical observatory and houses for professors. Landon C. Garland was Vanderbilt’s first chancellor, serving from 1875 to 1893. He advised McTyeire in selecting the faculty, arranged the curriculum and set the policies of the university.

    For the first 40 years of its existence, Vanderbilt was under the auspices of the Methodist Episcopal Church, South. The Vanderbilt Board of Trust severed its ties with the church in June 1914 as a result of a dispute with the bishops over who would appoint university trustees.

    kirkland hallFrom the outset, Vanderbilt met two definitions of a university: It offered work in the liberal arts and sciences beyond the baccalaureate degree and it embraced several professional schools in addition to its college. James H. Kirkland, the longest serving chancellor in university history (1893-1937), followed Chancellor Garland. He guided Vanderbilt to rebuild after a fire in 1905 that consumed the main building, which was renamed in Kirkland’s honor, and all its contents. He also navigated the university through the separation from the Methodist Church. Notable advances in graduate studies were made under the third chancellor, Oliver Cromwell Carmichael (1937-46). He also created the Joint University Library, brought about by a coalition of Vanderbilt, Peabody College and Scarritt College.

    Remarkable continuity has characterized the government of Vanderbilt. The original charter, issued in 1872, was amended in 1873 to make the legal name of the corporation “The Vanderbilt University.” The charter has not been altered since.

    The university is self-governing under a Board of Trust that, since the beginning, has elected its own members and officers. The university’s general government is vested in the Board of Trust. The immediate government of the university is committed to the chancellor, who is elected by the Board of Trust.

    The original Vanderbilt campus consisted of 75 acres. By 1960, the campus had spread to about 260 acres of land. When George Peabody College for Teachers merged with Vanderbilt in 1979, about 53 acres were added.

    wyatt centerVanderbilt’s student enrollment tended to double itself each 25 years during the first century of the university’s history: 307 in the fall of 1875; 754 in 1900; 1,377 in 1925; 3,529 in 1950; 7,034 in 1975. In the fall of 1999 the enrollment was 10,127.

    In the planning of Vanderbilt, the assumption seemed to be that it would be an all-male institution. Yet the board never enacted rules prohibiting women. At least one woman attended Vanderbilt classes every year from 1875 on. Most came to classes by courtesy of professors or as special or irregular (non-degree) students. From 1892 to 1901 women at Vanderbilt gained full legal equality except in one respect — access to dorms. In 1894 the faculty and board allowed women to compete for academic prizes. By 1897, four or five women entered with each freshman class. By 1913 the student body contained 78 women, or just more than 20 percent of the academic enrollment.

    National recognition of the university’s status came in 1949 with election of Vanderbilt to membership in the select Association of American Universities. In the 1950s Vanderbilt began to outgrow its provincial roots and to measure its achievements by national standards under the leadership of Chancellor Harvie Branscomb. By its 90th anniversary in 1963, Vanderbilt for the first time ranked in the top 20 private universities in the United States.

    Vanderbilt continued to excel in research, and the number of university buildings more than doubled under the leadership of Chancellors Alexander Heard (1963-1982) and Joe B. Wyatt (1982-2000), only the fifth and sixth chancellors in Vanderbilt’s long and distinguished history. Heard added three schools (Blair, the Owen Graduate School of Management and Peabody College) to the seven already existing and constructed three dozen buildings. During Wyatt’s tenure, Vanderbilt acquired or built one-third of the campus buildings and made great strides in diversity, volunteerism and technology.

    The university grew and changed significantly under its seventh chancellor, Gordon Gee, who served from 2000 to 2007. Vanderbilt led the country in the rate of growth for academic research funding, which increased to more than $450 million and became one of the most selective undergraduate institutions in the country.

