Category Archives: Cell Biology

Cell Biology

Lunaphore Technologies, University of Bern Partner on Colorectal Cancer Study – GenomeWeb

NEW YORK Lunaphore Technologies said on Thursday that it has partnered with the University of Bern to study tumor budding in colorectal cancer.

The partners will use Lunaphore's Comet immunostaining platform to study colorectal cancer tumor buds, which the company said are defined as a single tumor cell or a cluster of up to four cells that are lying at the invasive front of the primary tumor site and can be seen streaming through the stroma and entering vessels.

The platform, which combines a high-throughput stainer and a fluorescent microscope, will enable multiplexed immunostaining of tumor buds and the surrounding microenvironment in cancer tissue sections, according to Tolochenaz, Switzerland-based Lunaphore.

"We believe that [tumor buds] are a key component in the process of tumor dissemination and metastasis," Inti Zlobec, director of the translational research unit at the University of Bern's Institute of Pathology, said in a statement. "This project will be crucial to further our understanding of their biology and to extract novel prognostic factors from the tumor microenvironment."

The collaboration is being funded with a grant from the Swiss Innovation Agency.

In early 2020, Lunaphore raisedabout $2.1 million in Series C2 financing.

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Lunaphore Technologies, University of Bern Partner on Colorectal Cancer Study - GenomeWeb

Cell Biology

New Research Helps Explain the Diversity of Life and Paradox of Sex – SciTechDaily

New University of Arizona research finds that sexual reproduction and multicellularity drive diversity among different species.

There are huge differences in species numbers among the major branches of the tree of life. Some groups of organisms have many species, while others have few. For example, animals, plants, and fungi each have over 100,000 known species, but most others such as many algal and bacterial groups have 10,000 or less.

A new University of Arizona-ledstudy, published in the Proceedings of the Royal Society B, tested whether sexual reproduction and multicellularity might help explain this mysterious pattern.

We wanted to understand the diversity of life, said paper co-authorJohn Wiens, a professor in theDepartment of Ecology and Evolutionary Biology. Why are most living things animals, plants, and fungi?

To address this, Wiens worked with a visiting scientist in his lab, Lian Chen from Nanjing Forestry University in China. They estimated rates of species proliferation in 17 major groups that spanned all living organisms, including bacteria, protists, fungi, plants and animals. The hard part was to estimate how many species in each group were multicellular versus unicellular and how many reproduced sexually versus asexually. For five years, Chen sifted through more than 1,100 scientific papers and characterized the reproductive modes and cellularity of more than 1.5 million species.

They found that both multicellularity and sexual reproduction helped explain the rapid proliferation of animal, plant and fungal species. The rapid proliferation of these three groups explains why they now include more than 90% of Earths known species.

The duo also found that the rapid proliferation of sexual species may help explain the paradox of sex. The paradox is why so many species reproduce sexually, despite the disadvantages of sexual reproduction.

For sexual species, only half the individuals are directly producing offspring. In an asexual species, every individual is directly producing offspring, Wiens said. Sexual reproduction is not as efficient. Another disadvantage of sexual reproduction is that you do need two individuals to make something happen, and those two individuals have to be the right sexes. Asexual species, on the other hand, only need one individual to reproduce.

Chen and Wiens found a straightforward answer to the paradox of sex. The reason why there are so many sexual species is because sexual species actually proliferate more rapidly than asexual species. This had not been shown across all of life before.

They also found that another explanation for the large number of sexual species is that sexual reproduction and multicellularity are strongly associated across the tree of life, and that multicellularity helps drive the large number of sexual species.

Multicellularity is actually more important than sexual production. We did a statistical analysis that showed it is probably at least twice as important for explaining these patterns of diversity as sexual reproduction, Wiens said.

And while this study alone cant pinpoint exactly why multicellularity is so important, researchers have previously suggested that it has to do with the variety of cell types within a multicellular organism.

If youre a single cell, theres not much variety there, Wiens said. But multicellularity allows for different tissues or cell types and allows for diversity. But how exactly it leads to more rapid proliferation will need more study.

Chen and Wiens also tested how their conclusions might change if most living species on Earth were species of bacteria that are still unknown to science.

Most bacteria are unicellular and asexual. But because bacteria are much older than plants, animals, and fungi, they have not proliferated as rapidly, even if there are billions of bacterial species, Wiens said. Therefore, multicellularity and sexual reproduction still explain the rapid proliferation of animals, plants, and fungi.

Future work will be needed to understand how multicellularity and sexual reproduction drive biodiversity. Wiens is also interested in how some groups are both multicellular and reproduce sexually yet dont proliferate rapidly.

We have some ideas, he said. One example is rhodophytes, the red algae. These are mostly marine, and we know from animals that marine groups dont seem to proliferate as rapidly.

