Tag Archives: Katalin Karikó

2023 Nobel prizes (medicine, physics, and chemistry)

For the first time in the 15 years this blog has been around, the Nobel prizes awarded in medicine, physics, and chemistry all are in areas discussed here at one or another. As usual where people are concerned, some of these scientists had a tortuous journey to this prestigious outcome.

Medicine

Two people (Katalin Karikó and Drew Weissman) were awarded the prize in medicine according to the October 2, 2023 Nobel Prize press release, Note: Links have been removed,

The Nobel Assembly at Karolinska Institutet [Sweden]

has today decided to award

the 2023 Nobel Prize in Physiology or Medicine

jointly to

Katalin Karikó and Drew Weissman

for their discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19

The discoveries by the two Nobel Laureates were critical for developing effective mRNA vaccines against COVID-19 during the pandemic that began in early 2020. Through their groundbreaking findings, which have fundamentally changed our understanding of how mRNA interacts with our immune system, the laureates contributed to the unprecedented rate of vaccine development during one of the greatest threats to human health in modern times.

Vaccines before the pandemic

Vaccination stimulates the formation of an immune response to a particular pathogen. This gives the body a head start in the fight against disease in the event of a later exposure. Vaccines based on killed or weakened viruses have long been available, exemplified by the vaccines against polio, measles, and yellow fever. In 1951, Max Theiler was awarded the Nobel Prize in Physiology or Medicine for developing the yellow fever vaccine.

Thanks to the progress in molecular biology in recent decades, vaccines based on individual viral components, rather than whole viruses, have been developed. Parts of the viral genetic code, usually encoding proteins found on the virus surface, are used to make proteins that stimulate the formation of virus-blocking antibodies. Examples are the vaccines against the hepatitis B virus and human papillomavirus. Alternatively, parts of the viral genetic code can be moved to a harmless carrier virus, a “vector.” This method is used in vaccines against the Ebola virus. When vector vaccines are injected, the selected viral protein is produced in our cells, stimulating an immune response against the targeted virus.

Producing whole virus-, protein- and vector-based vaccines requires large-scale cell culture. This resource-intensive process limits the possibilities for rapid vaccine production in response to outbreaks and pandemics. Therefore, researchers have long attempted to develop vaccine technologies independent of cell culture, but this proved challenging.

Illustration of methods for vaccine production before the COVID-19 pandemic.
Figure 1. Methods for vaccine production before the COVID-19 pandemic. © The Nobel Committee for Physiology or Medicine. Ill. Mattias Karlén

mRNA vaccines: A promising idea

In our cells, genetic information encoded in DNA is transferred to messenger RNA (mRNA), which is used as a template for protein production. During the 1980s, efficient methods for producing mRNA without cell culture were introduced, called in vitro transcription. This decisive step accelerated the development of molecular biology applications in several fields. Ideas of using mRNA technologies for vaccine and therapeutic purposes also took off, but roadblocks lay ahead. In vitro transcribed mRNA was considered unstable and challenging to deliver, requiring the development of sophisticated carrier lipid systems to encapsulate the mRNA. Moreover, in vitro-produced mRNA gave rise to inflammatory reactions. Enthusiasm for developing the mRNA technology for clinical purposes was, therefore, initially limited.

These obstacles did not discourage the Hungarian biochemist Katalin Karikó, who was devoted to developing methods to use mRNA for therapy. During the early 1990s, when she was an assistant professor at the University of Pennsylvania, she remained true to her vision of realizing mRNA as a therapeutic despite encountering difficulties in convincing research funders of the significance of her project. A new colleague of Karikó at her university was the immunologist Drew Weissman. He was interested in dendritic cells, which have important functions in immune surveillance and the activation of vaccine-induced immune responses. Spurred by new ideas, a fruitful collaboration between the two soon began, focusing on how different RNA types interact with the immune system.

The breakthrough

Karikó and Weissman noticed that dendritic cells recognize in vitro transcribed mRNA as a foreign substance, which leads to their activation and the release of inflammatory signaling molecules. They wondered why the in vitro transcribed mRNA was recognized as foreign while mRNA from mammalian cells did not give rise to the same reaction. Karikó and Weissman realized that some critical properties must distinguish the different types of mRNA.

RNA contains four bases, abbreviated A, U, G, and C, corresponding to A, T, G, and C in DNA, the letters of the genetic code. Karikó and Weissman knew that bases in RNA from mammalian cells are frequently chemically modified, while in vitro transcribed mRNA is not. They wondered if the absence of altered bases in the in vitro transcribed RNA could explain the unwanted inflammatory reaction. To investigate this, they produced different variants of mRNA, each with unique chemical alterations in their bases, which they delivered to dendritic cells. The results were striking: The inflammatory response was almost abolished when base modifications were included in the mRNA. This was a paradigm change in our understanding of how cells recognize and respond to different forms of mRNA. Karikó and Weissman immediately understood that their discovery had profound significance for using mRNA as therapy. These seminal results were published in 2005, fifteen years before the COVID-19 pandemic.

Illustration of the four different bases mRNA contains.
Figure 2. mRNA contains four different bases, abbreviated A, U, G, and C. The Nobel Laureates discovered that base-modified mRNA can be used to block activation of inflammatory reactions (secretion of signaling molecules) and increase protein production when mRNA is delivered to cells.  © The Nobel Committee for Physiology or Medicine. Ill. Mattias Karlén

In further studies published in 2008 and 2010, Karikó and Weissman showed that the delivery of mRNA generated with base modifications markedly increased protein production compared to unmodified mRNA. The effect was due to the reduced activation of an enzyme that regulates protein production. Through their discoveries that base modifications both reduced inflammatory responses and increased protein production, Karikó and Weissman had eliminated critical obstacles on the way to clinical applications of mRNA.

mRNA vaccines realized their potential

Interest in mRNA technology began to pick up, and in 2010, several companies were working on developing the method. Vaccines against Zika virus and MERS-CoV were pursued; the latter is closely related to SARS-CoV-2. After the outbreak of the COVID-19 pandemic, two base-modified mRNA vaccines encoding the SARS-CoV-2 surface protein were developed at record speed. Protective effects of around 95% were reported, and both vaccines were approved as early as December 2020.

The impressive flexibility and speed with which mRNA vaccines can be developed pave the way for using the new platform also for vaccines against other infectious diseases. In the future, the technology may also be used to deliver therapeutic proteins and treat some cancer types.

Several other vaccines against SARS-CoV-2, based on different methodologies, were also rapidly introduced, and together, more than 13 billion COVID-19 vaccine doses have been given globally. The vaccines have saved millions of lives and prevented severe disease in many more, allowing societies to open and return to normal conditions. Through their fundamental discoveries of the importance of base modifications in mRNA, this year’s Nobel laureates critically contributed to this transformative development during one of the biggest health crises of our time.

