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Biotechnology

Silencing gene expression to cure complex diseases

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Many people think of new medicines as bullets, and in the pharmaceutical industry, frequently used terms like “targets” and “hits” reinforce that idea. Immuneering co-founder and CEO Ben Zeskind ’03, PhD ’06 prefers a different analogy.

His company, which specializes in bioinformatics and computational biology, sees many effective drugs more like noise-canceling headphones.

Rather than focusing on the DNA and proteins involved in a disease, Immuneering focuses on disease-associated gene signaling and expression data. The company is trying to cancel out those signals like a pair of headphones blocks out unwanted background noise.

The approach is guided by Immuneering’s decade-plus of experience helping large pharmaceutical companies understand the biological mechanisms behind some of their most successful medicines.

“We started noticing some common patterns in terms of how these very successful drugs were working, and eventually we realized we could use these insights to create a platform that would let us identify new medicine,” Zeskind says. “[The idea is] to not just make existing medicines work better but also to create entirely new medicines that work better than anything that has come before.”

In keeping with that idea, Immuneering is currently developing a bold pipeline of drugs aimed at some of the most deadly forms of cancer, in addition to other complex diseases that have proven difficult to treat, like Alzheimer’s. The company’s lead drug candidate, which targets a protein signaling pathway associated with many human cancers, will begin clinical trials within the year.

It’s the first of what Immuneering hopes will be a number of clinical trials enabled by what the company calls its “disease-canceling technology,” which analyzes the gene expression data of diseases and uses computational models to identify small-molecule compounds likely to bind to disease pathways and silence them.

“Our most advanced candidates go after the RAS-RAF-MEK [protein] pathway,” Zeskind explains. “This is a pathway that’s activated in about half of all human cancers. This pathway is incredibly important in a number of the most serious cancers: pancreatic, colorectal, melanoma, lung cancer — a lot of the cancers that have proven tougher to go after. We believe this is one of the largest unsolved problems in human cancer.”

A good foundation

As an undergraduate, Zeskind participated in the MIT $100K Entrepreneurship Competition (the $50K back then) and helped organize some of the MIT Enterprise Forum’s events around entrepreneurship.

“MIT has a unique culture around entrepreneurship,” Zeskind says. “There aren’t many organizations that encourage it and celebrate it the way MIT does. Also, the philosophy of the biological engineering department, of taking problems in biology and analyzing them quantitatively and systematically using principles of engineering, that philosophy really drives our company today.”

Although his PhD didn’t focus on bioinformatics, Zeskind’s coursework did involve some computational analysis and offered a primer on oncology. One course in particular, taught by Doug Lauffenburger, the Ford Professor of Biological Engineering, Chemical Engineering, and Biology, resonated with him. The class tasked students with uncovering some of the mechanisms of the interleukin-2 (IL-2) protein, a molecule found in the immune system that’s known to severely limit tumor growth in a small percentage of people with certain cancers.

After Zeskind earned his MBA at Harvard Business School in 2008, he returned to MIT’s campus to talk to Lauffenburger about his idea for a company that would decipher the reasons for IL-2’s success in certain patients. Lauffenburger would go on to join Immuneering’s advisory board.

Of course, due to the financial crisis of 2007-08, that proved to be difficult timing for launching a startup. Without easy access to capital, Zeskind approached pharmaceutical companies to show them some of the insights his team had gained on IL-2. The companies weren’t interested in IL-2, but they were intrigued by Immuneering’s process for uncovering the way it worked.

“At first we thought, ‘We just spent a year figuring out IL-2 and now we have to start from scratch,’” Zeskind recalls. “But then we realized it would be easier the second time around, and that was a real turning point because we realized the company wasn’t about that specific medicine, it was about using data to figure out mechanism.”

In one of the company’s first projects, Immuneering uncovered some of the mechanisms behind an early cancer immunotherapy developed by Bristol-Myers Squibb. In another, they studied the workings of Teva Pharmaceuticals’ drug for multiple sclerosis.

As Immuneering continued working on successful drugs, they began to notice some counterintuitive patterns.

“A lot of the conventional wisdom is to focus on DNA,” Zeskind says. “But what we saw over and over across many different projects was that transcriptomics, or which genes are turned on when — something you measure through RNA levels — was the thing that was most frequently informative about how a drug was working. That ran counter to conventional wisdom.”

In 2018, as Immuneering continued helping companies appreciate that idea in drugs that were already working, it decided to start developing medicines designed from the start to go after disease signals.

Today the company has drug pipelines focused around oncology, immune-oncology, and neuroscience. Zeskind says its disease-canceling technology allows Immuneering to launch new drug programs about twice as fast and with about half the capital as other drug development programs.