Reference: Multicellularity and sex helped shape the Tree of Life by Lian Chen and John J. Wiens, 28 July 2021, Proceedings of the Royal Society B.DOI: 10.1098/rspb.2021.1265

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New Research Helps Explain the Diversity of Life and Paradox of Sex - SciTechDaily

Cell Biology

Autophagy disruption may be at the root of early cognitive changes in Huntingtons disease – News-Medical.Net

Huntington's Disease (HD) is a progressive neurodegenerative condition characterized by motor, cognitive, and psychiatric symptoms, and motor symptoms are often preceded by cognitive changes. Recent evidence indicates that autophagy plays a central role in synaptic maintenance, and the disruption in autophagy may be at the root of these early cognitive changes. Understanding this mechanism better may help researchers develop treatments for patients with HD early in their disease progression, report scientists in a review article published in the Journal of Huntington's Disease.

In this review, experts describe how autophagy, the cellular process responsible for clearing old or damaged parts of the cell, plays a critical role supporting synaptic maintenance in the healthy brain, and how autophagy dysfunction in HD may thereby lead to impaired synaptic maintenance and thus early manifestations of disease. The line of research discussed in this review represents a previously unexplored avenue for identifying potential disease-modifying therapies for HD.

Like many neurodegenerative conditions affecting primarily cognition, such as Alzheimer's disease, preclinical and clinical data indicate that synapses, the part of brain cells responsible for communication between cells, are affected early in HD. We have long thought that autophagy played a role in the pathophysiology of HD, but what this role is has been unclear until recently. Recent evidence indicates that autophagy may be important in maintaining the synapse. This line of research has the potential to lead to identification of a drug target to treat HD early in the disease process."

Hilary Grosso Jasutkar, MD, PhD, Department of Neurology, Columbia University, and Ai Yamamoto, PhD, Departments of Neurology and Pathology and Cell Biology, Columbia University, New York, NY, USA

The authors first explore how cognitive dysfunction is an early manifestation of HD, and that similarly to other neurodegenerative diseases that primarily affect cognition, such as Alzheimer's disease, dementia with Lewy bodies, and frontotemporal dementia, early deficits in synaptic function may underlie these cognitive symptoms. Next, they review the growing evidence that the lysosome-mediated degradation pathway autophagy plays a central role in synaptic maintenance, and how the disruption in autophagy may contribute to early cognitive changes in HD.

The authors conclude that there are pathologic and imaging data in individuals with mutations in the Huntingtin protein (mHtt), as well as evidence from animal models with HD, that suggest that synapse dysfunction may occur early in HD, prior to cell death.

"Autophagy plays a specialized role in the maintenance and function of the synapse, and mHtt may disrupt this function, leading to the early synaptic changes seen in HD patients and model systems," explained Dr. Grosso Jasutkar. "These synaptic changes may then manifest as impairments in synaptic plasticity and thus cognitive changes early in the disease course. Given that neurons rely on synaptic input and feedback for cell health, it is possible that this disruption in synaptic signaling in and of itself contributes to cell death in HD."

"There is much work yet to be done in this field," added Dr. Yamamoto. "Although various groups have demonstrated individual components of this pathway, a direct causal relationship of mutant Htt leading to synaptic dysfunction and, in turn, cognitive impairments, has yet to be demonstrated."

"If the model described here is borne out, therapeutics aimed at enhancing the efficiency of synaptic autophagy early in the course of HD could be protective against early cognitive changes and potentially degeneration itself," concluded the authors.

HD is a fatal genetic neurodegenerative disease that causes the progressive breakdown of nerve cells in the brain. An estimated 250,000 people in the United States are either diagnosed with, or at risk for, the disease. Symptoms include personality changes, mood swings and depression, forgetfulness and impaired judgment, unsteady gait, and involuntary movements (chorea). Every child of an HD parent has a 50% chance of inheriting the gene. Patients typically survive 10-20 years after diagnosis.

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Journal reference:

Grosso Jasutkar, H & Yamamoto, A., (2021) Do Changes in Synaptic Autophagy Underlie the Cognitive Impairments in Huntingtons Disease?. Journal of Huntington's Disease. doi.org/10.3233/JHD-200466.

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Autophagy disruption may be at the root of early cognitive changes in Huntingtons disease - News-Medical.Net

Cell Biology

Synthetic Biology Could Be the Next Big Thing. Here Are 3 Stocks. – Barron’s

Synthetic biology is in its infancy, but its drawing comparisons to the internet of a generation ago. Bill Gates, Cathie Wood, and venture capitalist John Doerr are among those who are investing in synthetic biology companies.

What excites investors is the promise of programming the DNA of microorganisms like yeast as if they were computers and getting them to produce products more cheaply and with a lower carbon footprint than traditional manufacturing.

Synthetic biology could reduce the need for petroleum-based chemicals as well as for plant- and animal-based products, benefiting the environment. Proponents say that the total addressable market is over $1 trillion.

This is what it might have been like 25 years ago if some guy had walked up to you and said the internet was going to be an amazing investment and you had no idea what he was talking about, says Rick Schottenfeld, the general partner of the Schottenfeld Opportunities fund, an investor in Amyris. This is where we are with synthetic biology.

Yet for all the bold claims and hopes for an industry once known as industrial biotech, revenue overall currently totals less than $1 billion. And no one is making a profit.

