NYSCF News Update: Vol 15, Issue 1

NEWSupdate

NYSCF

VOLUME 15 ISSUE 1: 2022

The New York Stem Cell Foundation Research Institute

STEM CELLS ILLUMINATE WHAT MAKES SOMEONE LIKELY TO DEVELOP PTSD Pages 2 & 3

STEM CELLS TAKE THE STAGE

PREVENTING LEUKEMIA RELAPSE

WHEN GOOD BRAIN CELLS GO BAD

UNPROVEN STEM CELL THERAPIES

NYSCF presents at SNF Nostos Conference

Helping the immune system to ‘see’ cancer cells

New findings in Alzheimer’s and multiple sclerosis

How to spot them and protect yourself

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Page 9

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Why do only some people develop PTSD? Stem cells provide clues

Iraq War veteran Frank Lesnefsky | Image credit: CBS NEWS

“I was immobilized. It’s like being frozen, just watching time pass.”

“I was unable to attend my children’s school concerts or take them to the pictures as I would have panic attacks.”

These are experiences of people with posttraumatic stress disorder (PTSD) – an often debilitating condition in which memories of trauma are accompanied by intense emotional and physical reactions. Scientists aren’t sure why a minority of people who experience trauma develop PTSD, or how to treat it effectively.

A new collaborative study in press at Nature Neuroscience led by Rachel Yehuda, PhD, of the Icahn School of Medicine at Mount Sinai in collaboration with NYSCF’s Daniel Paull, PhD, and NYSCF – Robertson Stem Cell Investigator Alumna Kristen Brennand, PhD, of Yale School of Medicine, creates the 2

first-ever stem cell model of PTSD to look inside the brains of patients, helping researchers understand how someone’s genes may put them at risk for developing the disorder.

“Stem cells give you a ‘time machine’ to go back and look at how someone’s brain cells looked prior to trauma and ask how trauma changes them,” said Dr. Brennand.

Dr. Yehuda’s group first collected blood and skin biopsies from combat veterans with and without PTSD, and NYSCF scientists turned these skin cells into stem cells.

With these stem cells, the team created the specific neurons implicated in PTSD, and exposed them to synthetic hormones called corticosteroids that mimic the body’s stress response.

“So we’ve got these cells in a dish with all the genetic risk factors that we think contribute to PTSD,” said Dr. Brennand. “We then exposed them to a chemical stressor to explore how genetics influences the cells’ response.”

Interestingly, the scientists found that neurons from PTSD-affected veterans were hypersensitive to the stress hormones.

“We discovered a set of genes that are particularly active in cells exposed to stressors, and importantly, we also found this signature present in brain samples from deceased individuals with PTSD,” explained Dr. Paull.

“This study is a true testament to the power of team science,” added Dr. Paull. “When researchers combine forces, we are able to ask bigger questions, find bigger answers, and make a bigger difference for patients.”

“Knowing the genetic signatures that increase risk for PTSD is important because it could help us to potentially identify individuals who would be especially vulnerable,” he continued.

“We next want to study more cell types,” said Dr. Brennand. “We’re also working on coming up with a list of already-approved drugs that we suspect could perhaps reverse the hypersensitivity we’re seeing in neurons.”

The scientists emphasized that these findings would not have been possible without collaboration between several talented teams across different disciplines.

Tomasz Rusielewicz, PhD, co-first author of the study Top Cell Image: Neurons from a PTSD patient Image credit: Barry McCarthy

Learn more at nyscf.org/news

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BOARD OF DIRECTORS Roy Geronemus, MD, Chairman Susan L. Solomon, CEO Margo Alexander Marilyn G. Breslow Peggy Brim Karen E. Burke, MD, PhD Francesco Clark Paul Goldberger George Lazarus, MD Richard J. Massey, PhD Paul M. Meister Siddhartha Mukherjee, MD, DPhil Stephen M. Ross Derrick Rossi, PhD Stephen M. Scherr Kay Unger Clyde Williams