    On March 1, 2008, Nicholas S. Zeppos was named Vanderbilt’s eighth chancellor after serving as interim chancellor beginning Aug. 1, 2007. Prior to that, he spent 2002-2008 as Vanderbilt’s provost, overseeing undergraduate, graduate and professional education programs as well as development, alumni relations and research efforts in liberal arts and sciences, engineering, music, education, business, law and divinity. He first came to Vanderbilt in 1987 as an assistant professor in the law school. In his first five years, Zeppos led the university through the most challenging economic times since the Great Depression, while continuing to attract the best students and faculty from across the country and around the world. Vanderbilt got through the economic crisis notably less scathed than many of its peers and began and remained committed to its much-praised enhanced financial aid policy for all undergraduates during the same timespan. The Martha Rivers Ingram Commons for first-year students opened in 2008 and College Halls, the next phase in the residential education system at Vanderbilt, is on track to open in the fall of 2014. During Zeppos’ first five years, Vanderbilt has drawn robust support from federal funding agencies, and the Medical Center entered into agreements with regional hospitals and health care systems in middle and east Tennessee that will bring Vanderbilt care to patients across the state.

    studentsToday, Vanderbilt University is a private research university of about 6,500 undergraduates and 5,300 graduate and professional students. The university comprises 10 schools, a public policy center and The Freedom Forum First Amendment Center. Vanderbilt offers undergraduate programs in the liberal arts and sciences, engineering, music, education and human development as well as a full range of graduate and professional degrees. The university is consistently ranked as one of the nation’s top 20 universities by publications such as U.S. News & World Report, with several programs and disciplines ranking in the top 10.

    Cutting-edge research and liberal arts, combined with strong ties to a distinguished medical center, creates an invigorating atmosphere where students tailor their education to meet their goals and researchers collaborate to solve complex questions affecting our health, culture and society.

    Vanderbilt, an independent, privately supported university, and the separate, non-profit Vanderbilt University Medical Center share a respected name and enjoy close collaboration through education and research. Together, the number of people employed by these two organizations exceeds that of the largest private employer in the Middle Tennessee region.
    Related links

  • richardmitnick 12:51 pm on February 13, 2018 Permalink | Reply
    Tags: , , DropSynth, Genetics, ,   

    From UCLA Newsroom: “UCLA scientists develop low-cost way to build gene sequences” 

    UCLA Newsroom

    February 12, 2018
    Sarah C.P. Williams

    UCLA scientists used DropSynth to make thousands of bacterial genes with different versions of phosphopantetheine adenylyltransferase, or PPAT (pictured). Sriram Kosuri/UCLA.

    A new technique pioneered by UCLA researchers could enable scientists in any typical biochemistry laboratory to make their own gene sequences for only about $2 per gene. Researchers now generally buy gene sequences from commercial vendors for $50 to $100 per gene.

    The approach, DropSynth, which is described in the January issue of the journal Science, makes it possible to produce thousands of genes at once. Scientists use gene sequences to screen for gene’s roles in diseases and important biological processes.

    “Our method gives any lab that wants the power to build its own DNA sequences,” said Sriram Kosuri, a UCLA assistant professor of chemistry and biochemistry and senior author of the study. “This is the first time that, without a million dollars, an average lab can make 10,000 genes from scratch.”

    Increasingly, scientists studying a wide range of subjects in medicine — from antibiotic resistance to cancer — are conducting “high-throughput” experiments, meaning that they simultaneously screen hundreds or thousands of groups of cells. Analyzing large numbers of cells, each with slight differences in their DNA, for their ability to carry out a behavior or survive a drug treatment can reveal the importance of particular genes, or sections of genes, in those abilities.

    Such experiments require not only large numbers of genes but also that those genes are sequenced. Over the past 10 years, advances in sequencing have enabled researchers to simultaneously determine the sequences of many strands of DNA. So the cost of sequencing has plummeted, even as the process of generating genes has remained comparatively slow and expensive.

    “There’s an ongoing need to develop new gene synthesis techniques,” said Calin Plesa, a UCLA postdoctoral research fellow and co-first author of the paper. “The more DNA you can synthesize, the more hypotheses you can test.”

    The current methods for synthesizing genes, he said, either limit the length of a gene to about 200 base pairs — the sets of nucleotides that made up DNA — or are prohibitively expensive for most labs.

    The new method involves isolating small sections of thousands of genes in tiny droplets of water suspended in an oil. Each section of DNA is assigned a molecular “bar code,” which identifies the longer gene to which it belongs.

    Then, the sections, which initially are present in only very small amounts, are copied many times to increase their number. Finally, small beads are used to sort the mixture of DNA fragments into the right combinations to make longer genes, and the sections are combined. The result is a mixture of thousands of the desired genes, which can be used in experiments.