Read more about this year’s prize

Scientific background: Discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19

Katalin Karikó was born in 1955 in Szolnok, Hungary. She received her PhD from Szeged’s University in 1982 and performed postdoctoral research at the Hungarian Academy of Sciences in Szeged until 1985. She then conducted postdoctoral research at Temple University, Philadelphia, and the University of Health Science, Bethesda. In 1989, she was appointed Assistant Professor at the University of Pennsylvania, where she remained until 2013. After that, she became vice president and later senior vice president at BioNTech RNA Pharmaceuticals. Since 2021, she has been a Professor at Szeged University and an Adjunct Professor at Perelman School of Medicine at the University of Pennsylvania.

Drew Weissman was born in 1959 in Lexington, Massachusetts, USA. He received his MD, PhD degrees from Boston University in 1987. He did his clinical training at Beth Israel Deaconess Medical Center at Harvard Medical School and postdoctoral research at the National Institutes of Health. In 1997, Weissman established his research group at the Perelman School of Medicine at the University of Pennsylvania. He is the Roberts Family Professor in Vaccine Research and Director of the Penn Institute for RNA Innovations.

The University of Pennsylvania October 2, 2023 news release is a very interesting announcement (more about why it’s interesting afterwards), Note: Links have been removed,

The University of Pennsylvania messenger RNA pioneers whose years of scientific partnership unlocked understanding of how to modify mRNA to make it an effective therapeutic—enabling a platform used to rapidly develop lifesaving vaccines amid the global COVID-19 pandemic—have been named winners of the 2023 Nobel Prize in Physiology or Medicine. They become the 28th and 29th Nobel laureates affiliated with Penn, and join nine previous Nobel laureates with ties to the University of Pennsylvania who have won the Nobel Prize in Medicine.

Nearly three years after the rollout of mRNA vaccines across the world, Katalin Karikó, PhD, an adjunct professor of Neurosurgery in Penn’s Perelman School of Medicine, and Drew Weissman, MD, PhD, the Roberts Family Professor of Vaccine Research in the Perelman School of Medicine, are recipients of the prize announced this morning by the Nobel Assembly in Solna, Sweden.

After a chance meeting in the late 1990s while photocopying research papers, Karikó and Weissman began investigating mRNA as a potential therapeutic. In 2005, they published a key discovery: mRNA could be altered and delivered effectively into the body to activate the body’s protective immune system. The mRNA-based vaccines elicited a robust immune response, including high levels of antibodies that attack a specific infectious disease that has not previously been encountered. Unlike other vaccines, a live or attenuated virus is not injected or required at any point.

When the COVID-19 pandemic struck, the true value of the pair’s lab work was revealed in the most timely of ways, as companies worked to quickly develop and deploy vaccines to protect people from the virus. Both Pfizer/BioNTech and Moderna utilized Karikó and Weissman’s technology to build their highly effective vaccines to protect against severe illness and death from the virus. In the United States alone, mRNA vaccines make up more than 655 million total doses of SARS-CoV-2 vaccines that have been administered since they became available in December 2020.

Editor’s Note: The Pfizer/BioNTech and Moderna COVID-19 mRNA vaccines both use licensed University of Pennsylvania technology. As a result of these licensing relationships, Penn, Karikó and Weissman have received and may continue to receive significant financial benefits in the future based on the sale of these products. BioNTech provides funding for Weissman’s research into the development of additional infectious disease vaccines.

Science can be brutal

Now for the interesting bit: it’s in my March 5, 2021 posting (mRNA, COVID-19 vaccines, treating genetic diseases before birth, and the scientist who started it all),

Before messenger RNA was a multibillion-dollar idea, it was a scientific backwater. And for the Hungarian-born scientist behind a key mRNA discovery, it was a career dead-end.

Katalin Karikó spent the 1990s collecting rejections. Her work, attempting to harness the power of mRNA to fight disease, was too far-fetched for government grants, corporate funding, and even support from her own colleagues.

“Every night I was working: grant, grant, grant,” Karikó remembered, referring to her efforts to obtain funding. “And it came back always no, no, no.”

By 1995, after six years on the faculty at the University of Pennsylvania, Karikó got demoted. [emphasis mine] She had been on the path to full professorship, but with no money coming in to support her work on mRNA, her bosses saw no point in pressing on.

She was back to the lower rungs of the scientific academy.

“Usually, at that point, people just say goodbye and leave because it’s so horrible,” Karikó said.

There’s no opportune time for demotion, but 1995 had already been uncommonly difficult. Karikó had recently endured a cancer scare, and her husband was stuck in Hungary sorting out a visa issue. Now the work to which she’d devoted countless hours was slipping through her fingers.

In time, those better experiments came together. After a decade of trial and error, Karikó and her longtime collaborator at Penn — Drew Weissman [emphasis mine], an immunologist with a medical degree and Ph.D. from Boston University — discovered a remedy for mRNA’s Achilles’ heel.

You can get the whole story from my March 5, 2021 posting, scroll down to the “mRNA—it’s in the details, plus, the loneliness of pioneer researchers, a demotion, and squabbles” subhead. If you are very curious about mRNA and the rough and tumble of the world of science, there’s my August 20, 2021 posting “Getting erased from the mRNA/COVID-19 story” where Ian MacLachlan is featured as a researcher who got erased and where Karikó credits his work.

‘Rowing Mom Wins Nobel’ (credit: rowing website Row 2K)

Karikó’s daughter is a two-time gold medal Olympic athlete as the Canadian Broadcasting Corporation’s (CBC) radio programme, As It Happens, notes in an interview with the daughter (Susan Francia). From an October 4, 2023 As It Happens article (with embedded audio programme excerpt) by Sheena Goodyear,

Olympic gold medallist Susan Francia is coming to terms with the fact that she’s no longer the most famous person in her family.

That’s because the retired U.S. rower’s mother, Katalin Karikó, just won a Nobel Prize in Medicine. The biochemist was awarded alongside her colleague, vaccine researcher Drew Weissman, for their groundbreaking work that led to the development of COVID-19 vaccines. 

“Now I’m like, ‘Shoot! All right, I’ve got to work harder,'” Francia said with a laugh during an interview with As It Happens host Nil Köksal. 

But in all seriousness, Francia says she’s immensely proud of her mother’s accomplishments. In fact, it was Karikó’s fierce dedication to science that inspired Francia to win Olympic gold medals in 2008 and 2012.

“Sport is a lot like science in that, you know, you have a passion for something and you just go and you train, attain your goal, whether it be making this discovery that you truly believe in, or for me, it was trying to be the best in the world,” Francia said.

“It’s a grind and, honestly, I love that grind. And my mother did too.”