Synthetic biology has so far produced mostly niche products like squalane, a moisturizer formerly sourced from shark liver; vitamin E; a sugar substitute; and vanillin. Amyris, which makes an estimated 70% of the worlds squalane using engineered yeast cells and sugar cane, says its efforts have saved as many as three million sharks a year.

The small scale of the industry at present hasnt dimmed investor interest in the three main plays on synthetic biology: Amyris (ticker: AMRS), Zymergen (ZY), and Ginkgo Bioworks. Ginkgo is due to go public in the current quarter through a merger with Soaring Eagle Acquisition (SRNG), a special-purpose acquisition company, or SPAC. It will be renamed Ginkgo Bioworks Holdings.

Investors may want to take a basket approach to the stocks. The combined market value of the three is $25 billion.

Synthetic biology, which blends biotechnology and industrial chemistry, isnt an easy concept to grasp. The magic of biology, Ginkgo CEO Jason Kelly has noted, is that cells run on something akin to a computers digital code. Instead of zeros and ones, the four DNA base pairs adenine, cytosine, guanine, and thymine guide cells.

Think of synthetic biology as hijacking the natural biology of the cell and reprogramming it to produce something of interest, says Doug Schenkel, a Cowen analyst who has Outperform ratings on Amyris and Zymergen. Rather than have yeast make beer, you hijack it to make the scent of a flower.

Programming DNA, of course, is harder than programming computers, but progress is coming quickly.

With impressive DNA coding capabilities, Ginkgo views itself as the industrys Amazon Web Services, working with companies in consumer, pharmaceutical, and agricultural areas to design microorganisms and cells from mammals to make desired products or drugs. It provided help to Moderna (MRNA) in its development of the Covid-19 vaccine.

Ginkgo is looking to build a platform to make biology and cells as easy to program as computers, says Kirsty Gibson, a portfolio manager at Baillie Gifford, which is buying stock in Ginkgo as part of the SPAC deal. Whats really exciting is that its not limited by industry verticalsagricultural, flavor and fragrances, pharmaceuticals, food.

Amyris controlling shareholder is one of the countrys most successful venture capitalists, John Doerr, who was an early investor in Alphabet (GOOGL) and Amazon.com (AMZN).

I believe synthetic biology will continue to be a big part of making our planet healthier and our future more sustainable, Doerr tells Barrons. Amyris is delivering on the promise of synthetic biology. Doerr is chairman of Kleiner Perkins, the Silicon Valley venture-capital firm.

Synthetic-biology manufacturing often involves large fermentation tanks filled with genetically re-engineered microorganisms like yeast that are filtered out of the finished product. This manufacturing technique uses little energy, but is unproven on a major scale.

Amyris is the furthest along, based on revenue and products. It projects $400 million in 2021 sales and break-even results based on earnings before interest, taxes, depreciation, and amortization, or Ebitda. Amyris, whose shares trade around $13.50, is valued at $4 billion and looks like the best bet. Its CEO, John Melo, sees a potential $2 billion in sales and $600 million of Ebitda in 2025.

With an all-star investor lineup including Gates Cascade Investment, Ginkgo has generated the most buzz. Based on the SPAC transaction, it has the highest market value of the threeabout $18 billion. Its projected 2021 revenue, however, is very modest, about $100 million.

Perhaps reflecting its lofty valuation, Soaring Eagle Acquisition shares havent budged since the May SPAC deal. The result is that investors can buy the stock for $9.95, a slight discount to the price of $10 at which several prominent investment firms including Cathie Woods Ark Investment Management and Baillie Gifford, an early backer of Tesla (TSLA), agreed to invest $775 million as part of the SPAC merger with Ginkgo.

Ginkgo calls its microorganism design fees foundry revenues. It has royalty deals or equity stakes in 54 partners, and is working with Bayer (BAYRY), Roche Holding (RHHBY), Sumitomo Chemical (4005.Japan), and Robertet (RBT.France), a maker of flavors and fragrances.

Zymergen, which went public in April at $31, is focused on consumer electronics. It has developed a durable optical film called Hyaline, which can be used on foldable cellphones and tablets. Now trading around $35, Zymergen is valued at $3.5 billion. SoftBank Goups (SFTBY) venture fund and Baillie Gifford are investors.

E=estimate. *SRNG is in the process of merging with Ginkgo Bioworks, with the result of Ginkgo becoming a publicly-traded company. **Since IPO earlier this year. Note: Ginkgo sales are foundry only; SRNG market value is post Ginkgo merger.

Sources: Bloomberg; company reports; HSBC

Amyris shares have doubled this year as the company has delivered strong revenue growth.

Amyris takes sugar, selling for under 50 cents per kilogram (22 cents a pound), and converts it into skin creams and other direct consumer-care products that retail for over $50 for a 50 milliliter bottle (1.7 ounces), wrote HSBC analyst Sriharsha Pappu in initiating coverage of Amyris with a Buy rating and $20 price target.

