What are quantum dots (QDs)?

“They are very small particles made by crystals that consist of just a few thousand atoms. If we imagine how small a soccer ball is compared to the entire planet Earth, a QD is that small compared to the soccer ball. In chemistry, colors arise from various molecules. However, with QDs, a distinctive mechanism is at play. In this case, it’s not the atoms that vary but rather the quantity of them that determines the resulting color. When a nanoparticle contains more atoms, it is bigger, emitting a redder color. Conversely, fewer atoms result in a smaller nanoparticle that emits a blue-shifted color. This phenomenon is fundamentally rooted in a quantum mechanical effect.”

Could you explain this further?

“QDs are typically made of semiconducting materials where the absorption of a photon can create a free electron. When an electron is confined to a compact space, its wave function becomes compressed. The crucial principle here is that the smaller the confinement, the higher the energy level of the electron. With increased energy, an electron can store more energy and impart more energy to a photon. Consequently, light emitted from a confined, small space tends to be bluer in color, while light from a more expansive space leans towards the redder end of the spectrum.”

When the ability to change a material’s properties by its size became accessible it captured people’s imagination due to the myriad of applications it could potentially offer.”

Why did the Nobel Prize Committee decide to give the award for QD research?

“One of the motivations is that the discovery of these nanoparticles generated a lot of interest in the field of nanoscience. I think it’s clear that this discovery helped to catalyze the development of nanoscience, and many people, chemists in particular, have become very interested. When the ability to change a material’s properties by its size became accessible it captured people’s imagination due to the myriad of applications it could potentially offer.”

Which biomedical applicability do QDs have?

“The most extensive use of QDs is for bioimaging. Due to its fluorescent properties, they are used for live cell imaging, which is the visualization of intracellular components, and also in vivo imaging for the visualization of organs and tissues. Also, when studying tumors, QDs can distinguish multiple species within the tumor milieu in vivo. Solid tumors are complex and composed of cancer and host cells embedded in an extracellular matrix and nourished by blood vessels. By dissecting and tracking these elements, researchers can gain deeper insights into the complex mechanisms at play in tumorigenesis and tumor progression.”

QDs can also be used as traceable drug delivery vectors for killing cancer cells. They travel through the blood vessel of a tumor and diffuse inside the cell due to the presence of enzymes, depositing the drugs into the tumor, for example in hepatocellular carcinoma and pancreatic cancer.”

“QDs can also be used as traceable drug delivery vectors for killing cancer cells. They travel through the blood vessel of a tumor and diffuse inside the cell due to the presence of enzymes, depositing the drugs into the tumor, for example in hepatocellular carcinoma and pancreatic cancer. Researchers can assess the drug delivery due to the fluorescence of the QDs. In medical diagnosis they can replace the classic contrast dyes and radioactive isotopes. They can be used to detect the Sentinel Lymph Node (SLN) during breast cancer operations, or even for the detection of micrometastases which occur in 30% of breast cancers.”

What clinical trials exist regarding QDs?

“The clinical applicability of QDs is not yet happening but there exist a limited number of ongoing clinical trials. It’s an area that still requires extensive exploration and further research to fully unlock their capabilities. QDs need a close evaluation from a clinical perspective. However, there exist clinical trials such as a bioimaging and anticancer phase I study for breast and skin cancer, and other phase I and II studies where QDs are used as an immunologic monitoring tool for vaccines against type I Diabetes Mellitus.”

On a broader level we’ll continue seeing these nanoparticles as one kind of material, and its optical properties will be popping up everywhere.”

What is in the future scope?

“On a broader level we’ll continue seeing these nanoparticles as one kind of material, and its optical properties will be popping up everywhere. Regarding energy production we need sustainable methods. Solar power, for instance, is intermittent and requires complementing solutions like energy storage through batteries, which come with their own sustainability challenges. In this context, there is a significant need for efficient ways of producing solar fuels where QDs may play a role. One potential application is in water-splitting photocatalysis to produce hydrogen as a fuel. This process involves the dissociation of water into hydrogen and oxygen using a catalyst and light energy such as sunlight.”

About the Author

Paula Pérez González-Anguiano, M.Sc. in Scientific, Medical and Environmental Communication, is a Science Journalist and Illustrator based in Barcelona, Spain.

The post “The discovery of quantum dots has helped to catalyze the development of nanoscience” appeared first on NLS.

So first of all, what are nucleosides and nucleoside base modifications? A nucleoside is composed of a sugar moiety and nucleobase, whereas a nucleotide is composed of a sugar, nucleobase, and at least one phosphate (or phosphate-like) group. Nucleosides play a key role in biology processes. They are involved in the retention, replication and transcription of gene information. In the most important nucleosides, the sugar is either ribose (RNA) or deoxyribose (DNA), and the nitrogen-containing compound is either a pyrimidine (cytosine, thymine (DNA), or uracil (RNA)) or a purine (adenine or guanine).

In nucleoside-modified messenger RNA (mRNA) some nucleosides have been replaced by other naturally modified nucleosides or by synthetic nucleoside analogues. These modRNA can be used to induce the production of a desired protein in certain cells.

A novel therapeutic technology

RNA was first injected into an animal with the idea of using it as a therapeutic in 1990, but it did not go anywhere. It was not until Karikó and Weissman started working on RNA, after a chance meeting in the late 1990s, and figured out why it was so inflammatory (and how to make it non-inflammatory) that the field became relevant and interesting, as Weissman described in an interview with Penn Medicine in 2020. In short, they discovered how to modify mRNA in a way that boosts protein production while minimizing harmful inflammatory responses. Their key discovery, that mRNA could be altered and delivered effectively into the body to activate the body’s immune system, was published in 2005 (Karikó et al., Immunity, 2005).

Their findings have fundamentally changed our understanding of how mRNA interacts with our immune system.”

Their discoveries have led to a novel therapeutic technology, including the rapid development of mRNA-based vaccines that elicit a robust immune response, including high levels of antibodies that attack a specific infectious disease that has not previously been encountered.

“Their findings have fundamentally changed our understanding of how mRNA interacts with our immune system and the Laureates contributed to the unprecedented rate of vaccine development during one of the greatest threats to human health in modern times,” wrote the Nobel Assembly at Karolinska Institutet at the time of the announcement.

A COVID-19 vaccine in record time

At an early stage of the COVID-19 pandemic, both Pfizer/BioNTech and Moderna utilized Karikó and Weissman’s nucleoside-modified mRNA technology (and other mRNA vaccine-related improvements) to develop their COVID-19 vaccines. What usually takes 10-20 years to develop was now developed in record time and to date, hundreds of millions of people all over the world have received mRNA vaccines against the coronavirus.

Unlike other types of vaccines, a live or attenuated virus is not injected or required at any point with mRNA vaccines. Since RNA is the producer of proteins you can make an RNA that codes for a protein, and for COVID-19 this was the spike protein found on the virus. When you inject the RNA that codes for the spike protein, the cells will take it up and produce it in large quantities. The advantage of using RNA is that each RNA can make 1,000 to 100,000 proteins. In addition, RNA itself is a very rapid platform and you only need the sequence to start producing a vaccine, described Weissman in the interview with Penn Medicine in 2020.

In addition, the mRNA in the vaccine candidate is produced synthetically and means it can be created much faster than has been done for past vaccines.”

“The mRNA vaccines are promising because of their potential for high potency and ability to boost immune responses, engaging several arms of the immune system, such as antibody-producing B cells and anti-viral T-cells,” explained Michael Dolsten, CSO of Pfizer, in a previous interview with NLS. “This is different from adenovirus-based vaccines, which traditionally can only be given as a single, likely short-lasting administration, and protein-based vaccines that usually mainly give rise to protective antibodies and less to T-cell immunity. In addition, the mRNA in the vaccine candidate is produced synthetically and means it can be created much faster than has been done for past vaccines.”

What’s next?

