Category Archives: Cell Biology

Cell Biology

Jounce Therapeutics, Inc. (JNCE) Q4 2019 Earnings Call Transcript – Motley Fool

Image source: The Motley Fool.

Jounce Therapeutics, Inc.(NASDAQ:JNCE)Q42019 Earnings CallFeb 27, 2020, 8:00 a.m. ET

Operator

Good morning ladies and gentlemen and welcome to the Jounce Therapeutics Fourth Quarter and Full Year 2019 Earnings Conference Call. [Operator Instructions].

I will now turn the call over to your host Komal Joshi with Jounce Therapeutics. Please go ahead.

Komal Joshi -- Head of Investor Relations

Thank you operator. Good morning and welcome to the Jounce Therapeutics Quarter and Full Year 2019 Financial Results Conference Call. This morning we issued a press release which outlines the topics that we plan to discuss today. The release is available in the Investors and media section of our website at http://www.jouncetex.com. Speaking on today's call will be our CEO and President Dr. Rich Murray who will discuss our pipeline progress and key milestones for 2020 followed by our CMO Dr. Beth Trehu who will provide an update on our clinical activities. And lastly our CFO Kim Drapkin will review our full year 2019 financial results and 2020 guidance. We will then open the call for your questions.

Before we begin I would like to remind everyone that today's discussion will include statements about our future expectations plans and prospects that constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors including the risk factors discussed in our SEC filings. In addition any forward-looking statements represent our views only as of today February 27 2020 and should not be relied upon as representing our views as of any subsequent date. While we may elect to update these forward-looking statements at some point in the future we specifically disclaim any obligation to do so even if our views change.

With that I will now turn the call over to Rich.

Richard Murray, Ph.D. -- Chief Executive Officer and President

Thanks Komal and good morning everyone. As we reflect on 2019 I'd like to note the meaningful advancements Johns has made to further progress our growing IO pipeline toward several key milestones that we set forth in early 2019. That progress stems from our translational science platform driving new IO therapies to the clinic as well as analyzing patient samples from our clinical trials to inform new science-driven development paths. The latter is best illustrated by our lead Phase II program vopratelimab which represents what we believe will be necessary to make a meaningful impact for patients who are not benefiting from today's IO therapies. For vopra we made significant progress over the course of 2019. First the introduction of our two vopra development paths. Based on the results of extensive reverse translation allowances we identified important biomarker differences between responding and non responding patients enabling the emerge and select trials. Next the exciting data from ICONIC at AACR where we showed improved responses progression-free survival and overall survival directly linked to the treatment-emergent ICOS hi CD4 T cells.

These cells are a vopra-associated pharmacodynamic biomarker not seen with PD-1 inhibitors. Next the identification of a predictive biomarker TIs vopra to be used for patient selection in upcoming select trial which we believe will allow us to select patients more likely to generate ICOS hi CD4 T cells in the presence of vopra and potentially experience clinical benefit. And the work we've done with dosing and schedule which may be an important feature of how to optimize activity of stimulatory rather than inhibitory based immunotherapies. As we look to 2020 the significant unmet need faced by many cancer patients continues to be at the forefront of everything we do. Beth will take you through more details on both EMERGE and SELECT in a moment. But before turning the call over to her I'd like to take this opportunity to reflect on the unmet need vopra could have a major impact starting in non-small cell lung cancer. The last decade has been very exciting with game-changing treatment advances in oncology made by approved checkpoint inhibitors. As PD-1 inhibitors expand further and further into frontline therapy a growing number of patients who have progressed on these therapies need new treatment options. For example we estimate approximately 90% and of non-driver mutation frontline non-small cell lung cancer patients in the U.S. receive a PD-1 or PD-L one inhibitor as part of their initial therapy.

And the majority of those patients either relapse or do not respond creating a new growing area of unmet need. Standard of care for this patient population is docetaxel which has a low response rate and the challenging toxicities associated with chemotherapy. Part of the vote provision is to provide better treatment options for patients in this setting. And that market opportunity is substantial. With more than 40000 patients in the U.S. each year in just this particular setting. We continue to believe that novel approaches that are independent of the PD-1 inhibitor CD8 focused biology will be required to derive meaningful benefit in the growing population of patients who progressed on PD-1 inhibitors. Fundamental immunology research over the decades emphasize the importance of CD4 T cells and their central role in orchestrating a more complete overall immune response and speaks to the potential opportunity for vopra. Our vopra strategy is highly differentiated from the majority of other studies in this patient population most of which employ retreatment of patients who have already progressed on a PD-1 inhibitor with a PD-1 inhibitor again along with another agent. In the PD-1 inhibitor naive population the use of a predictive biomarker may support improved outcomes in a chemo-free immunotherapy combo regimen.

As we recently presented our upcoming select trial uses the TIs vopra biomarker to select patients for treatment with vopra plus our PD-1 inhibitor JTX-4014. We believe TIs vopra positive patients at baseline have a higher likelihood of generating ICOS hi CD4 T cells in the presence of vopra and that's a potentially greater chance of clinical benefit. Beyond our clinical programs we continue to make progress advancing our earlier-stage pipeline using our translational science platform. We continue to believe that our strategy of discovery and developing IO therapies aimed at immune cell types beyond the traditional CD8 cell is an area of opportunity to bring more benefit to patients. Notably we advanced our next development candidate to come from our platform JTX-1811 which is currently an IND-enabling activities and is on track for first half 2021 IND filing. JTX-1811 is a monoclonal antibody engineered to deplete tumor resident T regulatory cells. While sparing other types of T cells.

We tried to present additional scientific data supporting the development of JTX-1811 at the upcoming AACR meeting in April. On the corporate development front we demonstrated external validation with the out-licensing of our macrophage candidate JTX-8064 to celgene. That was part of a broader renegotiation with Celgene and we now have the full unencumbered global rights to vopra JTX-4014 GTX-1811 and our entire discovery pipeline. On the heels of a strong 2019 of pipeline execution and corporate development we are poised for an important year of new clinical data and key milestones in 2020. To reiterate we plan to report preliminary efficacy and related biomarker data for vopra from the IMERGE trial in the second half of 2020 initiate the SELECT trial using TIs vopra in mid-2020 present data on JTX-1811 at the 2020 AACR meeting continue IND-enabling activities for JTX-1811 with an expected IND filing in the first half of 2021 and continue to work on advancing multiple new targets from our discovery pipeline.

With that I'll now turn the call over to Beth to further discuss our clinical pipeline and science in more detail.

Elizabeth Trehu, M.D. -- Chief Medical Officer

Thanks Rich and good morning everyone. As Rich mentioned 2020 is an important year of new clinical data and key milestones for Jounce building on our key clinical learnings in 2019. Beginning with our vopra program we continue to make significant progress and have introduced two different development paths based on our reverse translational analyses. The first approach is our induction strategy in the EMERGE trial; and the second is our patient selection strategy in the SELECT trial using our predictive biomarker TIs vopra. Both EMERGE and select trials are based on three major learnings from ICONIC. First we identified treatment-emergent ICOS hi CD4 T cells in the peripheral blood of patients treated with vopra alone or in combination with nivolumab that are associated with clinical benefit including response rate progression-free survival and overall survival. We've shown that emergence of these cells does not occur with PD-1 inhibitor therapy and therefore we believe that they are vopra-specific cells. We have also demonstrated that ICOS hi CD4 T cells expand and persist throughout durable responses some over two years. Second we identified an RNA signature in baseline tumor biopsies which we call TIS vopra which is optimized for prediction of emergence of ICOS hi CD4 T cells and predicted clinical benefit in ICONIC. And third we identified what we believe is a more optimal dosing regimen for vopra.

