Category Archives: Human Genetic Engineering

Takeaways

Scientists have made progress growing human liver in the lab.

The challenge has been to direct stems cells to grow into a mature, functioning adult organ.

This study shows that stem cells can be programmed, using genetic engineering, to grow from immature cells into mature tissue.

When a tiny lab-grown liver was transplanted into mice with liver disease, it extended the lives of the sick animals.

Imagine if researchers could program stem cells, which have the potential to grow into all cell types in the body, so that they could generate an entire human organ. This would allow scientists to manufacture tissues for testing drugs and reduce the demand for transplant organs by having new ones grown directly from a patients cells.

Im a researcher working in this new field called synthetic biology focused on creating new biological parts and redesigning existing biological systems. In a new paper, my colleagues and I showed progress in one of the key challenges with lab-grown organs figuring out the genes necessary to produce the variety of mature cells needed to construct a functioning liver.

Induced pluripotent stem cells, a subgroup of stem cells, are capable of producing cells that can build entire organs in the human body. But they can do this job only if they receive the right quantity of growth signals at the right time from their environment. If this happens, they eventually give rise to different cell types that can assemble and mature in the form of human organs and tissues.

The tissues researchers generate from pluripotent stem cells can provide a unique source for personalized medicine from transplantation to novel drug discovery.

But unfortunately, synthetic tissues from stem cells are not always suitable for transplant or drug testing because they contain unwanted cells from other tissues, or lack the tissue maturity and a complete network of blood vessels necessary for bringing oxygen and nutrients needed to nurture an organ. That is why having a framework to assess whether these lab-grown cells and tissues are doing their job, and how to make them more like human organs, is critical.

Inspired by this challenge, I was determined to establish a synthetic biology method to read and write, or program, tissue development. I am trying to do this using the genetic language of stem cells, similar to what is used by nature to form human organs.

I am a researcher specializing in synthetic biology and biological engineering at the Pittsburgh Liver Research Center and McGowan Institute for Regenerative Medicine, where the goals are to use engineering approaches to analyze and build novel biological systems and solve human health problems. My lab combines synthetic biology and regenerative medicine in a new field that strives to replace, regrow or repair diseased organs or tissues.

I chose to focus on growing new human livers because this organ is vital for controlling most levels of chemicals like proteins or sugar in the blood. The liver also breaks down harmful chemicals and metabolizes many drugs in our body. But the liver tissue is also vulnerable and can be damaged and destroyed by many diseases, such as hepatitis or fatty liver disease. There is a shortage of donor organs, which limits liver transplantation.

To make synthetic organs and tissues, scientists need to be able to control stem cells so that they can form into different types of cells, such as liver cells and blood vessel cells. The goal is to mature these stem cells into miniorgans, or organoids, containing blood vessels and the correct adult cell types that would be found in a natural organ.

One way to orchestrate maturation of synthetic tissues is to determine the list of genes needed to induce a group of stem cells to grow, mature and evolve into a complete and functioning organ. To derive this list I worked with Patrick Cahan and Samira Kiani to first use computational analysis to identify genes involved in transforming a group of stem cells into a mature functioning liver. Then our team led by two of my students Jeremy Velazquez and Ryan LeGraw used genetic engineering to alter specific genes we had identified and used them to help build and mature human liver tissues from stem cells.

The tissue is grown from a layer of genetically engineered stem cells in a petri dish. The function of genetic programs together with nutrients is to orchestrate formation of liver organoids over the course of 15 to 17 days.

I and my colleagues first compared the active genes in fetal liver organoids we had grown in the lab with those in adult human livers using a computational analysis to get a list of genes needed for driving fetal liver organoids to mature into adult organs.

We then used genetic engineering to tweak genes and the resulting proteins that the stem cells needed to mature further toward an adult liver. In the course of about 17 days we generated tiny several millimeters in width but more mature liver tissues with a range of cells typically found in livers in the third trimester of human pregnancies.

Like a mature human liver, these synthetic livers were able to store, synthesize and metabolize nutrients. Though our lab-grown livers were small, we are hopeful that we can scale them up in the future. While they share many similar features with adult livers, they arent perfect and our team still has work to do. For example, we still need to improve the capacity of the liver tissue to metabolize a variety of drugs. We also need to make it safer and more efficacious for eventual application in humans.

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Our study demonstrates the ability of these lab livers to mature and develop a functional network of blood vessels in just two and a half weeks. We believe this approach can pave the path for the manufacture of other organs with vasculature via genetic programming.

The liver organoids provide several key features of an adult human liver such as production of key blood proteins and regulation of bile a chemical important for digestion of food.

When we implanted the lab-grown liver tissues into mice suffering from liver disease, it increased the life span. We named our organoids designer organoids, as they are generated via a genetic design.

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Genetic engineering transformed stem cells into working mini-livers that extended the life of mice with liver disease - The Conversation US

The lab of KrisSaha at the University of WisconsinMadison has developed an innovative combination of gene-editing tools and computational simulations that can be used to develop new strategies for editing genes associated with genetic disorders.

In proof-of-concept experiments, the labs researchers efficiently corrected multiple mutations responsible for a rare metabolic disorder, known as Pompe disease, in cells containing the disease-causing errors. They also used computer simulations to design the ideal gene-editing approach for treating human patients, a boon for rare disorders like Pompe disease that lack useful animal models.

Their promising platform advances the CRISPR genome-editing field and could lead to effective treatments for many diseases, not just Pompe disease.

The exact mutations seen in the Pompe patients are not in an existing animal model, so we cannot do all of the preclinical studies that we would like to do in order to evaluate the safety and efficacy of different genome editing strategies, says Saha, a professor of biomedical engineering at UWMadisons Wisconsin Institute for Discovery. We need a way to think about how we go from patient material to a therapy without having to build an animal model, a process that takes months to years and hundreds of thousands of dollars.

The lab of Kris Saha (standing) has developed an innovative combination of gene-editing tools and computational simulations that can be used to develop new strategies for editing genes associated with genetic disorders. Photo: Stephanie Precourt

Sahas team published its findings Dec. 8 in the journal Nature Communications.

In the first few months of life, an infant with Pompe disease becomes weaker and weaker as glycogen builds up in their muscles, their cells unable to break the complex sugar down. Multiple mutations in a gene calledGAAprevent their cells from correctly producing the proteins needed to make lysosomes, which turn glycogen into glucose, the fuel that powers cells. Left untreated, most patients with Pompe die within a year.

Developing effective therapies for such diseases can be difficult for a number of reasons. First, diseases like Pompe have no animal models in which to test treatments, a typical step in therapy development. And diseases like Pompe and many other inherited diseases are autosomal recessive, which means that mutations are present on both copies of a chromosome. Two sets of mutations require two successful gene-repair events for maximum effect. Further complicating the matter is the fact that many diseases are polygenic, resulting from mutations in two or more genes or multiple mutations spread across a single gene, as is the case for Pompe disease.

The Saha labs new approach uses precise gene-editing tools to edit both faulty alleles simultaneously within individual cells to restore function. In its new report, the research team used induced pluripotent stem cells derived from Pompe patients to reproduce the exactGAAmutations that cause the disease and to approximate the resulting tissue pathology.

To fix these Pompe mutations, the lab turned to a specially designed, ultra-precise genome-editing system described in aprevious studyled by Jared Carlson-Stevermer, who was at the time a graduate student in Sahas group. That report established an up to 18-fold increase in precision of gene edits by combining a DNA repair template with the cutting machinery of CRISPR in one particle.

In the current study, the researchers used the method to fix two mutations at once in Pompe-derived cells. By doing so, the researchers improved cell function dramatically, bringing lysosome protein production up to the level of healthy cells without any major adverse effects, which sometimes emerge from gene editing.

The research advances the CRISPR genome-editing field and could lead to effective treatments for many diseases.

But treating cells in the laboratory, while providing crucial insight, is not the same as creating a therapy for patients. A critical step in developing treatments usually involves testing on animal models to evaluate efficacy and safety, a major obstacle for Pompe disease and other genetic conditions that lack viable animal models.

To determine the best therapeutic strategy for polygenic diseases evaluating different doses, delivery mechanisms and timing, risks and other factors the research team instead built a computational model that allows it to predict the outcomes of various conditions.

This allows us to survey a wider scope of many different gene therapies during the design of a strategy, says coauthor Amritava Das, a postdoctoral associate at the Morgridge Institute for Research. The computational approach is critical when you dont have an animal model that resembles the human disease.

After pumping close to a million simulation conditions through the computational model, Das, Carlson-Stevermer and Saha have gained key insights about the delivery of gene editors into the livers of human infants with Pompe disease without having to subject a single patient to experimental treatments. And those insights establish that the multiple-correction genome-editing approach tested in stem cells may be an effective treatment for Pompe and other polygenic recessive disorders.

The computational model, which can be easily adapted for other polygenic conditions, is a big step for the development of therapies for diseases like Pompe and lays the groundwork for a bridge from laboratory studies to the clinic. And as more measurements are added to the model, it will gain more predictive power.

Its a very broad, adaptable platform, Das says about the combined stem cell model and computational tool, and a very different way of thinking about gene therapy.

This work was supported by the National Science Foundation (CBET-1350178, CBET-1645123), the National Institutes of Health (1R35GM119644-01), the Environmental Protection Agency (EPA-G2013 STAR-L1), the University of Wisconsin Carbone Cancer Center (P30 CA014520), the Wisconsin Alumni Research Foundation, and the Wisconsin Institute for Discovery.

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Multiple gene edits and computer simulations could help treat rare genetic diseases - University of Wisconsin-Madison

Heres how the mechanism works: Humans alone observe the world and ask questions that demand why, how and what. They answer their questions by looking for if-and-then patterns, such as, if I boil an egg for eight minutes, then the yolk will be hard, and if I boil an egg for four minutes, then the yolk will be soft. They use those patterns to build theories, which they then repeatedly test, looking always for systems to further employ and exploit.

Grand theories aside, Baron-Cohen is at his most striking when he writes about people with autism, like Jonah, who was slow to talk but who taught himself to read. When Jonah eventually learned to speak, he used language less as a tool for communication than as a system for categorizing the world around him. As a young child, he was endlessly fascinated by how things worked, and he spent hours experimenting, like flipping a light switch on and off to test and retest its effect. At school he showed great brilliance in his observations about the natural world, he was a born pattern seeker, but at the same time he was taunted by other children for being so different. In group reading time, which he hated, he would shut his eyes and put his fingers in his ears. Jonahs weekend hobby as a young man was helping fishermen locate shoals by being able to read the signs from surface waves. Yet despite his incredible talents, Jonah was lonely and frustrated because he couldnt find a job that would allow him to live an independent life. Baron-Cohen argues with feeling and conviction that society must do a better job of making room for people like Jonah, and that it will benefit enormously when it does.

Mostly, though, The Pattern Seekers is about the idea of using autism as a key to unlock the mystery of human cognition, and on this front, its less convincing. Sometimes its simply because the books framing is misleading. Baron-Cohen takes great care to set up the idea that all humans possess a Systemizing Mechanism, that some people are hyper-systemizers, and that a comparatively high number of those hyper-systemizers are autistic. But the subtitle of the book is not how systemizing drives human invention, its how autism drives human invention. At the same time, he cautions against speculation that people, living or dead, might be autistic. The term should be reserved only for diagnosis when people are struggling to function, he explains.

In addition, Baron-Cohen divides humans into five brain types, grouping people who are more or less likely to systemize or empathize. He believes that humans also uniquely possess an Empathy Circuit. But he establishes his five groups by conducting large surveys about individual tendencies and traits, so they are not brain types at all. They are, at best, mind types.

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Does Autism Hold the Key to What Makes Humans Special? - The New York Times

SOUTH SAN FRANCISCO, Calif. & LEXINGTON, Mass.--(BUSINESS WIRE)--Maze Therapeutics, a company focused on translating genetic insights into new medicines, and Alloy Therapeutics, a company developing platforms and services to enable drug discovery, today announced the formation of Broadwing Bio to develop targeted antibody therapies for the treatment of ophthalmic diseases. Broadwing Bio will advance programs directed to genetically validated ophthalmology targets identified using Mazes human genetics and functional genomics platform, the COMPASS platform. Alloy Discovery Services will generate therapeutic candidates using Alloys broad suite of antibody discovery technologies, including the ATX-Gx mouse platform.

Under the terms of the agreement, Maze and Alloy will fund Broadwing Bio to rapidly advance its programs through preclinical and clinical development with the opportunity for independent financing and partnering. Maze and Alloy will retain certain rights to participate in the development and commercialization of products originating from Broadwing Bio. The company will be led by Andrew Peterson, Ph.D., founder and chief executive officer of Broadwing Bio.

We are very excited to partner with Alloy on the formation of Broadwing Bio, with a mission to advance therapeutics for ophthalmology indications, said Jason Coloma, Ph.D., chief executive officer of Maze. Maze is advancing a pipeline of programs based on genetic insights of disease, without restrictions on modality or therapeutic area. This joint venture will allow us to pursue compelling Maze-identified targets through a dedicated organization with the experience and focus to develop highly differentiated therapies addressing unmet needs in ophthalmology, while retaining significant financial participation and product rights.

Broadwing Bio is a great example of the high impact partnerships Alloy Discovery Services will conduct on a very select basis, where we can invest heavily in the success of the partnership, said Errik Anderson, chief executive officer and founder of Alloy Therapeutics. We are honored to be working with an incredible scientist-entrepreneur like Andy, in partnership with Mazes team, to advance these exciting drug targets designated by Maze.

Broadwing Bio has established a team of experienced leaders and scientific advisors, including

There are a number of ophthalmic diseases for which effective therapeutic options are limited, but recent genetic insights provide avenues to change this situation, said Dr. Peterson. Broadwing Bio has the very unique opportunity to bring together the capabilities of two exceptional companies in order to develop novel treatments targeted at these diseases. Im thrilled to join the company as CEO and look forward to building the Broadwing Bio team, while leveraging Maze and Alloys insights and experience in drug discovery in order to bring medicines to patients in need.

About Maze Therapeutics

Maze Therapeutics is a biopharmaceutical company developing a broad portfolio of therapeutic candidates for a number of genetically defined diseases. Maze is focused on translating genetic insights into new medicines by utilizing an approach that combines the analysis of large-scale human genetics data, cutting-edge functional genomics and an array of drug discovery approaches. The Maze COMPASS platform reveals modifier genes that confer protection and provides deeper understanding of the target biology and how these targets can be best targeted with drug therapies. Maze was launched in 2019 by Third Rock Ventures, with funding from ARCH Venture Partners, GV, Foresite Capital, Casdin Capital, Alexandria Venture Investments, City Hill and other undisclosed investors. Maze is based in South San Francisco. For more information please visit mazetx.com.

About Alloy Therapeutics

Alloy Therapeutics is a biotechnology company dedicated to empowering scientists in the relentless pursuit of making better medicines for all. To this end, Alloy seeks to democratize access to foundational drug discovery platforms and services to scientists worldwide. Alloys first platform, the ATX-Gx mouse platform, is a suite of transgenic mice designed for best-in-class in vivo discovery of fully human monoclonal antibodies. Alloys partners include academic scientists, small and medium biotech, and Fortune 50 biopharma. Founded in 2018 and privately funded by visionary investors, Alloy Therapeutics is headquartered in Boston, Massachusetts with European labs in Cambridge, UK. As a reflection of our irrational commitment to the scientific community, 100% of our revenue from platforms and services is reinvested in innovation and supporting access to innovation. To join the revolution, visit alloytx.com or schedule a 15-minute chat with our Founder and CEO at alloytx.com/ceo.

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Maze Therapeutics and Alloy Therapeutics Form Broadwing Bio to Develop Antibody Therapies for Genetically Validated Targets in Ophthalmic Diseases -...

Researchers at the University of Pittsburgh School of Medicine have combined synthetic biology with a machine-learning algorithm to create human liver organoids with blood- and bile-handling systems. When implanted into mice with failing livers, the lab-grown replacement livers extended life.

The study, published today in Cell Systems, shows that its possible to trigger and speed up the maturation of a lab-grown organ without sacrificing precision or control.

Mo Ebrahimkhani lab featurePregnancy is nine monthsit takes that long and even months after birth for new organs to maturebut if a person needs a liver, they may not be able to wait that long, said study author Mo Ebrahimkhani, M.D., associate professor of pathology and bioengineering, and member of the Pittsburgh Liver Research Center and the McGowan Institute for Regenerative Medicine. We showed its possible to get human liver tissue with four main cell types and vasculature in 17 days. We can mature tissue almost to the third trimester in only three months.

Other groups have attempted to coax organoid maturation in a dish using growth factors, but its expensive, inconsistent and prone to human error, Ebrahimkhani said. Often, there are unwanted tissue or cell typessuch as intestine or brain cells growing in the middle of what should be solid liver.

Using genetic engineering is cleaner but also more complex to orchestrate. So, Ebrahimkhani partnered with Patrick Cahan, Ph.D., at Johns Hopkins University to use a machine-learning system that can reverse engineer the genes necessary for human liver maturation.

Ebrahimkhani Vasculature releaseThen, Ebrahimkhani together with his collaborator at Pitt, Samira Kiani, M.D., applied genetic engineering techniques, including CRISPR, to turn a mass of immature liver tissueoriginally derived from human stem cellsinto what the team calls designer liver organoids.

The more mature the organoids got, the more capillaries and rudimentary bile duct cells snaked their way through the thin sheet of tissue, and the more closely the function of the tiny organ rivaled its full-size natural human model. Energy storage, fat accumulation, chemical transport, enzyme activity and protein production were all closer to adult human liver function, though still not a perfect match.

Ebrahimkhani imagines designer organoids having three main uses: drug discovery, disease modeling and organ transplant. Since the stem cells can come from the patients own body, lab-grown organs could be personalized, so there would be no threat of immune rejection.

When transplanted into mice with damaged livers, Ebrahimkhanis designer liver organoids successfully integrated into the animals bodies and continued to workproducing human proteins that showed up in the animals blood and prolonging the animals lives.

This is a proof-of-principle to show that its possible, Ebrahimkhani said. The technique could potentially go much further.

Our reference was a nature-designed human liver, but you can go after any design you like. For instance, you can make a genetic switch that protects the tissue from a virus, target the DNA of the virus and destroy it, Ebrahimkhani said. That sets this method apart.

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Synthetic Biology Speeds the Creation of Lab-Grown Livers - India Education Diary

LOGAN Genetically engineered golden Syrian hamsters developed by Utah State University researchers played a key role in animal trials of a possible vaccine to protect against the virus that causes COVID-19.

The Rega Institute in Leuven, Belgium, has used the hamsters produced by professor Zhongde Wang and his lab at USU to test the safety and effectiveness of a possible vaccine.

Details of the research conducted by the Rega Institute and its findings were published online in the journal Nature this week.

The candidate vaccine was found to be safe and effective in several animal models by a team of scientists at the institute.

Animal models play a vital role in vaccine research "because we cannot directly test them in humans. We need to use animal models, (it's) very critical," Wang said.

Wang said two pairs of hamsters were shipped to the Belgium lab in 2018 to start a breeding colony in an agreement with his lab.

"The scientists in my lab and I are very gratified that our research is contributing to combating this raging COVID-19 pandemic," Wang said in a statement.

"We also feel grateful for the excellent support from USU's Laboratory Animal Research Center to help us to carry out the research."

The Wang lab, established at USU in 2012, developed the first genetic hamster models in the world. The models are used in more than a dozen labs and institutions including the National Institutes of Health, the U.S. Army Medical Research Institute of Infectious Diseases, and Public Health Agency of Canada.

Hamsters from Wang's lab are also utilized in COVID-19 and other studies in USU's Institute for Antiviral Research.

"We pioneered development of genetic engineering techniques in this species and now we have about 30 different models. These are 30 different genetic modifications," Wang said in an interview Wednesday,

Typically, rodents carry many disease-causing organisms without becoming sick. The USU lab genetically engineered the golden Syrian hamsters to be susceptible to viruses that infect humans.

Viruses frequently attach to receptors in humans that are not present in animals, which limits effective testing of potential drugs to prevent or treat diseases. Hamsters from Wang's lab have a human gene inserted into their DNA for the receptor to which this coronavirus binds to facilitate testing, according to a university press release.

Because the hamsters are designed specifically to react to disease challenges more like humans, it takes fewer experiments to verify results, which expedites the process and can reduce numbers of animals used in research.

"We take animal welfare extremely seriously, and only the minimum numbers of animals required are used," said Wang, a professor in the Department of Animal, Dairy and Veterinary Sciences, in an article posted on a university website.

"In addition to that, all procedures are approved by Institutional Animal Care and Use Committees. It is essential to use these animals in vaccine studies before trials can be done in human subjects."

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Hamsters genetically engineered by USU researchers are on the front lines of COVID-19 vaccine trials in Belgium - KSL.com