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New AI Tool Makes Speedy Gene-Editing Possible

New AI Tool Makes Speedy Gene-Editing Possible
PR Newswire
NEW YORK, Jan. 26, 2023

NEW YORK, Jan. 26, 2023 /PRNewswire/ — An artificial intelligence program may enable the first simple production of customizable proteins called zinc fingers to tre…

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New AI Tool Makes Speedy Gene-Editing Possible

PR Newswire

NEW YORK, Jan. 26, 2023

NEW YORK, Jan. 26, 2023 /PRNewswire/ -- An artificial intelligence program may enable the first simple production of customizable proteins called zinc fingers to treat diseases by turning genes on and off.

The researchers at NYU Grossman School of Medicine and the University of Toronto who designed the tool say it promises to accelerate the development of gene therapies on a large scale.  

Illnesses including cystic fibrosis, Tay-Sachs disease, and sickle cell anemia are caused by errors in the order of DNA letters that encode the operating instructions for every human cell. Scientists can in some cases correct these mistakes with gene editing methods that rearrange these letters.

Other conditions are caused, not by a mistake in the code itself, but by problems in how the cellular machinery reads DNA (epigenetics). A gene, which provides the recipe for a particular protein, often partners with molecules called transcription factors that tell the cell how much of that protein to make. When this process goes awry, over- or underactive genes contribute to diabetes, cancer, and neurological disorders. As a result, researchers have been exploring ways to restore normal epigenetic activity.  

One such technique is zinc-finger editing, which can both change and control genes. Among the most abundant protein structures in the human body, zinc fingers can guide DNA repair by grabbing onto scissor-like enzymes and directing them to cut faulty segments out of the code.

Similarly, zinc fingers can also hook onto transcription factors and pull them toward a gene segment in need of regulation. By customizing these instructions, genetic engineers can tailor any gene's activity. A drawback, however, is that artificial zinc fingers are challenging to design for a specific task. Since these proteins attach to DNA in complex groups, researchers would need to be able to tell — out of  countless possible combinations — how every zinc finger interacts with its neighbor for each desired genetic change.

The study authors' new technology, called ZFDesign, overcomes this obstacle by using artificial intelligence (AI) to model and design these interactions. The model is based on data generated by the screen of nearly 50 billion possible zinc finger-DNA interactions in the researchers' labs. A report on the tool is publishing online Jan. 26 in the journal Nature Biotechnology.

"Our program can identify the right grouping of zinc fingers for any modification, making this type of gene editing faster than ever before," says study lead author David Ichikawa, PhD, a former graduate student at NYU Langone Health.

Ichikawa notes that zinc-finger editing offers a potentially safer alternative to CRISPR, a key gene-editing technology with applications that range from finding new ways to kill cancer cells to designing more nourishing crops. Unlike the entirely human-derived zinc fingers, CRISPR, which stands for clustered regularly interspaced short palindromic repeat, relies on bacterial proteins to interact with genetic code. These "foreign" proteins could trigger patients' immune defense systems, which may attack them like any other infection and lead to dangerous inflammation.

The study authors add that besides posing a lower immune risk, the small size of zinc-finger tools may also provide more flexible gene therapy techniques compared with CRISPR by enabling more ways to deliver the tools to the right cells in patients.

"By speeding up zinc-finger design coupled with their smaller size, our system paves the way for using these proteins to control multiple genes at the same time," says study senior author Marcus Noyes, PhD. "In the future, this approach may help correct diseases that have multiple genetic causes, such as heart disease, obesity, and many cases of autism." 

To test the computer's AI design code, Noyes and his team used a customized zinc finger to disrupt the coding sequence of a gene in human cells. In addition, they built several zinc fingers that successfully reprogrammed transcription factors to bind near a target gene sequence and turn up or down its expression, demonstrating that their technology can be used for epigenetic changes.

Noyes, an assistant professor in the Department of Biochemistry and Molecular Pharmacology at NYU Langone, cautions that, while promising, zinc fingers can be difficult to control. Since they are not always specific to a single gene, some combinations can affect DNA sequences beyond a particular target, leading to unintended changes in genetic code.

As a result, Noyes says the team next plans to refine their AI program so it can build more precise zinc-finger groupings that only prompt the desired edit. Noyes is also a member of NYU Langone's Institute for System Genetics.

Funding for the study was provided by National Institutes of Health grants R01GM118851 and R01GM133936. Further funding was provided by Canadian Institutes of Health Research Project grant PJT-159750, the Compute Canada Resource Allocation, the Frederick Banting and Charles Best Canada Graduate Scholarship, and the Ontario Graduate Scholarship.