The company uses bioengineered yeast to produce an array of products from sugar cane, including vitamin E, squalane, vanillin (the flavoring for vanilla), and a sugar substitute using a compound called Reb M that is normally found in the stevia plant.

The vanillin, CEO Melo says, is equivalent in quality to Madagascar vanillin and is sustainably produced from sugar cane. We dont have to worry about water or land use or child labor. Madagascar is the worlds top producer of vanillin.

Cosmetics are a major focus. Amyris launched the Biossance line of products in 2017, selling directly to consumers and through retailers like Sephora. A major ingredient in many Biossance products is squalane, a version of squalene, a naturally occurring moisturizer in the skin.

Melo sees the companys consumer branded business, including Biossance and Purecane, a sugar substitute, as the key growth drivers. Up next is an acne product. Amyris is also an ingredient supplier. Melo sees branded products generating $150 million of sales this year, up from about $50 million in 2020, and topping $300 million in 2022.

Amyris has introduced its own brands and built its own factories, in contrast with Ginkgo, which pursues an asset-light strategy of developing microorganisms and letting partners do the manufacturing and marketing.

Our focus and what makes us successful is that weve figured out which products to go into first to drive real revenue and a business rather than being a science experiment, says Melo, who isnt fond of the Ginkgo approach, saying that it has yielded little in the way of recurring revenue so far. Having your own factory is critical. It [manufacturing] is the bottleneck today for unleashing the power of synthetic biology.

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It also matters for profits. When we sell a kilo of squalane directly to the consumer, we get $2,500 per kilo, Melo says. When I sell it to another beauty company, I am getting about $30 per kilo. $30 versus $2,500think about that math.

Randy Baron, a portfolio manager at Pinnacle Associates, believes that there is huge potential in Amyris. It could generate 35% top-line growth for the next decade-plus, he says. Trading at a big discount to Ginkgo, Amyris could hit $30 by the end of this year and $75 by the end of 2022, he says.

Zymergens goal is to develop bioengineered products in half the time and at a tenth the cost of conventional manufacturing. None of its products are on the market yetits Hyaline film is now being evaluated by partners. Zymergen is also developing an insect repellent free of DEET, a chemical that makes many consumers uneasy.

Zymergen has a large addressable market, and it can work with different host microbes, says Cowen analyst Schenkel, referring to yeast, bacteria, and fungi. He has an Outperform rating on the stock. If it can succeed with Hyaline, there will be greater confidence that it can succeed with some of the 10 other disclosed products in development.

Ginkgo generates revenue from allowing companies to use its cell-programming infrastructure. In a presentation, Ginkgo projected that cell programming, or foundry revenue, would rise to $1.1 billion in 2025 from $100 million this year.

CEO Kelly says this revenue understates the value creation because of the royalties or the equity stakes in its customers, which the company put at roughly $500 million. Ginkgo projected that it could have over 500 partner programs by 2025, up almost tenfold from now. Kelly says it will take time for royalties to materialize, but the rising value of the stakes is an indication of value creation.

We are effectively an app store or ecosystem for folks to write cell programs and bring them to market, he says. We improve with scale. The more programs we develop, the better it gets. Its a network effect.

The CEO plays down the manufacturing issue, noting that it isnt a problem in drug development, where the company has a focus. Amyris business is bringing products to market; Ginkgo is the app store, he says.

Its too early to say whether synthetic biology will live up to the hype, but these three stocks looked poised to manufacture gains for investors.

If a small percentage of programs that Ginkgo and Zymergen are working on become real, says Cowens Schenkel, the revenue numbers could get really big. The question is when does that happen and how much credit do you give them now.

Write to Andrew Bary at andrew.bary@barrons.com

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Synthetic Biology Could Be the Next Big Thing. Here Are 3 Stocks. - Barron's

Cell Biology

Professor’s Drive to Help the Community Gets Underway for 13th Year | Newsroom – UC Merced University News

Merced is a community with a lot of poverty, made worse with the Great Recession in 2009 and the COVID-19 pandemic. To help people in need, Professor Patti LiWang has been leading a diaper and toilet paper drive for the past 12 years.

When we moved here, the recession hit. It was hard for us, a two-income family, so I understood it must be much harder for one- and low-income families, she said. Then I read an interview with a social worker who said she had seen people re-using diapers and taking napkins from fast-food restaurants for toilet paper. I thought we had to do something.

She arranged to put a donation box in the Science and Engineering 1 Building, where her department, Molecular and Cell Biology, is housed and told everyone she knew about the drive. People began donating, sometimes boxes of diapers, sometimes money. Over the years, a few others put donation boxes in their buildings and helped gather more goods.

LiWang takes the donations to the Merced County Food Bank, which distributes them either directly or through many local food pantries.

Last year, during the pandemic lockdown, LiWang took more monetary donations and gathered some boxes of diapers and packages of toilet paper from peoples front porches and doorsteps contact-free and managed to donate more than 6,000 diapers.

We need all size diapers, all size packages, she said. I usually buy the Target brand because the name-brands are more expensive, but we accept any kind.