Building on Karikó and Weismann’s groundbreaking work, researchers are now developing modified mRNA therapies within a number of different areas, including cancer, infectious disease and autoimmune disorders. Before COVID-19 hit, Weissman and Karikó had also already set up clinical trials for mRNA vaccines for genital herpes, influenza, and HIV, and the clinical potential extends beyond vaccines to other advanced therapies, such as protein replacement, gene therapy, and cancer immunotherapy.

Within cancer the difference, compared to the COVID-19 vaccine which is prophylactic and protects people from a virus, is that a cancer mRNA vaccine is an intervention, a treatment given to patients with the aim that their immune systems would be activated in a way that would attack tumor cells. Recently Moderna and Merck announced that when used together with Merck’s cancer immunotherapy, Keytruda, their mRNA cancer vaccine reduced the risk of certain skin cancers from returning and patient deaths by 44% (compared with Keytruda alone). The British government also announced that it was partnering with BioNTech to enroll as many as 10,000 patients in trials of a new mRNA cancer vaccine.

The biggest challenge in developing these types of mRNA vaccines for cancer, though, is just how personal it has to be.

We could see a scenario where patients are put on an off-the-shelf vaccine immediately while a personalized vaccine is being produced, if the patient harbors the antigens in an available off-the-shelf cancer vaccine.”

“Personalized cancer vaccines can be tailor-made to each patient, but will always need to undergo manufacturing before administration and therefore take a bit longer before being administered to the patient. Universal cancer vaccines, or off-the-shelf cancer vaccines, have the benefit of immediate administration to the patient, but they require the patient to harbor specific antigen targets. We could see a scenario where patients are put on an off-the-shelf vaccine immediately while a personalized vaccine is being produced, if the patient harbors the antigens in an available off-the-shelf cancer vaccine,” described Michael Engsig, CEO of Nykode Therapeutics, in a previous interview with NLS (2023).

Development & manufacturing of mRNA

Due to the great progress made during the COVID-19 pandemic, mRNAs are a fast-emerging class of biotherapeutics. These therapies offer a new opportunity for targeted treatment of challenging diseases and flexible manufacturing. However, mRNA is a still-young process modality with diverse challenges. NLS asked Dr. Maya Fuerstenau-Sharp, Head of Marketing, Cell Culture Technologies, Bioprocess Solutions, at Sartorius about her experiences of mRNA development and manufacturing, and her view on the field and its potential.

The potential of mRNA is broad, she says, “mRNA is highly multivalent, making it a good candidate for targets with high variation, such as combining strains for COVID and influenza or generating effective cancer vaccines.”

Early studies have for example demonstrated the ability for in vivo mRNA delivery to create CAR-T cells to treat cancer and heart disease. She says, “mRNA can also turn cells in the body into factories for functional proteins or antibodies. Altogether, mRNA is a powerful new therapeutic class.”

Fuerstenau-Sharp and her colleagues at Sartorius offer equipment for mRNA therapeutics process development, manufacturing and analysis. They have created new analytical chromatography tools to address the developing analytical methods for both development and process characterization. “We have published data on generating GMP mRNA in volumes as low as 100mL in our rocking motion bioreactor, which is useful for indications like cancer vaccines that require very low process volumes. These types of activities will enable our customers to unleash the full potential of mRNA from personalized medicines to global-scale vaccinations,” she describes.

Challenges for mRNA development and manufacturing include the cost of raw materials, the yield of reactions that produce mRNA, and scale of manufacturing processes to meet emerging indications.”

Challenges for mRNA development and manufacturing include the cost of raw materials, the yield of reactions that produce mRNA, and scale of manufacturing processes to meet emerging indications, explains Fuerstenau-Sharp. “In vitro transcription reactions have expensive enzymes and reagents, which cause the cost per volume to be drastically higher than traditional biological manufacturing. This high raw material cost means that development work done in traditional bioprocessing equipment, which is comparatively oversized, is highly expensive,” she says.

Together with her colleagues she has been working hard to create publicly accessible methods to increase productivity, lower the scale of GMP manufacturing and decrease the cost of goods necessary to produce IVT batches. “Additionally, stability and tissue-specific targeting remain areas for improvement and we have launched a set of novel cationic lipid nanoparticles as a step towards addressing these challenges,” describes Fuerstenau-Sharp.

New RNA classes, such as self-amplifying (saRNA) and circular (circRNA), have distinct advantages over traditional mRNA.”

Current trends within mRNA development and manufacturing include new indications, new RNA sub-classes and smaller process volumes. The multivalency of mRNA makes it highly suitable for personalized medicine like cancer vaccines, believes Fuerstenau-Sharp. “New RNA classes, such as self-amplifying (saRNA) and circular (circRNA), have distinct advantages over traditional mRNA. The saRNA is more efficient and requires a lower dosage to achieve the same effect. The circRNA is less sensitive to degradation and has a longer-term expression profile in the body. These new technologies require significantly smaller process volumes than traditional biopharma due to the nature of personalized indications and highly efficient RNA molecules,” she says.

Finally I ask Maya Fuerstenau-Sharp what areas she thinks will benefit next from the nucleoside-modified mRNA technology.

“Nucleoside-modified mRNA elicits a reduced immune response while increasing target protein production. This makes it a promising candidate for continued adoption across all mRNA fields, including vaccines, cancer therapy, and regenerative medicine,” Fuerstenau-Sharp concludes.

The post A path out of the pandemic appeared first on NLS.

The 2020 Nobel Prize in Chemistry was awarded to Emmanuelle Charpentier and Jennifer Doudna’s discovery of CRISPR/Cas9 genetic scissors. This enzyme system, which utilizes a very delicate and targeted mechanism to cleave DNA and insert new DNA parts, holds enormous power that affects us all, stated the Nobel Committee for Chemistry announcement.

“Within basic research CRISPR has revolutionized the simplicity, for example in identifying genes that affect different biological processes. Within clinical research we are starting to see the first examples of how rare monogenic diseases probably could be cured by using CRISPR to affect the disease-creating mutations. This fundamentally changes how we envision the future of healthcare.”

The groundbreaking factor in this discovery is in short that it is so easy to alter genes in a cell. Previously this would take a very long time, it was expensive and precision was low, explains researcher Fredrik Wermeling, PhD, at the Department of Medicine at Karolinska Institutet in Solna.

“Within basic research CRISPR has revolutionized the simplicity, for example in identifying genes that affect different biological processes. Within clinical research we are starting to see the first examples of how rare monogenic diseases probably could be cured by using CRISPR to affect the disease-creating mutations. This fundamentally changes how we envision the future of healthcare.”

Left: Illustration of CRISPR/Cas9. Right: Fredrik Wermeling, Assistant professor, Karolinska Institutet. Photo: Erik Holmgren

Reshaping life sciences

Ever since the molecular structure of DNA was reported in 1953, scientists have been trying to manipulate genes in cells and organisms. Down the years, important findings and advancements have been made, eventually leading to this year’s Nobel Prize and opening the door to this enormous potential to rewrite the code of life.

These findings include the discovery of unusual repeated structures common in procaryotes’ genomes containing the same features, suggesting an ancestral origin and high biological relevance, and the introduction of the term for these, CRISPR, Clustered Regularly Interspaced Short Palindromic Repeats. Both the repeats and the spacer sequences between them, remnants of genetic code from past invaders, DNA remnants or DNA scars, gave the scientists more clues and they came to the conclusion that CRISPR was in fact the bacteria’s immune system against virus, and that bacteria had memory. It was discovered that bacteria transcribe these DNA elements into RNA upon viral infection. The RNA guides a nuclease (a protein that cleaves DNA) to the viral DNA to cut it, providing protection against the virus. The nucleases are named “Cas”, meaning “CRISPR-associated”.

”This is an excellent example of how basic science research on RNA in a humble bacterium could facilitate crucial development of biotechnologies, and ultimately treatment of diseases. The technology is now used in almost every scientific field, ranging from basic to translational research.”