… one of her [Karikó] favourite headlines so far comes from a little blurb on the rowing website Row 2K: “Rowing Mom Wins Nobel.”

Nowadays, scientists are trying to harness the power of mRNA to fight cancer, malaria, influenza and rabies. But when Karikó first began her work, it was a fringe concept. For decades, she toiled in relative obscurity, struggling to secure funding for her research.

“That’s also that same passion that I took into my rowing,” Francia said.

But even as Karikó struggled to make a name for herself, she says her own mother, Zsuzsanna, always believed she would earn a Nobel Prize one day.

Every year, as the Nobel Prize announcement approached, she would tell Karikó she’d be watching for her name. 

“I was laughing [and saying] that, ‘Mom, I am not getting anything,'” she said. 

But her mother, who died a few years ago, ultimately proved correct. 

Congratulations to both Katalin Karikó and Drew Weissman and thank you both for persisting!

Physics

This prize is for physics at the attoscale.

Aaron W. Harrison (Assistant Professor of Chemistry, Austin College, Texas, US) attempts an explanation of an attosecond in his October 3, 2023 essay (in English “What is an attosecond? A physical chemist explains the tiny time scale behind Nobel Prize-winning research” and in French “Nobel de physique : qu’est-ce qu’une attoseconde?”) for The Conversation, Note: Links have been removed,

“Atto” is the scientific notation prefix that represents 10-18, which is a decimal point followed by 17 zeroes and a 1. So a flash of light lasting an attosecond, or 0.000000000000000001 of a second, is an extremely short pulse of light.

In fact, there are approximately as many attoseconds in one second as there are seconds in the age of the universe.

Previously, scientists could study the motion of heavier and slower-moving atomic nuclei with femtosecond (10-15) light pulses. One thousand attoseconds are in 1 femtosecond. But researchers couldn’t see movement on the electron scale until they could generate attosecond light pulses – electrons move too fast for scientists to parse exactly what they are up to at the femtosecond level.

Harrison does a very good job of explaining something that requires a leap of imagination. He also explains why scientists engage in attosecond research. h/t October 4, 2023 news item on phys.org

Amelle Zaïr (Imperial College London) offers a more technical explanation in her October 4, 2023 essay about the 2023 prize winners for The Conversation. h/t October 4, 2023 news item on phys.org

Main event

Here’s the October 3, 2023 Nobel Prize press release, Note: A link has been removed,

The Royal Swedish Academy of Sciences has decided to award the Nobel Prize in Physics 2023 to

Pierre Agostini
The Ohio State University, Columbus, USA

Ferenc Krausz
Max Planck Institute of Quantum Optics, Garching and Ludwig-Maximilians-Universität München, Germany

Anne L’Huillier
Lund University, Sweden

“for experimental methods that generate attosecond pulses of light for the study of electron dynamics in matter”

Experiments with light capture the shortest of moments

The three Nobel Laureates in Physics 2023 are being recognised for their experiments, which have given humanity new tools for exploring the world of electrons inside atoms and molecules. Pierre Agostini, Ferenc Krausz and Anne L’Huillier have demonstrated a way to create extremely short pulses of light that can be used to measure the rapid processes in which electrons move or change energy.

Fast-moving events flow into each other when perceived by humans, just like a film that consists of still images is perceived as continual movement. If we want to investigate really brief events, we need special technology. In the world of electrons, changes occur in a few tenths of an attosecond – an attosecond is so short that there are as many in one second as there have been seconds since the birth of the universe.

The laureates’ experiments have produced pulses of light so short that they are measured in attoseconds, thus demonstrating that these pulses can be used to provide images of processes inside atoms and molecules.

In 1987, Anne L’Huillier discovered that many different overtones of light arose when she transmitted infrared laser light through a noble gas. Each overtone is a light wave with a given number of cycles for each cycle in the laser light. They are caused by the laser light interacting with atoms in the gas; it gives some electrons extra energy that is then emitted as light. Anne L’Huillier has continued to explore this phenomenon, laying the ground for subsequent breakthroughs.

In 2001, Pierre Agostini succeeded in producing and investigating a series of consecutive light pulses, in which each pulse lasted just 250 attoseconds. At the same time, Ferenc Krausz was working with another type of experiment, one that made it possible to isolate a single light pulse that lasted 650 attoseconds.

The laureates’ contributions have enabled the investigation of processes that are so rapid they were previously impossible to follow.

“We can now open the door to the world of electrons. Attosecond physics gives us the opportunity to understand mechanisms that are governed by electrons. The next step will be utilising them,” says Eva Olsson, Chair of the Nobel Committee for Physics.

There are potential applications in many different areas. In electronics, for example, it is important to understand and control how electrons behave in a material. Attosecond pulses can also be used to identify different molecules, such as in medical diagnostics.

Read more about this year’s prize

Popular science background: Electrons in pulses of light (pdf)
Scientific background: “For experimental methods that generate attosecond pulses of light for the study of electron dynamics in matter” (pdf)

Pierre Agostini. PhD 1968 from Aix-Marseille University, France. Professor at The Ohio State University, Columbus, USA.

Ferenc Krausz, born 1962 in Mór, Hungary. PhD 1991 from Vienna University of Technology, Austria. Director at Max Planck Institute of Quantum Optics, Garching and Professor at Ludwig-Maximilians-Universität München, Germany.

Anne L’Huillier, born 1958 in Paris, France. PhD 1986 from University Pierre and Marie Curie, Paris, France. Professor at Lund University, Sweden.

A Canadian connection?

An October 3, 2023 CBC online news item from the Associated Press reveals a Canadian connection of sorts ,

Three scientists have won the Nobel Prize in physics Tuesday for giving us the first split-second glimpse into the superfast world of spinning electrons, a field that could one day lead to better electronics or disease diagnoses.

The award went to French-Swedish physicist Anne L’Huillier, French scientist Pierre Agostini and Hungarian-born Ferenc Krausz for their work with the tiny part of each atom that races around the centre, and that is fundamental to virtually everything: chemistry, physics, our bodies and our gadgets.

Electrons move around so fast that they have been out of reach of human efforts to isolate them. But by looking at the tiniest fraction of a second possible, scientists now have a “blurry” glimpse of them, and that opens up whole new sciences, experts said.

“The electrons are very fast, and the electrons are really the workforce in everywhere,” Nobel Committee member Mats Larsson said. “Once you can control and understand electrons, you have taken a very big step forward.”

L’Huillier is the fifth woman to receive a Nobel in Physics.

L’Huillier was teaching basic engineering physics to about 100 undergraduates at Lund when she got the call that she had won, but her phone was on silent and she didn’t pick up. She checked it during a break and called the Nobel Committee.

Then she went back to teaching.