    To show that technique worked, the scientists used DropSynth to make thousands of bacterial genes — each as long as 669 base pairs in length. Each gene encoded a different bacterium’s version of the metabolic protein phosphopantetheine adenylyltransferase, or PPAT, which bacteria need to survive. Because PPAT is critical to bacteria that cause everything from sinus infections to pneumonia and food poisoning, it’s being studied as a potential antibiotic target.

    The researchers created a mixture of the thousands of versions of PPAT with DropSynth, and then added each gene to a version of E. coli that lacked PPAT and tested which ones allowed E. coli to survive. The surviving cells could then be used to screen potential antibiotics very quickly and at a low cost.

    DropSynth could potentially also be useful in engineering new proteins. Currently, scientists can use computer programs to design proteins that meet certain parameters, such as the ability to bind to certain molecules, but DropSynth could offer researchers hundreds or even thousands of options from which to choose the proteins that best fit their needs.

    The team is still working on reducing DropSynth’s error rate. In the meantime, though, the scientists have made the instructions publicly available on their website. All of the chemical substances needed to replicate the approach are commercially available.

    The study’s other authors are graduate students Nathan Lubock and Angus Sidore of UCLA, and Di Zhang of the University of Pennsylvania.

    Funding for the study was provided by the Netherlands Organisation for Scientific Research, the Human Frontier Science Program, the National Science Foundation, the National Institutes of Health, the Searle Scholars Program, the U.S. Department of Energy, and Linda and Fred Wudl.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    UC LA Campus

    For nearly 100 years, UCLA has been a pioneer, persevering through impossibility, turning the futile into the attainable.

    We doubt the critics, reject the status quo and see opportunity in dissatisfaction. Our campus, faculty and students are driven by optimism. It is not naïve; it is essential. And it has fueled every accomplishment, allowing us to redefine what’s possible, time after time.

    This can-do perspective has brought us 12 Nobel Prizes, 12 Rhodes Scholarships, more NCAA titles than any university and more Olympic medals than most nations. Our faculty and alumni helped create the Internet and pioneered reverse osmosis. And more than 100 companies have been created based on technology developed at UCLA.

  • richardmitnick 8:31 am on January 31, 2018 Permalink | Reply
    Tags: , , , Genetics, Multipurpose enhancers and promoters in embryonic development   

    From EMBL: “Multipurpose enhancers and promoters in embryonic development” 

    EMBL European Molecular Biology Laboratory bloc

    European Molecular Biology Laboratory

    30 January 2018
    Iris Kruijen

    Enhancer activity (green) and promoter activity (purple) in the same regulatory element. IMAGE: EMBL / Eileen Furlong.

    EMBL scientists show that some promoters can act as enhancers and vice versa.

    During gene expression, the information stored in our DNA is transcribed: turned into instructions to produce RNA and proteins that perform specific functions within each cell. DNA regions called promoters are located at the beginning of genes, and determine the starting point where transcription is initiated. Other snippets of DNA called enhancers control when and where specific genes are expressed. Enhancers are often located far away from genes and must relay their regulatory information to a gene’s promoter.

    Now, Olga Mikhaylichenko and colleagues in Eileen Furlong’s group at EMBL have gained new insights into the role of enhancers and promoters during embryonic development, a life stage where very tight regulation of gene expression is essential. Furlong explains the main findings of the paper, that explores the balance between enhancer and promoter activity within individual regulatory elements in vivo, and that was published in Genes & Development on January 29, 2018.

    What is the key finding in this paper?

    “It used to be thought that there was a black-and-white distinction between enhancers and promoters: they can only act as one or the other. Our paper shows that there is actually a large grey area in-between, with elements that can perform both functions to varying degrees. The level of enhancer or promoter activity is reflected by both the amount and the direction of transcription from the regulatory element, so whether the element can be read in one or two directions, unidirectional or bidirectional. We also developed a new framework to measure enhancer and promoter activity for the same element, in the same embryo (see figure), which we suggest should become the standard for future studies.”

    Why is this important?

    “First of all, we were able to show that things are not as black and white as they seemed. Enhancers and promoters are in various states of evolution with some having exclusive promoter function, others having predominantly enhancer function, and yet other elements, distal enhancers, having weak promoter activity.

    One of the findings that I am most excited about is when we looked at activity in the other direction, asking if gene promoters can act as developmental enhancers. Here, we found that promoters that are bidirectionally transcribed can function as both strong enhancers and promoters, for the same gene. This suggests that they regulate both the levels (promoters) and spatial expression (enhancer) of the gene. Interestingly, promoters that are unidirectionally transcribed cannot perform this function.