Emmanuelle Charpentier discovered a previously unknown molecule tracrRNA when she studied streptococcus pyogenes, and she showed in 2011 that this molecule is part of the CRISPR/Cas system. Emmanuelle Charpentier and Jennifer Doudna managed to decode the functions of the repeated DNA sequences (CRISPR) together with Cas (CRISPR-associated) proteins. They were able to recreate the bacteria’s genetic scissors in a test tube and the two scientists simplified the molecular components of the scissors so they were easier to use. They had uncovered a fundamental mechanism in a bacterium that causes great suffering for humanity. But it did not stop there, they were also able to reprogram the genetic scissors so that they could cut any DNA molecule at a predetermined site. They demonstrated that RNAs could be constructed to guide a Cas nuclease (Cas9 was the first used) to any DNA sequence. In their game-changing paper they concluded that there was “considerable potential for gene-targeting and genome-editing applications”. Now, just eight years later, their discovery has literally reshaped life science.

”This is an excellent example of how basic science research on RNA in a humble bacterium could facilitate crucial development of biotechnologies, and ultimately treatment of diseases. The technology is now used in almost every scientific field, ranging from basic to translational research,” says Edmund Loh, researcher at the Department of Microbiology, Tumor and Cell biology at Karolinska Institutet, and a collaborator and friend of Emmanuelle Charpentier.

Left: Edmund Loh, Principal investigator, Karolinska Institutet. Photo: Francesco Righetti. Right: Illustration CRISPR/Cas9

There are now a number of different CRISPR/Cas systems known and these are divided into two major classes. In the Class 1 systems, specialized Cas proteins assemble into a large CRISPR-associated complex for antiviral defense (Cascade). The Class 2 systems are simpler and contain a single multidomain crRNA-binding protein (e.g., Cas9) that contains all the activities necessary for interference, described the Nobel Committee for Chemistry. The system has been found in around 40 percent of all known bacteria and even 90 percent of all known archaea. Each system has a different protospacer adjacent motif (PAM). This motif is the only absolute requirement for CRISPR to work.

“Hopefully, the discovery will generate more attention from policy makers such as the government, pharmaceutical industries and philanthropic foundations to focus on and fund basic science research.”

In short it works like this. When a researcher aims to edit a genome they artificially construct what is known as a guideRNA (gRNA), which matches the DNA code where the cut is to be made. The scissor protein, Cas9, forms a complex with the gRNA, which takes the scissors to the place in the genome where the cut is to be made.

“I think the CRISPR/Cas9 discovery and technology benefit all life science fields. In addition, the background story and discovery could encourage more young people and women to be interested in basic science. Hopefully, the discovery will generate more attention from policy makers such as the government, pharmaceutical industries and philanthropic foundations to focus on and fund basic science research,” says Edmund Loh.

Exciting possibilities and realities

Since the discovery the field has exploded with applications and CRISPR has become a cost-effective and convenient tool for many different purposes. It can be used for genome editing (knockouts, knockins, exchange of base pairs, removal of genetic elements, homologous recombination) and gene regulation using CRISPR activation (attraction of transcription factors) and CRISPR inhibition (usage of KRAB repressor). It can also be used for tagging genetic elements, reporters, and for functional studies it is possible to have inducible CRISPR systems. According to the Biomedical Centre at the University of Iceland, it may also be used for dynamic imaging of genomic loci in living cells (comparable to FISH, without the need of cell fixation), and can be used in all cells of all organisms.

The development potential of the CRISPR system is also enormous and scientists all over the world are making progress almost every day. Just last year, a person with a genetic condition that causes blindness became the first person to receive a CRISPR/Cas9 gene therapy administered directly into their body. The treatment is part of a landmark clinical trial to test the ability of CRISPR/Cas9 gene-editing techniques to remove mutations that cause a rare condition called Leber’s congenital amaurosis 10 (LCA10).

“A third example is gene therapy for different severe inherited monogenic diseases related to the hematopoietic system, such as sickle cell anemia, beta-thalassemia, SCID and WASP.”

According to Wermeling, another very relevant example of recent progress is the SHERLOCK method. “In this method a modified CRISPR system is used to quickly identify if a sample contains a specific nucleotide sequence. This method is used for example to identify if a sample contains SARS-CoV-2 and it can be used as a quick and sensitive diagnostic test.”

The possibility to tailor make organs for transplantation is another application that has huge potential to solve many of the challenges related to transplant care. Wermeling says, “A third example is gene therapy for different severe inherited monogenic diseases related to the hematopoietic system, such as sickle cell anemia, beta-thalassemia, SCID and WASP.”

CRISPR (= Clustered Regularly Interspaced Short Palindromic Repeats) + DNA fragment, E.Coli Deposition authors: Mulepati, S., Bailey, S.; visualization author: User:Astrojan – http://www.rcsb.org/pdb/explore/explore.do?structureId=4qyz

Scientists have already started some clinical studies and the initial results look promising, according to Wermeling. “This could hopefully open up for treatments of inherited monogenic diseases affecting other organs, for example cystic fibrosis and Huntingtons disease. In the long run, the possibility to treat more common and more genetically complex diseases, such as cardiovascular diseases and cancer, but also dementia, allergies and autoimmune disease, is of course very appealing. It is however, not as clear how these diseases may be tackled using CRISPR,” says Wermeling.

He also mentions exciting possibilities related to immunotherapy treatments in cancer, where immune cells are instructed to attack the patient’s tumor and metastases. “Clinical studies are already ongoing where the immune cells are modified with CRISPR to become more aggressive and resistant.”

“We are using CRISPR to inactivate genes in different cells, and hence identify how these genes are affecting different disease processes. We are doing this using pre-clinical models and patient material to try to identify new targets for pharmaceuticals to treat these diseases.”

In his own research, Fredrik Wermeling and his research group at Karolinska Institutet are studying the immune defense in relation to autoimmune diseases and immunotherapy in cancer.

“We are using CRISPR to inactivate genes in different cells, and hence identify how these genes are affecting different disease processes. We are doing this using pre-clinical models and patient material to try to identify new targets for pharmaceuticals to treat these diseases,” he explains.

Wermeling sees great potential in how he and his colleagues are using CRISPR screening to understand how cancer cells develop resistance against different cancer treatments. When a drug is administrated to a cancer patient single cancer cells that succeed in avoiding the negative effects of the treatment will have survival advantages.

“Through a classic ‘survival of the fittest’ evolution process, over time the patient is therefore developing tumors that are made of more and more cancer cells that are resistant against the pharmaceutical and eventually the tumor is not responding at all to the drug,” he says. “This is still a long way away, but to be able to use CRISPR screening to identify in what ways specific cancer cells avoid an initial effective pharmaceutical, and develop resistance, creates possibilities for highly effective combination treatments. There are conceptual similarities with the cocktail of three antiviral drugs that together effectively inhibit the life cycle of HIV, but where the virus quickly develops resistance if the patient is treated with only one drug at a time.”

Regulations are required

As with every powerful technology, the genetic scissors require regulation to avoid unethical applications. Causing changes in a germ cell or embryo, so that the change is inherited by coming generations, is far more controversial than editing the ordinary cells of a human being suffering from a genetic disorder via gene therapy. In 2018, CRISPR was for example used by the Chinese biologist He Jiankui to modify twin embryos used for IVF, resulting in the birth of two girls allegedly with alleles that would confer protection from infection by HIV. He bypassed ethical regulations and chose to use germline editing for pre-emptive protection, in addition, he did not show any clear evidence that the procedure was safe. Jiankui’s actions were condemned by the biological community.

The Nobel Committee for Chemistry also states, “Experiments that involve humans and animals must always be reviewed and approved by ethical committees before they are carried out.”

Another controversial aspect is the possibility of improving or refining perfectly normal human conditions with the help of CRISPR/Cas9. Perhaps adjustments in the genome might eventually lead to more intelligent, more productive or more beautiful human beings.

For many years there have been laws and regulations that control the application of genetic engineering. The regulations include prohibitions on modifying the human genome in a way that allows the changes to be inherited. The Nobel Committee for Chemistry also states, “Experiments that involve humans and animals must always be reviewed and approved by ethical committees before they are carried out.”