Agostini, an emeritus professor at Ohio State University, was in Paris and could not be reached by the Nobel Committee before it announced his win to the world

Here’s the Canadian connection (from the October 3, 2023 CBC online news item),

Krausz, of the Max Planck Institute of Quantum Optics and Ludwig Maximilian University of Munich, told reporters that he was bewildered.

“I have been trying to figure out since 11 a.m. whether I’m in reality or it’s just a long dream,” the 61-year-old said.

Last year, Krausz and L’Huillier won the prestigious Wolf prize in physics for their work, sharing it with University of Ottawa scientist Paul Corkum [emphasis mine]. Nobel prizes are limited to only three winners and Krausz said it was a shame that it could not include Corkum.

Corkum was key to how the split-second laser flashes could be measured [emphasis mine], which was crucial, Krausz said.

Congratulations to Pierre Agostini, Ferenc Krausz and Anne L’Huillier and a bow to Paul Corkum!

For those who are curious. a ‘Paul Corkum’ search should bring up a few postings on this blog but I missed this piece of news, a May 4, 2023 University of Ottawa news release about Corkum and the 2022 Wolf Prize, which he shared with Krausz and L’Huillier,

Chemistry

There was a little drama where this prize was concerned, It was announced too early according to an October 4, 2023 news item on phys.org and, again, in another October 4, 2023 news item on phys.org (from the Oct. 4, 2023 news item by Karl Ritter for the Associated Press),

Oops! Nobel chemistry winners are announced early in a rare slip-up

The most prestigious and secretive prize in science ran headfirst into the digital era Wednesday when Swedish media got an emailed press release revealing the winners of the Nobel Prize in chemistry and the news prematurely went public.

Here’s the fully sanctioned October 4, 2023 Nobel Prize press release, Note: A link has been removed,

The Royal Swedish Academy of Sciences has decided to award the Nobel Prize in Chemistry 2023 to

Moungi G. Bawendi
Massachusetts Institute of Technology (MIT), Cambridge, MA, USA

Louis E. Brus
Columbia University, New York, NY, USA

Alexei I. Ekimov
Nanocrystals Technology Inc., New York, NY, USA

“for the discovery and synthesis of quantum dots”

They planted an important seed for nanotechnology

The Nobel Prize in Chemistry 2023 rewards the discovery and development of quantum dots, nanoparticles so tiny that their size determines their properties. These smallest components of nanotechnology now spread their light from televisions and LED lamps, and can also guide surgeons when they remove tumour tissue, among many other things.

Everyone who studies chemistry learns that an element’s properties are governed by how many electrons it has. However, when matter shrinks to nano-dimensions quantum phenomena arise; these are governed by the size of the matter. The Nobel Laureates in Chemistry 2023 have succeeded in producing particles so small that their properties are determined by quantum phenomena. The particles, which are called quantum dots, are now of great importance in nanotechnology.

“Quantum dots have many fascinating and unusual properties. Importantly, they have different colours depending on their size,” says Johan Åqvist, Chair of the Nobel Committee for Chemistry.

Physicists had long known that in theory size-dependent quantum effects could arise in nanoparticles, but at that time it was almost impossible to sculpt in nanodimensions. Therefore, few people believed that this knowledge would be put to practical use.

However, in the early 1980s, Alexei Ekimov succeeded in creating size-dependent quantum effects in coloured glass. The colour came from nanoparticles of copper chloride and Ekimov demonstrated that the particle size affected the colour of the glass via quantum effects.

A few years later, Louis Brus was the first scientist in the world to prove size-dependent quantum effects in particles floating freely in a fluid.

In 1993, Moungi Bawendi revolutionised the chemical production of quantum dots, resulting in almost perfect particles. This high quality was necessary for them to be utilised in applications.

Quantum dots now illuminate computer monitors and television screens based on QLED technology. They also add nuance to the light of some LED lamps, and biochemists and doctors use them to map biological tissue.

Quantum dots are thus bringing the greatest benefit to humankind. Researchers believe that in the future they could contribute to flexible electronics, tiny sensors, thinner solar cells and encrypted quantum communication – so we have just started exploring the potential of these tiny particles.

Read more about this year’s prize

Popular science background: They added colour to nanotechnology (pdf)
Scientific background: Quantum dots – seeds of nanoscience (pdf)

Moungi G. Bawendi, born 1961 in Paris, France. PhD 1988 from University of Chicago, IL, USA. Professor at Massachusetts Institute of Technology (MIT), Cambridge, MA, USA.

Louis E. Brus, born 1943 in Cleveland, OH, USA. PhD 1969 from Columbia University, New York, NY, USA. Professor at Columbia University, New York, NY, USA.

Alexei I. Ekimov, born 1945 in the former USSR. PhD 1974 from Ioffe Physical-Technical Institute, Saint Petersburg, Russia. Formerly Chief Scientist at Nanocrystals Technology Inc., New York, NY, USA.


The most recent ‘quantum dot’ (a particular type of nanoparticle) story here is a January 5, 2023 posting, “Can I have a beer with those carbon quantum dots?

Proving yet again that scientists can have a bumpy trip to a Nobel prize, an October 4, 2023 news item on phys.org describes how one of the winners flunked his first undergraduate chemistry test, Note: Links have been removed,

Talk about bouncing back. MIT professor Moungi Bawendi is a co-winner of this year’s Nobel chemistry prize for helping develop “quantum dots”—nanoparticles that are now found in next generation TV screens and help illuminate tumors within the body.

But as an undergraduate, he flunked his very first chemistry exam, recalling that the experience nearly “destroyed” him.

The 62-year-old of Tunisian and French heritage excelled at science throughout high school, without ever having to break a sweat.

But when he arrived at Harvard University as an undergraduate in the late 1970s, he was in for a rude awakening.

You can find more about the winners and quantum dots in an October 4, 2023 news item on Nanowerk and in Dr. Andrew Maynard’s (Professor of Advanced Technology Transitions, Arizona State University) October 4, 2023 essay for The Conversation (h/t October 4, 2023 news item on phys.org), Note: Links have been removed,

This year’s prize recognizes Moungi Bawendi, Louis Brus and Alexei Ekimov for the discovery and development of quantum dots. For many years, these precisely constructed nanometer-sized particles – just a few hundred thousandths the width of a human hair in diameter – were the darlings of nanotechnology pitches and presentations. As a researcher and adviser on nanotechnology [emphasis mine], I’ve [Dr. Andrew Maynard] even used them myself when talking with developers, policymakers, advocacy groups and others about the promise and perils of the technology.

The origins of nanotechnology predate Bawendi, Brus and Ekimov’s work on quantum dots – the physicist Richard Feynman speculated on what could be possible through nanoscale engineering as early as 1959, and engineers like Erik Drexler were speculating about the possibilities of atomically precise manufacturing in the the 1980s. However, this year’s trio of Nobel laureates were part of the earliest wave of modern nanotechnology where researchers began putting breakthroughs in material science to practical use.