“As long as we have a good gene-expression signature from human patient data for a particular disease, we’ll find targets and biological insights that let us go after them in new ways,” he says. “It’s a systematic, quantitative, efficient way to get those biological insights compared to a more traditional process, which involves a lot of trial and error.”

An inspired path

Even as Immuneering advances its drug pipelines, its bioinformatics services business continues to grow. Zeskind attributes that success to the company’s employees, about half of which are MIT alumni — the continuation of trend that began in the early days of the company, when Immuneering was mostly made up of recent MIT PhD graduates and postdocs.

“We were sort of the Navy Seals of bioinformatics, if you will,” Zeskind says. “We’d come in with a small but incredibly well-trained team that knew how to make the most of the data they had available.”

In fact, it’s not lost on Zeskind that his analogy of drugs as noise-canceling headphones has a distinctively MIT spin: He was inspired by longtime MIT professor and Bose Corporation founder Amar Bose.

And Zeskind’s attraction to MIT came long before he ever stepped foot on campus. Growing up, his father, Dale Zeskind ’76, SM ’76, encouraged Ben and his sister Julie ’01, SM ’02 to attend MIT.

Unfortunately, Dale passed away recently after a battle with cancer. But his influence, which included helping to spark a passion for entrepreneurship in his son, is still being felt. Other members of Immuneering’s small team have also lost parents to cancer, adding a personal touch to the work they do every day.

“Especially in the early days, people were taking more risk [joining us over] a large pharma company, but they were having a bigger impact,” Zeskind says. “It’s all about the work: looking at these successful drugs and figuring out why they’re better and seeing if we can improve them.”

Indeed, even as Immuneering’s business model has evolved over the last 12 years, the company has never wavered in its larger mission.

“There’s been a ton of great progress in medicine, but when someone gets a cancer diagnosis, it’s still, more likely than not, very bad news,” Zeskind says. “It’s a real unsolved problem. So by taking a counterintuitive approach and using data, we’re really focused on bringing forward medicines that can have the kind of durable responses that inspired us all those years ago with IL-2. We’re really excited about the impact the medicines we’re developing are going to have.”

Source: https://news.mit.edu/2020/immuneering-gene-expression-1026

Bioengineer

Electronic skin has a strong future stretching ahead

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A material that mimics human skin in ?strength, stretchability and sensitivity could be used to collect biological data in real time. Electronic skin, or e-skin, may play an important role in next-generation prosthetics, personalized medicine, soft robotics and artificial intelligence.

“The ideal e-skin will mimic the many natural functions of human skin, such as sensing temperature and touch, accurately and in real time,” says KAUST postdoc Yichen Cai. However, making suitably flexible electronics that can perform such delicate tasks while also enduring the bumps and scrapes of everyday life is challenging, and each material involved must be carefully engineered.

Most e-skins are made by layering an active nanomaterial (the sensor) on a stretchy surface that attaches to human skin. However, the connection between these layers is often too weak, which reduces the durability and sensitivity of the material; alternatively, if it is too strong, flexibility becomes limited, making it more likely to crack and break the circuit.

“The landscape of skin electronics keeps shifting at a spectacular pace,” says Cai. “The emergence of 2D sensors has accelerated efforts to integrate these atomically thin, mechanically strong materials into functional, durable artificial skins.”

A team led by Cai and colleague Jie Shen has now created a durable e-skin using a hydrogel reinforced with silica nanoparticles as a strong and stretchy substrate and a 2D titanium carbide MXene as the sensing layer, bound together with highly conductive nanowires.

“Hydrogels are more than 70 percent water, making them very compatible with human skin tissues,” explains Shen. By prestretching the hydrogel in all directions, applying a layer of nanowires, and then carefully controlling its release, the researchers created conductive pathways to the sensor layer that remained intact even when the material was stretched to 28 times its original size.

Their prototype e-skin could sense objects from 20 centimeters away, respond to stimuli in less than one tenth of a second, and when used as a pressure sensor, could distinguish handwriting written upon it. It continued to work well after 5,000 deformations, recovering in about a quarter of a second each time. “It is a striking achievement for an e-skin to maintain toughness after repeated use,” says Shen, “which mimics the elasticity and rapid recovery of human skin.”

Such e-skins could monitor a range of biological information, such as changes in blood pressure, which can be detected from vibrations in the arteries to movements of large limbs and joints. This data can then be shared and stored on the cloud via Wi-Fi.