In 2017, a report from an international committee convened by the U.S. National Academy of Sciences (NAS) and the National Academy of Medicine in Washington, D.C., concluded that human embryo editing could be ethically permissible one day – but only in rare circumstances and with safeguards in place. “Those situations could be limited to couples who both have a serious genetic disease and for whom embryo editing is “really the last reasonable option” if they want to have a healthy biological child,” says committee co-chair Alta Charo, a bioethicist at the University of Wisconsin in Madison.

CRISPR/Cas9. Illustration: Innovative Genomics Institute

The post CRISPR/Cas9 – Rewriting the code of life appeared first on NLS.

The Nobel Prize in Chemistry 2019 was awarded jointly to John B. Goodenough, M. Stanley Whittingham and Akira Yoshino “for the development of lithium-ion batteries.” Their lightweight, rechargeable and powerful battery is used in mobile phones, laptops and electric vehicles, and it can store significant amounts of energy from solar and wind power. Lithium-ion batteries have also paved the way for pacemakers, one of the medtech industry’s greatest innovations.

A lightweight hardwearing battery

The development of the lithium-ion battery began during the oil crisis in the 1970s, when methods that could lead to fossil fuel-free energy technologies were developed, describe the Royal Swedish Academy of Sciences. Whittingham discovered an extremely energy-rich material and he created a cathode in a lithium battery. The cathode was made from titanium, disulfide which at a molecular level has spaces that can house (intercalate) lithium ions. The battery’s anode was made from metallic lithium, which has a strong drive to release electrons. His battery had great potential but the drawback was that lithium is reactive and this made it too explosive.

The Nobel Laureates in Chemistry 2019, John Goodenough, Stanley Whittingham and Akira Yoshino. Illustration: Niklas Elmehed/Nobel Media AB

Goodenough then demonstrated in 1980 that cobalt oxide with intercalated lithium ions could produce as much as four volts, resulting in much more powerful batteries.

Then Yoshino created the first commercially viable lithium-ion battery in 1985. He used petroleum coke, a carbon material that can intercalate lithium-ions. A lightweight hardwearing battery that could be charged hundreds of times before it deteriorates was born, described the Royal Swedish Academy of Sciences in their press release about the Nobel announcement.

Maintaining heart rhythms

The pacemaker has saved millions of lives and its history is a fascinating one, and it also includes several scientists, engineers and clinicians, all around the world. Already in the 1800s it was discovered that the heart possesses electrical activity, but it was not until 1932 that the first device, an artificial pacemaker, was built (by the American physiologist Albert Hyman). His pacemaker was only tested in animals and at that time artificial heart stimulation was a controversial subject.

The first cardiac pacemaker was invented in 1952 by Paul Zoll, among others. It had the size of a small cathode ray tube television. When smaller batteries and more reliable transistors were developed the device became smaller in size and at the end of the 1950s it could be worn around the neck. Another hurdle along the way to developing the pacemaker was how to prevent water in the body affecting the pacemaker’s electronics. This problem was solved by using hermetically sealed titanium cases. Other scientists, engineers and clinicians who have contributed to the development of the pacemaker include Mark Lidwell, Wilfred Bigelow, John Callaghan, John Hopps, Aubrey Leatham, Geoffrey Davies, Earl Bakken, C. Walton Lillehei, and many more.

The first implantable pacemaker

The first fully implantable cardiac pacemaker was actually developed and inserted for the first time in a patient in Sweden. It was invented by physician and engineer Rune Elmqvist together with surgeon Åke Senning, and was inserted into the first patient, Arne Larsson, in 1958. Larsson was suffering from heart rhythm disturbances called Strokes-Adams syndrome. His symptoms made him faint up to 20 to 30 times a day. On October 8th 1958 he became world famous when he became the first person in the world to have a pacemaker operated into his body. The pacemaker had the same size as a matchbox. Time was short for Larsson and Elmqvist had to mold the components of his device in a simple plastic cup with synthetic resin, according to the Siemens Healthineers MedMuseum. It was a successful operation, but after only three hours the pacemaker stopped. Another copy of the device was operated in the next morning and this second one lasted for weeks.

Rune Elmqvist is adjusting a galvanometer at the University of Lund, Sweden. Copyright: Håkan Elmqvist

All in all, Arne Larsson had 26 different pacemakers in his body over the 43 years following the first implantation. He died in 2001, aged 86, not from his heart problem or his pacemaker but from other causes. The pacemaker had given Larsson quality of life, like the ability to swim and ride a bicycle, and he could work and travel by plane. Today over three million people have a pacemaker.

The Elmqvist pacemaker was developed by his company Elema-Schönander AB, but shortly after the first operation the company was acquired by Siemens and in 1972 Siemens-Elema AB was founded. In 1994 the pacemaker division of the company was sold to the US company Pacesetter, which is and was a part of St. Jude Medical.

“The pacemaker had given Larsson quality of life, like the ability to swim and ride a bicycle, and he could work and travel by plane.”

”In 1994 when Pacesetter and its owner, St. Jude Medical, acquired the pacemaker division from the company that Rune Elmqvist founded, this spurred innovation and patenting work. Over a period of ten years Groth & Co both wrote and applied around 50 patents originating from the company’s facility in Järfälla that related to the pacemaker. These patents concerned improvements within most of the pacemaker’s functions. Patent filings were perhaps primarily within the detection of deviating heart rhythms, but also to some degree concerned the battery and its capacity, status and process of replacement,” says Mathias Loqvist, Head Patent Department, Groth & Co.

In 2011, the pacemaker left Sweden when St. Jude Medical moved their manufacturing of pacemakers and electrodes to facilities in Malaysia and Puerto Rico and shifted R&D focus. Around 450 out of 600 employees lost their jobs. Today the remaining staff are focusing on developing products and services built on communication with pacemakers, which nowadays have a small radio antenna. For example, the new developments can be technology to monitor health and analyze how the information can be used in a new way.

From mercury to lithium-iodine cells

Another very important innovator behind the pacemaker was the electrical engineer Wilson Greatbatch. He was working on an oscillator to aid in the recording of tachycardias at the University of Buffalo, USA, in 1960 when he accidentally discovered a way to make an implantable pacemaker (Aquilina, Images Paediatr Cardiol, 2006). The oscillator required a 10 KΩ resistor at the transistor base, but Greatbatch misread the color coding on his resistor box and got a 1 MΩ resistor by mistake. When he plugged in the resistor the circuit started to “squeg” with a 1.8 millisecond pulse followed by a 1 second interval during which the transistor was cut off and drew practically no current. He realized that this small device could drive a human heart. In 1959, he patented his pacemaker, and William Chardack, Chief of Surgery at Buffalo’s Veteran’s Hospital, reported the first success in a human with this unit in 1960.

Wilson Greatbatch. Photo: University of Buffalo

It was also Wilson Greatbatch who convinced the industry to change from mercury to lithium-iodine cells. Early pacemaker batteries had short, unreliable lifetimes until he developed the long-life lithium-battery in the 1970s. The first pacemaker using a lithium-ion battery was introduced and implanted in a patient in 1972 (source: The Central Intelligence Agency). Greatbatch’s battery soon became used in more than 90 percent of the world’s pacemakers. His innovation gave the pacemaker reliability and the long lifetime needed for it to become standard in cardiac care. With Greatbatch’s battery a patient could expect to only have one pacemaker inserted during his or her lifetime.

In addition to longevity, lithium-ion batteries have another advantage in pacemakers. When the battery is getting closer to the end of its life, the voltage begins to decrease, and due to the decreasing voltage electrical designers can design an end of life indicator for the pacemaker that allows the device to inform the doctor that a new battery is needed. It can then be changed safely before it discharges completely.

“Early pacemaker batteries had short, unreliable lifetimes until Wilson Greatbatch developed the long-life lithium battery.”

Lithium-ion batteries can also be used for other medical applications, such as neuro-stimulation and in insulin pumps for diabetics. The pacemaker has paved the way for the development of implantable defibrillators, diabetes insulin pumps, hip replacements and artificial limbs.