LEADERSHIP COUNCIL Katherine Bristor & William Priest David A. Carmel Russell L. Carson Chuck Close* Alan M. Cohen Shirley Cook Fiona Druckenmiller Jodie & John* Eastman Frank Gehry Lawrence E. Golub & Karen Finerman April Gornik Marlene Hess Tania Higgins Dorothy Lichtenstein Sandra Lloyd Stephen Meringoff David Mitnick Nancy & Fred Poses Carol Roaman Julian Robertson* David Rockwell Clifford Ross Kara Ross Andy Russell Susan & Stephen Scherr Ian Schrager Barbara Stovall Smith Martha Stewart David & Jane* Walentas John Whitehead* Dick Wolf *In Memoriam

Hello all, We have talked for a long time about the promise of personalized medicine, and we are now at the moment where it is moving from promise to reality– and the NYSCF Research Institute is at the forefront of the exciting advances that are making this happen.

We were thrilled to travel to Athens in June to present our new drug discovery platform at this year’s SNF Nostos Conference (see page 5), an international conference focused on developments in health. At NYSCF, we have combined our unmatched stem cell expertise with our pioneering automation system and advanced artificial intelligence to create a unique platform that will use stem cells to design individualized treatments for specific patients. This is the revolution we have been waiting for, and we are excited to continue accelerating this work to the clinic.

At NYSCF we have always said that research is personal, and at the moment this truth has a particular poignancy for us, as we have lost several key members of our community this year, including Julian H. Robertson, Jr., John L. Eastman, Robert B. Menschel, Susan Lasker Brody, Jill Iscol, Lori Zabar, Morton Janklow, and Sabrina Bertucci – all friends and critical supporters who made so much of our progress possible. Everyone knows a patient or is one themselves, and this is what drives our commitment to cures. This is why we have made “Showing Up for Patients” the theme of this year’s NYSCF Gala on October 11th, when we look forward to celebrating the lives and legacies of our community members and patients everywhere.

We will share more encouraging updates in treating diseases such as Alzheimer’s, Parkinson’s, PTSD, and cancer. We hope to see you there.

Speaking of community, one of the cornerstones of the NYSCF community is the extraordinary group of scientists we support, the NYSCF – Robertson Investigators and NYSCF – Druckenmiller Fellows. Before the Covid-19 pandemic, this group gathered for our annual Innovators Retreat each May to share work and exchange ideas, an event that like so many switched to a virtual format in 2020 and 2021. This year we went back to meeting in person again, and it was a great joy to have the group gathered together once more (see page 6). I am confident that the bonds formed and the problems tackled will catalyze even more new discoveries.

Thank you all for your continued support. Together, we will help stem cell research bring us to a brighter future.

With warm regards,

Susan L. Solomon, JD CEO and Founder

Stem Cell Science in Action: NYSCF Introduces New Drug Discovery Platform at SNF Nostos Health Conference

“My colleagues and I are delighted to bring the NYSCF lab to you here at SNF Nostos Health today, and to show you in real time how we have developed a new unique platform, combining the power of AI and biology, to harness the potential of stem cells to better understand – and cure – human disease,” remarked NYSCF CEO and Founder Susan L. Solomon, JD, to the audience at the 10th annual SNF Nostos Conference in Athens, Greece.

The NYSCF Discovery Platform has the potential to distinguish between patients with a disease and healthy individuals, test drugs on actual patient cells, and accelerate precision medicine for all. NYSCF scientists Valentina Fossati, PhD, and Daniel Paull, PhD, explained how it’s able to do so.

Dr. Fossati & Dr. Paull prepare cells under a microscope

“We have used AI to identify which cells come from healthy individuals vs. Parkinson’s patients,” said Dr. Paull. “We are now testing which drugs can make the Parkinson’s cells look like healthy ones.”

“Valentina and I are able to handle about six samples at a time, but what if we could handle 600 samples at the same time?” posited Dr. Paull. “We have automation technology [The NYSCF Global Stem Cell Array®] that we built so the work we do by hand can be done by robots.”

“We can generate huge amounts of data very quickly, but human eyes cannot possibly look at every detail within every image,” he continued. “To help in this, we’ve turned to the same technology that is changing our everyday lives: artificial intelligence.”