“One remaining obstacle to the widespread use of e-skins lies in scaling up of high-resolution sensors,” adds group leader Vincent Tung; “however, laser-assisted additive manufacturing offers new promise.”

“We envisage a future for this technology beyond biology,” adds Cai. “Stretchable sensor tape could one day monitor the structural health of inanimate objects, such as furniture and aircraft.”

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Source: https://bioengineer.org/electronic-skin-has-a-strong-future-stretching-ahead/

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Bioengineer

German researchers compile world’s largest inventory of known plant species

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Leipzig could mean for the future of plant taxonomy what Greenwich meant for world time until 1972: it could become the reference city for correct scientific plant names. In an outstanding feat of research, the curator of the Botanical Garden of Leipzig University, Dr Martin Freiberg, and colleagues from iDiv and UL have compiled what is now the largest and most complete list of scientific names of all known plant species in the world. The Leipzig Catalogue of Vascular Plants (LCVP) enormously updates and expands existing knowledge on the naming of plant species, and could replace The Plant List (TPL) – a catalogue created by the Royal Botanic Gardens, Kew in London which until now has been the most important reference source for plant researchers.

“In my daily work at the Botanical Garden, I regularly come across species names that are not clear, where existing reference lists have gaps,” said Freiberg. “This always means additional research, which keeps you from doing your actual work and above all limits the reliability of research findings. I wanted to eliminate this obstacle as well as possible.”

World’s most comprehensive and reliable catalogue of plant names

With 1,315,562 scientific names, the LCVP is the largest of its kind in the world describing vascular plants. Freiberg compiled information from accessible relevant databases, harmonized it and standardised the names listed according to the best possible criteria. On the basis of 4500 other studies, he investigated further discrepancies such as different spellings and synonyms. He also added thousands of new species to the existing lists – species identified in recent years, mainly thanks to rapid advances in molecular genetic analysis techniques.

The LCVP now comprises 351,180 vascular plant species and 6160 natural hybrids across 13,460 genera, 564 families and 84 orders. It also lists all synonyms and provides further taxonomic details. This means that it contains over 70,000 more species and subspecies than the most important reference work to date, TPL. The latter has not been updated since 2013, making it an increasingly outdated tool for use in research, according to Freiberg.

“The catalogue will help considerably in ensuring that researchers all over the world refer to the same species when they use a name,” says Freiberg. Originally, he had intended his data set for internal use in Leipzig. “But then many colleagues from other botanical gardens in Germany urged me to make the work available to everyone.”

LCVP vastly expands global knowledge of plant diversity

“Almost every field in plant research depends on reliably naming species,” says Dr Marten Winter of iDiv, adding: “Modern science often means combining data sets from different sources. We need to know exactly which species people refer to, so as not to compare apples and oranges or to erroneously lump different species.” Using the LCVP as a reference will now offer researchers a much higher degree of certainty and reduce confusion. And this will also increase the reliability of research results, adds Winter.

“Working alone, Martin Freiberg has achieved something truly incredible here,” says the director of the Botanical Garden and co-author Prof Christian Wirth (UL, iDiv). “This work has been a mammoth task, and with the LCVP he has rendered an invaluable service to plant research worldwide. I am also pleased that our colleagues from iDiv, with their expertise in biodiversity informatics, were able to make a significant contribution to this work.”

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This research was in part supported by the DFG – Deutsche Forschungsgemeinschaft (FZT-118).

Source: https://bioengineer.org/german-researchers-compile-worlds-largest-inventory-of-known-plant-species/

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Biotechnology

Benefits of Purchasing Used Lab Equipment

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In the laboratory industry, there can be a lot of pressure to always have the newest and latest technology. Due to concerns about having outdated or inefficient equipment, many professionals don’t even consider purchasing used equipment. However, there are numerous advantages to doing so. Here are some of the key benefits of purchasing used lab equipment to keep in mind next time you need to purchase equipment.


Financial Benefits

One of the most significant and obvious benefits of purchasing used lab equipment is that doing so can save you a lot of money. Used laboratory equipment is significantly less expensive than brand new models. Often laboratories can save up to 50 percent or more by purchasing quality second-hand equipment.

Because laboratory equipment is often one of the top expenses that laboratories incur, purchasing used can substantially reduce laboratory costs and free up some much-needed room in tight budgets.

 

Environmental Benefits

Large laboratory equipment can take up a lot of room in landfills and often contain toxic components such as lead or mercury. Such toxins can seep into the earth and contaminate groundwater over time. By purchasing used laboratory equipment rather than new, you can reduce the amount of equipment that ends up in landfills. Plus, you will also reduce the number of raw materials used to manufacture new equipment which will decrease your lab’s negative impact on the environment.