The drive has begun for this year. Theres a donation box in S&E1 near the vending machines and one at the Downtown Campus Center near the Public Relations Department on the first floor.

If you would like to host a box in your building and can serve as the point person to let LiWang know when donations are ready for pickup, or if you would like to donate money (cash or checks), email LiWang. She also has a Venmo account, @Patricia-LiWang, to accept donations.

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Professor's Drive to Help the Community Gets Underway for 13th Year | Newsroom - UC Merced University News

Cell Biology

Unlocking the role of biological clock molecules in cancer cells – Research Matters

An artistic representation of the L-I-C network in cancer cells depicted in the Indian art form, Yakshagana and Somana Kunitha style (Credit Kirti Lathoria)

Our body functions tune to the circadian rhythm the 24- hour day-night cycle. A biological clock comprising special cell components and genes keep track of time and operate synchronously in a complex molecular mechanism. The timekeeping molecules control several crucial physiological processes like metabolism, cell division and proliferation, immune response, and gene expression (decoding genetic information to produce proteins) to maintain the delicate balance of the rhythm. However, science has shown that when the circadian rhythm is severely hampered, some cells break away from the clock control and turn cancerous.

Existing literature shows that cancer cells have an erratic circadian rhythm and abnormal metabolism. Besides, they sustain the onslaught of cytokines from the immune system. However, how exactly these processes promote cancer cell growth has remained elusive.

A team of researchers from the National Brain Research Centre, Manesar, has decoded the interplay between cancer cell metabolism, pro-inflammatory cytokines (inflammation-causing immune molecules), and the biological clock molecules. Their study shows that the cancer cells chemically rewire the production of an inflammation-inducing mediatorIL-1 and lactate - a by-product of cancer cell metabolism. Furthermore, these two components chemically manipulate the clock machinery to trigger further production of lactate and IL-1. Thus the three components work in tandem to promote a vicious loop of tumour growth. The team has published their results in the journal Molecular and Cellular Biology.

The results of this research will provide a framework for cancer chronotherapy a novel treatment method by which anticancer drugs are administered at optimal timings to enhance their chemotherapeutic potential.

The team conducted laboratory experiments on cultured brain cancer cells by employing several molecular testing methods to observe the function of the cell processes.

Cancer cells hoodwink the circadian checkpoints and alter their metabolism to feed the rapidly growing cells. The common feature of cancer cell metabolic reprogramming is glucose addiction a heightened glucose uptake as compared to a normal cell, says Dr Ellora Sen, Principal Investigator of the study. Unlike healthy cells, cancer cells metabolise glucose even in the presence of oxygen. This aerobic glycolysis produces large amounts of lactate, resulting in a highly acidic environment around the tumour a hallmark feature of cancer. Also, the high acidic environment triggers some genes which help tumour growth.

When there is a disease or injury, the immune system dispatches pro-inflammatory cytokines to induce a mild inflammation at the injury site. The inflammation destroys the diseased cells and facilitates healing. IL-1 is once such cytokine released in response to cancerous growths. Our findings indicate that high lactate levels trigger expression of IL-1, says Dr Sen.

The rapidly multiplying cancer cells activate the immune system to send a surge of IL-1 cytokines. In our earlier study, we found that the cancer cells use IL-1 to enhance the expression of another protein called Hexokinase (HK2), which increases the glucose uptake, adds Pruthvi Gowda, first author of the study. With HK2 promoting glucose intake, the cancer cells get more fuel to multiply.

The team then found that high lactate and IL-1 also increased two crucial circadian molecules, Clock and Bmal1. Bmal1 regulates cell division and is bound to the Clock molecule in what is chemically called a transcriptional dimer. In healthy cells, Clock and Bmal1 work in a complementary manner to control cell growth. However, the researchers noticed that both lactate and IL-1 chemically modify Bmal1 to increase the Clock -Bmal1 binding stability.

Further molecular experiments revealed that Clock/Bmal1 activated a Lactate producing enzyme called LDH-A and IL-1, suggesting the presence of a feed-forward network, says Dr Sen. The researchers thus posit that the three components work in a mutually supportive loop that facilitates the rapid growth of the tumour cells.

To establish their results, the team knocked down Clock-Bmal1 molecules in cancer cells. They noticed that downregulating the clock proteins resulted in lower lactate and IL-1 levels. The team further correlated their results for stomach and cervical cancer cell lines and conducted computer simulations on clinical samples data. They observed that patients who had lower Clock, Bmal1, LDHA and IL-1 levels in their samples survived longer.

The team now looks forward to developing a mathematical model for Lactate- IL-1- Clock (LIC) feed-forward regulatory structure in collaboration with IIT Mumbai. When fitted to the patient molecular profile of LIC components, the model could provide valuable inputs for cancer chronotherapy.

This article has been run past the researchers, whose work is covered, to ensure accuracy.

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Cell Biology

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…

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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.

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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Cell Biology

Bioengineering discovery paves way for improved production of bio-based goods using Bakers yeast – Newswise

Newswise Scientists have uncovered a way to control many genes in engineered yeast cells, opening the door to more efficient and sustainable production of bio-based products.