All of our vopra trials are built upon the fundamental science of our founders coupled with the reverse translational analyses from our ICONIC trial. Another key learning has been that vopra activity requires the presence of primed ICOS hi CD4 T cells. All of this work has culminated in our two vopra development paths. First the induction path in which ICOS hi CD4 T cells are induced by another agent prior to administration of vopra. The study for the induction path is the EMERGE trial which is a Phase II open-label multicenter trial using ipilimumab or ipi to induce ICOS hi CD4 T cells prior to vopra administration. The trial is under way in PD-1 experienced patients with non-small cell lung cancer. As Rich mentioned this is an area of high unmet need as PD-1 inhibitors have moved into frontline settings. As we have detailed previously we are implementing a new combination dosing strategy for the EMERGE and SELECT trials which we believe is more appropriate for an agonist. Given our understanding of the kinetics of induction and expansion of ICOS hi CD4 T cells by ipi and vopra respectively we believe that the unique combination dosing and sequencing strategy that we are using in EMERGE optimizes both ICOS hi CD4 T cells and co-stimulatory biology. We believe JOunce has a compelling and differentiated approach to immuno-oncology combination therapy.

We expect to report data from the EMERGE trial including preliminary efficacy and biomarker relationships to clinical outcomes for up to 40 non-small cell lung cancer patients in the second half of 2020. The study investigating the predictive biomarker path is the SELECT trial. Based on the evaluation of baseline tumor samples from patients in ICONIC we identified the gene signature and threshold to store which predicts rope associated ICOS hi CD4 T cells emergence as well as improved response rate overall survival and six and nine month progression-free survival in TIS vopra positive patients. The SELECT trial is designed to determine if patients with TIS vopra positive tumors will have a higher likelihood of generating ICOS hi CD4 T cells T cells in the presence of vopra resulting in potentially greater clinical benefit. TIS is an 18-gene signature that was originally developed as a predictive biomarker for PD-1 inhibitors. However TIS also includes genes associated with integral elements of CD4 T cell biology that may contribute to a more comprehensive immune response. In the upcoming Phase II select trial patients will be selected using TIS vopra. SELECT is a randomized ex U.S. trial in non-small cell lung cancer comparing vopra plus JTX-4014 RPD-1 inhibitor to JTX-4014 alone. We expect to enroll approximately 75 immunotherapy naive second line non-small cell lung cancer patients who will be selected using the TIs poker biomarker.

We estimate that approximately 20% of second-line non-small cell lung cancer patients will be above the h-hh. TIs for threshold and potentially eligible for the trial. We expect to initiate the select trial in mid-2020 and report interim clinical data in 2021. Turning to JTX-4014 we presented Phase I safety and preliminary efficacy data at the 2019 SITC meeting in November. Of note antitumor activity was observed with an overall response rate of 16.7% including one complete response and two partial responses all confirmed resist responses and with an acceptable safety profile in a difficult-to-treat population with no therapeutic options. Using our own PD-1 inhibitor in combination with vopra provides flexibility and cost savings. I'm proud of the accomplishments of our team in 2019 and look forward to continued progress in 2020 on clinical trial execution and readouts on clinical and biomarker data.

Now I would like to turn the call over to Tim for a discussion of our year-end financial results. Kim?

Kim Drapkin, CPA -- Chief Financial Officer

Thanks Beth and good morning everyone. As we reported in this morning's press release we ended 2019 with cash cash equivalents and investments totaling $170.4 million compared to $195.9 million for 2018. The decrease was primarily due to operating costs incurred during the year offset by the $50 million license fee received in July 2019 pursuant to our JTX-8064 license agreement with Celgene. Turning to the P&L. Our license and collaboration revenue was $147.9 million for full year 2019 compared to $65.2 million for 2018. The year-over-year increase includes $50 million of cash received under the JTX-8064 license agreement with Celgene and $97.9 million of noncash revenue recognition related to the Celgene upfront payment of $225 million that we received in 2016. During 2019 we incurred $67.1 million in research and development expenses compared to $70.1 million for 2018. The decrease in R&D expenses for the full year 2019 was due to $6 million of decreased manufacturing and IND-enabling costs and $0.9 million of decreased lab consumable costs. The decrease was partially offset by $3.1 million of increased employee compensation costs. General and administrative expenses were $27.9 million for 2019 compared to $26.4 million for 2018. The increase in G&A expenses is primarily the result of increased employee compensation costs.

Net income for 2019 was $56.8 million or basic net income per share of $1.72 and diluted net income per share of $1.66 as compared to a net loss of $27.4 million in 2018 or a basic and diluted net loss per share of $0.84. This increase was driven by the $147.9 million of license and collaboration revenue recognized under our agreement with Celgene. We reiterate the 2020 financial guidance we provided in January. We continue to expect gross cash burn on operating expenses and capital expenditures for the full year 2020 to be approximately $80 million to $95 million. We are no longer providing license and collaboration revenue guidance as potential future payments under our JTX-8064 license agreement with Celgene our royalty and milestone based. Given the strength of our balance sheet we expect our existing cash cash equivalents and investments to be sufficient to enable the funding of our operating expenses and capital expenditure requirements through the end of 2021. Additionally we continue to have the flexibility to drive our innovative immunotherapy pipeline while efficiently executing against our strategic plans and goals.

With that I'll hand the call to Rich for a final thought.

Richard Murray, Ph.D. -- Chief Executive Officer and President

Thanks Kim. Before we open the call for questions I'd like to bring the conversation back to the patients that we're trying to help. The success of the initial checkpoints has created benefit for patients where none was not possible less than a decade ago. But with that new challenges and therefore opportunities have arisen to treat patients who've progressed on PD-1 inhibitors in broader topic of moving IO therapies closer to a precision medicine concept. I believe our new trials reflect the scientific advancements that will need to be made from data gleaned from the lab and the clinic so that we can continue to envision a future with longer and broader durable benefit for patients that do not have those options today. As we look forward to updating you in the future.

And with that we'd now like to open the call for your questions. Operator?

Operator

[Operator Instructions]. Your First question comes from the line of Boris Speaker from Cowen Your line is open.

Boris Speaker -- Cowen -- Analyst

Good morning, Congratulations on all the progress. So question number one on the merge trial are you selecting out patients that don't show ICOS hi CD cells from IP induction? And maybe kind of a little more broadly what is the dosing in the EMERGE trial? And does it make sense to add an ipi booster in the middle of treatment.

Elizabeth Trehu, M.D. -- Chief Medical Officer

Sure. So I'll start with the second question. So the dosing is it is given every six weeks for up to four doses alternating with vopra so you get it on day one and three weeks later the patients get vopra. And then three weeks later they get another dose of ipi then vopra. So we do that alternating sequence for up up to four doses of ipi after which they receive vopra alone. So in terms of the ICOS CD4 cells it's a really interesting question. So we are tracking those cells very closely. So we're watching what they do after ipi and then before vopra and then after ipi again. Right now we're not doing any kind of selection. But we are following that very carefully and it certainly is something to think about in the future. We also although we're not using any selection in this study. We have we are testing a number of potential predictive biomarkers in baseline tumor samples that we'll be able to go back and look at. So right now the strategy is to induce the ICOS CD4 cells with vopra with it sorry and then to treat with vopra which as we expect to cause proliferation sustained activation of those cells over time which in our iCONIC study was associated with long-term clinical benefit.

Boris Speaker -- Cowen -- Analyst

Got you. My last question on the TIS vopra a biomarker test. If the SELECT trial is successful it looks like a very useful biomarker. What would you have to do to make the test approval by the FDA?

Elizabeth Trehu, M.D. -- Chief Medical Officer

Sure. So it's already a validated test so it's run on the nanostring platform. And there's just there's a series of steps to go through to create a companion diagnostic. And we've already mapped out what that path would look like. We would work with a vendor that would actually be the one to develop the companion diagnostic in partnership with us on our clinical trial.

Boris Speaker -- Cowen -- Analyst

So it wouldn't be limiting in terms of the regulatory strategy to do? that's all I wanted to know...

Kim Drapkin, CPA -- Chief Financial Officer

No. No no not at all.

Boris Speaker -- Cowen -- Analyst

Right. Thank you very much for taking my questions.

Kim Drapkin, CPA -- Chief Financial Officer

You're welcome.