An ongoing development

During the first decades after the pacemaker was invented, it could only emit one steady pulse. Several refinements have been made since then, for example the titanium casing (replacing the epoxy resin and silicone rubber), non-invasively programmable pacemakers, dual-chamber pacemakers, steroid-eluting leads, rate-responsive pacemakers, microprocessor-driven pacemakers, and bi-ventricular pacing for heart failure (Aquilina, Images Paediatr Cardiol, 2006).

“Today’s pacemakers are as small as a coin and weigh only 13 to 40 grams.”

Today the pacemaker can adjust itself to the patient’s individual heart rhythm, at any level of physical activity. It can also synchronize the right and the left chambers during congestive heart failure and via a computer it can communicate wirelessly with healthcare professionals 24 hours a day. Today’s pacemakers are as small as a coin and weigh only 13 to 40 grams. They are operated under the skin at the collar-bone and the stimulating electrode is inserted into the heart through a vein. The operation is performed through local anesthesia and takes less than one hour. In a typically modern pacemaker the battery’s capacity is similar to a cell phone’s battery, but it can last up to ten years.

In recent year there have also been several improvements when it comes to pacemaker technologies. Dave Fornell at Diagnostic and Interventional Cardiology (February 2018) has listed the most important of these. One of the greatest advancements has been the FDA cleared MRI-conditional models. These models allow patients to undergo MR imaging exams without harm to the device or changes to the device settings. Other improvements involve tracking device data and patient health through wireless remote monitoring systems, new data recording functionality to provide more information on patient health and device status, the introduction of single-chamber transcatheter-delivered, leadless pacemaker systems, and longer battery life and technology to help reduce pacing requirements to conserve battery power.

For future pacemakers micro turbines developed by scientists in Switzerland could also play an important role. The micro turbines can be placed in blood vessels and with the help of the blood circulation they could generate electricity. The idea is to provide the pacemaker with energy without using batteries. However, today the technique can cause blood clots and it has to be developed further.

Lithium-ion battery: Akira Yoshino developed the first commercially viable lithium-ion battery. He used Goodenoughs lithium-cobaly oxide in the cathode and in the anode he used a carbon material, petroleum coke, which can also intercalate lithium ions. The batterys functionality is not based upon any damaging chemical reactions. Instead, the lithium ions flow back and forth between the electrodes, which gives the battery a long life. Illustration: Johan Jarnestad/The Royal Swedish Academy of Sciences

The pacemaker – how it works

In a healthy heart a collection of nerve cells in the right atria of the heart (known as the Sinoatrial node) emits impulses to the heart muscle so that it contracts itself and relaxes at a regular rate. If the Sinoatrial node is damaged and not working as it should the heart beats too slowly, irregularly, or in the worst case, not at all.

Pacemakers use electrical impulses to regulate the beating of the heart. The device is battery-operated and consists of two parts; a generator and wires. The generator is a small battery-powered unit that produces the electrical impulses that stimulate the heart to beat. It may be implanted under the skin through a small incision, and it is connected to the heart through tiny wires that are implanted at the same time. The impulses flow through these leads to the heart and are timed to flow at regular intervals, just as impulses from your heart’s natural pacemaker would.

Pacemakers treat disorders making the heart’s rhythm too slow, fast or irregular.

The post Finding the right rhythm appeared first on NLS.

The Nobel Prize in Chemistry 2016 was awarded to three scientists, Jean-Pierre Sauvage, Sir J. Fraser Stoddart and Bernard L. Feringa, for the design and synthesis of molecular machines. Molecular machines have been defined as “an assembly of a distinct number of molecular components that are designed to perform machine-like movements, i.e. producing quasi-mechanical movements (output) as a result of an appropriate external stimulation (input)”. Molecular machines are also often referred to as molecular motors, and can be either synthetic or natural molecules that convert chemical energy into mechanical motion and forces. They require a supply of energy for their operation and they are so small that you need an electron microscope to see them. In fact, all life is powered by tiny biological machines. The most fundamental processes of life, such as translating genetic code to make proteins, require the use of molecular machines 10 000 times smaller than a human hair and functioning only on chemical energy.

Catenane, Rotaxane and a molecular motor

The first step towards a molecular machine was taken in 1983, when Jean-Pierre Sauvage succeeded in linking two molecules in a chain (a so-called catenane), hence creating several parts that can move relative to each other – a requirement for a machine. He used copper ions to develop molecular complexes and photochemistry to create active complexes that capture energy contained in solar rays to drive chemical reactions. Sauvage and his colleagues used this experiment to construct a ring-shaped and a crescent-shaped molecule so that they could be welded to the copper ion using the cohesive force that kept the molecules intact. Then they removed the copper ion, which had solved its purpose of providing a base to construct these chains.

Eight years later J. Fraser Stoddart was able to create a ring of molecules that moved along an axle in a controlled way when heat was added (a so-called rotaxane). He built an open ring that lacked electrons and a long axle that had electron-rich structures in two places. When the two molecules met in a solution, electron-poor was attracted to electron-rich and the ring threaded on to the axle. In the next step he closed the opening in the ring so that it remained on the molecular axle. When he added heat the ring jumped forwards and backwards, and a few years later Stoddart could completely control the movement. He had created the first “molecular shuttle”, according to Nature.

In 1999 Bernard L. Feringa was able to build the first molecular motor, consisting of two small rotor blades and two flat chemical structures joined with a double bond between two carbon atoms. A methyl group was attached to each rotor blade, forcing the molecule to keep rotating in the same direction. When exposed to a pulse of ultraviolet light one rotor blade jumped 180 degrees around the central double bond, then the ratchet moved into position and with the next light pulse the rotor blade jumped another 180 degrees, and so it continued.

Feringa’s research group has since optimized the design of the motor, making it rotate at a speed of 12 million revs per second and creating a four-wheel drive nanocar.

The first steps into a new world

But the magnitude of these discoveries is yet to come, according to the scientists themselves and the Nobel Prize committee. “Just like the molecules of life, Sauvage’s, Stoddart’s and Feringa’s artificial molecular systems perform a controlled task. Chemistry has thus taken the first steps into a new world. In terms of development, the molecular motor is about the same stage as the electric motor was in the 1830s, when researchers proudly displayed various spinning cranks and wheels in their laboratories without having any idea that they would lead to washing machines, fans and food processors,” stated the Royal Swedish Academy of Science in their press release, and in his first interview after the announcement of the Nobel Prize, Feringa said he felt like the Wright brothers. “When they flew for the first time, over 100 years ago, people asked why they needed a flying machine. Now we have a Boeing 747 and an Airbus. [With this technology] we will be able to build materials that will change, adapt or even store energy. There is endless opportunity.”

Since their discoveries the three scientists have constructed several molecular machines, including a molecular lift that can raise itself 0.7 nanometers above a surface (2004), an artificial muscle (2005), an elastic structure that is reminiscent of the filaments in a human muscle (2000) and a rotaxane-based computer chip with a 20 kB memory. However, the greatness of their discoveries is yet to come, and to quote Stoddart, “We’re on a very early part of a very steep learning curve. Chemistry is a fundamental science and it needs some space in which to develop the fundamentals. It’s going to be a slow process and it may take decades to develop the field to a stage where it’s applied to whatever the technology of the day is, but then suddenly it will take off, and people will see what all that fundamental development can lead to.”

Tiny robots injected in your veins

In the field of life science molecular machines will hopefully be able to deliver drugs within the body directly to cancer cells or a specific area of the tissue to medicate, and hence reduce, the damage treatment like chemotherapy does to a patient’s healthy cells. In a recent report by Scientific American, nanorobots that can be sent through blood vessels and nanomaterials that can monitor vital organ health may soon revolutionize healthcare. “Like tiny robots injected in your blood veins targeting the cancer cells,” suggested Feringa to the Nobel Media after the announcement.

Recent advances in the field include micro/nanoscale machines for biomedical applications like drug delivery, diagnostics, nanosurgery and biopsies of hard-to-reach tumors. In 2013 Dave Leigh at the University of Manchester was able to develop a molecular robot that can grasp and connect amino acids. Last year Nature reported that researchers have exploited the light-activated mechanism to develop some 100 drug-like compounds that switch on or off in response to light (Borowiak et al., Cell 2015, Jul). In 2014 US scientists reported that lab-made molecules whose parts come together when exposed to light might be used to treat macular degeneration or retinitis pigmentosa, like a photoswitchable molecule (Tochitsky et al., Neuron 2014, Feb)

Researchers have also shown that molecular machines could lead to the design of a molecular computer, placed inside the body to detect a disease before any symptoms are exhibited (Xing Jiang, University of California, Oct 4 2016).