The study, published in Nucleic Acids Research by researchers from DSMs Rosalind Franklin Biotechnology Center in Delft, the Netherlands, and the University of Bristol, has shown how to unlock CRISPRs potential for regulating many genes simultaneously.

Bakers yeast, or Saccharomyces cerevisiae to give it its full name, is considered as a workhorse for biotechnology. Not only has it been used for producing bread and beer for thousands of years, but today it can also be engineered to produce an array of other useful compounds that form the basis of pharmaceuticals, fuels, and food additives. However, achieving optimal production of these products is difficult, requiring the complex biochemical networks inside the cell to be rewired and extended through the introduction of new enzymes and the tuning of gene expression levels.

Klaudia Ciurkot, first author of the study and an EU-funded industrial PhD student based at DSM stated: To overcome the challenges of optimising S. cerevisiae cells for bio-production, we explored the use of a less widely employed CRISPR technology based on the Cas12a protein. Unlike the Cas9 protein that is more commonly used, Cas12a can be rapidly programmed to interact with sequences that are responsible for controlling gene expression and easily targeted to many different sequences at the same time. This made it an ideal platform for carrying out the complex gene regulation often required for producing industrially relevant compounds.

She went on to add: What was particularly exciting for me was that this study is the first to demonstrate Cas12as ability to control gene expression in S. cerevisiae and through joint research across DSM and the University of Bristol, we were able to figure out the rules for how this system is best designed and used.

Thomas Gorochowski, a co-author on the work and Royal Society University Research Fellow based in the School of Biological Sciences at the University of Bristol further stated: It is hugely exciting that Cas12a has been shown to work so well for gene regulation in the yeast S. cerevisiae, an organism that has huge industrial importance. In addition, the systematic approach we have taken to pull apart and analyse the many difficult aspects of the system, act as a firm foundation for future optimisation.

In addition to analysing how the Cas12a-based system is best engineered, the scientists went on to show its use in robustly controlling the production of -carotene an industrially important compound used in production of food additives and nutraceuticals.

Ren Verwaal, senior author and Senior Scientist at DSM ended by stating: By demonstrating the capabilities of this system to control the biosynthesis of -carotene, we have opened the gates to its broader application for other key bio-based products. I cannot wait to see how our system is used to develop more sustainable production platforms for everyday products we all rely on.

The study was funded by the European Unions Horizon 2020 Research and Innovation Programme (ITN SynCrop) under the Marie Skodowska-Curie grant agreement No 764591, BrisSynBio, a BBSRC/EPSRC Synthetic Biology Research Centre, the Royal Society, and supported by the Bristol BioDesign Institute (BBI).

Paper

Efficient multiplexed gene regulation inSaccharomyces cerevisiaeusing dCas12a inNucleic Acids Research by Klaudia Ciurkot, Thomas E. Gorochowski, Johannes A. Roubos and Ren Verwaal.

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Bioengineering discovery paves way for improved production of bio-based goods using Bakers yeast - Newswise

Cell Biology

New algorithm can be a more effective way to analyze models of biological systems – News-Medical.Net

From biochemical reactions that produce cancers, to the latest memes virally spreading across social media, simple actions can generate complex behaviors. For researchers trying to understand these emergent behaviors, however, the complexity can tax current computational methods.

Now, a team of researchers has developed a new algorithm that can serve as a more effective way to analyze models of biological systems, which in turn allows a new path to understanding the decision-making circuits that make up these systems. The researchers add that the algorithm will help scientists study how relatively simple actions lead to complex behaviors, such as cancer growth and voting patterns.

The modeling framework used consists of Boolean networks, which are a collection of nodes that are either on or off, said Jordan Rozum, doctoral candidate in physics at Penn State. For example, a Boolean network could be a network of interacting genes that are either turned on -- expressed -- or off in a cell.

Boolean networks are a good way to capture the essence of a system. It's interesting that these very rich behaviors can emerge out of just coupling little on and off switches together -- one switch is toggled and then it toggles another switch and that can lead to a big cascade of effects that then feeds back into the original switch. And we can get really interesting complex behaviors out of just the simple couplings."

Jordan Rozum, doctoral candidate in physics at Penn State

"Boolean models describe how information propagates through the network," said Rka Albert, distinguished professor of physics and biology in the Penn State Eberly College of Science and an affiliate of the Institute for Computational and Data Sciences. Eventually, the on/off states of the nodes fall into repeating patterns, called attractors, which correspond to the stable long-term behaviors of the system, according to the researchers, who report their findings in the current issue of Science Advances.

Even though these systems are based on simple actions, the complexity can scale up dramatically as nodes are added to the system, especially in the case when events in the system are not synchronous. A typical Boolean network model of a biological process with a few dozen nodes, for example, has tens of billions of states, according to the researchers. In the case of a genome, these models can have thousands of nodes, resulting in more states than there are atoms in the observable universe.