    Hints from other studies suggest that these general features are conserved from fruit flies to humans. Our findings uncover a new aspect of promoter and enhancer function during embryogenesis, and provide interesting insights into how these elements might have evolved to regulate robust embryonic development.”

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    EMBL European Molecular Biology Laboratory campus

    EMBL is Europe’s flagship laboratory for the life sciences, with more than 80 independent groups covering the spectrum of molecular biology. EMBL is international, innovative and interdisciplinary – its 1800 employees, from many nations, operate across five sites: the main laboratory in Heidelberg, and outstations in Grenoble; Hamburg; Hinxton, near Cambridge (the European Bioinformatics Institute), and Monterotondo, near Rome. Founded in 1974, EMBL is an inter-governmental organisation funded by public research monies from its member states. The cornerstones of EMBL’s mission are: to perform basic research in molecular biology; to train scientists, students and visitors at all levels; to offer vital services to scientists in the member states; to develop new instruments and methods in the life sciences and actively engage in technology transfer activities, and to integrate European life science research. Around 200 students are enrolled in EMBL’s International PhD programme. Additionally, the Laboratory offers a platform for dialogue with the general public through various science communication activities such as lecture series, visitor programmes and the dissemination of scientific achievements.

  • richardmitnick 1:19 pm on January 30, 2018 Permalink | Reply
    Tags: , , Cell differentiation, , Genetics, , Polycomb Repressive Complex 2 (PRC2)   

    From LBNL: “Silencing Is Golden: Scientists Image Molecules Vital for Gene Regulation” 

    Berkeley Logo

    Berkeley Lab

    January 29, 2018
    Dan Krotz
    (510) 486-4019

    Structure of the human Polycomb Repressive Complex 2 (PRC2) bound to cofactors obtained by cryo-electron microscopy. Both cofactors mimic the histone protein tail to stabilize and stimulate the enzymatic activity of PRC2. (Credit: Vignesh Kasinath)

    All the trillions of cells in our body share the same genetic information and are derived from a single, fertilized egg. When this initial cell multiplies during fetal development, its daughter cells become more and more specialized. This process, called cell differentiation, gives rise to all the various cell types, such as nerve, muscle, or blood cells, which are diverse in shape and function and make up tissues and organs. How can the same genetic blueprint lead to such diversity? The answer lies in the way that genes are switched on or off during the course of development.

    Scientists at Lawrence Berkeley National Laboratory (Berkeley Lab) have been studying the molecules that act at the genetic level to give rise to different types of cells. Some of these molecules are a complex of proteins called the Polycomb Repressive Complex 2 (PRC2) that is involved in “silencing” genes so that they are not “read” by the cellular machinery that decodes genetic information, effectively keeping the genetic information in the “off” state.

    In two new studies, a team of researchers led by Eva Nogales, senior faculty scientist in the Molecular Biophysics and Integrated Bioimaging (MBIB) Division, has gained insight into the structure of PRC2 and the ways in which it is regulated to affect gene silencing. Their work was reported on January 18 in the journal Science and on January 29 in Nature Structural and Molecular Biology by Eva Nogales and postdoctoral researchers Vignesh Kasinath and Simon Poepsel.

    Both publications provide a structural framework to understand PRC2 function, and in the case of the latter, the structures are the first to illustrate how a molecule of this type engages with its substrate. The structural descriptions of human PRC2 with its natural partners in the cell lend important insight into the mechanism by which the PRC2 complex regulates gene expression. This information could provide new possibilities for the development of therapies for cancer.

    PRC2 is a gene regulator that is vital for normal development. Genomic DNA is packaged into nucleosomes, which are formed by histone proteins that have DNA wrapped around them. Histone proteins have long polypeptide tails that can be modified by the addition and removal of small chemical groups. These modifications influence the interaction of nucleosomes with each other and other protein complexes in the nucleus. The function of PRC2 in the cell is to make a particular chemical change in one of the histones. The genes in the regions of the genome that have been modified by PRC2 are switched off, or become silenced.