NYSCF scientists recently demonstrated the power of their AI-powered platform by applying it to cells from patients with Parkinson’s disease.

Dr. Paull shares the Array’s capabilities

“Thanks to stem cells, we can make all the different cell types in the body, including brain cells,” added Dr. Fossati. “We’re also putting drugs onto these cells, not only new ones but pre-existing drugs that we already know are safe and could thus reach patients even faster.”

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Science by the Sea: Highlights of the NYSCF Innovators Retreat This May, the NYSCF – Robertson Investigators, NYSCF – Druckenmiller Fellows, and NYSCF Research Institute scientists gathered (in-person for the first time in two years) in Montauk, New York for the annual Innovators Retreat: a week of camaraderie, collaboration, and groundbreaking science.

NYSCF Innovators in Montauk, New York

The NYSCF Innovators shared many exciting updates on studies that are paving the way for better outcomes for patients. The retreat also featured a session focused on advancing Diversity, Equity, Inclusion, and Belonging (DEIB) in the scientific community, including breakout discussions on key topics: mentorship, lab- and team-centric activities, institutional initiatives/policies, and review processes for grantmaking and faculty searches.

“In review processes, we need to look beyond our traditional definitions of academic productivity to include things like lived experience and advocacy,” noted NYSCF – Robertson Stem Cell Investigator José Ordovás-Montañés, PhD, of Boston Children’s 6

Hospital. “It’s not just about the publications, but the way the publications came about.”

The retreat is unique in that it brings together stem cell scientists and neuroscientists to discuss many of each field’s biggest questions. “‘Innovator community’ is a very apt name, because this group is incredibly innovative in how they do science,” noted NYSCF – Robertson Stem Cell Investigator Samantha Morris, PhD, of Washington University School of Medicine. “At the retreat, I learn so much about areas that may be outside my immediate field, but that nonetheless teach me how to think creatively and ask questions in a new way.”

Meet our 2022 Class of NYSCF – Druckenmiller Fellows The NYSCF – Druckenmiller Fellowship supports young postdoctoral researchers in their pursuit of innovative stem cell science and is the largest dedicated stem cell fellowship in the world.

Fellows receive an annual stipend as well as support for their research, and are welcomed into the greater NYSCF community.

Sophie Morgani, PhD

Munisha Mumingjiang, MD, PhD

“Bone is really cool because it’s one of the few tissues in a human that can fully regenerate. Understanding how and why it can do this is really interesting, and can hopefully inform how we think about regenerating different tissues.”

“Once I got into the clinic, I found myself often wanting to go back to basics and understand the mechanisms actually causing a disease so we could figure out how to treat it. That’s why I went back to get my PhD.”

Noopur Khobrekar, PhD

Spencer Haws, PhD

Chandrika Rao, PhD

“You can’t really do good science in isolation. It’s always a team exercise, and joining the NYSCF Innovator community is a real privilege.”

“Stem cells are the perfect way to study fragile X syndrome. To explore it in the context of a real, human patient will be really critical for targeting it at its root.”

“Studying Alzheimer’s can be like trying to find a needle in a haystack, but I wanted to study it because it’s fascinating, challenging, and important.”

Memorial Sloan Kettering Cancer Center Autism Spectrum Disorder

New York University Grossman School of Medicine Bone Disease & Injury

University of Pennsylvania Fragile X Syndrome

Cornell University Preeclampsia & Pregnancy Loss

The NYSCF Research Institute Alzheimer’s Disease

Meet our 2022 Summer Interns!

We are thrilled to have had 20 talented students as members of our 2022 Class of Summer Interns. Our interns work across our laboratory, engineering, and programs administration teams to get a glimpse into the fast-paced world of stem cell research.

Learn more about opportunities for students at

nyscf.org/the-nyscf-academy

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Innovator Updates What Makes You Smell Tasty to a Mosquito?

Mosquitos are notorious superspreaders for diseases like Zika and dengue, and in some parts of the world, they hunt down humans almost exclusively. How do they target us so precisely?

