Tag Archives: #diseases

Using AI to Reveal Causes of Complex Diseases (Medicine)

Researchers within Mayo Clinic’s Center for Individualized Medicine have developed an artificial intelligence (AI) platform that can uncover causal drivers and relationships embedded within complex biomedical data.

Nicholas Chia, Ph.D., John Kalantari, Ph.D., and Kia Khezeli, Ph.D., recently tested their machine-learning framework, called Causal Relation and Inference Search Platform (CRISP) on multiomic colorectal cancer samples alongside NASA Frontier Development Lab data scientists and machine-learning engineers. The Mayo team presented and published its findings at the IEEE Global Conference on Life Sciences and Technologies.

“Identifying causal variables directly from observational data, and differentiating between causal relationships and misleading correlations, is a critical step toward understanding, diagnosing and treating rare and complex health conditions,” says Dr. Kalantari, a machine-learning scientist within the center’s Microbiome program. “No one, to our knowledge, has developed or applied such causal and invariant approaches for multiomic biomedical data before.” Dr. Kalantari is the principal investigator of the study.

“It’s like garden weeds,” Dr. Chia explains. “The dandelion keeps coming back because you don’t get rid of the root. Causal inference tells you how to get rid of the root; whereas, an association study just tells you that your poor lawn health is associated with dandelions. Association doesn’t tell you how to solve the problem.”

Dr. Kalantari says the novelty of such a platform comes from its ability to discover the underlying cause-and-effect relationships driving a patient’s disease progression.

“By leveraging all available multiomic and clinical data types, the platform’s algorithms can be used to reveal the hidden causes of a disease in order to identify new therapeutic targets and mechanisms for disease prevention,” Dr. Kalantari explains.

Using innovative algorithm to root out cause of cancer

The team emphasizes that efforts to apply machine learning methods to cancer research are ongoing, but most of these efforts are restricted to identifying data associations.

“Knowing the cause and effect of a problem means knowing how to root out the problem,” says Dr. Chia, the Bernard and Edith Waterman Co-Director for the Center’s Microbiome program.

“It’s like garden weeds,” Dr. Chia explains. “The dandelion keeps coming back because you don’t get rid of the root. Causal inference tells you how to get rid of the root; whereas, an association study just tells you that your poor lawn health is associated with dandelions. Association doesn’t tell you how to solve the problem.”

Identifying the causes of cancer development and progression is a challenging problem. Cancer develops through mutations in the DNA caused by an inherited gene alteration, exposure to toxic chemicals, poor diet, too much solar radiation and so on. These mutations collectively result in our cells multiplying uncontrollably, forming tumors, invading nearby tissue and eventually spreading to other distant organs.

Connecting the dots with AI

To decipher the causal relationships underlying a complex disease, such as cancer, the researchers designed the CRISP platform to automatically process and analyze the complex, high-dimensional and diverse data that is often encountered by clinicians and scientists in the biomedical sciences.

“As a cloud-computing platform, CRISP can run thousands of reproducible causal inference experiments in parallel, on any combination of data,” Dr. Kalantari explains.

This input data is analyzed by a set of causal inference and invariant prediction algorithms, which identify causal features responsible for a specific outcome, such as cancer subtype, patient survival or drug response, in a dataset.

A key component of CRISP is its ability to discover the causal drivers of any outcome variable within a dataset, or across many different datasets.

“The framework asks each of its individual causal learning algorithms to dig through the data, connect the dots and come up with an explanation for what is a cause versus an effect,” Dr. Kalantari says. “The final output model combines the explanations from each algorithm to provide the clinician with a set of predicted causal features.”

To better understand these cause-and-effect explanations, the CRISP Team also developed an intuitive, user-friendly visualization application that allows clinicians and scientists to explore the results with ease on a computer, tablet or smartphone.

Putting colorectal cancer samples to the test

After performing several preliminary validation experiments to evaluate the platform’s efficacy, the researchers chose to test the framework on a classification task, particularly which subtype of colorectal cancer does each tumor resemble and what are the most distinct features of that subtype?

To perform this task, the team used a very comprehensive multiomic cancer dataset of tumor samples from 109 patients with colorectal cancer.

“From each patient, there were somewhere between nine and 30 samples taken as swabs, scrapes and biopsies along different locations of the colon to gather broad datasets, including genomic, epigenetic and microbiome,” says Dr. Chia. 

After allowing the framework to analyze thousands of features, such as mutations, microbial species, age, body mass index and other comorbidities, that could cause each subtype of colorectal cancer, the team was able to demonstrate that the causal models inferred by CRISP performed as well as several noncausal machine-learning methods commonly used in practice in achieving a near-perfect test set accuracy.