Quantum dots brilliantly fluoresce: They absorb one color of light and reemit it nearly instantaneously as another color. A vial of quantum dots, when illuminated with broad spectrum light, shines with a single vivid color. What makes them special, though, is that their color is determined by how large or small they are. Make them small and you get an intense blue. Make them larger, though still nanoscale, and the color shifts to red.

The wavelength of light a quantum dot emits depends on its size. Maysinger, Ji, Hutter, Cooper, CC BY

There’s also an October 4, 2023 overview article by Tekla S. Perry and Margo Anderson for the IEEE Spectrum about the magazine’s almost twenty-five years of reporting on quantum dots

Red blue and green dots mass in rows, with some dots moving away

Image credit: Brandon Palacio/IEEE Spectrum

Your Guide to the Newest Nobel Prize: Quantum Dots

What you need to know—and what we’ve reported—about this year’s Chemistry award

It’s not a long article and it has a heavy focus on the IEEEE’s (Institute of Electrical and Electtronics Engineers) the road quantum dots have taken to become applications and being commercialized.

Congratulations to Moungi Bawendi, Louis Brus, and Alexei Ekimov!

Getting erased from the mRNA/COVID-19 story

Nathan Vardi’s August 17, 2021 article for Forbes magazine about Ian MacLachlan and the delivery system for mRNA vaccines tells a type of story I’ve more often seen in history books. It is reminiscent of the Thomas Edison and Nikola Tesla story of electricity. One gets all the glory while the other is largely forgotten.

I’m especially interested as much of this concerns players in the local (Vancouver, British Columbia, Canada) biotechnology scene. Vardi’s August 17, 2021 article sets the scene,

“The whole mRNA platform is not how to build an mRNA molecule; that’s the easy thing,” Bourla [Pfizer CEO Albert Bourla] says. “It is how to make sure the mRNA molecule will go into your cells and give the instructions.” 

Yet the story of how Moderna, BioNTech and Pfizer managed to create that vital delivery system has never been told. It’s a complicated saga involving 15 years of legal battles and accusations of betrayal and deceit. [emphases mine] What is clear is that when humanity needed a way to deliver mRNA to human cells to arrest the pandemic, there was only one reliable method available—and it wasn’t one originated in-house by Pfizer, Moderna, BioNTech or any of the other major vaccine companies. 

A months-long investigation by Forbes reveals that the scientist most responsible for this critical delivery method is a little-known 57-year-old Canadian biochemist named Ian MacLachlan. As chief scientific officer of two small companies, Protiva Biotherapeutics and Tekmira Pharmaceuticals, MacLachlan led the team that developed this crucial technology. Today, though, few people—and none of the big pharmaceutical companies—openly acknowledge his groundbreaking work, and MacLachlan earns nothing from the technology he pioneered. 

I have three stories (on this blog) mentioning Tekmira (all from 2014 or 2015) and none mentioning Protiva nor, for that matter, Ian MacLachlan.

Back to Vardi’s August 17, 2021 article,

Moderna Therapeutics vigorously disputes the idea that its mRNA vaccine uses MacLachlan’s delivery system, and BioNTech, the vaccine maker partnered with Pfizer, talks about it carefully. Legal proceedings are pending, and big money is at stake. 

Moderna, BioNTech and Pfizer are on their way to selling $45 billion worth of vaccines in 2021. They don’t pay a dime to MacLachlan. Other coronavirus vaccine makers, such as Gritstone Oncology, have recently licensed MacLachlan’s Protiva-Tekmira delivery technology for between 5% and 15% of product sales. MacLachlan no longer has a financial stake in the technology, but a similar royalty on the Moderna and Pfizer-BioNTech vaccines could yield as much as $6.75 billion in 2021 alone. …

Vardi provides evidence (Note: A link has been removed from the August 17, 2021 article excerpt,

Despite their denials, scientific papers and regulatory documents filed with the FDA [US Food and Drug Administration] show that both Moderna and Pfizer-BioNTech’s vaccines use a delivery system strikingly similar to what MacLachlan and his team created—a carefully formulated four-lipid component that encapsulates mRNA in a dense particle through a mixing process involving ethanol and a T-connector apparatus. 

For years, Moderna claimed it was using its own proprietary delivery system, but when it came time for the company to test its Covid-19 vaccine in mice, it used the same four kinds of lipids as MacLachlan’s technology, in identical ratios. 

According to Vardi’s LinkedIn profile: “I am a senior editor at Forbes, where I am responsible for the coverage of hedge funds, private equity, and other big investors. I lead investigative reporting efforts and have written 20 cover stories for Forbes Magazine,” he does not appear to have any medical or bioscience expertise (Bachelor of Journalism from Carleton University [Canada] and Masters of International Affairs from Columbia University [US].) Presumably someone he consulted or someone on his team provided the skills necessary for analyzing the scientific papers and documents.

You may recognize this scientist (from the August 17, 2021 article),

Not everyone ignores MacLachlan. “A lot of credit goes to Ian MacLachlan for the LNP [lipid nanoparticle],” says Katalin Karikó, [emphasis mine] the scientist who laid the groundwork for mRNA therapies before joining BioNTech in 2013. But Karikó, now a frontrunner for a Nobel Prize, is angry that MacLachlan didn’t do more to help her use his delivery system to build her own mRNA company years ago. “[MacLachlan] might be a great scientist, but he lacked vision,” she says.

I have more about Karikó and her role in the mRNA vaccine story here in a March 5, 2021 posting.

As for MacLachlan’s start (from the August 17, 2021 article),

… With a Ph.D. in biochemistry, MacLachlan joined Inex in 1996, his first job after completing a postdoctoral fellowship in a gene lab at the University of Michigan. 

Inex was cofounded by its chief scientific officer, Pieter Cullis, now 75, a long-haired physicist who taught at the University of British Columbia. From his perch there Cullis started several biotechs, cultivating an elite community of scientists that made Vancouver a hotbed of lipid chemistry. 

As companies rise and fall with intellectual property being assigned to one company or other, legal brawls ensue. This was the time that Karikó came knocking on the door, from the August 17, 2021 article,

It was in the midst of all this furious legal fighting that Hungarian biochemist Katalin Karikó first showed up at MacLachlan’s door. Karikó was early to grasp that MacLachlan’s delivery system held the key to unlocking the potential of mRNA therapies. As early as 2006, she began sending letters to MacLachlan urging him to encase her groundbreaking chemically altered mRNA in his four-lipid delivery system. Embroiled in litigation, MacLachlan passed on her offer. 