It is unknown today what the killer application (as Stoddart put it) will be, but without a doubt scientists believe that these tiny machines could have a huge impact on our future and revolutionize medicine and our quality of life.

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What Stoddart did find most surprising and gratifying was among all the well-wishes were hundreds of emails and notes from his former students and teaching assistants, not just congratulating him for well-deserved recognition, but also thanking him for his impact on their careers and personal lives.

Stoddart keeps in contact with many former students and thinks of them so fondly that he invited more than 80 of them and their significant others to join him and his family at the awards’ festivities in Stockholm.

“I rented a conference room and threw a big party,” Stoddart said of his time in Stockholm, adding that trimming the guest list was a bit tricky. “There are hundreds of them [former students] and I never forget the experience of working with them—sometimes I spend two-to five years working with them. It is quite a wrench when the day comes for them to leave.”

A change of lifestyle

Stoddart has spent almost half a century on his loves, research and teaching. Currently a professor at Northwestern University in Evanston, Illinois, in the U.S., some colleagues and staff members thought he was deserving of recognition from the Nobel committee for his work on mechanical bonds in molecular compounds (after all, 10 years ago he was knighted by the Queen of England). The university’s press office asked Stoddart in October to update his official biography just in case, but he said he didn’t see the need. Then the phone call came from Stockholm.

“It’s very exciting, very daunting, very demanding… it comes with a lot of surprises,” Stoddart said of the award. “I’m looking at what comes up next. I’m going to China at the drop of a hat to give a speech and have dinner with the prime minister. It changes your lifestyle in a dramatic way.”

A new field of organic chemistry

Stoddart’s breakthrough came in 1981 while he was working at Imperial Chemical Industries in the UK.  He is one of a small number of chemists over the past 25 years to have created a new field of organic chemistry — one in which the mechanical bond is a primary feature of molecular compounds, according to Northwestern. “It’s the invention of a new bond that I think is very important,” Stoddart noted. “There are probably thousands of new chemical compounds made every day; not so for new bonds in chemistry; they are few and far between. We have been able to make mechanical interlocking molecules quickly and easily. It means that we can start to look at machine-and motor-like properties.”

Stoddart has been working on these bonds since 1989. The two other Nobel Prize winners in chemistry, Jean-Pierre Sauvage of France and Bernard Feringa of the Netherlands, also work in that field. Stoddart and Sauvage learned of each other’s work, became friends, even “traded children,” as Stoddart put it, hosting each other’s children during summers and published papers together.

It is not just a science, but an art form

While it is a little early to talk about the practical applications of the mechanical bonding of molecules, according to Stoddart, but he envisions progress similar to the evolution of manned flight – steady with dramatic episodes. Only about 100 years have passed from the time of the Wright brothers’ first flight to huge Dreamliners carrying hundreds of people across the skies, he said, so he is optimistic that applications are on the horizon.

“The dream is that there is going to be an explosive development, which will go in many directions to harness the use of these tiny machines. The great thing about chemistry is that it is not just a science, but an art form. You can design and build anything within reason – the invention of the mechanical bond was a large extent driven by interlocked images in the art world.”

“It was total addiction”

Stoddart learned to be innovative a young age; he grew up on a farm south of Edinburgh, Scotland, that lacked electricity until he was 17. “You had to be quite creative in doing anything.”  He described his high-school chemistry teachers as excellent and went on to study chemistry at the University of Edinburgh. There one of his professors announced that he had designed a 10-week practical course that no one had finished, so Stoddart promptly signed up. He completed the course in seven weeks by doing three experiments at once. The results led to him being offered a position in a research lab. “Then, it was total addiction,” explained Stoddart. “I could not get away from it. This led to a door opening I was able to walk through.”

I’m 74 years young

Since 2008, he has been a Board of Trustees Professor of Chemistry at Northwestern and also director of the university’s Center for the Chemistry of Integrated Systems (CCIS).  During the past 45 years, more than 400 PhD and postdoctoral students have worked with Stoddart and more than 80 now have successful independent academic careers.

“Teaching is extremely important,” Stoddart said of his interconnected vocations. We’re creating quite a legacy in terms of people we’ve trained.”  Stoddart also plans to be around working with up-and-coming researchers. “I’m 74 years young, and I’m mapping out what I do for the next five years.”

Photo: Jenny Öhman

Fraser Stoddart

Award: Nobel Prize in Chemistry, for work on mechanical bonds

Age: 74

Born: Edinburgh, Scotland

Nationality: American

Work: Board of Trustees Professor of Chemistry at Northwestern University (U.S.) and also Director of the university’s Center for the Chemistry of Integrated Systems (CCIS).

Family: Two married daughters, five grandchildren

Education: BSc Edinburgh University 1964, PhD Edinburgh University 1966, DSc Edinburgh University 1980, National Research Council Postdoctoral Fellow – Queen’s University (Canada), Imperial Chemical Industries (ICI) Research Fellow – Sheffield University

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That interest in science narrowed to a fascination with chemistry, and culminated in 2016 with Sauvage winning one of the three Nobel Prizes for chemistry for his work connecting molecules with mechanical bonds. The other two winning chemists, who pursued research in the same field, were Sir J. Fraser Stoddart of the U.S. and Bernard L. Feringa of the Netherlands.

A good surprise

Sauvage’s revelation came in 1983 when he was able to create a chain called a catenane, by connecting two ring-shaped molecules together. Molecules usually join in covalent bonds in which the atoms share electrons, but in the chain created by Sauvage they were attached by a “free mechanical bond,” according to the Nobel Prize committee.

“It was a surprise, I did not expect it at all; of course it was a good surprise,” Sauvage said, in remembering when he heard the news of his award. “I was in my office on October 5, preparing myself to look at the Nobel website to see who the winners were. Then half an hour before the official announcement, I picked up the phone. I was not sure at first it was serious.”

The next few months were a whirlwind, culminating with the festivities in Stockholm in December, where he was joined by his family. “It was fantastic; like being on a small cloud,” noted Sauvage. “My impression is that it was like I was in a virtual world. The same was true for the others—we were disconnected from the real world, meeting princesses, kings and queens.”

Sauvage also had the chance to visit four high schools in Sweden and lecture to students. “Each time I delivered a lecture, I was thinking I can make our chemistry very accessible, I can talk about interlocking rings,” he added.

Classrooms, of course, are very familiar to Sauvage. Now formally retired, he still works as a professor emeritus at the “Institut de Sciences et Ingenierie Supramoleculaires” at the University of Strasbourg. He served as director of research at CNRS from 1979 to 2009, when he became a professor emeritus and a visiting professor at Northwestern University.

A very interesting challenge

Sauvage came to his critical scientific discovery by using his expertise in the field of inorganic photochemistry, inspired by the structure of one of the complexes his team was working on at the time. His area of expertise is photochemistry, which involves developing molecular complexes to capture energy from sun rays and using it to power chemical reactions, according to the Nobel Prize committee. The field of topological chemistry, in which researchers interlock molecules, had stalled because chemists had been unsuccessful in creating molecules held together by mechanical chains.  When Sauvage and his research team built a model of a photochemically active complex, he realized it was similar to a molecular chain and continued experimenting.

“Those kinds of molecules were considered impossible to make at a reasonable scale in the 1980s,” Sauvage said. “I found that to be a very interesting challenge and I had a good idea of how to make it.”

Be adventurous

The approach represents one of Sauvage’s key philosophies of life. “When I was a young faculty member, I was very adventurous, starting my group; I started several groups and projects. If you have an idea that something is very novel, just do it. Use what you know, start in a new field, even if you are not an expert in that field. Be adventurous, be self-confident, if you fail, no one is going to kill you.”