Increased Insight

Purchasing a new type of equipment right after it is released comes with some risks. When a piece of equipment is fresh on the market, there aren’t many reviews from past customers attesting to how well or poorly it operates.\

Used equipment, however, is far less risky. Because the equipment has been on the market for a while, there are likely plenty of reviews that you can reference and any potential issues have likely been well-documented. Just make sure to purchase from a reliable and trustworthy reseller that took the proper measures to ensure the equipment is in optimal operating condition.

Reduced Wait Time

If you need a piece of equipment in a short period of time, buying used is often the best option. Many manufacturers have long wait times that can require you to wait for several weeks or even months before the equipment will arrive. If you have deadlines you need to meet, that simply won’t do. In cases when you need equipment in a timelier manner, used equipment is already built and ready to go so you often only have to wait for shipping.


 

Source: Christina Duron is a freelance writer for multiple online publications where she can showcase her affinity for all things digital. She has focused her career around digital marketing and writes to explore topics that spark her interest.

 

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Bioengineer

An ionic forcefield for nanoparticles

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Tunable coating allows hitch-hiking nanoparticles to slip past the immune system to their target

Nanoparticles are promising drug delivery tools, offering the ability to administer drugs directly to a specific part of the body and avoid the awful side effects so often seen with chemotherapeutics.

But there’s a problem. Nanoparticles struggle to get past the immune system’s first line of defense: proteins in the blood serum that tag potential invaders. Because of this, only about 1 percent of nanoparticles reach their intended target.

“No one escapes the wrath of the serum proteins,” said Eden Tanner, a former postdoctoral fellow in bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS).

Now, Tanner and a team of researchers led by Samir Mitragotri, the Hiller Professor of Bioengineering and Hansjorg Wyss Professor of Biologically Inspired Engineering at SEAS, have developed an ionic forcefield that prevents proteins from binding to and tagging nanoparticles.

In mouse experiments, nanoparticles coated with the ionic liquid survived significantly longer in the body than uncoated particles and, surprisingly, 50 percent of the nanoparticles made it to the lungs. It’s the first time that ionic liquids have been used to protect nanoparticles in the blood stream.

“The fact that this coating allows the nanoparticles to slip past serum proteins and hitch a ride on red blood cells is really quite amazing because once you are able to fight the immune system effectively, lots of opportunities open up,” said Mitragotri, who is also a Core Faculty Member of Harvard’s Wyss Institute for Biologically Inspired Engineering

The research is published in Science Advances.

Ionic liquids, essentially liquid salts, are highly tunable materials that can hold a charge.

“We knew that serum proteins clear out nanoparticles in the bloodstream by attaching to the surface of the particle and we knew that certain ionic liquids can either stabilize or destabilize proteins,” said Tanner, who is now an Assistant Professor of Chemistry & Biochemistry at the University of Mississippi. “The question was, could we leverage the properties of ionic liquids to allow nanoparticles to slip past proteins unseen.”

“The great thing about ionic liquids is that every small change you make to their chemistry results in a big change in their properties,” said Christine Hamadani, a former graduate student at SEAS and first author of the paper. “By changing one carbon bond, you can change whether or not it attracts or repels proteins.”

Hamadani is currently a graduate student at Tanner’s lab at the University of Mississippi.

The researchers coated their nanoparticles with the ionic liquid choline hexenoate, which has an aversion to serum proteins. Once in the body, these ionic-liquid coated nanoparticles appeared to spontaneously attach to the surface of red-blood cells and circulate until they reached the dense capillary system of the lungs, where the particles sheared off into the lung tissue.

“This hitchhiking phenomenon was a really unexpected discovery,” said Mitragotri. “Previous methods of hitchhiking required special treatment for the nanoparticles to attach to red blood cells and even then, they only stayed at a target location for about six hours. Here, we showed 50 percent of the injected dose still in the lungs after 24 hours.”

The research team still needs to understand the exact mechanism that explains why these particles travel so well to lung tissue, but the research demonstrates just how precise the system can be.

“This is such a modular technology,” said Tanner, who plans to continue the research in her lab at University of Mississippi. “Any nanoparticle with a surface change can be coated with ionic liquids and there are millions of ionic liquids that can be tuned to have different properties. You could tune the nanoparticle and the liquid to target specific locations in the body.”

“We as a field need as many tools as we can to fight the immune system and get drugs where they need to go,” said Mitragotri. “Ionic liquids are the latest tool on that front.”

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The research was co-authored by Morgan J. Goetz.

Source: https://bioengineer.org/an-ionic-forcefield-for-nanoparticles/

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