Karikó didn’t give up easily. In 2013, she flew to meet with Tekmira’s executives, offering to relocate to Vancouver and work directly under MacLachlan. Tekmira passed. “Moderna, BioNTech and CureVac all wanted me to work for them, but my number one choice, Tekmira, didn’t,” says Karikó, who took a job at BioNTech in 2013. 

By this time, Moderna CEO Stéphane Bancel [emphasis mine] was also trying to solve the delivery puzzle. Bancel held discussions with Tekmira about collaborating, but talks stalled. At one point, Tekmira indicated it wanted at least $100 million up front, plus royalties, to strike a deal.

Instead, Moderna partnered with Madden [Thomas Madden], who was still working with Cullis at their drug delivery company, Acuitas Therapeutics.  …

I have been wondering why Acuitas Therapeutics hasn’t been getting all that much attention in the hyperbolic discussions about British Columbia’s (or Vancouver’s) thriving biotechnology scene. (I’ll have more about the ‘scene’ in a later posting.) Perhaps all this legal wrangling is not considered helpful when bragging. (I do have a November 12, 2020 post, which features Acuitas, an interview with its president and chief executive office Dr. Thomas Madden, and an explanation of their technology.)

As for Moderna, I have a special interest as the company has announced plans to open a production facility here in Canada and one of Moderna’s founders is Canadian, Derek Rossi. (He too is mentioned in the March 5, 2021 posting, scroll down to the ‘Entrepreneurs rush in’ subhead; he is not an altogether happy camper.)

Rossi has opinions on how we should be doing things here as noted in a June 17, 2021 article by Barbara Shecter for the Financial Post (Moderna founder says Canada needs to build a biotech hub to avoid ‘getting caught with its pants down next time’). Thank you, Mr. Rossi. (I’m more familiar with clusters than hubs [hubs were a popular topic of conversation about 20 years ago but in Canada we seem more interested in clusters; see John Newbigin’s “Hubs, clusters and regions” on britishcouncil.org for a description of the differences].)

As for Moderna’s response to all of the legal wrangling over mRNA delivery systems, from Vardi’s August 17, 2021 article,

Moderna pursued a different strategy. It filed lawsuits with the U.S. Patent and Trademark Office seeking to nullify a series of patents related to MacLachlan’s delivery system, now controlled by Genevant. But in July 2020, as Moderna was pushing its vaccine through clinical trials, an adjudicative body largely upheld the most important patent claims. (Moderna is appealing.)

I highly recommend reading Vardi’s August 17, 2021 article as I have not done justice to all of the ‘ins and outs’ of the story.

You can see how thoroughly MacLachlan has been erased form the lipid nanoparticle delivery system/COVID-19 vaccine story in this May 24 ,2021 posting (Lipid nanoparticles: The underrated invention behind the vaccine revolution) by Nada Salem at the Science Borealis blog. It is largely a description of the technology and in the last two paragraphs a history of its development with no mention of MacLachlan or any of his companies.

One last thought, I wonder how Vardi found out about MacLachlan. Could someone have brought the story to his attention and who might that have been?

mRNA, COVID-19 vaccines, treating genetic diseases before birth, and the scientist who started it all

This post was going to be about new research into fetal therapeutics and mRNA.But, since I’ve been very intrigued by the therapeutic agent, mRNA, which has been a big part of the COVID-19 vaccine story; this seemed like a good opportunity to dive a little more deeply into that topic at the same time.

It’s called messenger ribonucleic acid (mRNA) and until seeing this video I had only the foggiest idea of how it works, which is troubling since at least two COVID-19 vaccines are based on this ‘new’ technology. From a November 10, 2020 article by Damian Garde for STAT,

Garde’s article offers detail about mRNA along with fascinating insight into how science and entreneurship works.

mRNA—it’s in the details, plus, the loneliness of pioneer researchers, a demotion, and squabbles

Garde’s November 10, 2020 article provides some explanation about how mRNA vaccines work and it takes a look at what can happen to pioneering scientists (Note: A link has been removed),

For decades, scientists have dreamed about the seemingly endless possibilities of custom-made messenger RNA, or mRNA.

Researchers understood its role as a recipe book for the body’s trillions of cells, but their efforts to expand the menu have come in fits and starts. The concept: By making precise tweaks to synthetic mRNA and injecting people with it, any cell in the body could be transformed into an on-demand drug factory. [emphasis mine]

But turning scientific promise into medical reality has been more difficult than many assumed. Although relatively easy and quick to produce compared to traditional vaccine-making, no mRNA vaccine or drug has ever won approval [until 2021].

Whether mRNA vaccines succeed or not, their path from a gleam in a scientist’s eye to the brink of government approval has been a tale of personal perseverance, eureka moments in the lab, soaring expectations — and an unprecedented flow of cash into the biotech industry.

Before messenger RNA was a multibillion-dollar idea, it was a scientific backwater. And for the Hungarian-born scientist behind a key mRNA discovery, it was a career dead-end.

Katalin Karikó spent the 1990s collecting rejections. Her work, attempting to harness the power of mRNA to fight disease, was too far-fetched for government grants, corporate funding, and even support from her own colleagues.

It all made sense on paper. In the natural world, the body relies on millions of tiny proteins to keep itself alive and healthy, and it uses mRNA to tell cells which proteins to make. If you could design your own mRNA, you could, in theory, hijack that process and create any protein you might desire — antibodies to vaccinate against infection, enzymes to reverse a rare disease, or growth agents to mend damaged heart tissue.

In 1990, researchers at the University of Wisconsin managed to make it work in mice. Karikó wanted to go further.

The problem, she knew, was that synthetic RNA was notoriously vulnerable to the body’s natural defenses, meaning it would likely be destroyed before reaching its target cells. And, worse, the resulting biological havoc might stir up an immune response that could make the therapy a health risk for some patients.

It was a real obstacle, and still may be, but Karikó was convinced it was one she could work around. Few shared her confidence.

“Every night I was working: grant, grant, grant,” Karikó remembered, referring to her efforts to obtain funding. “And it came back always no, no, no.”

By 1995, after six years on the faculty at the University of Pennsylvania, Karikó got demoted. She had been on the path to full professorship, but with no money coming in to support her work on mRNA, her bosses saw no point in pressing on.

She was back to the lower rungs of the scientific academy.

“Usually, at that point, people just say goodbye and leave because it’s so horrible,” Karikó said.

There’s no opportune time for demotion, but 1995 had already been uncommonly difficult. Karikó had recently endured a cancer scare, and her husband was stuck in Hungary sorting out a visa issue. Now the work to which she’d devoted countless hours was slipping through her fingers.

“I thought of going somewhere else, or doing something else,” Karikó said. “I also thought maybe I’m not good enough, not smart enough. I tried to imagine: Everything is here, and I just have to do better experiments.”

