Author: Ken Doyle

Monoclonal Antibody (mAb) Therapy to Delay the Onset of Type 1 Diabetes

Posted on by Ken Doyle

On November 18, 2022, the US Food and Drug Administration (FDA) announced the approval of the first drug to delay the onset of stage 3 type 1 diabetes (T1D). The monoclonal antibody (mAb) drug, teplizumab, was approved for use in adults and pediatric patients 8 years and older.

3D illustration of a monoclonal antibody

The road to approval has been a bumpy one for the manufacturer, Provention Bio. In 2020, the FDA rejected the application for teplizumab due to several concerns, including the small size of the clinical trial. With the current approval, based on new clinical trial results, Provention Bio confirmed a co-promotion agreement with Sanofi US. The agreement included a $35 million Sanofi equity investment in the company.

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Left-Handed DNA: Is That Right?

Posted on by Ken Doyle

There’s a certain group of people (including this blog post author) who derive no small amount of amusement from seeing stock photos of DNA and pointing out flaws in the structure. It’s even more amusing when these photos are used in marketing by life science companies. The most common flaw: the DNA molecule is a left-handed double helix.

What does that even mean? DNA, like many organic chemicals in biology, is a chiral molecule. That is, it can exist in two structural forms that are mirror images of each other but are not superimposable (enantiomers). Just like your left and right hands are mirror images of each other, the two DNA structures are left-handed and right-handed double helices. The DNA double helix is chiral, because its building blocks (nucleotides) are chiral.

Two DNA helices that are mirror images

It can be challenging, at first glance, to tell whether an image of DNA is left-handed or right-handed. Various helpful hints are available; however, the one that I’ve found easiest to remember is described in a blog post by Professor Emeritus Larry Moran at the University of Toronto:

Imagine that the double helix is a spiral staircase, and you’re walking down the staircase. If you’re turning to the right as you descend, the DNA structure is right-handed; if turning to the left, it’s left-handed. In the image shown earlier, the DNA molecule on the right is a right-handed double helix, while its mirror image is left-handed.

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Cellular Senescence and Cancer Therapy: Overcoming Immortality?

Posted on by Ken Doyle

At the time of writing this post, no scientist had yet discovered the secret to immortality. In our world, we’ve come to accept that living things are born, grow old and die—the circle of life.

And yet, for many years, life scientists believed that the circle of life did not apply to our constituent cells when cultured in a laboratory. That is, cultured normal human cells were immortal, and they would continue to grow and proliferate forever, as long as they were provided with the necessary nutrients.

The animal cell cycle. Image by Kelvinsong; made available under the Creative Commons CC0 1.0 Universal Public Domain Dedication

Pioneering work published in 1961 by Leonard Hayflick and Paul Moorhead challenged that theory (reviewed in 1). Their research showed that normal cells in culture have a finite capacity to replicate. After they reach a certain number of replicative cycles, cells stop dividing. Hayflick and Moorhead made the important distinction between normal human cells and cultured cancer cells, which are truly immortal. In later years, the limit to the number of replicative cycles normal human cells can undergo became known as the Hayflick limit. Although some scientists still express skepticism about these findings, the Hayflick limit is widely recognized as a fundamental principle of cell biology.

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Neanderthal DNA and Modern Humans: Svante Pääbo Receives the 2022 Nobel Prize in Physiology or Medicine

Posted on by Ken Doyle

What makes humans “human”?

Neanderthal DNA sequencing from ancient bone samples

On October 3, 2022, the Nobel Assembly at Karolinska Institutet announced the 2022 Nobel Prize in Physiology or Medicine had been awarded to Svante Pääbo, director of the Department of Genetics at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. The Assembly cited his “discoveries concerning the genomes of extinct hominins and human evolution”. They mentioned the highlight of his research: the seemingly impossible task, at the time, of sequencing the Neanderthal genome. The discoveries that followed from this sequencing project continue to redefine our understanding of modern human origins.