Noyes is a co-founder of TBG Therapeutics, a company that develops methods to design zinc fingers and apply them to treatments for diseases with genetic components. NYU Langone has patents pending (PCT/US21/30267, 63145929) for these tools and approaches, from which both Noyes and NYU Langone may benefit financially. The terms and conditions of these relationships are being managed in accordance with the policies of NYU Langone.

In addition to Noyes, other NYU investigators involved in the study were Manjunatha Kogenaru, PhD; April Mueller, BS; David Giganti, PhD; Gregory Goldberg, PhD; Samantha Adams, PhD; Jeffrey Spencer, PhD; Courtney Gianco; Finnegan Clark, BS; and Timothee Lionnet, PhD. Other study investigators included Osama Abdin, BS; Nader Alerasool, PhD; Han Wen, MS; Rozita Razavi, PhD, MPH; Satra Nim, PhD; Hong Zheng, PhD; Mikko Taipale, PhD; and Philip Kim, PhD, at the University of Toronto. Study lead author David Ichikawa is at the Pandemic Response Lab in Long Island City, N.Y.

Media Inquiries
Shira Polan
212-404-4279
shira.polan@nyulangone.org

 

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Analyst revamps MicroStrategy stock price target after Bitcoin buy

Here’s what could happen to MicroStrategy shares next.

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10 hours ago

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March 20, 2024

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How does Michael Saylor feel about bitcoin? We'll let him tell you in his own words.

"Bitcoin is a swarm of cyberhornets serving the goddess of wisdom, feeding on the fire of truth, exponentially growing ever smarter, faster, and stronger behind a wall of encrypted energy," the executive chairman and co-founder of MicroStrategy  (MSTR)  once said.

Too subtle? Still not sure how the former CEO of the software intelligence company feels about the world's largest cryptocurrency? 

Maybe this will help.

"Bitcoin is a bank in cyberspace, run by incorruptible software, offering a global, affordable, simple and secure savings account to billions of people that don't have the option or desire to run their own hedge fund," Saylor said.

Okay, so the guy really likes bitcoin. And on March 19, the first day of spring, MicroStrategy took a bigger bite out of bitcoin when the company said it had bought 9,245 bitcoins for $623 million between March 11 and March 18.

MicroStrategy said it a completed a $603.75 million convertible debt offering — its second in a week — to raise money to buy bitcoin.

The company now holds about $13.5 billion of bitcoin, which adds up to more than 1% of the 21 million bitcoin that will ever exist, according to CoinDesk.

An analyst adjusts his price target for MicroStrategy

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Committed to developing bitcoin network

MicroStrategy said in a regulatory filing that it had paid roughly $7.53 billion for its bitcoin stash, an average of $35,160 per coin.

The company's stock fell on Tuesday, while bitcoin posted its biggest single-day loss since November 2022. MicroStrategy was off slightly to $1,416 at last check on Wednesday and bitcoin was up 2.3% to $63.607.

Related: Analyst unveils Nvidia stock price 'line in the sand'

Phong Le, MicroStrategy’s president and CEO, told analysts during the company’s Feb. 6 fourth-quarter-earnings call that "we remain highly committed to our bitcoin strategy with a long-term focus.."

"We consider MicroStrategy to be the world's first bitcoin development company," he said. "We are a publicly traded operating company committed to the continued development of the bitcoin network through activities in the financial markets, advocacy, and technology innovation."

MicroStrategy earned $4.96 a share in the quarter, beating the FactSet consensus of a loss of 64 cents, and light years beyond the year-ago loss of $21.93 a share.

Revenue totaled $124.5 million, compared with FactSet's call for $133 million and the year-earlier tally of $132.6 million.

During the call, Saylor told analysts that "2024 is the year of birth of bitcoin as an institutional-grade asset class."

MicroStrategy, he said, completed the first 15 years of the bitcoin life cycle, back when it was largely unregulated and misunderstood. 

"The next 15 years, I would expect, will be a regulated, institutional, high-growth period of bitcoin, very, very different in many ways from the last 15 years," Saylor said.

Crypto's dark days

"Bitcoin itself is performing well for a number of reasons, but one reason is because it represents the digital transformation of capital," he added.

Of course, life with bitcoin wasn't always sunshine and roses. 

More Wall Street Analysts:

We take you back now to those less-than-thrilling days yesteryear, when covid-19 was on the rampage and the price of bitcoin fell 30% from March 8 to March 12 2020.