The researchers use two transformations -- parity and time reversal -- to make the analysis of Boolean networks more efficient. The parity transformation offers a mirror image of the network, switching nodes that are on to off and vice versa, which helps identify which subnetworks have combinations of on and off values that can sustain themselves over time. Time reversal runs the dynamics of the network backward, probing which states can precede an initial input state.

The team tested their methods on a collection of synthetic Boolean networks called random Boolean networks, which have been used for than 50 years as a way to model how gene regulation determines the fate of a cell. The technique allowed the team to find the number of attractors in these networks for more than 16,000 genes, which, according to the researchers, are sizes larger than ever before analyzed in such detail.

According to the team, the technique could help medical researchers.

"For example, you might want a cancer cell to undergo apoptosis (programmed cell death), and so you want to be able to make the system pick the decisions that lead towards that desired outcome," said Rozum. "So, by studying where in the network these decisions are made, you can figure out what you need to do to make the system choose those options."

Other possibilities exist for using the methods to study issues in the social sciences and information technology.

"The propagation of information would also make an interesting application," said Albert. "For example, there are models that describe a society in which people have binary opinions on a matter. In the model people interact with each other, forming a local consensus. Our methods could be used to map the repertoire of consensus groups that are possible, including a global consensus."

She added that uses could extend to any area where researchers are trying to find ways to eliminate pathological behaviors, or drive the system into more normal behaviors.

"To do this, the theory existed, methodologies existed, but the computational expense was a limiting factor," said Albert. "With this algorithm, that has to a large part been eliminated."

The researchers have developed a publicly available software library and the algorithms have already been used in studies carried out by her group, according to Albert.

Computations for the study were performed using Penn State's Roar supercomputer.

Albert and Rozum worked with Jorge Gmez Tejeda Zaudo, postdoctoral associate at Broad Institute and Dana-Farber Cancer Institute; Xiao Gan, postdoctoral researcher at the Center for Complex Network Research; and Dvid Deritei, graduate research fellow at Semmelweis University.

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New algorithm can be a more effective way to analyze models of biological systems - News-Medical.Net

Cell Biology

Cross-Resistance: One Cancer Therapy Can Undermine the Next – The Scientist

Targeted therapy and immunotherapy are often employed as a one-two punch to treat certain cancers, but sometimes this approach falls short. In a study published on July 15 in Nature Cancer, researchers found that dendritic cells, cells crucial for activating the immune system during immunotherapy, were less active and less numerous in mouse models of melanoma that had become resistant to targeted therapy, explaining why these tumors were less sensitive to immunotherapy. Stimulating dendritic cells restored the tumors response to immunotherapy.

This study provides mechanistic insight into a phenomenon that many melanoma experts have observed firsthand in the clinic and that has recently been described in retrospective studies: poor response to immunotherapy following the development of resistance to [targeted] therapy, Brent Hanks, a medical oncologist at Duke University who was not involved in this study, tells The Scientistin an email.Overall, this is an important contribution to melanoma research that may have implications in the management of other . . . cancers as well.

Indeed, it was early clinical data that sparked the interest of Anna Obenauf, a cancer researcher at the Research Institute of Molecular Biology in Vienna, Austria, who led the international team behind the new study. This is a clinical puzzle in a way, because how can these two different types of therapies be connected to each other, and this resistance to one lead to cross-resistance to the other? While targeted therapy blocks specific molecular pathways within cancer cells to stop proliferation, immunotherapy works by stimulating immune cells to eradicate tumor cells.

Their work showing that you can reverse the phenotype by adding in these dendritic cellstimulating agents was a nice proof of principle to show that it really was those cells that were being restricted.

Brian Ruffell, Moffitt Cancer Center

Obenauf and her colleagues started by recapitulating these clinical observations in a mouse model. Using two murine melanoma cell lines, the researchers established tumors in mice, which they treated with dabrafenib, a targeted therapy approved for use in the treatment of melanoma patients who have a mutation in the BRAF gene. Dabrafenib interrupts the MAP kinase pathway by inhibiting the B-Raf enzyme. While the tumors initially responded to the therapy, the cancer eventually relapsed and became resistant. Taking cells from the treatment-sensitive tumors and the treatment-resistant tumors, the researchers established cell lines. These cells were again injected into mice, which were treated with anti-PD-1 or anti-CTL-4 checkpoint inhibitors, immunotherapies aimed at releasing the brake on the immune system. Anti-PD-1 and anti-CTL-4 checkpoint inhibitors are also approved for treating certain patients with melanoma.

Using this approach, the researchers could implant resistant tumors into mice that had not been exposed first to the targeted therapy. This allowed the team to assess whether the targeted therapy has a direct effect on immune cells that could lead to immunotherapy resistance, or if something else is going on within the tumor. It turned out to be the latter. [Treatment-resistant] tumors are indeed cross-resistant to checkpoint inhibitors, says Obenauf.

Immunotherapies usually act by promoting T cell responses, so the group looked more closely at how the mices T cells behaved. While T cells were able to kill treatment-resistant tumor cells in vitro,when the researchers used a mouse model lacking endogenous T cells and added T cells they could track using luciferase, they saw that the T cells couldnt infiltrate the resistant tumor; the tumor kept growing. That has led us to the question [of] whether the tumor microenvironment is mediating resistance, Obenauf recalls.