Mosquitos pick up on two chemicals (decanal and undecanal) in human odors to pinpoint us, and two structures called ‘glomeri’ ­– part of the olfactory system – allow them to do so, finds a new study in Nature by NYSCF – Robertson Neuroscience Investigator Lindy McBride, PhD, of Princeton University. This work opens the door for strategies to mask ourselves from mosquitos or lead them into traps, helping curb the spread of disease (and bites!).

Dr. McBride

The Double Life of a Parkinson’s-Related Protein The major hallmark of Parkinson’s disease is an accumulation of a protein in the brain called alpha-synuclein, but little is known about its role and how it contributes to the disease.

A new study in Cell by NYSCF – Robertson Stem Cell Investigator Vikram Khurana, MD, PhD, of Brigham and Women’s Hospital and Harvard Medical School finds that alpha-synuclein not only helps with cell maintenance, but it also binds to “P-body” structures – machinery in the cell that regulates the expression of genes. People with mutations in genes related to P-bodies appear to have a higher risk of developing Parkinson’s. This information will help scientists develop therapies that target the true dysfunction behind the disease.

The “two faces of alpha-synuclein” Image credit: Gergana Petrova

Replacing the Brain’s Cleanup Machinery in Neurological Disease Microglia are immune cells in the brain that constantly patrol the central nervous system to eliminate dead or damaged cells. Defects in microglia can contribute to the development of neurodegenerative conditions such as Alzheimer’s.

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A section of a mouse brain showing replacement of microglia (green) after a bone marrow transplant.

Image credit: Yohei Shibuya, Stanford School of Medicine

In a new breakthrough, scientists have invented a technique to replace malfunctioning microglia. The study, led by NYSCF – Robertson Stem Cell Investigator Alumnus and NYSCF – Robertson Stem Cell Prize Recipient Marius Wernig, MD, PhD, and including NYSCF – Druckenmiller Fellow Yongjin Yoo, PhD, from Stanford University, appears in Science Translational Medicine. These results overcome longstanding challenges in delivering therapeutics into the brain that could be helpful for treating many neurological conditions.

Innovator Updates

When Good Brain Cells Go Bad: New Findings from NYSCF, Johns Hopkins, and Bloomberg Philanthropies Precision Medicine Partnership Astrocytes are support cells in the brain that help our neurons function properly. However, groundwork done by NYSCF and others has shown that these typically helpful cells can ‘go rogue’ or ‘reactive’ in the presence of brain inflammation – a common hallmark of neurodegenerative diseases like Alzheimer’s or multiple sclerosis (MS) – making them harmful to the cells they typically support.

Dr. Fossati in the lab

partnership with Johns Hopkins University School of Medicine and Bloomberg Philanthropies) leverage stem cell-derived astrocytes to explore how reactive astrocytes contribute to disease.

A stem cell-derived astrocyte Image credit: Lili Barbar

Two new studies published in Frontiers in Molecular Neuroscience by NYSCF’s Valentina Fossati, PhD, in collaboration with Johns Hopkins’ Peter Calabresi, MD, (as part of NYSCF’s precision medicine

The first study provides the most in-depth characterization of these cells to date, and finds evidence of them in the brains of deceased Alzheimer’s patients. The second study discovers that reactive astrocytes may contribute to MS by inhibiting cells that create myelin – the insulation on neurons that is damaged in MS patients.

Making Leukemia Visible To The Immune System The most common treatment for acute myeloid leukemia is bone marrow transplant, in which healthy blood stem cells are infused into the bloodstream of the patient to kickstart a functional immune system.

However, nearly half of patients who relapse do so because their tumor cells hide special ‘HLA proteins’ on the cell surface that are essential for the immune system to recognize a tumor.

Using a class of drug called PRC2 inhibitors already in advanced clinical trials for other cancers, scientists at San Raffaele Telethon Institute for Gene Therapy in Italy led by NYSCF – Robertson Stem Cell Investigator and NYSCF – Druckenmiller Fellow Alumna Raffaella Di Micco, PhD, report in

Cancer Discovery a new way to force leukemia cells to bear their HLA proteins, making them visible to the immune system once again. Because the therapy employs a drug already in advanced clinical trials, the treatment is afforded an accelerated path to the clinic.