Operator

Your next question comes from the line of James Birchenough Alfaro Your line is open.

James Birchenough -- Alfaro -- Analyst

Hi, guys. Thanks for all the details for taking the questions. A couple. So just on the EMERGE study is there any early insights you have on the tolerability of the modified dosing protocol that you're pursuing? And any early indication of success at induction about ICOS hi CD4 T cells with ipi. And then maybe related to that is there a predictive rate of ipi induction how reliable is it the induction of like those high CD4 cells? And then I've got a follow-up.

Elizabeth Trehu, M.D. -- Chief Medical Officer

Sure. So all I can really tell you right now is enrollment is on track to support the interim analysis that we're planning to do later this year and that's when we'll report data. So we don't typically provide any information on data from the ongoing trial. As I said enrollment is going well and we're on track to have data in the second half of the year. And then to your other question...

James Birchenough -- Alfaro -- Analyst

J Just thinking about historical date on ipi for ICOS hi CD4 T cell for.

Elizabeth Trehu, M.D. -- Chief Medical Officer

Sure So it's a little hard to interpret sometimes. We've heard people say that all the cells get induced ICOS gets induced on all the cells but then it drops off very quickly. So it's a little bit hard to discern from the literature exactly what the expected rate of ICOS induction from just it would be. But of course our trial will answer that because we are measuring that in a prospective manner. Most of the studies in which that's been done it's been more of a retrospective finding so I think ours will be the first study to my knowledge that's prospectively looking at how the kinetics of ICOS induction after ipi and then with vopra added on.

Richard Murray, Ph.D. -- Chief Executive Officer and President

Yes what is published Jim and they tend to be a fairly decent number of small studies but with kind of a common theme to that and that tends to be done in PD-1 naive patients. And of course we're looking at a PD-1 experience. But from that kind of collection of small studies the numbers are always north of 50%. Some will claim almost all the patients but really what we think is extremely important is the maintenance and sustainability of these cells. And that's what we think our trial will be able to uniquely answer.

James Birchenough -- Alfaro -- Analyst

And then just one final question. Just on the SELECT study and what you learned from ICONIC. Were there other RNA signatures that you evaluated? Or was this the one that you prospectively thought would make sense and really the only one you evaluated? Just wondering if there were other RNA signatures that had a decent predictive value.

Elizabeth Trehu, M.D. -- Chief Medical Officer

Sure. So we actually we had a long list of genes that we looked at and a number of pre determined signatures that we assess. And this one came out as the one that looks the most predictive for clinical benefit. But then what we thought was really really important was to see if it also tracked with the ICOS hi CD4 T cells T cells. And so first it looked like it predicted clinical benefit. But since many of these patients were also treated with a PD-1 inhibitor we then took this biomarker and applied it to see its predictive value for ICOS hi CD4 T cells emergence and then it clearly predicted for that. And then we selected the threshold based on the ability to predict ICOS hi CD4 T cells. And then when we apply that to the clinical data it was clearly also predicted for clinical benefit. But yes we looked at a number of different genes isolated genes and gene signatures prospectively and this was the one that appeared to be the best.

James Birchenough -- Alfaro -- Analyst

Great, thanks for taking the questions.

Elizabeth Trehu, M.D. -- Chief Medical Officer

You're welcome.

Operator

Your next question comes from the line of Michael from Baird Your line is open.

James Birchenough -- Alfaro -- Analyst

Hey, guys, thanks for taking the question. Just another one on EMERGE and in terms of the interim update expect in the second half of this year. Can you just give us a sense of what types of biomarker data you plan to provide?

Elizabeth Trehu, M.D. -- Chief Medical Officer

Sure. Definitely the ICOS hi CD4 T cells target engagement since we're doing a new dosing schedule that other than what we've done before. So those are the two primary ones. We also as I said we plan to do some relooking at some baseline biomarkers and some other aspects of biology.

Michael -- Baird -- Analyst

Got it. And maybe just in terms of patient numbers you've mentioned potentially up to 40 patients. But can you maybe give us a sense of sort of average follow-up at that point in time. Just trying to get a sense of how meaningful?

Elizabeth Trehu, M.D. -- Chief Medical Officer

Yes. Yes yes absolutely. So yes so we've timed the interim analysiS to be done after every subject has had at least two post-treatment or on-treatment CT scans. So we'll have at least 18 weeks of data on all of those patients before we report any data.

Michael -- Baird -- Analyst

Okay, great. Thank you.

Elizabeth Trehu, M.D. -- Chief Medical Officer

You're welcome.

Operator

Your next question comes from the line of Debjit Chattopadhyay for H.C. Wainwright Your line is open.

Aaron Welch -- H.C. Wainwright -- Analyst

This is Aaron on for Debjit. So I have some questions about how you plan on tackling the enrollment challenges for the SELECT trial like given COVID-19 disruptions? And how do you expect enrollment to go in the SELECT study given that many of the non-small cell lung cancer patients are likely to have previously been treated with an anti-PD-1?

Elizabeth Trehu, M.D. -- Chief Medical Officer

Sure. So we're doing this study ex U.S. because there actually are many countries in which there's very limited access to the PD-1 inhibitors that are approved in this country. So there are places where patients are anxious to enroll in a clinical trial to be able to get access to a PD-1 inhibitor. So we're really happy that we're providing them with that opportunity. Regarding the challenges of enrollment probably the biggest challenge is posed by having a requirement for a selective biomarker. However if you think about some selective biomarkers like ALK or VET where you're talking about 3% to 7% of a population we estimate that the TIS vopra will select about 20% of the second line non-small cell lung cancer patients. And in our conversations with investigators 20% is they're very comfortable with screening one inside of their patients is likely to be positive for the trial. So we have a number of different strategies in place to tackle this. We have enough sites and have a a strategy to screen for patients in a way to enable us to enroll those 75 patients and have data preliminary data in 2021.

Richard Murray, Ph.D. -- Chief Executive Officer and President

And maybe could I jump in there. Sorry to interrupt Aaron just to be clear the study is on IO naive patients not PD-1 experienced patients ex U.S. right.

Aaron Welch -- H.C. Wainwright -- Analyst

Right. And just real quick will could we expect to see any TIS vopra evaluations of patients coming out of the EMERGE study?

Elizabeth Trehu, M.D. -- Chief Medical Officer

Yes. We are looking at tippin baseline samples in the EMERGE study as well as well as other predictive biomarkers but that's obviously the one that we're the most interested in right now.

Aaron Welch -- H.C. Wainwright -- Analyst

Okay, thank you.

Elizabeth Trehu, M.D. -- Chief Medical Officer

Thank you. You're welcome. [Operator Instructions] Your next question comes from the line of Steve Seedhouse from Raymond James Your line is open.

Daniel H. McMahon -- Raymond James -- Analyst

This is Daniel on for Steve. So some checkpoint inhibitors are approved in PD-L1 expressing patients after showing greater benefits in those populations compared to those that do not express PD-1 and that you have a biomarker for ICOS hi what are your thoughts on targeting patients that are both PD-L1 and also have biomarkers for ICOS hi.

Elizabeth Trehu, M.D. -- Chief Medical Officer

Read more here:
Jounce Therapeutics, Inc. (JNCE) Q4 2019 Earnings Call Transcript - Motley Fool

Cell Biology

University researchers win Canada-UK funding to develop AI-powered microrobots to capture brain – Mirage News

Researchers at the University of Torontos Donnelly Centre for Cellular and Biomolecular Research have received a funding boost to help realize their vision of using tiny robots controlled by artificial intelligence to one day find and capture rare stem cells from brain tissue for therapy.

Working with Mike Shaw, a machine learning expert at the University College London, U of Ts Aaron Wheeler and Cindi Morshead will receive more than $1 million from the new Canada-UK Artificial Intelligence Initiative.

Supported by the two countries federal governments, the initiative seeks to harness AI for societal benefit by bringing together experts from diverse disciplines.

We have previously developed microrobots for manipulating individual cells in a dish, says Wheeler, a professor in U of Ts department of chemistry in the Faculty of Arts & Science and the Institute of Biomaterials and Biomedical Engineering in the Faculty of Applied Science & Engineering.

Now we want to take it to the next level to design robots that can isolate single cells from a crowded environment such as brain tissue and make the system fully automated.

A total of 10 international teams shared approximately $5 million and 5 million over three years, according to an announcement made earlier this week by Navdeep Bains, Canadas minister of innovation, science and industry, and British High Commissioner to Canada Susan le Jeune dAllegeershecque. Other projects funded through the program, a collaboration between Canadas three research funding agencies and four UK research councils, seek to harness AI across different sectors, from countering abusive online language to improving labour market equality and monitoring global disease outbreaks.

Artificial intelligence is transforming all industries and sectors, opening up more opportunities for Canadians, Bains said in a statement. Today we take one step further toward ensuring that AI innovation and growth builds competitive and resilient economies, and maximizes the social and health benefits in both Canada and the UK.

Stem cells hold promise for regenerative medicine thanks to their ability to self-renew and turn into specialized cells in the body. Scientists around the world are exploring how resident stem cells in the brain can be harnessed to treat neurodegenerative diseases or repair injury.

Morshead, who is chair of anatomy in the department of surgery in the Faculty of Medicine and a stem cell scientist, and her team previously showed that brain stem cells can be directed to repair stroke injury in miceand they continue to investigate how to make the repair more efficient.

Optoelectronic microrobots designed by U of T researchers Shuailong Zhang and Aaron Wheeler can load, transport and deliver cellular material (photo courtesy of Shuailong Zhang)

The clues likely lie in the stem cells tissue microenvironment, where they are influenced by molecular signals released by neighbouring cells. Scientists are keen to map out this cellular cross-talk, which remains largely unexplored. A tool that can reproducibly pick out defined and intact cells from a complex mix of cells in brain tissue would be a huge asset. And tiny robots, working at the sub-millimetre scale, could be up for the task.

Having very methodical repetitive dissections will allow us to feel confident that the behaviours of cells will be similar across samples, which is important for stem cell biology and regenerative medicine, says Morshead.

With the help of their UK collaborators, the U of T researchers aim to teach the microrobots how to distinguish stem cells and their neighbours from microscopy images of brain tissue through AI and image-recognition algorithms.

A more immediate goal is to pair AI with the existing microrobotic platform developed by Wheeler and Morsheads teams for manipulating individual stem cells in the dish to gain insight into their molecular makeup and behavior. They previously demonstrated how cog-wheel shaped microrobots can scoop up and move the cells about. With AIs help, it should be possible to teach the microrobots how to recognize different types of cells based on their appearance and deliver them to various pipelines for molecular profiling.

In the long term, we would like to have one platform that can start with a slab of tissue and go to collecting the cells of interest, says Wheeler. We will end up with a tool thats useful for lots of folks in the life sciences who are trying to streamline and reproducibly collect interesting cells for further analysis.

Read the original here:
University researchers win Canada-UK funding to develop AI-powered microrobots to capture brain - Mirage News

Cell Biology

Rare disease in children: the key role of a protein revealed – Canada NewsWire

Children affected by Batten disease are born with no symptoms and develop normally, learning to walk, talk, and interact with others.Between 5 and 8years of age, however, they start to regress."The first symptom that leads parents to seek medical attention for their child is a loss of vision caused by retinal degeneration.This is followed by cognitive regression characterized by speech and mobility impairment.The life expectancy for people with the disease is usually around 30 years," explains Lefranois, who has been working on Batten disease for more than ten years.

A key protein

Professor Lefranois and his team in Laval are delving into the cellular biology of the CLN3 protein, which has been synthesized with the help of its namesake gene, in order to better understand the protein's function and identify therapeutic targets.They recently published findings about a key role played by CLN3 in the Journal of Cell Science.In the absence of the disease, CLN3 ensures a constant supply of proteins to the endosome, an intracellular compartment that serves as a sorting centre for proteins within the cell.

"Under this cellular process, a receptor acts as a truck that carries proteins from the Golgi apparatus, the production factory, to the sorting centre.Thanks to CLN3, this truck normally returns to the Golgi to pick up another load of proteins in an ongoing cycle," the researcher explains."In the presence of the mutations, however, the truck doesn't make the return trip.Instead, it is redirected to the lysosomes, where it's broken down as cellular waste."

Because the receptor is degraded, the proteins vital to lysosome function can't reach their destination.In consequence, these organelles are no longer able to break down cellular waste, so they accumulate and cause cellular degeneration."We think that children with the disease develop normally in their early years because their cells compensate by making more trucks.It's possible that the cells can't keep up, so the system becomes dysfunctional and starts to degrade," adds Professor Lefranois.

Professor Lefranois is working with a team of European researchers to re-establish normal CLN3 function with a promising drug. The aim is to prevent degradation of the receptor so it can continue carrying proteins.

Worldwide, it is estimated thatone person in 100,000has Batten's disease in all its forms.

About the study

The article entitled CLN3 regulates endosomal function by modulating Rab7A effector interactions, by Seda Yasa, Graziana Modica, Etienne Sauvageau, Abuzar Kaleem, Guido Hermey, Stephane Lefrancois, was published in the Journal of Cell Science. The research was supported by the Joint Programme on Neurodegenerative Diseases Grant, the Canadian Institutes of Health Research, the Canadian Foundation for Innovation, the National Contest for Life Foundation Germany and by the Deutsche Forschungsgemeinschaft, the Fondation Armand-Frappieret du Fonds de recherche du Qubec Sant (FRQS).DOI : 10.1242/jcs.234047

About the INRSThe Institut National de la Recherche Scientifique (INRS) is the only institution in Qubec dedicated exclusively to graduate level university research and training. The impacts of its faculty and students are felt around the world. INRS proudly contributes to societal progress in partnership with industry and community stakeholders, both through its discoveries and by training new researchers and technicians to deliver scientific, social, and technological breakthroughs in the future.

SOURCE Institut National de la recherche scientifique (INRS)

For further information: Audrey-Maude Vzina, Communications, INRS, 418-254-2156 (cell), [emailprotected]

Accueil

Read more:
Rare disease in children: the key role of a protein revealed - Canada NewsWire

Cell Biology

New study identifies trigger that turns dormant cancer stem cells into active ones – Yahoo Finance

A new study released today in STEM CELLS identifies, for the first time, two morphologically and functionally different types of cancer stem cells found in cervical cancer.

DURHAM, N.C., Feb. 26, 2020 /PRNewswire-PRWeb/ --A new study released today in STEM CELLS identifies, for the first time, two morphologically and functionally different types of cancer stem cells found in cervical cancer. Of the two types, one exhibits an overexpression of cPLA2, a key enzyme that triggers the transformation of dormant cancer stem cells into active ones, resulting in cervical cancer metastasis and recurrence. The information in this study could lead to new targets for treatments to halt tumor recurrence and metastatic spread. Also, it might accelerate the development of combination therapies.

The current standard of treatments for cervical cancer the second leading cause of cancer death in young women worldwide is radiotherapy and chemotherapy. However, the cancer's resistance to chemotherapy and radiation, combined with a tendency to metastasis in the lymph nodes or recur in the pelvis, leaves doctors searching for more effective treatments.

Cervical cancer stem cells (CCSCs) are considered the major culprit behind the cancer's ability to overcome these treatments. At the same time, a majority of cancer stem-like cells or tumor-initiating cells remain dormant. It takes a change in their microenvironment to spur them to metastasize.

"The mechanisms responsible for this must be identified to design more suitable therapies for the different subpopulations of cancer stem cells (CSCs) in various tissue-specific cancers," said Hua Guo, Ph.D., who headed up the investigation along with Yuchao He, Ph.D. The two are colleagues at Tianjin Medical University Cancer Institute and Hospital. Researchers at Tianjin University of Traditional Chinese Medicine and at the Center for Translational Cancer Research, Peking University First Hospital, also participated in the study.

Although several cell surface antigens have been identified in CCSCs, these markers vary among tumors because of CSC heterogeneity. However, whether these markers specifically distinguish CCSCs with different functions is unclear. The study published in STEM CELLS sought to resolve this question. And in fact, its findings demonstrate that CCSCs exist in two biologically distinct phenotypes, characterized by different levels of cPLA2 expression.

"Our study showed for the first time that overexpression of cPLA2 results in a phenotype associated with mesenchymal traits, including increased invasive and migration abilities. On the other hand, CCSCs with cPLA2 downregulation show dormant epithelial characteristics," said Dr. Guo. "In addition, cPLA2 regulates the reversible transition between mesenchymal and epithelial CCSC states through PKC, an atypical protein that governs cancer cell state changes."

Dr. He added, "Now that we know cPLA2 triggers this transformation, we believe that cPLA2 might be an attractive therapeutic target for eradicating different states of CCSCs to eliminate tumors more effectively."

"The novel study by Dr. Guo and team is of very high importance in understanding the transition between dormant cancer stem cells, which evade chemotherapy and radiation treatments, and actively dividing cells which can be better targeted, said Dr. Jan Nolta, Editor-in-Chief of STEM CELLS. "I applaud the group for this important discovery which will help researchers develop better treatments for cervical cancer."

###

The full article, "cPLA2 reversibly regulate different subsets of cancer stem cells transformation in cervical cancer," can be accessed at https://stemcellsjournals.onlinelibrary.wiley.com/doi/abs/10.1002/stem.3157.

Figure Caption: This study revealed that there are two morphologically and functionally distinct cancer stem cell populations regulated by cPLA2 in cervical cancer. cPLA2 might be a unique marker to identify different cancer stem cell populations and trigger quiescent epithelial cancer stem cells transform to invasive mesenchymal states. Overexpression of cPLA2 resulted in a CD44+CD24- phenotype with mesenchymal traits, whereas cervical cancer stem cells (CCSCs) with cPLA2 downregulation expressed CD133 and showed epithelial characteristics. cPLA2, as a key role to reversely regulate CCSCs states and EMT, might provide innovative therapeutic strategies intended to halt tumor recurrence and metastasis.

Story continues

About the Journal: STEM CELLS, a peer reviewed journal published monthly, provides a forum for prompt publication of original investigative papers and concise reviews. The journal covers all aspects of stem cells: embryonic stem cells/induced pluripotent stem cells; tissue-specific stem cells; cancer stem cells; the stem cell niche; stem cell epigenetics, genomics and proteomics; and translational and clinical research. STEM CELLS is co-published by AlphaMed Press and Wiley.

About AlphaMed Press: Established in 1983, AlphaMed Press with offices in Durham, NC, San Francisco, CA, and Belfast, Northern Ireland, publishes three internationally renowned peer-reviewed journals with globally recognized editorial boards dedicated to advancing knowledge and education in their focused disciplines. STEM CELLS (http://www.StemCells.com) is the world's first journal devoted to this fast paced field of research. THE ONCOLOGIST (http://www.TheOncologist.com) is devoted to community and hospital-based oncologists and physicians entrusted with cancer patient care. STEM CELLS TRANSLATIONAL MEDICINE (http://www.StemCellsTM.com) is dedicated to significantly advancing the clinical utilization of stem cell molecular and cellular biology. By bridging stem cell research and clinical trials, SCTM will help move applications of these critical investigations closer to accepted best practices.

About Wiley: Wiley, a global company, helps people and organizations develop the skills and knowledge they need to succeed. Our online scientific, technical, medical and scholarly journals, combined with our digital learning, assessment and certification solutions, help universities, learned societies, businesses, governments and individuals increase the academic and professional impact of their work. For more than 200 years, we have delivered consistent performance to our stakeholders. The company's website can be accessed at http://www.wiley.com.

SOURCE AlphaMed Press

Read the original:
New study identifies trigger that turns dormant cancer stem cells into active ones - Yahoo Finance

Cell Biology

On the Road to 3-D Printed Organs – The Scientist

For years, scientists have predicted that 3-D printingwhich has been used it to make toys, homes, scientific tools and even a plastic bunny that contained a DNA code for its own replicationcould one day be harnessed to print live, human body parts to mitigate a shortage of donor organs. So far, researchers also used 3-D printing in medicine and dentistry to create dental implants, prosthetics, and models for surgeons to practice on before they make cuts on a patient. But many researchers have moved beyond printing with plastics and metalsprinting with cells that then form living human tissues.

No one has printed fully functional, transplantable human organs just yet, but scientists are getting closer, making pieces of tissue that can be used to test drugs and designing methods to overcome the challenges of recreating the bodys complex biology.

A confocal microscopy image showing 3-Dprinted stem cells differentiating into bone cells

The first 3-D printer was developed in the late 1980s. It could print small objects designed using computer-aided design (CAD) software. A design would be virtually sliced into layers only three-thousandths of a millimeter thick. Then, the printer would piece that design into the complete product.

There were two main strategies a printer might use to lay down the pattern: it could extrude a paste through a very fine tip, printing the design starting with the bottom layer and working upward with each layer being supported by the previous layers. Alternatively, it could start with a container filled with resin and use a pointed laser to solidify portions of that resin to create a solid object from the top down, which would be lifted and removed from the surrounding resin.

When it comes to printing cells and biomaterials to make replicas of body parts and organs, these same two strategies apply, but the ability to work with biological materials in this way has required input from cell biologists, engineers, developmental biologists, materials scientists, and others.

So far, scientists have printed mini organoids and microfluidics models of tissues, also known as organs on chips. Both have yielded practical and theoretical insights into the function of the human body. Some of these models are used by pharmaceutical companies to test drugs before moving on to animal studies and eventually clinical trials. One group, for example, printed cardiac cells on a chip and connected it to a bioreactor before using it to test the cardiac toxicity of a well-known cancer drug, doxorubicin. The team showed that the cells beating rate decreased dramatically after exposure to the drug.

However, scientists have yet to construct organs that truly replicate the myriad structural characteristics and functions of human tissues. There are a number of companies who are attempting to do things like 3-D print ears, and researchers have already reported transplanting 3-D printed ears onto children who had birth defects that left their ears underdeveloped, notes Robby Bowles, a bioengineer at the University of Utah. The ear transplants are, he says, kind of the first proof of concept of 3-D printing for medicine.

THE SCIENTIST STAFF

Bowles adds that researchers are still a ways away from printing more-complex tissues and organs that can be transplanted into living organisms. But, for many scientists, thats precisely the goal. As of February 2020, more than 112,000 people in the US are waiting for an organ transplant, according to the United Network for Organ Sharing. About 20 of them die each day.

For many years, biological engineers have tried to build 3-D scaffolds that they could seed with stem cells that would eventually differentiate and grow into the shapes of organs, but to a large extent those techniques dont allow you to introduce kind of the organization of gradients and the patterning that is in the tissue, says Bowles. There is no control over where the cells go in that tissue. By contrast, 3-D printing enables researchers with to very precisely direct the placement of cellsa feat that could lead to better control over organ development.

Ideally, 3-D printed organs would be built from cells that a patients immune system could recognize as its own, to avoid immune rejection and the need for patients to take immunosuppressive drugs. Such organs could potentially be built from patient-specific induced pluripotent stem cells, but one challenge is getting the cells to differentiate into the subtype of mature cell thats needed to build a particular organ. The difficulty is kind of coming together and producing complex patternings of cells and biomaterials together to produce different functions of the different tissues and organs, says Bowles.

To imitate the patterns seen in vivo, scientists print cells into hydrogels or other environments with molecular signals and gradients designed to coax the cells into organizing themselves into lifelike organs. Scientists can use 3-D printing to build these hydrogels as well. With other techniques, the patterns achieved have typically been two-dimensional, Eben Alsberg, a bioengineer at the University of Illinois, tells The Scientist in an email. Three-dimensional bioprinting permits much more control over signal presentation in 3D.