In time, those better experiments came together. After a decade of trial and error, Karikó and her longtime collaborator at Penn — Drew Weissman, an immunologist with a medical degree and Ph.D. from Boston University — discovered a remedy for mRNA’s Achilles’ heel.

The stumbling block, as Karikó’s many grant rejections pointed out, was that injecting synthetic mRNA typically led to that vexing immune response; the body sensed a chemical intruder, and went to war. The solution, Karikó and Weissman discovered, was the biological equivalent of swapping out a tire.

Every strand of mRNA is made up of four molecular building blocks called nucleosides. But in its altered, synthetic form, one of those building blocks, like a misaligned wheel on a car, was throwing everything off by signaling the immune system. So Karikó and Weissman simply subbed it out for a slightly tweaked version, creating a hybrid mRNA that could sneak its way into cells without alerting the body’s defenses.

“That was a key discovery,” said Norbert Pardi, an assistant professor of medicine at Penn and frequent collaborator. “Karikó and Weissman figured out that if you incorporate modified nucleosides into mRNA, you can kill two birds with one stone.”

That discovery, described in a series of scientific papers starting in 2005, largely flew under the radar at first, said Weissman, but it offered absolution to the mRNA researchers who had kept the faith during the technology’s lean years. And it was the starter pistol for the vaccine sprint to come.

Entrepreneurs rush in

Garde’s November 10, 2020 article shifts focus from Karikó, Weissman, and specifics about mRNA to the beginnings of what might be called an entrepreneurial gold rush although it starts sedately,

Derrick Rossi [emphasis mine], a native of Toronto who rooted for the Maple Leafs and sported a soul patch, was a 39-year-old postdoctoral fellow in stem cell biology at Stanford University in 2005 when he read the first paper. Not only did he recognize it as groundbreaking, he now says Karikó and Weissman deserve the Nobel Prize in chemistry.

“If anyone asks me whom to vote for some day down the line, I would put them front and center,” he said. “That fundamental discovery is going to go into medicines that help the world.”

But Rossi didn’t have vaccines on his mind when he set out to build on their findings in 2007 as a new assistant professor at Harvard Medical School running his own lab.

He wondered whether modified messenger RNA might hold the key to obtaining something else researchers desperately wanted: a new source of embryonic stem cells [emphasis mine].

In a feat of biological alchemy, embryonic stem cells can turn into any type of cell in the body. That gives them the potential to treat a dizzying array of conditions, from Parkinson’s disease to spinal cord injuries.

But using those cells for research had created an ethical firestorm because they are harvested from discarded embryos.

Rossi thought he might be able to sidestep the controversy. He would use modified messenger molecules to reprogram adult cells so that they acted like embryonic stem cells.

He asked a postdoctoral fellow in his lab to explore the idea. In 2009, after more than a year of work, the postdoc waved Rossi over to a microscope. Rossi peered through the lens and saw something extraordinary: a plate full of the very cells he had hoped to create.

Rossi excitedly informed his colleague Timothy Springer, another professor at Harvard Medical School and a biotech entrepreneur. Recognizing the commercial potential, Springer contacted Robert Langer, the prolific inventor and biomedical engineering professor at the Massachusetts Institute of Technology.

On a May afternoon in 2010, Rossi and Springer visited Langer at his laboratory in Cambridge. What happened at the two-hour meeting and in the days that followed has become the stuff of legend — and an ego-bruising squabble.

Langer is a towering figure in biotechnology and an expert on drug-delivery technology. At least 400 drug and medical device companies have licensed his patents. His office walls display many of his 250 major awards, including the Charles Stark Draper Prize, considered the equivalent of the Nobel Prize for engineers.

As he listened to Rossi describe his use of modified mRNA, Langer recalled, he realized the young professor had discovered something far bigger than a novel way to create stem cells. Cloaking mRNA so it could slip into cells to produce proteins had a staggering number of applications, Langer thought, and might even save millions of lives.

“I think you can do a lot better than that,” Langer recalled telling Rossi, referring to stem cells. “I think you could make new drugs, new vaccines — everything.”

Within several months, Rossi, Langer, Afeyan [Noubar Afeyan, venture capitalist, founded and runs Flagship Ventures], and another physician-researcher at Harvard formed the firm Moderna — a new word combining modified and RNA.

Springer was the first investor to pledge money, Rossi said. In a 2012 Moderna news release, Afeyan said the firm’s “promise rivals that of the earliest biotechnology companies over 30 years ago — adding an entirely new drug category to the pharmaceutical arsenal.”

But although Moderna has made each of the founders hundreds of millions of dollars — even before the company had produced a single product — Rossi’s account is marked by bitterness. In interviews with the [Boston] Globe in October [2020], he accused Langer and Afeyan of propagating a condescending myth that he didn’t understand his discovery’s full potential until they pointed it out to him.

Garde goes on to explain how BioNTech came into the mRNA picture and contrasts the two companies’ approaches to biotechnology as a business. It seems BioNTech has not cashed in the same way as has Moderna. (For some insight into who’s making money from COVID-19 check out Giacomo Tognini’s December 23, 2020 article (Meet The 50 Doctors, Scientists And Healthcare Entrepreneurs Who Became Pandemic Billionaires In 2020) for Forbes.)

Garde ends his November 10, 2020 article on a mildly cautionary note,

“You have all these odd clinical and pathological changes caused by this novel bat coronavirus [emphasis mine], and you’re about to meet it with all of these vaccines with which you have no experience,” said Paul Offit, an infectious disease expert at Children’s Hospital of Philadelphia and an authority on vaccines.

What happened to Katalin Karikó?

Matthew Rosza’s January 25, 2021 article about Karikó and her pioneering work features an answer to my question and some advice,

“I want young people to feel — if my example, because I was demoted, rejected, terminated, I was even subject for deportation one point — [that] if they just pursue their thing, my example helps them to wear rejection as a badge,” Karikó, who today is a senior vice president at BioNTech RNA Pharmaceuticals, told Salon last month when discussing her story. “‘Okay, well, I was rejected. I know. Katalin was rejected and still [succeeded] at the end.’ So if it helps them, then it helps them.”

Despite her demotion, Karikó continued with her work and, along with a fellow immunologist named Dr. Drew Weissman, penned a series of influential articles starting in 2005. These articles argued that mRNA vaccines would not be neutralized by the human immune system as long as there were specific modifications to nucleosides, a compound commonly found in RNA.

By 2013, Karikó’s work had sufficiently impressed experts that she left the University of Pennsylvania for BioNTech RNA Pharmaceuticals.

Karikó tells Salon that the experience taught her one important lesson: In life there will be people who, for various reasons, will try to hold you back, and you can’t let them get you down.

“People that are in power, they can help you or block you,” Karikó told Salon. “And sometimes people select to make your life miserable. And now they cannot be happy with me because now they know that, ‘Oh, you know, we had the confrontation and…’ But I don’t spend too much time on these things.”