By the end of 2021, bitcoin had fallen nearly 30%. And 2023 saw the cryptocurrency sector wracked with bankruptcy and scandal, with the likes of FTX CEO Sam Bankman-Fried being convicted of fraud, conspiracy, and money laundering. 

SBF, as he has been known, is scheduled to be sentenced in Manhattan federal court on March 28. He faces a long stretch.

But bitcoin rose about 160% in 2023 and hit a record $73,750 on March 14.

Saylor recently said that his high hopes for bitcoin this year stemmed largely from the U.S. Securities and Exchange Commission approving spot bitcoin ETFs and the upcoming bitcoin halving, where when bitcoin's mining reward is split in half.

MicroStrategy is the first bitcoin development company, Saylor told analysts, but perhaps not for long. 

"We've published our playbook, and we're showing other companies how to do it," he said.

TD Cowen analyst Lance Vitanza cited MicroStrategy's latest bitcoin acquisition when he adjusted his price target for the company's shares on March 20.

The analyst cut the investment firm's price target on MicroStrategy to $1,450 from $1,560 and affirmed an outperform rating on the shares. 

He says the shares remain an attractive vehicle for investors looking to gain bitcoin exposure.

Related: Veteran fund manager picks favorite stocks for 2024

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FoxO6-mediated ApoC3 upregulation promotes hepatic steatosis and hyperlipidemia in aged rats fed a high-fat diet

“This discovery unveils a potential novel molecular target for therapeutic strategies against hepatic steatosis during the aging process […]” Credit:…

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13 hours ago

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March 20, 2024

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“This discovery unveils a potential novel molecular target for therapeutic strategies against hepatic steatosis during the aging process […]”

Credit: 2024 Kim et al.

“This discovery unveils a potential novel molecular target for therapeutic strategies against hepatic steatosis during the aging process […]”

BUFFALO, NY- March 20, 2024 – A new research paper was published in Aging (listed by MEDLINE/PubMed as “Aging (Albany NY)” and “Aging-US” by Web of Science) Volume 16, Issue 5, entitled, “FoxO6-mediated ApoC3 upregulation promotes hepatic steatosis and hyperlipidemia in aged rats fed a high-fat diet.”

FoxO6, an identified factor, induces hyperlipidemia and hepatic steatosis during aging by activating hepatic lipoprotein secretion and lipogenesis leading to increased ApoC3 concentrations in the bloodstream. However, the intricate mechanisms underlying hepatic steatosis induced by elevated FoxO6 under hyperglycemic conditions remain intricate and require further elucidation.

In this new study, researchers Dae Hyun Kim, Seulah Lee, Sang Gyun Noh, Jaewon Lee, and Hae Young Chung from Pusan National University aimed to delineate the regulatory pathway involving ApoC3 controlled by FoxO6 and its resultant functional impacts.

“[…] we employed a spectrum of models including liver cell cultures, aged rats subjected to HFD, transgenic mice overexpressing FoxO6 (FoxO6-Tg), and FoxO6 knockout mice (FoxO6-KO).”

Their findings indicate that FoxO6 triggered ApoC3-driven lipid accumulation in the livers of aged rats on an HFD and in FoxO6-Tg, consequently leading to hepatic steatosis and hyperglycemia. Conversely, the absence of FoxO6 attenuated the expression of genes involved in lipogenesis, resulting in diminished hepatic lipid accumulation and mitigated hyperlipidemia in murine models. Additionally, the upregulation of FoxO6 due to elevated glucose levels led to increased ApoC3 expression, consequently instigating cellular triglyceride mediated lipid accumulation. The transcriptional activation of FoxO6 induced by both the HFD and high glucose levels resulted in hepatic steatosis by upregulating ApoC3 and genes associated with gluconeogenesis in aged rats and liver cell cultures.

“Our conclusions indicate that the upregulation of ApoC3 by FoxO6 promotes the development of hyperlipidemia, hyperglycemia, and hepatic steatosis in vivo, and in vitro. Taken together, our findings underscore the significance of FoxO6 in driving hyperlipidemia and hepatic steatosis specifically under hyperglycemic states by enhancing the expression of ApoC3 in aged rats.”
 