So far, researchers have created patches of tissue that mimic portions of certain organs but havent managed to replicate the complexity or cell density of a full organ. But its possible that in some patients, even a patch would be an effective treatment. At the end of 2016, a company called Organovo announced the start of a program to develop 3-D printed liver tissue for human transplants after a study showed that transplanted patches of 3-D printed liver cells successfully engrafted in a mouse model of a genetic liver disease and boosted several biomarkers that suggested an improvement in liver function.

Only in the past few years have researchers started to make headway with one of the biggest challenges in printing 3-D organs: creating vasculature. After the patches were engrafted into the mouses liver in the Organovo study, blood was delivered to it by the surrounding liver tissue, but an entire organ would need to come prepared for blood flow.

For any cells to stay alive, [the organ] needs that blood supply, so it cant just be this huge chunk of tissue, says Courtney Gegg, a senior director of tissue engineering at Prellis Biologics, which makes and sells scaffolds to support 3-D printed tissue. Thats been recognized as one of the key issues.

Mark Skylar-Scott, a bioengineer at the Wyss Institute, says that the problem has held back tissue engineering for decades. But in 2018, Sbastian Uzel, Skylar-Scott, and a team at the Wyss Institute managed to 3-D print a tiny, beating heart ventricle complete with blood vessels. A few days after printing the tissue, Uzel says he came into the lab to find a piece of twitching tissue, which was both very terrifying and exciting.

For any cells to stay alive, [the organ] needs that blood supply, so it cant just be this huge chunk of tissue.

Courtney Gegg, Prellis Biologics

Instead of printing the veins in layers, the team used embedded printinga technique in which, instead of building from the bottom of a slide upwards, material is extruded directly into a bath, or matrix. This strategy, which allows the researchers to print free form in 3-D, says Skylar-Scott, rather having to print each layer one on top of the other to support the structure, is a more efficient way to print a vascular tree. The matrix in this case was the cellular material that made up the heart ventricle. A gelatin-like ink pushed these cells gently out of the way to create a network of channels. Once printing was finished, the combination was warmed up. This heat caused the cellular matrix to solidify, but the gelatin to liquify so it could then be rinsed out, leaving space for blood to flow through.

But that doesnt mean the problem is completely solved. The Wyss Institute teams ventricle had blood vessels, but not nearly as many as a full-sized heart. Gegg points out that to truly imitate human biology, an individual cell will have to be within 200 microns of your nearest blood supply. . . . Everything has to be very, very close. Thats far more intricate than what researchers have printed so far.

Due to hurdles with adding vasculature and many other challenges that still face 3-Dprinted tissues, laboratory-built organs wont be available for transplant anytime soon. In the meantime, 3-D printing portions of tissue is helping accelerate both basic and clinical research about the human body.

Emma Yasinski is a Florida-based freelance reporter. Follow her on Twitter@EmmaYas24.

Read the original post:
On the Road to 3-D Printed Organs - The Scientist

Cell Biology

Breast cancer cells hibernate in the lung before forming secondary tumors – News-Medical.net

Feb 24 2020

Healthy lung cells support the survival of breast cancer cells, allowing them to hibernate in the lung before forming secondary tumors, according to new research from the Crick. The findings could help the development of new treatments that interfere with this behavior, reducing the number of secondary cancers.

Image showing mouse breast cancer cells (orange) within lung tissue (light pink), connected with protein fibres (purple).

The study, published in Nature Cell Biology, used a mouse model to show that, after cancer cells from a breast tumor arrive in the lungs, a signal sent out from the lung cells causes cancer cells to change shape and grow protrusions that latch onto the lung tissue. The lung cells then protect them within the lung tissue.

By using a treatment that interferes with the growth of these protrusions on the breast cancer cells, the researchers found that mice who received the treatment grew fewer secondary tumors than the control mice.

The researchers then analyzed the genes that are turned on in the hibernating cells. This enabled them to find a key gene, sFRP2, that regulates the formation of cell protrusions and the survival of breast cancer cells in the lung.

Cancer can survive, hibernating in different parts of the body, for many years. By showing how the microenvironment around the cancer cell can support its survival, in our case how the lung cells help the breast cancer cells, opens the door to potential new treatments which target this relationship.

Erik Sahai, co-lead author and group leader of the Cricks Tumour Cell Biology Laboratory

The cancer cells were tested over the course of up to four weeks, during which they remained inactive. In comparison, other cell types continued to remain active, showing that the hibernation of these cells is due to a special relationship they have with the lung environment around them.

The mechanism behind how cancer cells survive in tissues they have traveled to is not yet well understood. But with many cancers spreading around the body and consequently many patients suffering from relapses, a deeper understanding of the process is vital and something well continue to explore, says Marco Montagner, co-lead author and former postdoc in the Cricks Tumour Cell Biology Laboratory, who is now based at the University of Padua.

Around 55,000 people in the UK are diagnosed with breast cancer each year. This cancer can spread through the blood or lymphatic system to another part of the body, commonly the lungs, liver, brain or bones. Where breast cancer spreads to the lungs, there can be a long time between the cells arriving in the lungs and the formation of a secondary tumor. This gap is one factor that explains why people may relapse a long time after the initial disease.

The researchers are continuing to explore the relationship between cancer and non-cancerous cells in a secondary location in the body. At the Crick, researchers are now studying what happens when cells from colorectal cancer and melanomas form secondary tumors in the liver. While at the University of Padua, studies are ongoing into the genes which are over-expressed in hibernating breast cancer cells.

Source:

Journal reference:

Montagner, M., et al. (2020) Crosstalk with lung epithelial cells regulates Sfrp2-mediated latency in breast cancer dissemination. Nature Cell Biology. doi.org/10.1038/s41556-020-0474-3.

View original post here:
Breast cancer cells hibernate in the lung before forming secondary tumors - News-Medical.net

Cell Biology

Bit Bio Secures Distribution Agreement with Abcam to Democratize Access to Human Cells for Global Life Science Research – BioSpace

CAMBRIDGE, England, Feb. 25, 2020 /PRNewswire/ --Bit Bio announces agreement with Abcam, a global innovator in life science reagents and tools, to make Bit Bio's iPSC derived functional human cells widely available to the global life science community. Over the course of the next two years this new partnership will provide an increasing range of highly defined, scalable and consistent human cells for research and high-throughput screening applications. The first product available are brain cells (ioNEURONS/glutTM, glutamatergic neurons) serving the neuroscience community.

Access to human cells is a significant bottleneck in the field of medical research and drug development. Human cells differ from animal models, and therefore research using animal models often does not translate into clinical applications.

Bit Bio is commercializing opti-oxTM, a precise reprogramming proprietary technology platform that enables uniquely efficient and consistent production of human cells for use in research, drug discovery, and cell therapy.

"Bit Bio's goal is to develop a scalable technology platform capable of producing consistent batches of every human cell type," said Bit Bio CEO Mark Kotter, a neurosurgeon at Cambridge University, and stem cell biologist. "This agreement will accelerate our mission of putting highly defined human cells in the hands of the researchers who need them to pursue their life-saving work."

"Supporting enhanced access to complementary technologies that have the potential to improve and accelerate research is part of our growth strategy," said John Baker, Senior Vice President Product Portfolio and Innovation at Abcam. "Our industry expertise, and co-location in major biotechnology hubs throughout the world, enables our partners to rapidly put their innovations into the hands of the global research community, helping advance the understanding of biology and cause of disease to enable new treatments and improved health outcomes."

Bit Bio's breakthrough technology has been successfully employed to reprogram stem cells into functional neurons on a scalable and consistent basis. The proprietary approach ensures batch to batch reproducibility and unprecedented purity compared to current technologies and yields fully differentiated neurons within days. The protocol is also universally applicable, from small-scale laboratory research projects to high throughput screens in pharmaceutical R&D laboratories.

Bit Bio's human-induced glutamatergic neurons are a highly defined and consistent human model for the study of neurological physiology and disease, including neurodegeneration, and are available from the Abcam website.

"At Bit Bio we believe that world-wide access to our iPSC derived cells will drive human translational experiments and ultimately help to fuel the next generation of medicine," said Bit Bio Chief Business Officer Paul Morrill. "Abcam's reputation as a disruptive innovator in the field of biological reagents and dedicated global commercialization infrastructure make them the ideal partner. In line with our core value of democratizing access to human cells for research and drug development, our ioNEURONS/glut are offered at a highly competitive price point."

About Bit Bio

Bit Bio, the cell coding company, is based in Cambridge, UK. Bit Bio's team includes world leaders in stem cell biology, cellular reprogramming and cell therapy who are harnessing the power of synthetic biology to tackle the problem of inconsistency in the production of human cells. Bit Bio is developing opti-oxTM, a proprietary technology platform capable of producing any human cell for research, drug discovery and cell therapy.

We areintroducing ioNEURONS/glutTM,human-induced glutamatergic neuronscells, providing a high-quality human model for research, drug development and high-throughput screening.ioNEURONS/glut cells have been reprogrammed from human induced pluripotent stem cells (hiPSC) using a precise reprogramming technology.

To find out more, please visit http://www.bit.bio

Bit Bio press contact:Dr Farah Patell-Socha, press@bit.bio

About AbcamAs a global life sciences company, Abcam identifies, develops, and distributes high-quality biological reagents and tools that are crucial to research, drug discovery and diagnostics. Working across the industry, the Company supports life scientists to achieve their mission, faster. Abcam partners with life science organisations to co-create novel binders for use in drug discovery,in vitrodiagnostics and therapeutics, driven by the Company's proprietary discovery platforms and world-leading, antibody expertise.

By constantly innovating its binders and assays, Abcam is helping advance the global understanding of biology and causes of disease, which enables new treatments and improved health. The Company's pioneering data-sharing approach gives scientists increased confidence in their results by providing validation, user comments and peer-reviewed citations for its 110,000 products. With eleven sites globally, many of Abcam's 1,100 strong team are located in the world's leading life science research hubs, complementing a global network of services and support.

To find out more, please visitwww.abcam.comandwww.abcamplc.com.

Abcam press contact:Dr Lynne Trowbridge, lynne.trowbridge@abcam.com

View original content:http://www.prnewswire.com/news-releases/bit-bio-secures-distribution-agreement-with-abcam-to-democratize-access-to-human-cells-for-global-life-science-research-301010337.html

SOURCE Bit Bio

See more here:
Bit Bio Secures Distribution Agreement with Abcam to Democratize Access to Human Cells for Global Life Science Research - BioSpace

Cell Biology

Cellular metabolism plays key role in dictating the fate decision between pathogenic and regulatory T cells – The Medical News

Patients with autoimmune diseases like multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis have an imbalance between two types of immune system T cells. Destructive Th17 cells that mediate chronic inflammation are elevated, and regulatory T cells, or Treg cells, which suppress inflammatory responses and play a protective role in autoimmune disorders, are diminished.

Both cells differentiate from the same precursors -- nave CD4 T cells -- and the beginning of their change to either Th17 or Treg cells starts with the same signal. Subsequently, a fate decision occurs, like a fork in the road, steering the changing CD4 cells to become either inflammatory T cells or regulatory T cells.

New, preclinical research, led by Laurie Harrington, Ph.D., associate professor in the UAB Department of Cell, Developmental and Integrative Biology at the University of Alabama at Birmingham, shows a pivotal role for cellular metabolism to regulate that fate decision, a decision that occurs very early in the activation of CD4 T cells. This opens a possibility that manipulating the cellular metabolism of T cells may provide a new, promising therapeutic intervention to modulate the balance between pathogenic Th17 and Treg cells in chronic autoimmune disorders. The research is published in the journal Cell Reports.

Upon activation, T cells were known to rapidly increase metabolism, including glycolysis and mitochondrial oxidative phosphorylation, or OXPHOS, to meet the energetic demands of differentiation. But the precise contribution of OXPHOS to that Th17 differentiation was not defined.

The UAB researchers, and one colleague at New York University, found that ATP-linked mitochondrial respiration during Th17 differentiation was essential to upregulate glycolysis and the TCA cycle metabolism. Strikingly, it also was essential to promote inflammation of the central nervous system by Th17, as shown in a mouse model for multiple sclerosis.

In the mouse model, experimental autoimmune encephalitis, Th17 cells cause the disease progression. For the experiment, harvested CD4 T cells were differentiated using a combination of Th17-polarizing cytokines. One group was the polarized control, and one group was polarized in the presence of oligomycin, an inhibitor of mitochondrial OXPHOS. Then the T cells were transferred into experimental mice. Mice receiving the T cells treated with oligomycin during polarizing conditions showed a significantly delayed onset of disease and reduced disease severity. Both groups of T cells proliferated robustly after transfer.

In mechanistic experiments, the researchers detailed the early molecular events that differ between cells polarized in the presence or absence of oligomycin. These included gene sets that are upregulated or downregulated, presence or absence of Th17 or Treg cell markers, expression of signature transcription factors needed for Th17 differentiation, and expression of gene products that play a role in T cell receptor signaling.

A surprise was found in the timing of the fate decision. In an experiment, CD4 T cells were exposed to Th17-polarizing conditions with oligomycin present only during the first 24 hours. They were then washed and allowed to continue differentiation in the polarizing conditions. The effects of this brief exposure to oligomycin were T cells that lacked Th17 markers and instead showed hallmarks of Treg cells, including expression of Foxp3. Thus, the brief early exposure to oligomycin imprinted the Foxp3 fate decision.

Overall, Harrington said:

Inhibition of mitochondrial OXPHOS ablates Th17 pathogenicity in a mouse model of multiple sclerosis and results in generation of functionally suppressive Treg cells under Th17 conditions."

Source:

Journal reference:

Shin, B., et al. (2020) Mitochondrial Oxidative Phosphorylation Regulates the Fate Decision between Pathogenic Th17 and Regulatory T Cells. Cell Reports. doi.org/10.1016/j.celrep.2020.01.022.

Here is the original post:
Cellular metabolism plays key role in dictating the fate decision between pathogenic and regulatory T cells - The Medical News

Cell Biology

Stan Harrison, Georgia Bio’s Biotech Teacher of the Year – Morgan County Citizen

By Tia Lynn Ivey

managing editor

Stan Harrison, a biotech teacher at Morgan County High School, is preaching the good news of science to his students and fellow teachers across the state.

I am evangelizing, said Harrison, who sees a scientific revolution on the horizon that will change the landscape of Americas economy and medical industry. It will be as significant as the industrial revolution was, and its coming fast. My goal is to get my students equipped with the skillset and training to take advantage of the new jobs that are coming, that will be higher paying jobs.

Harrisons passion for science is precisely what won him Georgia Bios Biotech Teacher of the Year award. The organization announced Harrison as this years recipient earlier this week. He will be presented with the award at the March 13 Golden Helix Awards & Annual Gala at Factory Atlanta in Chamblee. Harrison is honored to be chosen for this award.

I was overwhelmed and very surprised, said Harrison, who has been teaching at Morgan County High School since 2006. I wasnt expecting it at all. There are so many great teachers out there, I didnt expect to win this.

I am very proud of Mr. Harrison, said Dr. James Woodard, superintendent of Morgan County Schools. He began the program in 2014 to respond to the needs of Baxter (Shire) now Takeda. The program is preparing students for an awesome career in the biosciences.

According to Georgia Bio, The Golden Helix Awards celebrate the contributions and achievements of Georgia legislative, academic, corporate and other organizational leaders working to advance the growth of the life sciences industry and foster strategic partnerships that can create a healthier world. The event is expected to draw 300 of the states life sciences industry leaders.

Im honored to be recognized as the Teacher of the Year by Georgia Bio at the 2020 Golden Helix Award Dinner in March, honoring achievement and excellence in the Georgia life sciences industries, said Harrison. Im grateful, but a bit nervous to be recognized in front of nearly 300 of the states life sciences industry leaders. This is a big tip-of-the-hat to Morgan s biotech program and the academic and community supporting it!

Harrison was selected as this years Biotech Teacher of the Year because he is a biotechnology high school teacher who exhibits excellence in STEM teaching and support for the biotechnology pathway.

The award aims to honor a teacher who fits the following criteria. Experienced Biotechnology Teacher skilled in Program Development, Training, Project Management, and Professional Writing (Reports, Grants & Presentations). Strong research professional with a M.Ed. focused in biotech from The University of Georgia with ongoing RET Fellowships at Georgia Institute of Technology and the Regenerative Bioscience Center at U.G.A. Lead Instructor team at GaBioEd Institute and contributing member of Cell Manufacturing Technologies consortium.

In 2003, Harrison began teaching, after spending a couple decades as a businessman, consultant and software developer. But he wanted to pursue a career in biology and teach it others.

Biology has always been my first love, said Harrison. With teaching, I really believe you have to have a calling. And I did. I wanted to teach what I love.

Harrison earned his Masters Degree from the University of Georgia and conducts research on stem cells and cancer for University of Georgia.

With the encouragement of Superintendent Dr. James Woodard and MCHS Principal Dr. Miki Edwards. Harrison set out to create one of the best biotech high school programs in the state.

We wanted to build the finest biotech program in the state. If we havent done that, were pretty darn close, said Harrison. But we came from humble beginnings.

Harrison remembers the days when the program held labs in a leaky storage room in the basement of the old high school.

We called it the dungeon, laughed Harrison.

Now, the the new high school boasts of three state-of-the-art labs, stocked full of the finest equipment to conduct a wide variety of scientific endeavors.

The Biotech program encompasses a lot of thingsits engineering with the biological sciences. Its agricultural, forensic, genetic, and medical, explained Harrison. We are doing things that will blow your mind.

Under Harrisons supervision, students in the College and Career Academy program are raising adult stem cells, examining forensic evidence, splicing genes, and even raising tilapia. The program partners with both the University of Georgia and Georgia Tech. Students pick a long-term research topic and present their findings at one of the colleges.

Harrison believes students in this rigorous program will be uniquely equipped to obtain well-paying jobs in the emerging biotech field.

This is an opportunity, said Harrison. And I want our kids to be a part of it. I saw this coming a mile away. Georgia right now is number one in country for biotechnology.

When students graduate from this program, they not only earn college credit, but come out as certified beginning level biotechnicians.

Its incredible the kind of opportunities this line of work will open up for our kids. I believe in it and thats what Im preaching.

Like Loading...

Related

See the rest here:
Stan Harrison, Georgia Bio's Biotech Teacher of the Year - Morgan County Citizen

Cell Biology

Nanosize Device ‘Uncloaks’ Cancer Cells in Mice And Reveals Them to The Immune System – Newswise

Newswise Scientists at Johns Hopkins report they have designed and successfully tested an experimental, super small package able to deliver molecular signals that tag implanted human cancer cells in mice and make them visible for destruction by the animals immune systems. The new method was developed, say the researchers, to deliver an immune system uncloaking device directly to cancer cells.

Conventional immune therapies generally focus on manipulating patients immune system cells to boost their cancer-killing properties or injecting drugs that do the same but often have toxic side effects.

Results of the proof-of-concept experiments were published online Feb. 7 in the Proceedings of the National Academy of Sciences.

A hallmark of cancer biology is a tumor cells ability to essentially hide from the immune system cells whose job is to identify and destroy cancer cells. Current cellular immunotherapies, notably CAR-T, require scientists to chemically alter and enhance a patients own harvested immune system T-cells an expensive and time-consuming process, say the researchers. Other weapons in the arsenal of immunotherapies are drugs, including so-called checkpoint inhibitors, which have broad effects and often lead to unwanted immune-system-associated side effects, including damage to normal tissue.

By contrast, the Johns Hopkins team sought an immune system therapy that can work like a drug but that also individually engineers a tumor and its surrounding environment to draw the immune system cells to it, says Jordan Green, Ph.D.

Green is the director of the biomaterials and drug delivery laboratory and a professor of biomedical engineering at the Johns Hopkins University School of Medicine. And our process happens entirely within the body, Green says, requiring no external manipulation of a patients cells.

To develop the new system, Green and his team, including Stephany Tzeng, Ph.D., a research associate in the Department of Biomedical Engineering at Johns Hopkins, took advantage of a cancer cells tendency to internalize molecules from its surroundings. Cancer cells may be easier to directly genetically manipulate because their DNA has gone haywire, they divide rapidly, and they dont have the typical checks and balances of normal cells, says Green.

The team created a polymer-based nanoparticle a tiny case that slips inside cells. They guided the nanoparticles to cancer cells by injecting them directly into the animals tumors.

The nanoparticle method we developed is widely applicable to many solid tumors despite their variability on an individual and tumor type level, says Green, also a member of the Johns Hopkins Kimmel Cancer Center.

Once inside the cell, the water-soluble nanoparticle slowly degrades over a day. It contains a ring of DNA, called a plasmid, that does not integrate into the genome and is eventually degraded as the cancer cell divides, but it stays active long enough to alter protein production in the cell.

The additional genomic material from the plasmid makes the tumor cells produce surface proteins called 4-1BBL, which work like red flags to say, Im a cancer cell, activate defenses. The plasmid also forces the cancer cells to secrete chemicals called interleukins into the space around the cells. The 4-1BBL tags and interleukins are like magnets to immune system cells, and they seek to kill the foreign-looking cancer cells.

Essentially, were forcing the tumor to open itself up and instruct immune cells to kill it, says Tzeng.

In their animal experiments, Tzeng and the Johns Hopkins team injected the loaded nanoparticles into tumors created by implanting mice with either human melanoma or colon cancer cells.

A control group of mice implanted with melanoma cells received systemically an immunotherapy drug known as anti-PD-1 antibody. All of those mice died quickly, within 2.5 to three weeks, due to tumor growth.

Then, the research team injected other groups of mice, which were also injected with the cancer cells, with nanoparticles containing only one or both of the uncloaking signals the genetically encoded 4-1BBL tags and interleukins. In mice with implanted melanomas, the nanoparticles that combined the two signals had a stronger effect than either signal alone. The median, or midpoint, survival of the mice with the combo signal package was 40 days, and about 20% of them lived through the end of the 60-day study period.

The researchers also saw that some of the mice in the treated melanoma group developed vitiligo, a condition in which skin cells lose their pigment. It occurs in humans too, including in people undergoing immunotherapy for melanoma. Its generally thought that vitiligo in melanoma patients is a sign that the immunotherapy treatment is working, and the immunotherapy is spreading to other parts of the body where other melanocytes reside, says Tzeng.

The tumor shrank away in all of the mice with implanted colon tumors that received the nanoparticles with both signals, and they survived through the entire 60-day study period. When the researchers reinjected human colon cancer cells into the sides of mice opposite the original tumors, unlike with age-matched controls, the newly implanted cancer cells failed to form a tumor, suggesting a lasting effect of the boosted immune system.

The hope is that, eventually, we could develop nanoparticles that hold instructions for a variety of immune-related signals, says Green, who cautioned that use of the nanoparticle system will remain experimental for years to come. We are developing this system as an off-the-shelf therapy that can induce a personalized systemic anti-tumor response without needing to know the specific genetic makeup of the tumor beforehand.

Funding for the research was provided by the National Institutes of Health National Cancer Institute (R01CA228133) and the National Institute of Biomedical Imaging and Bioengineering (P41EB028239).

Other scientists who contributed to the research include Kisha Patel, David Wilson, Randall Meyer and Kelly Rhodes of Johns Hopkins.

The researchers have filed for patents related to this work.

DOI: 10.1073/pnas.1916039117

Link:
Nanosize Device 'Uncloaks' Cancer Cells in Mice And Reveals Them to The Immune System - Newswise