    This montage of the full PRC2 with two nucleosomes is based on the superposition of the cryo-EM maps of PRC2 with and without the nucleosomes to show the consistency of the observed nucleosome binding configuration with the full PRC2 structure. (Credit: Simon Poepsel)

    “Not surprisingly, elaborate mechanisms have evolved to ensure that PRC2 marks the correct regions for silencing at the right time,” said Nogales, who is also a Howard Hughes Medical Investigator and professor of Biochemistry, Biophysics and Structural Biology at the University of California, Berkeley. Failure of this regulation not only impairs the process of development, but also contributes to the reversal of cell differentiation and the uncontrolled cell growth that are the hallmarks of cancer. “Therefore,” Nogales continued, “gaining insight into how PRC2 function is adjusted both in space and time is crucial to understanding cell development.”

    Nogales and her team use structural biology to elucidate how biomolecules, particularly proteins and nucleic acids (DNA, RNA), are organized and combine to form functional biological assemblies. Obtaining detailed insights into their three-dimensional shape will not only help to understand how they function but also how this function is regulated in the cell. These two studies rely on cryo-electron microscopy for imaging the biomolecules, a technique that can see large biomolecules on a very small scale and in multiple conformations. Kasinath and Poepsel, have now solved the structure of PRC2, which provides a framework to understand how this complex is regulated to modify histone proteins.

    The first study, published January 18 in Science by Kasinath, Poepsel, Nogales, and coworkers, visualized the architecture of the complete PRC2 in atomic detail. First author Vignesh Kasinath said, “It took three years of work to obtain this high-resolution structure of all the parts, or subunits, that make up a functional PRC2, as well as visualize how additional protein subunits, called cofactors, may help regulate its activity. Remarkably, both cofactors mimic the histone protein tail in their binding to PRC2 suggesting that cofactors and histone tails together work hand-in-hand to regulate PRC2 function. This structural work holds great promise for new drug development to fight PRC2 dysfunction in cancer.”

    This work is complemented by a second study that presents snapshots of PRC2 binding to the histone proteins that it modifies as a signal for gene silencing. The structures, which have been published in Nature Structural and Molecular Biology on January 29 by Poepsel, Kasinath and Nogales this week, illustrate beautifully the action of this sophisticated complex. “PRC2 can simultaneously engage two nucleosomes,” said Poepsel, first author of this study. “Our cryo-EM images help us understand how the complex can recognize the presence of a histone modification in one nucleosome and place the same tag onto a neighboring nucleosome.” This cascade of activity enables PRC2 to spread this modification over the entire neighboring gene loci, thereby marking it for silencing. Nogales added, “The visualization of such interactions is notoriously hard. We have made an important step forward in our general understanding of how gene regulators can bind to and recognize nucleosomes.”

    PRC2 is essential to gene regulation and expression in all multicellular organisms. The findings from both studies open up tremendous possibilities for combatting cancer while simultaneously expanding our knowledge of gene regulation at a molecular level. “Because PRC2 is deregulated in cancers, it makes a good target for potential therapeutics,” said Nogales. The fundamental understanding of PRC2 arising from these studies will have broad implications in both plant and animal biology.

    This work was funded by the Howard Hughes Medical Institute and Eli Lilly. This research used cryo-electron microscopy (cryo-EM) and made use of the unique resources of the Bay Area Cryo-EM Facility. Image analysis relied on heavy computational work that was carried out at Berkeley Lab’s National Energy Research Scientific Computing Center (NERSC), a DOE Office of Science User Facility.

    NERSC Cray XC40 Cori II supercomputer

    LBL NERSC Cray XC30 Edison supercomputer

    The Genepool system is a cluster dedicated to the DOE Joint Genome Institute’s computing needs. Denovo is a smaller test system for Genepool that is primarily used by NERSC staff to test new system configurations and software.


    PDSF is a networked distributed computing cluster designed primarily to meet the detector simulation and data analysis requirements of physics, astrophysics and nuclear science collaborations.

    Vignesh Kasinath was supported by a postdoctoral fellowship from Helen Hay Whitney and Simon Poepsel was supported by the Alexander von Humboldt foundation (Germany) as a Feodor-Lynen postdoctoral fellow.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    A U.S. Department of Energy National Laboratory Operated by the University of California

    University of California Seal

    DOE Seal

Compose new post
Next post/Next comment
Previous post/Previous comment
Show/Hide comments
Go to top
Go to login
Show/Hide help
shift + esc
%d bloggers like this: