Monthly Archives: July 2021

ByGina Wadas

Viruses are experts at infiltrating the body, as the SARS-CoV-2 virus (and resulting COVID-19 pandemic) have amply demonstrated. But their efficiency in targeting specific and isolated cells also make them useful drug delivery vehicles, known as viral vectors.

Viral vectors are modified viruses that can act as couriers to transport therapeutic "packages" to specific diseased cells. These packages contain instructions with modified or designed DNA or RNA to correct or supplement a faulty or missing gene. For instance, the Johnson & Johnson COVID-19 vaccine uses viral vectors to transport modified genetic material from the SARS-CoV-2 virus to cells, generating an immune response.

Though viral vector-based gene therapies are among the most advanced treatments for many congenital and acquired diseases, producing them is complex and costly.

"One of the major challenges in viral vector gene therapy is how to improve the quality, purity, and cost of the manufactured viral vectors, so that we can use the smallest possible effective dose, reduce immune side effects, and lower the cost of treatments," said Hai-Quan Mao, associate director and core faculty member of the Institute for NanoBioTechnology. He is also a professor in the departments of Materials Science and Engineering and Biomedical Engineering and a core faculty member at the Translational Tissue Engineering Center.

Hai-Quan Mao

Associate director, Institute for NanoBioTechnology

To address this challenge, Mao and his team are teaming up with Nolan Sutherland, senior scientist at bluebird bio, a Cambridge, Massachusetts-based biotechnology company that develops gene therapies. The partnership started about two years ago when Yizong Hu, a biomedical engineering PhD student under the mentorship of Mao, was at an annual meeting for the American Society for Gene and Cell Therapy presenting his research on a new particle assembly technology. Sutherland heard the presentation and approached Hu to discuss the technology and its application to the production of lentiviral vectors, which are made from a family of viruses that infect people by reverse transcription of their RNA into DNA in their host cells' genome.

Sutherland thought that the Mao team's approach might help streamline transfection, a key step in producing viral vectors. During transfection, a polymer solution is combined with a mixture of DNA plasmids to form transfection particles, a cumbersome procedure involving complicated solution blending and strictly timed dosing.

Mao, Hu, and Yining Zhu, also a biomedical engineering PhD student, developed a more effective and shelf-stable formulation of DNA particles in a ready-to-dose form. They also discovered that size-controlled sub-micron particles are most effective in transfecting cells and producing viral vectors. This production method is based on the team's years of experience in controlling transfection vehicle characteristics to enhance performances and stability.

The team members validated their findings with Sutherland at bluebird bio using that company's bioreactor. They compared the new method with the industry standard, and the results showed improved vector production yield, shelf stability, handling stability, and quality control of the transfection process.

"With the drastic increase in demand for lentiviral vector-based cell therapy products ... this new technology will greatly improve the production quality, consistency, and yield of our therapeutic LVVs," Sutherland said.

The team reported its findings in Nano Letters and is scaling up production with an eye to transferring the technology to the marketplace.

"This work represents a great example how we can partner with corporate collaborators to accelerate the translation of discoveries on the bench to the industry. This type of collaboration with industry provides us opportunities to identify the technical gaps in the engineering solutions that we develop, and fine tune them to better address the real-world problems in a more targeted fashion," Mao said.

According to Sutherland, the partnership with Mao and his team has "allowed bluebird to pursue high risk/reward innovation in a space outside of its core expertise. The team has a keen eye for application to industry which has made the partnership incredibly productive."

Team members say that this new particle engineering technology will find a wide range of applications in the manufacture of a variety of viral vectors for gene and cell therapy applications.

Also contributing to the project are Jordan Green, professor in the Department of Biomedical Engineering and associate member at the INBT, and Sashank Reddy, assistant professor of plastic and reconstructive surgery at Johns Hopkins Medicine, medical director at Johns Hopkins Technology Ventures, and affiliate faculty member at the INBT.

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Researchers partner with industry to create better gene therapy tools - The Hub at Johns Hopkins

AMHERST, Mass. A scientific team has shown that the release of neurotransmitters in the brain is impaired in patients with schizophrenia who have a rare, single-gene mutation known to predispose people to a range of neurodevelopmental disorders.

Significantly, the results from the research with human-derived neurons validated previous and new experiments that found the same major decrease in neurotransmitter release and synaptic signaling in genetically engineered human neurons with the same genetic variant the deletion of neurexin 1 (NRXN1). NRXN1 is a protein-coding gene at the synapse, a cellular junction that connects two nerve cells to communicate efficiently.

Both the research with human-derived and engineered human neurons also found an increase in the levels of CASK, an NRXN1-binding protein, which were associated with changes in gene expression.

Losing one copy of this neurexin 1 gene somehow contributes to the etiology or the disease mechanism in these schizophrenia patients, says molecular neuroscientist ChangHui Pak, assistant professor of biochemistry and molecular biology at the University of Massachusetts Amherst and lead author of the research published in the Proceedings of the National Academy of Sciences. It causes a deficit in neural communication.

Pak is quick to add that although this single-gene mutation puts people at risk for schizophrenia, autism, Tourette syndrome and other neuropsychiatric disorders, at the end of the day, we dont know what causes schizophrenia. This variant gives us insight into what cellular pathways would be perturbed among people with schizophrenia and a lead to study this biology.

When she conducted most of the research, Pak was working in the Stanford University lab of Thomas Sdhof, a neuroscientist who shared the 2013 Nobel Prize in Physiology or Medicine for helping to lay the molecular basis for brain chemistry, including neurotransmitter release.

The research team obtained cell specimens from schizophrenia patients with an NRXN1 deletion who donated samples to a national biorepository for genetic studies of psychiatric disorders. Pak and colleagues converted the participants specimens into stem cells and then turned them into functional neurons to study. Were rewinding these cells back, almost like a time machine what did these patients brains look like early on, Pak explains.

Labs at Stanford, Rutgers University and FUJIFILM Cellular Dynamics were independently involved in the generation and analysis of neurons. For comparison with the human-derived neurons, Pak and team also created human neurons from embryonic stem cells, engineering them to have one less copy of the NRXN1 gene. With engineered human neurons, they had previously noted the neurotransmitter impairment and were interested in whether they would have the same findings with patient-derived neurons.

It was good to see the consistent biological finding that indeed the neurexin 1 deletion in these patients actually does mess up their neuronal synaptic communication, and secondly that this is reproducible across different sites whoever does the experiment, Pak says.

Notably, the researchers did not see the same decrease in neurotransmitter release and other effects in engineered mouse neurons with analogous NRXN1 deletion. What this suggests is there is a human-specific component to this phenotype. The human neurons are particularly vulnerable to this genetic insult, compared to other organisms, adding to the value of studying human mutations in human cellular systems, Pak says.

Being able to reproduce the results is key to the development of drugs that can better treat schizophrenia. Everything was done blindly and at different sites. We wanted to not only learn about the biology but also be at the top of our game to ensure rigor and reproducibility of these findings, Pak says. We showed the field how this can be done.

Pak and her team are now continuing the research in the Pak Lab, supported by a five-year, $2.25 million grant from the National Institute of Mental Health. The scientists are using the latest stem cell and neuroscience methodologies to explore the molecular basis of synaptic dysfunction in schizophrenia and other neuropsychiatric disorders.

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Decrease in Neurotransmitter Release Found in Neurons Derived from People with Schizophrenia and a Rare Genetic Mutation - UMass News and Media...

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The figure above summarizes the findings of the team in terms of genetic, epigenetic and stochastic differences among the EGFR-mutant lung cancer cells studied.

Leonard Harris, assistant professor of biomedical engineering, led a team of researchers from Vanderbilt Universitythat has shown how an in vitro model of tumor heterogeneity, or diversity, resolves three different sources of cell state variability in cancer cells.

The paper has been published in PLOS Biology, part of the Public Library of Science.

A heterogeneous tumor is a tumor that is made up of many different types of cancer cells. Often, the cells have different types of genetic mutations and co-exist within a tumor. The diversity of the tumor is what makes cancer difficult to treat.

"It's like the success of a diverse team," Harris explains. "A team made up of people from different backgrounds, ages, stages of their career, etc., are often better at tackling problems because the team members provide different perspectives."

In a tumor, different cells respond to drug treatments differently. Some cells are able to survive and regrow the tumor and spread, which is why Harris and his team continue to research the ways surviving cancer cells differ from the other tumor cells.

But genetic mutations are not the only way cancer cells can differ from each other. Cells that have the exact same DNA can exist in very different states. For example, your skin cells and your liver cells have exactly the same DNA but they function very differently; that is an example of epigenetic heterogeneity. Moreover, when a skin cell divides, it produces two skin cells. The cells do not inherit the skin cell state from the DNA; it has to come through some other means. It is this non-genetic form of inheritance that makes the process epigenetic.

Cancer cells also differ due to random fluctuations in molecule numbers inside each cell: molecules randomly interact with each other, degrade, are synthesized by the cell, secrete into and out of the cell, etc. This type of non-genetic heterogeneity is called stochastic variability and is not heritable, unlike epigenetic processes. It might not seem like a big deal, but researchers have shown that stochastic variability can have major effects.

The experimental and computational work reported in the paper was performed at Vanderbilt University in collaboration with Corey E. Hayford, Darren R. Tyson, C. Jack Robbins III, Peter L. Frick and Vito Quaranta and has motivated many additional research projects. It is now the foundation for Harris' U of A laboratory.

"Cancer is commonly referred to as a 'genetic disease', meaning it is caused by mutations in critical parts of the DNA that cause cells to grow out of control," Harris said. "This has led to decades of research on the genetics of cancer, which has resulted in significant advances, including the development of numerous therapeutic drugs that target so-called 'driver oncogenes.' While exceptionally effective in the short term, these targeted drugs fail almost universally, with patient tumors recurring within a few months to a few years. This has led many researchers to begin considering the role of non-genetic processes in the response of tumors to drugs."

Modeling and experimental techniques were used to distinguish the three different sources of variability among lung cancer cells: genetic, epigenetic and stochastic. As stated above, epigenetic and stochastic variabilities are different types of non-genetic variability. Epigenetically distinct cells look different, like the skin and liver cells from the example above, whereas stochastically distinct cells appear nearly identical but may act completely different.

"Distinguishing genetic from non-genetic, and epigenetic from stochastic, factors in drug response is crucial for developing new therapies that can kill tumor cells before they have a chance to acquire genetic resistance mutations," Harris said. "They all contribute to tumor drug response in different ways."

A framework for distinguishing genetic and non-genetic sources of heterogeneity in tumors has been proposed previously but is not yet widely accepted within the cancer research community because of a lack of strong experimental evidence. The team's paper provides strong support for this framework.

The analysis presented in the paper was applied specifically to EGFR-mutant non-small cell lung cancer. Harris' lab is currently applying these ideas to other cancer types as well, including small cell lung cancer, melanoma and bone-metastatic breast cancer.

"In my laboratory, we are working on building computational models of the molecular networks within cancer cells that give rise to the different epigenetic states, across which cells can transition to survive drug treatments," Harris said. "The long-term goal of my lab's research is to expand these models until they are of sufficient detail to act as virtual platforms for testing the effects of various drugs and identifying novel drug targets."

By constructing these so-called "digital twins," the hope is to one day use them to perform virtual drug screens on models built from samples of real patient tumors and then design personalized treatment options for those patients. This will require forming collaborations with bioinformaticians, experimentalists and clinicians here at U of A, the Winthrop P. Rockefeller Cancer Institute at the University of Arkansas for Medical Sciencesin Little Rock, and elsewhere. "Hopefully, the publication of this paper will help spark some of those collaborations," Harris said.

About the Public Library of Science: The Public Library of Science states on its website, "PLOS Biology empowers authors to publish the full arc of their research without compromising quality. Researchers can more fully and accurately represent their science and get credit for all their work."

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Research Shows Non-Genetic Tumor Diverseness Contributes to Treatment Failure in Cancer Patients - University of Arkansas Newswire

SAN DIEGO, July 16, 2021 (GLOBE NEWSWIRE) -- Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer, today announced that management will host a virtual event to highlight interim Phase 1 clinical data from its FT596 and FT516 programs for the treatment of relapsed / refractory B-cell lymphomas on August 19, 2021 at 4:30 p.m. ET.

The live webcast of the presentation can be accessed under "Events & Presentations" in the Investors section of the Company's website at http://www.fatetherapeutics.com. The archived webcast will be available on the Company's website beginning approximately two hours after the event.

About Fate Therapeutics iPSC Product PlatformThe Companys proprietary induced pluripotent stem cell (iPSC) product platform enables mass production of off-the-shelf, engineered, homogeneous cell products that can be administered with multiple doses to deliver more effective pharmacologic activity, including in combination with other cancer treatments. Human iPSCs possess the unique dual properties of unlimited self-renewal and differentiation potential into all cell types of the body. The Companys first-of-kind approach involves engineering human iPSCs in a one-time genetic modification event and selecting a single engineered iPSC for maintenance as a clonal master iPSC line. Analogous to master cell lines used to manufacture biopharmaceutical drug products such as monoclonal antibodies, clonal master iPSC lines are a renewable source for manufacturing cell therapy products which are well-defined and uniform in composition, can be mass produced at significant scale in a cost-effective manner, and can be delivered off-the-shelf for patient treatment. As a result, the Companys platform is uniquely capable of overcoming numerous limitations associated with the production of cell therapies using patient- or donor-sourced cells, which is logistically complex and expensive and is subject to batch-to-batch and cell-to-cell variability that can affect clinical safety and efficacy. Fate Therapeutics iPSC product platform is supported by an intellectual property portfolio of over 350 issued patents and 150 pending patent applications.

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About FT516FT516 is an investigational, universal, off-the-shelf natural killer (NK) cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line engineered to express a novel high-affinity 158V, non-cleavable CD16 (hnCD16) Fc receptor, which has been modified to prevent its down-regulation and to enhance its binding to tumor-targeting antibodies. CD16 mediates antibody-dependent cellular cytotoxicity (ADCC), a potent anti-tumor mechanism by which NK cells recognize, bind and kill antibody-coated cancer cells. ADCC is dependent on NK cells maintaining stable and effective expression of CD16, which has been shown to undergo considerable down-regulation in cancer patients. In addition, CD16 occurs in two variants, 158V or 158F, that elicit high or low binding affinity, respectively, to the Fc domain of IgG1 antibodies. Numerous clinical studies with FDA-approved tumor-targeting antibodies, including rituximab, trastuzumab and cetuximab, have demonstrated that patients homozygous for the 158V variant, which is present in only about 15% of patients, have improved clinical outcomes. FT516 is being investigated in a multi-dose Phase 1 clinical trial as a monotherapy for the treatment of acute myeloid leukemia and in combination with CD20-targeted monoclonal antibodies for the treatment of advanced B-cell lymphoma (NCT04023071). Additionally, FT516 is being investigated in a multi-dose Phase 1 clinical trial in combination with avelumab for the treatment of advanced solid tumor resistant to anti-PDL1 checkpoint inhibitor therapy (NCT04551885).

About FT596FT596 is an investigational, universal, off-the-shelf natural killer (NK) cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line engineered with three anti-tumor functional modalities: a proprietary chimeric antigen receptor (CAR) optimized for NK cell biology that targets B-cell antigen CD19; a novel high-affinity 158V, non-cleavable CD16 (hnCD16) Fc receptor, which has been modified to prevent its down-regulation and to enhance its binding to tumor-targeting antibodies; and an IL-15 receptor fusion (IL-15RF) that augments NK cell activity. In preclinical studies of FT596, the Company has demonstrated that dual activation of the CAR19 and hnCD16 targeting receptors enhances cytotoxic activity, indicating that multi-antigen engagement may elicit a deeper and more durable response. Additionally, in a humanized mouse model of lymphoma, FT596 in combination with the anti-CD20 monoclonal antibody rituximab showed enhanced killing of tumor cells in vivo as compared to rituximab alone. FT596 is being investigated in a multi-center Phase 1 clinical trial for the treatment of relapsed / refractory B-cell lymphoma as a monotherapy and in combination with rituximab, and for the treatment of relapsed / refractory chronic lymphocytic leukemia (CLL) as a monotherapy and in combination with obinutuzumab (NCT04245722).

About Fate Therapeutics, Inc.Fate Therapeutics is a clinical-stage biopharmaceutical company dedicated to the development of first-in-class cellular immunotherapies for patients with cancer. The Company has established a leadership position in the clinical development and manufacture of universal, off-the-shelf cell products using its proprietary induced pluripotent stem cell (iPSC) product platform. The Companys immuno-oncology pipeline includes off-the-shelf, iPSC-derived natural killer (NK) cell and T-cell product candidates, which are designed to synergize with well-established cancer therapies, including immune checkpoint inhibitors and monoclonal antibodies, and to target tumor-associated antigens using chimeric antigen receptors (CARs). Fate Therapeutics is headquartered in San Diego, CA. For more information, please visit http://www.fatetherapeutics.com.

Contact:Christina TartagliaStern Investor Relations, Inc.212.362.1200christina@sternir.com

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Fate Therapeutics to Host Virtual Event Highlighting Interim Phase 1 Clinical Data from its Off-the-Shelf, iPSC-derived NK Cell Franchise for B-cell...

When someone close to you develops signs of mental illness, you spring into detective mode. You ask questions, but the answers seem vague and incomplete. You scour your memory for any years-old signs, any warnings that might have seemed innocuous in the moment but raise red flags in retrospect.

You wonder: If anyone had noticed then, would things be different now? And if they refuse to seek treatment, you think, it doesnt have to be this way if only you could figure out how to break through.

If this sounds familiar, you might be interested in Projections: A Story of Human Emotions by Karl Deisseroth and A Sense of Self: Memory, the Brain, and Who We Are by Veronica OKeane, two recent entrants in the vast arena of nonfiction books that explore both the biology of mental illness and how the brain works in general. Both authors use patient stories as conduits to talk about advancements in neuroscience, illuminating the brains various structures and the connections between them.

BOOK REVIEW Projections: A Story of Human Emotions, by Karl Deisseroth (Random House, 256 pages).

Patient narratives across both books show that not all who receive psychiatric treatment survive the storm in their minds, while others regain a sense of themselves that was lost. And though scientists may be inconceivably far away from revealing how a 3-pound fatty organ in the skull gives rise to all the complexities of mental life, at least the questions can be well posed, as Deisseroth puts it.

Deisseroth, a professor at Stanford University, is best known for developing new and influential technologies for studying the brain. But in this book he draws from his work as an emergency psychiatrist at a hospital in Silicon Valley, and explores how confronting people in crisis influenced the way he investigates the brain in both humans and animals, potentially laying the groundwork for future clinical treatments. It is enthralling to consider: the experiences of suffering human beings, and thoughts about mouse and fish brains, are informing each other, he writes.

Presenting a cast of characters encountered in the cramped, windowless Room Eight of the hospital, Deisseroth reflects on a broad swath of his psychiatry experiences, from his residency in the early 2000s to his more recent patient work. His book resembles a series of connected short stories interwoven with recent findings from research on the neural circuits that give rise to mental illness. At times it may feel like reading fiction because it partly is Deisseroth freely uses his imagination in his portrayal of patients and their inner lives. But he pulls these threads together with his own memoir-ish voice, revealing the struggles, frustrations, and triumphs of someone driven to understand both the cold science of the brain and the hot mess of the mind.

A man loses his pregnant wife in a car accident and doesnt know why he cant cry. A patent lawyer believes her neighbor has installed a satellite dish to channel her thoughts. After a breakup, a 19-year-old begins cutting his arms. Deisseroth ends up in a dramatic chase when a patient slips out of the exam room, only to find shed gone to binge-eat and vomit. Unlike Psychology 101 disease prototypes, these feel like real people. And while theyre actually projections, filtered through the lens of a doctor who fictionalizes details to protect patients privacy, they are vivid reminders that mental health can be a fragile, elusive thing.

But psychotherapy and imagination arent the only ways Deisseroth peers into the brain. Seeking answers to tough questions that have confounded psychiatrists for decades, Deisseroth helped pioneer a technology called optogenetics. Once patients leave the hospital, Deisseroth has no control over their behavior, let alone their brains. But with optogenetics, he and other researchers can turn on and off individual neural circuits, or even neurons themselves at least, in laboratory animals.

In optogenetics, researchers hijack genes called microbial opsins from bacteria and algae and encode them in the brain cells of lab animals mostly mice, rats, and fish. These exotic genes lead to the creation of proteins with a special power to convert light to electrical current. Normally, most neurons dont turn on in the presence of light (although a 2019 study questions that assumption). But as a result of this feat of genetic engineering, scientists can activate individual brain cells by delivering light to them. With unprecedented precision, they can then investigate how different parts of the brain participate in both typical behaviors and symptoms of mental illness.

It is enthralling to consider: the experiences of suffering human beings, and thoughts about mouse and fish brains, are informing each other, Deisseroth writes.

The impact of optogenetics has been far-reaching in revealing the brains inner workings, at least in animal models. And after more than 15 years of laboratory study, its potential is moving into the human realm. In May 2021, too recent to make it into this book, scientists reported in Nature Medicine that a blind patient regained partial vision as a result of optogenetic therapy.

But in terms of innovations in psychiatric patient care, what are the lessons from optogenetics? A lot of this work is still in its infancy. Deisseroth says his laboratory research informs the psychiatric patient care that he continues to give, yet many of the landmark studies are about causations and chemical pathways in genetically modified mice, not humans. Scientists can model eating disorders in rodents, but no one is talking about removing the skull flaps of people with anorexia, genetically modifying particular brain cells and zapping them with light to restart the drive to eat normally. Nor might it be that simple. Yet there is some hope that by understanding the fundamental mechanisms at work, new treatments could one day be developed.

One of the most direct feedback loops between Deisseroths hospital and lab work is a patient named Charles, who changed Deisseroths thinking about autism. Charles comes to Deisseroth as a young information technology specialist who, among other social impairments, consistently avoids eye contact. One morning, Deisseroth asks him what makes him look away. Charles tells him, It overloads the rest of me.

This introspection is so profound to Deisseroth that he says it justifies his entire career progression: All the extra years of both MD and Ph.D. training, all the pain and personal challenges of internship, all the call nights as a single father, worrying about my lonely son. This alone was enough.

While information overload seems like an abstract concept, it could be rooted in too much firing of excitatory cells, which stimulate other neurons, compared to inhibitory cells, which do the opposite. In 2011, Deisseroths team used optogenetics to increase the activity of excitatory cells in the prefrontal cortex of mice, which appeared to cause them to be less social with other mice. This part of the book is a bit technical, but the bottom line is that an imbalance in cellular activity could play a role in the asocial behaviors associated with autism.

Tantalizingly, it appears that this imbalance might be corrected. In 2017, Deisseroths team reversed social impairment in mice carrying genetic mutations associated with autism through opposite methods in the prefrontal cortex making inhibitory cells fire more, or lowering the activity in excitatory cells. In fact, such experiments suggest that social avoidance can be turned on or off in adult mice, a revelation that may generate new hope for future interventions in adult humans.

BOOK REVIEW A Sense of Self: Memory, the Brain, and Who We Are, by Veronica OKeane (W. W. Norton & Company, 288 pages).

Deisseroths most compelling narratives detail brief encounters with patients in vulnerable, distressing circumstances. Veronica OKeane, on the other hand, describes longer-term relationships with her patients in A Sense of Self: Memory, the Brain, and Who We Are although patient stories take more of a backseat to science in this book. She is a professor of psychiatry at Trinity College Dublin, and has been practicing for more than 30 years. Like all psychiatrists, as a patient once said to me, I am like a detective, she writes.

OKeane draws from her clinical experiences to offer a comprehensive tour of the current state of knowledge about how memory operates in the brain. Individuals with psychiatric illnesses have a great deal to tell neuroscience, and the larger world, about the processes involved in the organization of memory, she writes.

A Sense of Self at times reads like a textbook, complete with a few diagrams. Anyone who has read a neuroscience book previously will recognize H.M., who was famously unable to form new memories after undergoing brain surgery, as well as Phineas Gage, who was impaled with an iron rod and how the tragic circumstances of their impairments taught the fledging field of neuroscience a lot about what does what in the brain.

But what makes OKeanes book engaging is how she incorporates references to literature and folklore, putting a different spin on familiar stories like Lewis Carrolls Through the Looking- Glass, in which Alices adventures closely mimic feelings of psychosis.

Another is Charlotte Perkins Gilmans 1892 short story The Yellow Wallpaper, about a woman trapped in the wall of her bedroom. Its often portrayed as a tale of the oppression of women at that time, but OKeane has a different take: Its a perfect description of experience of what we now call postpartum psychosis, she writes.

Postpartum psychosis, a condition seldom spoken about, can make otherwise healthy new mothers lose sight of what is real and what is not. Perkins Gilman herself experienced postpartum psychosis, and years later, after her cancer treatments failed, ended her own life in 1935.

OKeane describes a patient, Edith, who developed delusions about her baby being an imposter, as well as her own husband. With the help of antipsychotic medications, Edith heals and comes back to reality. Yet she still feels terror when she sees the gravestone that she had believed to be the site of her babys burial the memories are real, she tells the author. This distinction set me on a long-term pathway of inquiry about the nature of the matter of memory, OKeane writes.

Some who suffer psychosis are so accustomed to the voices in their heads and other delusions that they decline medicine to make them go away. They feel scared to let go of their inner lives and participate in the same reality that others share.

Like much of life, mental health can be seen as a matter of achieving some kind of equilibrium. Everyone, psychotic or not, operates by balancing ones inner world full of thoughts, feelings, and memories with the external world and all of the stuff of society. If there is anything that I have learned from my work with mentally ill patients it is that the achievement of an easy equilibrium between oneself and the world is what determines ones happiness, OKeane writes.

As it happens, OKeane also briefly touches on innovations in optogenetics. She focuses on an experiment by Susumu Tonegawa using optogenetics to implant false memories in mice, which I covered as a CNN reporter in 2013. By genetically altering neurons and shining blue light on them, scientists made mice believe they had been shocked in one chamber, even though they were shocked in a different chamber. The mice eventually froze up in fear even when the researchers were not activating the memory in their brains.

OKeanes take on this research is that artificial modification of memory is fascinating, but that in some sense the mouse memories arent false because the neural matter of the experience is formed regardless. Just as Edith regarded her hallucinations about her babys death as real memories, these mice have real memories of something that never occurred. Edith brought home to me how memory is, in essence, neurally coded experience, OKeane writes.

As we go about our lives, according to OKeane, we tag experiences with emotions, which are then triggered later as we are reminded of them, but we never re-live them in quite the same way. Is there ever a boundaried memory untouched by the present, like a walled cement garden? she writes. The answer in her view is decidedly no, for each time we recall a moment, it is colored by who we have become since it happened.

If there is anything that I have learned from my work with mentally ill patients it is that the achievement of an easy equilibrium between oneself and the world is what determines ones happiness, OKeane writes.

OKeanes book will be useful for anyone looking for a deep dive into how memory works, but it is not as much of a page-turner as Projections. Still, I was moved by both authors concerns for their patients and acknowledgement that science has only scratched the surface of learning how psychiatric illness works at a fundamental level in the brain. The double-edged sword here is that you are not alone, but also, no one really understands.

Yet, there is hope. The stories in both works reveal a range of humanity that is barely understood by people who devote their lives to the study of mental illness and is often stigmatized by those who do not. They are in some sense thank-you notes to the patients who have taught the authors about the nature of the brain and given them more to investigate in the future.

And while a person battling with delusions of paranoia may seem far removed from academic papers on genetically engineered mice, both authors argue that the gap between laboratory insights and clinical practice is narrowing. As this science develops, psychiatric illness will become a major target of investigation, and I believe this will be the beginning of the ending of the stigmatization of psychiatric illness, OKeane writes.

An important caveat here, she adds, is that most of my patients do not feel similarly optimistic.

Elizabeth Landau is a science journalist and communicator living in Washington, D.C. She has contributed to The New York Times, The Washington Post, Quanta Magazine, Smithsonian, and Wired, among other publications. Find her on Twitter at @lizlandau.

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Book Review: Lessons Learned From the Wayward Brain - Undark Magazine

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Tessera Therapeutics, a biotechnology company pioneering a new approach in genetic medicine known as Gene Writing, announced today the appointment of Howard Liang, Ph.D., as President and Chief Financial Officer. The company also expanded its executive bench with newly promoted talent and hires: Madhusudan Peshwa, Ph.D., as Chief Technology Officer for Cell Therapy; Bill Querbes, Ph.D., as Senior Vice President, Therapeutic Discovery & Translational Sciences; Cecilia Cotta-Ramusino, Ph.D. as Senior Vice President, Platform Development; Vikram Ranade, Ph.D., as Senior Vice President, Corporate Development; David Pollard, Ph.D., as Head of Bioprocess, and Steve Garbacz as Head of Finance.

These additions represent the latest leadership expansion for the company, following the appointments of Elliott Sigal, M.D., Ph.D., and Mary Rozenman, Ph.D., to the Board of Directors in June, and the appointments of David Davidson, M.D., as Chief Medical and Development Officer, Hari Pujar, Ph.D., as Chief Operating Officer, and Lin Guey, Ph.D., as Senior Vice President of Rare Diseases Program Strategy and Operations in March. Tessera also announced the successful completion of $230 million Series B financing in January.

Outstanding people are the lifeblood of great companies and Im thrilled to welcome these accomplished individuals to the Tessera leadership team, said Dr. Geoffrey von Maltzahn, CEO and Co-Founder of Tessera and General Partner, Flagship Pioneering. Howards track record in both strategy and finance at BeiGene and in the capital markets will play a key role in guiding Tessera to new territory in Gene Writing. I am excited to be working with him, and our other new senior leaders, each of whom will be instrumental in expanding the limits of how we discover life-changing medicines.

Howard Liang, Ph.D., President and Chief Financial OfficerHoward Liang joined Tessera in 2021 as President and Chief Financial Officer. Dr. Liang brings nearly three decades of combined experience in management, financing, strategy, and research in the biotechnology and pharmaceutical industries and investment research on Wall Street. Prior to joining Tessera, he was Chief Financial Officer and Chief Strategy Officer at BeiGene for six years, where he was a member of the senior team that led the companys growth from a research organization with fewer than 200 employees to a fully integrated global biotechnology company with more than 6,000 employees on five continents. At BeiGene, he led the companys IPOs on NASDAQ and the Hong Kong Stock Exchange and its ongoing effort to list on the Shanghai Stock Exchange, raising more than $8 billion to date through equity and alternative financings, and overseeing the growth of the companys market capitalization from less than $300 million to more than $30 billion during his tenure. Prior to BeiGene, Dr. Liang spent 10 years at Leerink Partners, where he was Managing Director and Head of Biotechnology Equity Research. His prior investment research experience included positions at A.G. Edwards, JMP Securities, and Prudential Securities, covering biotechnology, and major and specialty pharmaceutical sectors. He started his career in R&D at Abbott Laboratories, where he was a Senior Scientist and member of an industry-leading structure-based drug discovery team. Dr. Liang is a member of the Hong Kong Stock Exchange Biotech Advisory Panel. He was named a member of the All-America Research Team by Institutional Investor magazine and Best of the Street by The Wall Street Journal. As a scientist, he authored 14 papers, including 6 in Nature, Science, and Proceedings of the National Academy of Sciences, and a review in the Journal of Molecular Biology. He received his Ph.D. in Biochemistry and Molecular Biology and M.B.A. from the University of Chicago and his B.S. in Chemistry from Peking University.

Tessera is developing a first-of-its-kind technology with the potential to cure diseases across multiple categories by writing in the code of life itself, said Dr. Howard Liang. I look forward to helping the company realize the full breadth of Gene Writings potential.

Madhusudan Peshwa, Ph.D., Chief Technology Officer for Cell TherapyDr. Peshwa joined Tessera in May 2021 and is responsible for developing the strategy and executing the operating plan encompassing the design, development, and manufacture of Tesseras proprietary mobile gene element engineered cell therapy product portfolio. Recently, in March 2020, Dr. Peshwa was inducted into the College of Fellows at the American Institute for Medical and Biological Engineering (AIMBE), in recognition of Lifetime contributions in Regenerative Medicine to the advancements in the field of cell & gene therapies.

Prior to joining Tessera, Dr. Peshwa was CTO at Mana Therapeutics, an immunotherapy company focused on the development of allogeneic, multi-tumor-antigen-targeted, non-engineered, T-cell immunotherapies with additional oversight of Quality Assurance and Quality Control functions. Previously, Dr. Peshwa was CTO and Global Head of R&D for the Cell and Gene Therapies business at GE Healthcare (GEHC), with responsibilities that include GEHCs CGT product and service portfolio to enable and accelerate the development of robust, scalable, industrialized manufacturing and delivery of cell and gene therapies. Prior to these roles, Dr. Peshwa held various executive positions at MaxCyte, Inc., NewNeural LLC, and Dendreon Corporation. At MaxCyte, as CSO and EVP, Cellular Therapies, Dr. Peshwa was responsible for leading the development and commercialization of ex vivo cell loading platform technology. Additionally, he also established MaxCytes proprietary therapeutic product portfolio with lead program being a non-viral mRNA engineered CAR Immunotherapy (CARMA) with one-day manufacturing process under company sponsored IND for treatment of solid cancers; and additional collaborative programs under CRADA Agreement with Investigators at NIAID and NHLBI, for ex vivo gene correction in autologous hematopoietic stem cells, as cell therapy for potential treatment of monogenic diseases. As Vice President of Process Sciences and Manufacturing, at Dendreon Corporation, Dr. Peshwa was responsible for leading the CMC and GMP manufacturing for Provenge (Sipuleucel-T), an autologous cellular immunotherapy product for treatment of prostate cancer, the first ever active cellular immunotherapy product approved by the US FDA.

In addition to his broad industry experience, Dr. Peshwa has served as Principal Investigator / Co-Investigator on multiple grant-funded research studies, is an inventor of six issued US patents in the field of cell therapy, and has served in various consultative, advisory, and board capacities to industry, government, not-for-profit, and financial organizations. Dr. Peshwa earned his Ph.D. in Chemical Engineering from the University of Minnesota and his B.Tech. in Chemical Engineering from the Indian Institute of Technology in Kanpur, India.

Tesseras Gene Writing platform represents an opportunity to drive a fundamental change in our ability to treat disease, said Dr. Madhusudan Peshwa. I look forward to joining the executive team to help move Tesseras bold mission forward.

Bill Querbes, Ph.D., Senior Vice President, Therapeutic Discovery & Translational SciencesBill Querbes joined Tessera in April of 2021 as Senior Vice President of Therapeutic Discovery and Translational Sciences. He brings a strong background in genetic medicine and a passion for rare disease drug development with over 15 years of experience leading cross-functional teams from early discovery through clinical trials.

Before joining Tessera, Dr. Querbes held the position of Vice President and Fabry Program Lead at AVROBIO. Prior to this role, as Senior Director at Synlogic, he led clinical program teams in PKU and urea cycle disorders. Earlier in his career he spent 12 years at Alnylam Pharmaceuticals where he made important contributions to the maturation of both the siRNA delivery platforms and therapeutic pipeline. Dr. Querbes led the discovery and early clinical development of GIVLAARI (givosiran) for the treatment of acute hepatic porphyria, which was the first FDA approved RNAi therapeutic utilizing GalNAc conjugate technology.

He holds a B.S. in Biology from SUNY Geneseo and a Ph.D. from Brown University.

Cecilia Cotta-Ramusino, Ph.D., Senior Vice President, Platform DevelopmentCecilia Cotta-Ramusino joined Tessera in 2019 as the Head of Platform Development. She drives the discovery and optimization of novel Gene Writers, enabling their translation into gene therapy tools. Dr. Cotta-Ramusino has spent more than 20 years in academia and biotech, working in the areas of gene editing, cell engineering, and DNA damage. Dr. Cotta-Ramusino was the first employee at insitro where she was the Head of Functional Genomics. Prior to insitro, she was one of the first scientists hired at Editas, the first CRISPR-based therapeutic company, where she helped to define and shape the vision of the Editas platform. She spearheaded numerous academic collaborations devoted to platform optimization and led the development of a T cell gene therapy treatment aiming to treat an immunodeficiency disease. She conducted her postdoc in Steve Elledges lab at Harvard Medical School where she performed whole genome high-throughput screens in mammalian cells using siRNA/shRNA to identify novel components of the DNA damage response. Dr. Cotta-Ramusino obtained her Ph.D. in genetics at University of Milan, Italy and has been principal author and co-author on several publications in high impact factor journals, such as Science, Nature, Nature Communications and Molecular Cell. She has invented several foundational patents in all of the early-stage companies in which she has worked.

Vikram Ranade, Ph.D., Senior Vice President, Corporate DevelopmentDr. Ranade joined Tessera in 2020 as the Head of Corporate Development. In this role, he drives corporate strategy, business development, and investor relations for Tessera.

Dr. Ranade was previously at McKinsey & Company, where he was an Associate Partner in the healthcare practice. At McKinsey, he worked with large biopharma and early-stage biotech companies on strategy, M&A, and R&D topics. He led diligence efforts for more than $15B in completed deals and advised on clinical strategy for more than 20 programs. Dr, Ranade also co-led McKinseys Center for Asset Optimization, which focuses on clinical-stage asset development strategy. He holds a Ph.D. in Genetics and Development from Columbia University, where he studied transcriptional regulation of developmentally important genes at the molecular level. He has a B.S. in biochemistry from Brandeis University, where he was awarded highest honors for his research on DNA damage repair pathways.

David Pollard, Ph.D., Head of BioprocessDavid Pollard has over 25 years of bioprocess development for a range therapeutics including novel mAbs, peptides, anti infectives, biocatalysts and more recently cell and gene therapies. During his career at Merck & Co. Inc, Dr. Pollard led early and late stage CMC teams, providing contributions to multiple INDs & BLAs for Biologics & Vaccines. Dr. Pollard also led an innovation team that co-developed the state-of-the-art ambr250 high throughput bioreactor system and also pioneered lights out automated continuous mAb production. More recently Dr. Pollard pursued processing for personalized neoantigen T cell therapies and helped create corporate research for the technology provider Sartorius. Dr. Pollard will help Tessera drive digital workflows and high throughput automation to accelerate sustainable gene therapy process development.

Steve Garbacz, Head of FinanceSteve Garbacz joined Tessera in 2021 as the Head of Finance and is responsible for financial reporting, planning, taxes, and treasury. Garbacz has more than 25 years of experience in financial management for a range of companies, including Biogen, Epizyme, Spero, and Anika. He has a passion for building scalable financial organizations leveraging new technology, and drove successful IPOs at Epizyme and Spero. At Anika, Garbacz was a key leader in acquiring and integrating two private companies. Garbacz has a B.S. in Economics from George Mason University and an MBA in Finance from the Leonard Stern School of Business at New York University.

For more information about Tessera, including how Gene Writing works, partnership opportunities, and job openings, visit http://www.tesseratherapeutics.com.

About Tessera TherapeuticsTessera Therapeutics is an early-stage life sciences company pioneering Gene Writing, a new biotechnology designed to offer scientists and clinicians the ability to write small and large therapeutic messages into the genome, thereby curing diseases at their source. Gene Writing holds the potential to become a new category in genetic medicine, building upon recent breakthroughs in gene therapy and gene editing while eliminating important limitations in their reach, utilization, and efficacy. Tessera Therapeutics was founded by Flagship Pioneering, a life sciences innovation enterprise that conceives, resources, and develops first-in-category bioplatform companies to transform human health and sustainability.

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Leading Gene Writing Company Tessera Therapeutics Announces Pivotal Expansion of Leadership Team - Business Wire

The NK program has taken off with multiple indications. According to Dan Kemp, its lead product, WU-NK-101, is already proving itself in an ongoing Phase I/II trial, demonstrating an "impressive complete response rate in relapsed/refractory AML." It's the promising results of these memory NK cells drivingthis week's announcementof a $172 million Series B raise.

Company founder John McKearntold BioSpacein January that Wugen "started as a twinkle in his eye" to bring a durable, allogeneic CAR-T therapy on the market. At that time, the biotech's natural killer (NK) cell program was a recent addition to its core focus on CAR-T therapy.

A potential clincher is that Wugen also believes its memory NK cell platform can go where CAR-T treatments have thus far failed solid tumors.

According toresearchfrom Wugen co-founder Todd Fehniger and his team at Washington University School of Medicine, memory NK cells respond better than normal NK cells against cancers. By being primed in the lab before being administered to the patient, they're more potent in vivo at attacking cancer, even in melanoma, where immunotherapies have seen just a 50% response rate.

By using an allogeneic approach, where the cells come from healthy donors instead of the patient, the treatments would be readily available "off-the-shelf," improving access and lowering costs. With Wugen's technology, a single donation can create hundreds of individual therapies.

NK-based therapy also gets a leg up on CAR-T in that NK cells do not trigger a cytokine storm.

"Our Memory NK cells don't require any genetic engineering to be potent cancer cell killers, and we've demonstrated this effectively in AML patients, with none of the toxic side effects that are commonly seen with CAR-T cell therapies. We've also developed a proprietary process that enables us to scale up the manufacturing so we can produce a commercially viable off-the-shelf product," Kemp told BioSpace.

Cytokine storm is a prevalent side effect in CAR-T cell recipients. An overresponse by the immune system caused by the release of cytokines by the CAR T cells can lead to widespread organ dysfunction.

Kemp took over as founding CEO McKearn transitioned to the board in April. Kemp's resume boasts decades of experience in pharma and biotech, with his most recent role heading up Takeda's cell therapies. A perfect match for spearheading Wugen's rapidly advancing cell therapies.

Just before Kemp came on, Wugeninked a dealwith Shanghai's Alpha Biopharma to commercialize its off-the-shelf cell products in Asia.

Funds from the Series B raise will go into propelling the memory NK platform, advancing the current program for severe AML, and take its other indications to their next steps both as monotherapies and in combination with antibody drugs - head & neck cancer, melanoma and solid tumors. Wugen's CD7-targeting CAR-T cell therapy will also advance for the treatment of T-cell leukemia and lymphoma.

"We are gearing up for a Wugen-sponsored multi-site open-label Phase I/II study of WU-NK-101 in AML, which is slated to open early 2022. Trials of WU-NK-101 in solid tumors will follow later in 2022," Kemp said.

He accredits their rapid success in the field of immunotherapies to his predecessor: "It's important to recognize that the solid foundation that we're benefiting from now with this financing event was carefully and skillfully built by John McKearn over the past 2-3 years."

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With $172 Million Raise, Wugen Brings Natural Killer Therapies to Solid Tumors Next - BioSpace