Before moving onto the genetic research which prompted this posting, I have an answer to the following questions:

Could an mRNA vaccine affect your DNA (deoxyribonucleic acid) and how do mRNA vaccines differ from the traditional ones?

No, DNA is not affected by the COVID-19 mRNA vaccines, according to a January 5, 2021 article by Jason Murdock for Newsweek,

The type of vaccines used against COVID-19 do not interact with or alter human genetic code, also known as DNA, scientists say.

In traditional vaccines, a piece of a virus, known as an “antigen,” would be injected into the body to force the immune system to make antibodies to fight off future infection. But mRNA-based methods do not use a live virus, and cannot give someone COVID.

Instead, mRNA vaccines give cells the instructions to make a “spike” protein also found on the surface of the virus that causes COVID. The body kickstarts its immune response by creating the antibodies needed to combat those specific virus proteins.

Once the spike protein is created, the cell breaks down the instructions provided by the mRNA molecule, leaving the human immune system prepared to combat infection. The mRNA vaccines are not a medicine—nor a cure—but a preventative measure.

Gavi, a vaccine alliance partnered with the World Health Organization (WHO), has said that mRNA instructions will become degraded in approximately 72 hours.

It says mRNA strands are “chemical intermediaries” between DNA in our chromosomes and the “cellular machinery that produces the proteins we need to function.”

But crucially, while mRNA vaccines will give the human body the blueprints on how to assemble proteins, the alliance said in a fact-sheet last month that “mRNA isn’t the same as DNA, and it can’t combine with our DNA to change our genetic code.”

It explained: “Some viruses like HIV can integrate their genetic material into the DNA of their hosts, but this isn’t true of all viruses… mRNA vaccines don’t carry these enzymes, so there is no risk of the genetic material they contain altering our DNA.”

The [US] Centers for Disease Control and Prevention (CDC) says on its website that mRNA vaccines that are rolling out don’t “interact with our DNA in any way,” and “mRNA never enters the nucleus of the cell, which is where our DNA (genetic material) is kept.”

Therapeutic fetal mRNA treatment

Rossi’s work on mRNA and embryonic stem cells bears a relationship of sorts to this work focusing on prebirth therapeutics. (From a January 13, 2021 news item on Nanowerk), Note: A link has been removed,

Researchers at Children’s Hospital of Philadelphia and the School of Engineering and Applied Science at the University of Pennsylvania have identified ionizable lipid nanoparticles that could be used to deliver mRNA as part of fetal therapy.

The proof-of-concept study, published in Science Advances (“Ionizable Lipid Nanoparticles for In Utero mRNA Delivery”), engineered and screened a number of lipid nanoparticle formulations for targeting mouse fetal organs and has laid the groundwork for testing potential therapies to treat genetic diseases before birth.

A January 13, 2021 Children’s Hospital of Philadelphia (CHOP) news release (also on EurekAlert), which originated the news item, delves further into the research,

“This is an important first step in identifying nonviral mediated approaches for delivering cutting-edge therapies before birth,” said co-senior author William H. Peranteau, MD, an attending surgeon in the Division of General, Thoracic and Fetal Surgery and the Adzick-McCausland Distinguished Chair in Fetal and Pediatric Surgery at CHOP. “These lipid nanoparticles may provide a platform for in utero mRNA delivery, which would be used in therapies like fetal protein replacement and gene editing.”

Recent advances in DNA sequencing technology and prenatal diagnostics have made it possible to diagnose many genetic diseases before birth. Some of these diseases are treated by protein or enzyme replacement therapies after birth, but by then, some of the damaging effects of the disease have taken hold. Thus, applying therapies while the patient is still in the womb has the potential to be more effective for some conditions. The small fetal size allows for maximal therapeutic dosing, and the immature fetal immune system may be more tolerant of replacement therapy.

Of the potential vehicles for introducing therapeutic protein replacement, mRNA is distinct from other nucleic acids, such as DNA, because it does not need to enter the nucleus and can use the body’s own machinery to produce the desired proteins. Currently, the common methods of nucleic acid delivery include viral vectors and nonviral approaches. Although viral vectors may be well-suited to gene therapy, they come with the potential risk of unwanted integration of the transgene or parts of the viral vector in the recipient genome. Thus, there is an important need to develop safe and effective nonviral nucleic acid delivery technologies to treat prenatal diseases.

In order to identify potential nonviral delivery systems for therapeutic mRNA, the researchers engineered a library of lipid nanoparticles, small particles less than 100 nanometers in size that effectively enter cells in mouse fetal recipients. Each lipid nanoparticle formulation was used to encapsulate mRNA, which was administered to mouse fetuses. The researchers found that several of the lipid nanoparticles enabled functional mRNA delivery to fetal livers and that some of those lipid nanoparticles also delivered mRNA to the fetal lungs and intestines. They also assessed the lipid nanoparticles for toxicity and found them to be as safe or safer than existing formulations.

Having identified the lipid nanoparticles that were able to accumulate within fetal livers, lungs, and intestines with the highest efficiency and safety, the researchers also tested therapeutic potential of those designs by using them to deliver erythropoietin (EPO) mRNA, as the EPO protein is easily trackable. They found that EPO mRNA delivery to liver cells in mouse fetuses resulted in elevated levels of EPO protein in the fetal circulation, providing a model for protein replacement therapy via the liver using these lipid nanoparticles.

“A central challenge in the field of gene therapy is the delivery of nucleic acids to target cells and tissues, without causing side effects in healthy tissue. This is difficult to achieve in adult animals and humans, which have been studied extensively. Much less is known in terms of what is required to achieve in utero nucleic acid delivery,” said Mitchell. “We are very excited by the initial results of our lipid nanoparticle technology to deliver mRNA in utero in safe and effective manner, which could open new avenues for lipid nanoparticles and mRNA therapeutics to treat diseases before birth.”

Here’s a link to and a citation for the paper,

Ionizable lipid nanoparticles for in utero mRNA delivery by Rachel S. Riley, Meghana V. Kashyap, Margaret M. Billingsley, Brandon White, Mohamad-Gabriel Alameh, Sourav K. Bose, Philip W. Zoltick, Hiaying Li, Rui Zhang, Andrew Y. Cheng, Drew Weissman, William H. Peranteau, Michael J. Mitchell. Science Advances 13 Jan 2021: Vol. 7, no. 3, eaba1028 DOI: 10.1126/sciadv.aba1028

This paper appears to be open access. BTW, I noticed Drew Weissman’s name as one of the paper’s authors and remembered him as one of the first to recognize Karikó’s pioneering work. I imagine that when he co-authored papers with Karikó he was risking his reputation.

Funny how a despised field of research has sparked a ‘gold rush’ for research and for riches, yes?.