According to information from the Nobel Prize committee, Sauvage’s research group built a ring-shaped and crescent-shaped molecule that were attracted to a copper ion, which held the molecules together. Then the group was able to weld the crescent-shaped molecule to a third molecule representing the first link in a chain. The copper ion was then removed.

The molecular chains, called catenanes, were not only a new class of molecule, but that he had also taken the first step towards creating a molecular machine. In 1994, Sauvage’s research group produced a catenane in which one ring rotated in a controlled manner, one revolution around the other ring, when energy was added.

Fruitful collaborations

He and co-winner Stoddart also interacted over the years. “We were such good friends that we did not want to be competitors; we were careful not to overlap with what the other was doing. We had some pleasant and fruitful collaborations.” During his career, Sauvage also spent three years at Northwestern University, where Stoddart teaches, as a part-time visiting professor.

For the most part, though, since attending the University of Strasbourg, Sauvage has remained in the city, happy for a chance to put down roots. When he arrived at the university at age 18, he had moved 15 times in his life. “I told my family I wasn’t moving again, I was staying there, and I did.”

Perhaps his travels growing up made him more adaptable, Sauvage added, and helped form his other key approach to life: Encounters are important. “When you are meeting new people, meeting people with whom you interact, you bring each other ideas,” Sauvage said. “The successes of my groups were related to encounters with various people.”

Jean-Pierre Sauvage, PhD

Award: Nobel Prize in Chemistry, for the design and synthesis of molecular machines

Age: 72

Nationality: French

Born: Paris, France

Education: University of Strasbourg

Personal: Married, one married son and one grandson

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Neural transplants offer a new path to possible Huntington disease (HD) treatments. Experiments with an HD mouse model show that transplanting human neuronal cells delays HD symptoms and death in the mice. The results, published in Nature Communications, were from Steven A. Goldman’s group at the Center for Translational Neuromedicine, University of Rochester, and the Center of Basic and Translational Neuroscience, University of Copenhagen.

HD is an inherited neurodegenerative disorder characterized by loss of movement control, cognitive decline, and eventually death. HD currently has no cure. The disease causes deterioration of medium spiny neurons, which are abundant in the brain striatrum. When affected by HD, the neurons do not properly take up potassium, which is essential for nervous system signalling. The study by Goldman’s group did not focus directly on medium spiny neurons, though. The researchers worked on glial cells instead.

Why and how glial cells might protect against HD

Glial cells support the health and function of other neural cells so they are an obvious candidate for protecting or correcting defects in medium spiny neurons. Goldman and colleagues were the first to explore the effects of glial cells on HD development, though. The researchers generated human glial precursor cells with and without the genetic mutation that causes HD. They introduced these cells, at birth, into mice engineered to have HD and found that the human cells were incorporated into the brains of the chimeric mice.

The researchers then compared lifespan, learning ability, and motor performance of animals with HD and non-HD glial cells. They examined brain structure and measured signalling function of striatal neurons. On all tests, mice that received non-HD glial precursor cells were healthier than mice with HD glial cells—they had slower disease progression and lived longer. Additional experiments provided a possible explanation.

Mice with HD glial cells had too many potassium ions around the cells. The non-HD glial cells from the transplanted human cells maintained a normal potassium balance. These results point to glial cells as a possible target for HD therapy. “We’re progressing to preclinical assessment of glial progenitor cell transplants in different mouse models,” Goldman says. For example, his group is exploring transplanting the cells in adult rather than newborn mice. “Our priority is learning the therapeutic potential of the transplanted glial cells,” he says. NovoSeeds is supporting this early stage work.

An unexpected link to a Nobel-winning field

The HD study is one of several recent high-impact publications from the Goldman group. Another paper in an entirely different area brought them into a Nobel award-earning field. The 2016 Nobel Prize in Physiology or Medicine went to Professor Yoshinori Ohsumi for work on autophagy. This internal cell recycling process has implications for all of biology, including human disease. Goldman and his colleagues were collaborators on a study published in Cell Stem Cell that showed Zika virus, which can cause brain damage in a fetus if the mother is infected during pregnancy, inappropriately activates autophagy.

The Nobel Prize was “well deserved,” Goldman says. “Knowing about the pathway and the biologic process of autophagy has changed our conception of how cells age and what can go wrong in cell homeostasis.” Goldman’s primary interest is studying how nervous system stem and progenitor cells might be used for new therapies for neurological diseases. Every piece of information about how cells operate is valuable in that research. The autophagy work, he says, is a “spectacular observation, in terms of potentially modulating autophagy for therapeutic purposes.”

REFERENCE: Benraiss A, Wang S, Herrlinger S, Li X, Chandler-Militello D, Mauceri J, Burm HB, Toner M, Osipovitch M, Xu QJ, Ding F, Wang F, Kang N, Kang J, Curtin PC, Brunner D, Windrem MS, Munoz-Sanjuan I, Nedergaard M, Goldman SA. Human glia can both induce and rescue aspects of disease phenotype in Huntington disease. 2016. Nature Communications 7:11758

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When Nobel Laureate in chemistry Dr. Bernard L. (Ben) Feringa’s colleagues at the Netherlands’ University of Groningen heard the news of his award, they erupted in cheers and applause. Later some people presented him with gifts, including a toy Ferrari, a nod to Feringa’s successful creation of a molecular car.

Feringa is one of three chemists—including American Sir. J. Fraser Stoddart and Frenchman Dr. Jean-Pierre Sauvage—honored this year by the Nobel Committee for their work designing and producing molecular “machines.”  The chemists “developed molecules with controllable movements, which can perform a task when energy is added,” according to the Nobel Committee and are part of what Feringa calls “the supramolecular and molecular machines’ community.”

An ambassador for science

Feringa was recognized for being the first person to develop a molecular motor. In 1999, he created a molecular rotor blade that could spin continually in the same direction while under the influence of light and heat.

“Using molecular motors, he has rotated a glass cylinder that is 10,000 times bigger than the motor” according to the Nobel Committee. The molecular car, or nanocar, he created consisted of a molecular chassis held together with four motors that functioned as wheels.

As for his reaction to news of his award, Feringa said,

“It took me by surprise. Initially, I did not know what to say, but my next remark was that I was deeply honored.”  Suddenly he is being recognized by people on the streets and on trains and juggling numerous speaking invitations. “My experience has been that people are proud that a Dutch scientist is a Nobel laureate.”  He also is happy to serve as an ambassador for science.

“I consider it extremely important to inform the public about the value of scientific inquiry,” explained Feringa. “This is more important than ever these days as even in politics, you hear alarming messages such as ‘science is also only an opinion.’ There is a clear task for outreach by scientists these days.”

Smart drugs

Feringa began working on molecular switches and motors about 30 years ago. “The initial molecule that formed a basis for the later switches and motors I designed [was created] exactly 40 years ago while working on my Ph.D. thesis,” he said.
Currently he is the leader of the Ben Feringa Research Group at the Stratingh Institute for Chemistry at the University of Groningen, in the Netherlands, where he has taught since 1988. The group’s research focuses on synthetic and physical organic chemistry, with a goal of using the full potential of synthetic chemistry to “create new structures and functions,” according to the group’s website.

“We are currently heavily involved in designing responsive biosystems, like smart drugs that can be switched on and off by light,” Feringa explained. “Also, we are trying to build on our nanocar by making molecular cars and dragsters that can move on self-assembled ‘molecular roads,’ controlling movement under ambient conditions and demonstrating cargo transport.”

One of the most important aspect of his group’s research is the ability to control dynamic functions on a molecular scale, he added. “This means controlled motion and triggering all kinds of functions,” said Feringa. This could lead to self-healing materials or smart drugs for future precision therapeutics, he added.

Your own molecular world

The creative aspects and practical applications of chemistry attracted him to the discipline, according to Feringa. “The fact that you can ‘design your own molecular world’ was very appealing to me,” he noted.  “There is the beauty of molecules and the fact that you can make molecules and materials that never existed before. On the one hand, you have the creativity and creating power of chemistry and on the other hand, the practicality. Think of the products, from paint to drugs, that chemistry brings. And let’s not forget the fascinating molecular world in living systems.”