So the researchers created mix-and-match melanoma mice. When they placed treatment-resistant tumor cells within a large treatment-sensitive tumor, the resistant tumor cells were killed. It seemed that treatment-sensitive tumors had an immune-permissive tumor microenvironment, Obenauf explains. Conversely, when the researchers placed treatment-sensitive cells within a large treatment-resistant tumor, the cells survived, apparently shielded from T cellmediated killing.

A tumor naive to targeted therapy (top) contains many more immune cells (red and green) than one that has acquired resistance (bottom).

IMP/Izabela Krecioch

RNA sequencing and flow cytometry analysis revealed that dendritic cells, a cell type crucial for activating the immune system during immunotherapy, were less abundant in mice with treatment-resistant tumors. When the researchers co-cultured dendritic cells with T cells, they saw that the dendritic cells from resistant tumors didnt activate T cells or spur them to proliferate as dendritic cells from sensitive tumors did. Collaborating with a team at the University of Sydney in Australia, the group acquired biopsies from patients with melanoma who were treated with a targeted therapy. Once the patients had become resistant to the treatment, their tumors contained fewer dendritic cells than before.

Collectively, the results suggest that a drop in dendritic cells generates an immune-evasive tumor microenvironment that is poorly responsive to subsequent checkpoint inhibitor immunotherapy, Hanks explains.

Notably, the effect was reversible. After treating the mouse models with experimental immunostimulants that mature and expand dendritic cell pools, the researchers saw greater numbers of T cells infiltrating the animals tumors, which shrunk as a result. Their work showing that you can reverse the phenotype by adding in these dendritic cellstimulating agents was a nice proof of principle to show that it really was those cells that were being restricted, Brian Ruffell, a cancer immunologist at the Moffitt Cancer Center who was not involved in this study, tells The Scientist.

I think this [study] really breaks down some of the biology of why youd want to treat patients with immunotherapy before you come in and allow resistant clones to develop from targeted therapy, Ruffell adds. From a basic science point of view, it really helps to add to the growing body of literature that we need to study all therapies in the context of immunotherapy or the immune system.

To understand how cells were developing cross-resistance, Obenauf and colleagues analyzed the transcriptomes of cells from both mice and patient samples that had grown resistant to a therapy that targeted the MAP kinase signaling pathway. A hyperactive MAP kinase pathway leads to uncontrolled cell proliferation but is turned down by the inhibitor, and tumors shrink in response. When tumors relapse and become resistant to inhibitors, the MAP kinase pathway is frequently re-activated.

We can very strongly conclude that that pathway reactivation is whats driving the immune therapy resistance.

Kristian Hargadon, Hampden-Sydney College

In their samples, Obenaufs team identified a signature of genes that are differentially expressed in targeted therapyresistant tumors versus sensitive tumors. Using a computational analysis to find the regulators that govern this genetic signature, the scientists found that the MAP kinase signaling pathway was turned on again in resistant tumors and apparently now driving immune evasion. It was surprising that the differences between the [treatment-sensitive] and the [treatment-resistant] tumors were predicted to be driven by the MAP [kinase] pathway, Obenauf says, because the [treatment sensitive] tumors, despite the MAPK pathway being already hyperactive, were so sensitive to immunotherapy, whereas the [treatment resistant] tumors, where the MAPK pathway is being re-activated, were so resistant to immunotherapy.

It turned out that the MAP kinase pathway in resistant tumors more strongly drives gene expression of target genes than it does in sensitive tumors. Components of the pathway also had access to new gene regulatory sites, meaning that they could drive the expression of different genes. The MAP kinase pathway, the same pathway that is very important for tumor initiation, is rewired and enhanced in this process of therapy resistance to establish a very different immune phenotype, says Obenauf.

We can very strongly conclude that that pathway reactivation is whats driving the immune therapy resistance, saysKristian Hargadon, a biologist at Hampden-Sydney College not connected with the study. And that is something that people would not have expected up until this point, yet now that explains a lot of previous observations.

Pulling all these strands together, the team treated mice that had targeted treatmentresistant tumors with a MEK inhibitor, which inhibits the MAP kinase pathway at a different point than does the targeted treatment used initially. In vitro, this inhibition reverted the expression of 80 percent of the genes that formed the signature for resistance back to the treatment-sensitive expression signature. When mice with a treatment-resistant tumor were given the MEK inhibitor, dendritic cells became more numerous and active, inducing T cell proliferation. When the researchers gave the animals immunotherapy, the T cells were able to bring the tumors under control, and the mice survived longer. The effects were quite drastic, indicating that the MAP kinase pathway along with the dendritic cells really are responsible for mediating cross-resistance, says Obenauf.

This is a very elegant, intricate, thorough study, Hargadon concludes. Several different tumor models were studied, several different therapeutic regimens were evaluated, all pointing to the same phenomenon here.

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Cross-Resistance: One Cancer Therapy Can Undermine the Next - The Scientist