Dr. Di Micco with co-senior author Dr. Luca Vago Image credit: San Raffaele Telethon Institute for Gene Therapy

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Education and Outreach Read highlights and watch the full discussions at

nyscf.org/events

To Achieve Precision Medicine, Diverse Stem Cell Biobanks are Key Even though breakthroughs in biomedical research have reduced mortality for most major diseases of our time, the gaps in mortality between ethnic minorities and white patients – known as racial health disparities – are actually increasing.

Our recent panel delved into topics such as building patient trust, effective community engagement, what resources are needed to make an impact, and actions scientists and supporters can take to help.

“Disparities in health outcomes are almost overwhelmingly due to socioeconomic policies, biases, and racism. As researchers, we must bring the same amount of genomic insights to all populations so that we can provide the same care to everybody, no matter their ancestry.”

- John Greally, DMed, PhD, FACMG | Albert Einstein College of Medicine

New Hope for Women’s Reproductive Cancers In honor of Women’s History Month, we convened a panel of experts to discuss health equity, the latest in research for women’s reproductive cancers, and the path to better patient outcomes. Scientists also discussed how our Women’s Reproductive Cancers Initiative uses stem cells to create avatars of patient tumors for research and drug testing, and how new advances in genetics are improving our understanding of the disease.

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“What we’re finding is that we can start to group patients based on the pattern of alterations in their genomes. This is not only a biological grouping, but these patients respond differently to treatments, and this is where personalized medicine can be implemented.”

- Sohrab Shah, PhD | Memorial Sloan Kettering Cancer Center

Unlocking New Brain Disease Treatments with Artificial Intelligence

“Rare diseases could overlap with diseases that affect larger patient populations,” noted Leena Panwala of INADcure, who is working with NYSCF to understand INAD, a rare neurological disease with similarities to Parkinson’s and Alzheimer’s. “If we can use these technologies to figure out how to treat a smaller disease group, we could apply it to other diseases as well.”

-Leena Panwala | INADcure Foundation

This February, we gathered leaders in research, medicine, and patient advocacy to discuss how artificial intelligence can shed new light on brain diseases. The panel explored challenges in understanding and treating these diseases, what artificial intelligence is revealing about them (including our new study of Parkinson’s mentioned on page 5), and how NYSCF’s integration of AI and stem cell technology is paving the way for new, effective treatments for rare and common diseases.

Unproven Stem Cell Therapies: What are the Dangers, and How Can You Avoid Them?

“[When considering a stem cell therapy] talk to someone you trust who has knowledge. That to me is the most important thing: find someone in healthcare who you trust, and ask them.”

-Jeffrey Kahn, PhD, MPH | Johns Hopkins Berman Institute of Bioethics

While promising stem cell therapies are in development for many diseases, unregulated clinics worldwide are exploiting the excitement around stem cells to sell expensive, unproven therapies to vulnerable patients. This April, we convened experts to explore the science behind legitimate stem cell therapies, the dangers unproven therapies can pose to patients, and how to protect yourself.

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Cures begin with your support today!

Please make a gift to help NYSCF advance stem cell research toward the clinic. You can donate online at nyscf.org/donate or by mail to: The New York Stem Cell Foundation 619 West 54th Street, 3rd Fl, New York, NY 10019

619 W 54 th Street New York , NY 10019

Legacy of Cures Join our Legacy of Cures Society by including The New York Stem Cell Foundation in your will.

Together, we can accelerate cures for the major diseases of our time. Your support will benefit generations to come.

Please contact the Development team at (212) 365-7434 or legacyofcures@nyscf.org.

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NYSCFNEWSupdate SHOW UP for PATIENTS

October 11, 2022 In Person at Hearst Tower & Online Worldwide

Honoring Stem Cell Heroes the

NYSCF

GALA

& Science Fair

nyscf.org/gala

Sanjay Gupta, MD Siddhartha Mukherjee, MD, DPhil Irving Weissman, MD

for transforming the lives of patients through their extraordinary contributions to science, medicine, and media