The award showcases the technological advancements made in the analysis of ancient DNA. However, Pääbo’s research had an inauspicious beginning. In 1985, he published the results of his early work, cloning and sequencing DNA fragments from a 2,400-year-old Egyptian mummy (1). Unfortunately, later analysis revealed that the samples could have been contaminated by the researchers’ own DNA (2).

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mRNA Vaccine Manufacturing: Responding Effectively to a Global Pandemic

Posted on by Ken Doyle

We’ve learned a few important lessons from the COVID-19 pandemic.

Perhaps the most significant one is the importance of an early and rapid global response to the initial outbreak. A coordinated response—including widespread use of masks and other personal protective equipment (PPE), travel restrictions, lockdowns and social distancing—could save lives and reduce long-term health effects (1). Widespread availability of effective vaccines goes hand in hand with these measures.

New Boosters to Fight Omicron

Last month, Pfizer/BioNTech announced the US Food and Drug Administration (FDA) had granted emergency use authorization (EUA) for a new adapted-bivalent COVID-19 booster vaccine for individuals 12 years and older. This vaccine combines mRNA encoding the wild-type Spike protein from the original vaccine with another mRNA encoding the Spike protein of the Omicron BA.4/BA.5 subvariants. Moderna also announced FDA EUA for its new Omicron-targeting COVID-19 booster vaccine. The Omicron variant of SARS-CoV-2 shows multiple mutations across its subvariants, and it is currently the dominant SARS-CoV-2 variant of concern across the world.

Genomic epidemiology of SARS-CoV-2 with subsampling focused globally over the past 6 months. This phylogenetic tree shows evolutionary relationships of SARS-CoV-2 viruses from the ongoing COVID-19 pandemic. Image from Nextstrain.org; generated September 20, 2022

Booster doses of vaccines have become a way of life, both due to declining effectiveness of the original vaccines especially in older adults (2), and the rapid mutation rate of SARS-CoV-2 (3). Clinical data for the new Pfizer/BioNTech booster vaccine showed superior effectiveness in eliciting an immune response against Omicron BA.1 compared to the original vaccine. Previously, Moderna published interim results from an ongoing phase 2-3 clinical trial, showing that the new bivalent booster vaccine elicited a superior neutralizing antibody response against Omicron, compared to its original COVID-19 vaccine (4).

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COVID-19 Intranasal Vaccines: Right on the Nose?

Posted on by Ken Doyle
covid-19 intranasal vaccines

COVID-19 is still a global pandemic. Around the world, as of 5:40pm CEST, 20 June 2022, there have been 536,590,224 cumulative confirmed cases of COVID-19, including 6,316,655 deaths, reported to the World Health Organization. As of 16 June 2022, a total of 11,902,271,619 vaccine doses have been administered. The adoption of vaccines worldwide continues to increase, yet periodic spikes and surges in infection rates continue to occur with new SARS-CoV-2 variants, such as that observed in Australia over the past few months. Vaccine booster doses provide effective protection against developing severe disease and hospitalization, but vaccine adoption and distribution face ongoing challenges in low- and middle-income (LMIC) countries (1). Therapeutic interventions for those already infected are in development, with one (Paxlovid) currently available under emergency use authorization (EUA) in the US.

COVID-19 cumulative statistics reported to the WHO.

Cumulative COVID-19 statistics by country: WHO COVID-19 Dashboard. Geneva: World Health Organization, 2020. Available online: https://covid19.who.int/ (last cited: June 20, 2022).

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The Spectrum CE System: Capillary Electrophoresis for This Generation—and the Next

Posted on by Ken Doyle

Massively parallel sequencing (MPS) has gained popularity for specialized forensic applications. However, the amplification of short tandem repeats (STRs) and analysis by capillary electrophoresis (CE) remains the gold standard for the vast majority of forensic laboratories.