Stimulate creativity

A dynamic high-school chemistry teacher and a superior mentor for his doctoral thesis at the University of Groningen, Prof. Hans Wynberg, also inspired him to do experimental work with molecules. Feringa now strives to inspire his own students as well; the world of molecules is wide open.

“I like to make students enthusiastic,” he noted. “To explain to them how things work and why certain knowledge and insights are important to know and why. [To help them appreciate] the beauty of nature and look with surprise and wonder at the world around us. And to discuss with the students challenging questions that help to stimulate their creativity. These are the drivers for me for teaching.”

Photo: Jenny Öhman

FACTS
Bernard L. (Ben) Feringa, Ph.D.

Award: Nobel Prize in Chemistry, for creating the first molecular motor.

Current Position: Leader of the Ben Feringa Research Group at the Stratingh Institute for Chemistry, University of Groningen, Netherlands

Jacobus van’t Hoff Distinguished Professor of Molecular Sciences

Age: 66

Nationality: Dutch

Born: Barger-Compascuum, Netherlands

Education: Ph.D. University of Groningen

Personal: Married, three daughters

Interests: “Chemistry; science is my hobby. But I also enjoy my garden, growing my own vegetables, long distance ice skating, reading, history and of course, spending time with my family.”

Jacobus van’t Hoff Distinguished Professor of Molecular Sciences

Age: 66

Nationality: Dutch

Born: Barger-Compascuum, Netherlands

Education: Ph.D. University of Groningen

Personal: Married, three daughters

Interests: “Chemistry; science is my hobby. But I also enjoy my garden, growing my own vegetables, long distance ice skating, reading, history and of course, spending time with my family.”

The post Nobel Laureate Chemistry 2016: Bernard L. Feringa appeared first on NLS.

On 7 December 2016, Professor Yoshinori Ohsumi from the Tokyo Institute of Technology received the Nobel Prize in Physiology or Medicine. Ohsumi was honored for research on autophagy, a ubiquitous cell process that previously received little public attention. Since the Nobel announcement, Ohsumi received a Life Sciences Breakthrough Prize from the technology pioneers and funders of Facebook and Google.

After the Nobel announcement, Ohsumi talked with Adam Smith, chief scientific officer of Nobel Media, about the growth in the field. “When I started my work,” he said, “probably every year, 20 or less papers appeared on autophagy. Now more than 5 000 or something like that. It’s a huge change within probably these 15 years or so.”

What autophagy is and why it matters

Autophagy, from the Greek words for self and eating, is often described using terms like “garbage” and “recycling.” It is, however, a vital service provided by the cell’s vesicular system for the entire organism. Autophagy breaks down organelles such as mitochondria, rescuing their components to construct other cell parts. Autophagy destroys pathogens. It sacrifices nonessential enzymes to supply amino acids for essential proteins.

In praising Ohsumi, basic and applied scientists noted that autophagy touches on human conditions from cancer to cognitive impairment. Understanding this process is critical for understanding aging. Cell biologists said that when Ohsumi began, he certainly never expected that his research would have such diverse implications. For an example of how Ohsumi’s work advances basic and clinical research, see our report in this issue on work by Steven Goldman, including a study about Zika and autophagy.

Earlier Nobel winners inspire a career change

Ohsumi was born in 1945 in Japan and earned a PhD from the University of Tokyo. He did postdoctoral work at Rockefeller University in New York and the University of Tokyo, later moving to the National Institute for Basic Biology, Okazaki, Japan. He is now at the Tokyo Institute of Technology. He began his award-winning work, which is a combination of classic genetics and innovative cell biology, during his postdoctoral period.

Ohsumi works on yeast, a common model organism with strengths in genetic manipulation but weaknesses in microscopy because of its small cell size. Ohsumi used yeast mutants that allowed him to use microscopy to view autophagy. He applied standard yeast genetic methods to identify genes that direct autophagy. He was not always a yeast geneticist, however.

The Nobel Prize is “richly deserved” and “wonderful recognition” for Ohsumi, says S. Michal Jazwinski, director of the Tulane Center for Aging and professor of medicine at Tulane University. He adds that the award helps balance difficulties that Ohsumi experienced early in his career. Jazwinski and Ohsumi were postdoctoral fellows together in the 1970s in Gerald Edelman’s group at Rockefeller University. Edelman was awarded a 1972 Nobel Prize for work on the immune system.

Jazwinski says that when he arrived in the lab in 1975, Ohsumi was already there. “At that time in the Edelman lab,” Jazwinski says, “we were all focusing on how cells interact with other cells. One of models was recognition of egg by sperm, but Yoshinori was the only person working on that project. It was a bit of a struggle and wasn’t terribly exciting for him.” For his own project, Jazwinski took a new direction that changed his career and Ohsumi’s.

Jazwinski’s original project was studying how agents that bind to the surface of tissue culture cells trigger a series of responses that lead to DNA replication. “We now call that ‘signal transduction,’” he says. Seeking better methods, Jazwinski recalled a seminar by Lee Hartwell, who won a 2001 Nobel Prize for characterizing the cell cycle using yeast mutants. The Edelman lab didn’t work with yeast, so Jazwinski set up yeast genetic experiments from scratch, starting with store-bought yeast.

Ohsumi and Jazwinski now shared a bond – their differences. “We didn’t have much in common with others in lab or each other,” Jazwinski says, “but we were doing something different from everyone else, so I think that’s why we gravitated to each other.” Ohsumi and his wife and toddler son lived in the same building as Jazwinski, so the two scientists also socialized.

“I introduced him to working with yeast,” Jazwinski says, “and he enjoyed it. A year or two later he went back to Japan, got more experience with yeast, and started working on autophagy.”

Jazwinski learned of the Nobel when a Japanese reporter surprised him by calling for comments on the morning of the announcement. He was “delighted” and “elated” for his friend. “The work Yoshinori did was extremely important,” Jazwinski says. “The work Yoshinori did was extremely important,” Jazwinski says. “People saw autophagy by microscopy in the 60s and 70s but didn’t know what was going on. Yoshinori opened up autophagy as field of study and exploited tools that he created to define the molecular mechanism. That’s a big deal.”

Applications of autophagy

The human applications of a process discovered using yeast are hard to imagine. Jazwinski’s research, though, is a prime example of the connection between yeast and human cells. Jazwinski’s group works on aging, applying both yeast genetics and analyses of human population-based data. Although Jazwinski does not directly study autophagy, he uses Ohsumi’s yeast autophagy mutants to identify what limits a cell’s ability to divide indefinitely, a critical factor in human aging.

Ohsumi himself shows no signs of stopping. In the Nobel Media interview, he said, “I believe there are fundamental functions of the cells should be conserved from yeast to mammals.” He hinted that he’ll continue researching those similarities. “Still we have so many questions,” he said. “Even now we have more questions than when I started.”

Yoshinori Ohsumi

Award: Nobel Prize in Physiology or Medicine

Born: 1945, Fukuoka, Japan

Affiliation at the time of the award: Tokyo Institute of Technology, Tokyo, Japan

Career: Undergraduate student, the University of Tokyo (1963-1967), Graduate student, Department of Biochemistry, the University of Tokyo with Prof. Kazutomo Imahori (1967-1972), Research Fellow, Department of Agricultural Chemistry, the University of Tokyo (1972-1974), Postdoctoral Fellow, Rockefeller University (1974-1977) with Prof. Gerald M. Edelman, Research Associate, Department of Biology, the University of Tokyo (1986-1988), Associate Professor, Department of Biology, the University of Tokyo (1988-1996), Professor, Department of Cell Biology, National Institute for Basic Biology (1996-2009), Professor, The graduate university for advanced studies (2004-2009), Professor, Advanced Research Organization, Tokyo Institute of Technology (2009-2010), Professor, Frontier Research Center, Tokyo Institute of Technology (2010-2016), Honorary Professor, Tokyo Institute of Technology (2014-present), Professor, Institute of Innovative Research, Tokyo Institute of Technology (2016-present).

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