Read the full paper: DOI: https://doi.org/10.18632/aging.205610 

Corresponding Author: Hae Young Chung

Corresponding Email: hyjung@pusan.ac.kr 

Keywords: HFD-feeding, aging, forkhead transcription factor O6, ApoC3, lipid accumulation, hepatic steatosis

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About Aging:

Aging publishes research papers in all fields of aging research including but not limited, aging from yeast to mammals, cellular senescence, age-related diseases such as cancer and Alzheimer’s diseases and their prevention and treatment, anti-aging strategies and drug development and especially the role of signal transduction pathways such as mTOR in aging and potential approaches to modulate these signaling pathways to extend lifespan. The journal aims to promote treatment of age-related diseases by slowing down aging, validation of anti-aging drugs by treating age-related diseases, prevention of cancer by inhibiting aging. Cancer and COVID-19 are age-related diseases.

Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

Please visit our website at www.Aging-US.com​​ and connect with us:

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For media inquiries, please contact media@impactjournals.com.

 

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Journal

Aging-US

DOI

10.18632/aging.205610

Method of Research

Experimental study

Subject of Research

People

Article Title

FoxO6-mediated ApoC3 upregulation promotes hepatic steatosis and hyperlipidemia in aged rats fed a high-fat diet

Article Publication Date

3-Mar-2024

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ARPA-H appoints Etta Pisano to lead its Advancing Clinical Trials Readiness Initiative

The Advanced Research Projects Agency for Health (ARPA-H) has appointed Etta D. Pisano, MD, FACR, senior portfolio lead, to build the agency’s clinical…

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17 hours ago

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March 20, 2024

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The Advanced Research Projects Agency for Health (ARPA-H) has appointed Etta D. Pisano, MD, FACR, senior portfolio lead, to build the agency’s clinical trial portfolio and lead the ARPA-H Advancing Clinical Trials Readiness Initiative under ARPA-H Resilient Systems Mission Office Director Jennifer Roberts.

Credit: N/A

The Advanced Research Projects Agency for Health (ARPA-H) has appointed Etta D. Pisano, MD, FACR, senior portfolio lead, to build the agency’s clinical trial portfolio and lead the ARPA-H Advancing Clinical Trials Readiness Initiative under ARPA-H Resilient Systems Mission Office Director Jennifer Roberts.

The first radiologist to be appointed to such a role, Dr. Pisano is an internationally recognized expert in women’s health, breast cancer research, and the use of artificial intelligence in medical imaging applications.

“I am honored to be working for ARPA-H to identify and promote research that can improve healthcare quality, efficacy and delivery, and to improve patient care and access to clinical trials for all Americans, including women, rural residents, and the underserved,” said Dr. Pisano.

Dr. Pisano will continue to serve as study chair of the large-scale Tomosynthesis Mammographic Imaging Screening Trial (TMIST) for the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN). TMIST is led by ECOG-ACRIN with funding from the National Cancer Institute, part of the National Institutes of Health. She will also continue to serve as the American College of Radiology® (ACR®) Chief Research Officer (CRO). Dr. Pisano previously served as the principal investigator of the landmark Digital Mammographic Imaging Screening Trial (DMIST).

The TMIST breast cancer screening study is among the fastest growing National Cancer Institute (NCI) trials of the COVID-19 era. Under Dr. Pisano’s leadership, TMIST is assembling one of the most diverse cancer screening trial populations ever. Approximately 21% of TMIST U.S. participants are Black—more than double the average rate for Black participation in NCI-funded clinical trials (9%).

With ARPA-H, Dr. Pisano will work to build underserved and minority participation in clinical trials—including identifying and onboarding rural facilities and those outside of large academic medical centers—such as emerging retail healthcare sites. 

These duties are also very consistent with the missions of ECOG-ACRIN and ACR, which include promoting the exploration and identification of next-generation technologies that can benefit patients and providers.

“This is a great opportunity for Etta, and I’m excited about the impact she will make on our approach to clinical trials,” said Mitchell D. Schnall, MD, PhD, group co-chair of ECOG-ACRIN.

About ECOG-ACRIN

The ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) is an expansive membership-based scientific organization that designs and conducts cancer research involving adults who have or are at risk of developing cancer. The Group comprises nearly 1400 member institutions and 21,000 research professionals in the United States and around the world. ECOG-ACRIN is known for advancing precision medicine and biomarker research through its leadership of major national clinical trials integrating cutting-edge genomic approaches. Member researchers and advocates collaborate across more than 40 scientific committees to design studies spanning the cancer care spectrum, from early detection to management of advanced disease. ECOG-ACRIN is funded primarily by the National Cancer Institute, part of the National Institutes of Health. Visit ecog-acrin.org, and follow us on X @eaonc, Facebook, LinkedIn, and Instagram.

Media Contact: Diane Dragaud, Director of Communications, communications@ecog-acrin.org.

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