Spectrum CE System in the lab

Recently, Promega announced the launch of the Spectrum CE System, a new capillary electrophoresis instrument that supports future 8-color technology while maintaining compatibility with existing 5- and 6-color kits—even ones that Promega does not sell. In a market with limited instrumentation options for CE analysis, the Spectrum CE system offers features designed to streamline the workflow for analyzing casework and database samples.

Cristopher Cowan, Director of Instrumentation R&D at Promega, discusses the key features of the Spectrum CE System.
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PROTACs: Just the FAQs

Posted on by Ken Doyle
protac drug discovery

While PROTACs might not be the topic of conversation at high society cocktail parties, or merit cover stories in glamor magazines, they’re certainly shaking up the drug discovery industry. PROTAC® degraders, together with related compounds like molecular glues and LYTACs, are the basic tools for a targeted protein degradation strategy. Research in this field is advancing rapidly, enabling the development of therapies for disease targets disease targets previously thought to be “undruggable”. This blog post provides an overview of PROTACs based on frequently asked questions.

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GPCRs and PROTACs: New Approaches for Designing More Effective Drug Candidates

Posted on by Ken Doyle
NanoBRET target engagement assay

G protein-coupled receptors (GPCRs) comprise a large group of cell surface receptors, characterized by the unique structural property of crossing the cell membrane seven times. They respond to a diverse group of signaling molecules, such as peptides, neurotransmitters, cytokines, hormones and other small molecules (1). Upon activation, GPCRs interact with GTP-binding (G) proteins and arrestins to regulate a wide variety of signaling pathways. This broad range of functions makes GPCRs attractive targets for drug discovery. The importance of GPCR research was highlighted in 2012, with the Nobel Prize in chemistry being awarded to Robert Lefkowitz and Brian Kobilka “for studies of G-protein–coupled receptors”.

Based on structure and function, GPCRs are categorized into six classes, A–F. The class A GPCRs, or rhodopsin-like receptors, have been studied extensively due to their association with many types of diseases (2). Within the class A GPCRs is a group that share a highly conserved structural motif (3) and respond to chemokines—small “chemotactic cytokines” that stimulate cell migration, especially that of white blood cells (4). A subfamily of class A GPCRs respond to chemokines that have two cysteine residues near the N-terminus, known as CC chemokines. GPCRs activated by CC chemokines are called CC chemokine receptors or CCRs, and these interactions have been implicated in both pro- and anti-cancer pathways (5).

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COVID-19 Antiviral Therapies: What Are the New Drugs, and How Do They Work?

Posted on by Ken Doyle

We’re entering the third year of the global COVID-19 pandemic, and it’s far from over. There has been considerable progress with SARS-CoV-2 vaccine development, with most of the focus on mRNA vaccines and adenoviral vector vaccines. Meanwhile, novel vaccine delivery systems are being tested among efforts to develop a “pan-coronavirus” vaccine that is effective against multiple variants. One such example is ferritin nanoparticle technology developed by researchers at the Walter Reed Army Institute of Research and their collaborators. Encouraging results from nonhuman primate studies, using several SARS-CoV-2 antigens, were published in 2021 (1–3).

New COVID-19 antiviral therapies offer promise, but further data are needed before they become widely available.

The current surge in COVID-19 cases that began last month is largely due to the Omicron variant in the US, according to data from the US Centers for Disease Control and Prevention (CDC). At present, we still don’t know enough about this variant, but it’s clear that its rapid spread is forcing us to re-examine what we know about SARS-CoV-2 (4). As the virus continues to mutate, new variants will continue to emerge and spread. Although current vaccines can provide protection against multiple variants, breakthrough infections are a concern. Vaccination is still the best option to reduce the risk of infection, hospitalization, and death compared to unvaccinated people.

It’s clear that vaccines are only part of an effective response to fighting the pandemic. Along with continued vaccine development efforts, attention must also be given to antiviral drug development for people already infected with COVID-19. Due to the lengthy process for new drug development, early efforts focused on repurposing existing drugs.

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