“However, unlike noncausal approaches, CRISP selected putative features whose causal nature were found to be supported by empirical evidence in the clinical literature,” Dr. Kalantari says.

Interpreting multiomic datasets to advance treatments

The team aims to demonstrate the feasibility of the algorithm to study a larger cohort of patients with colorectal cancer and further apply the algorithm to other cancers and chronic diseases.

Dr. Khezeli, a machine-learning scientist within the center, says that’s why they designed the algorithm to be “data-agnostic” — meaning that the algorithm can receive data in multiple formats or from multiple sources, and still process that data effectively.

“In colorectal cancer, the microbiome plays a significant role, but in other cancers, features unique to proteomics or epigenetics may have higher importance,” says Dr. Khezeli. “This ability for the platform to be able to interpret all data types opens the door to understanding these diseases better. Our ultimate goal is that this will lead to identifying and developing effective treatments.”

Teaming up with NASA for cancer research, beyond

In addition to this work the Mayo researchers teamed up with data scientists from the NASA Frontier Development Laboratory to optimize the causal inference framework for multiomics data integration and causal modeling.

Mayo Clinic and the Frontier Development Laboratory are working together to further develop causal inference approaches like CRISP to prevent and treat cancer and other complex health conditions in space and on Earth. The laboratory is studying the effect of space radiation on an astronaut’s health.

“NASA wants to get astronauts to Mars in the next decade, and they want to get them there in a healthy state,” says Dr. Chia. “They have an incentive to understand what causes cancer with more depth, and we’re working with them to advance that knowledge.”

The team aims to create an extended federated causal learning platform for multi-institutional collaborations. This will enable the team to build predictive models that are more robust and fairer because they will be optimized across institutions with diverse data populations.


Provided by Mayo Clinic

Regular Meat Consumption Linked With a Wide Range of Common Diseases (Food)

Regular meat consumption is associated with a range of diseases that researchers had not previously considered, according to a large, population-level study conducted by a team at the University of Oxford. 

The results associate regular meat intake with a higher risk of various diseases, including heart disease, pneumonia and diabetes, but a lower risk of iron-deficiency anaemia. The study is published today in BMC Medicine.

Consistent evidence has shown that excess consumption of red meat and processed meat (such as bacon and sausages) may be associated with an increased likelihood of developing colorectal cancer. But up to now, it was not clear whether high meat consumption in general might raise or lower the risk of other, non-cancerous diseases.

This has been investigated in a new large-cohort study which used data from almost 475,000 UK adults, who were monitored for 25 major causes of non-cancerous hospital admissions. At the start of the study, participants completed a questionnaire which assessed their dietary habits (including meat intake), after which they were followed-up for an average period of eight years.

Overall, participants who consumed unprocessed red meat and processed meat regularly (three or more times per week) were more likely than low meat-eaters to smoke, drink alcohol, have overweight or obesity, and eat less fruit and vegetables, fibre, and fish.

However, after taking these factors into account, the results indicated that:

  • Higher consumption of unprocessed red meat and processed meat combined was associated with higher risks of ischaemic heart disease, pneumonia, diverticular disease, colon polyps, and diabetes. For instance, every 70 g higher red meat and processed meat intake per day was associated with a 15% higher risk of ischaemic heart disease and a 30% higher risk of diabetes.
  • Higher consumption of poultry meat was associated with higher risks of gastro-oesophageal reflux disease, gastritis and duodenitis, diverticular disease, gallbladder disease, and diabetes. Every 30g higher poultry meat intake per day was associated with a 17% higher risk of gastro-oesophageal reflux disease and a 14% greater risk of diabetes.
  • Most of these positive associations were reduced if body mass index (BMI, a measure of body weight) was taken into account. This suggests that regular meat eaters having a higher average body weight could be partly causing these associations.
  • The team also found that higher intakes of unprocessed red meat and poultry meat were associated with a lower risk of iron deficiency anaemia. The risk was 20% lower with every 50g higher per day intake of unprocessed red meat and 17% lower with every 30g higher per day intake of poultry meat. A higher intake of processed meat was not associated with the risk of iron deficiency anaemia.

The research team suggest that unprocessed red meat and processed meat may increase the risk of ischaemic heart disease because they are major dietary sources of saturated fatty acids. These can increase low-density lipoprotein (LDL) cholesterol, an established risk factor for ischaemic heart disease.

Lead author Dr Keren Papier, from the Nuffield Department of Population Health at the University of Oxford, said: ‘We have long known that unprocessed red meat and processed meat consumption is likely to be carcinogenic and this research is the first to assess the risk of 25 non-cancerous health conditions in relation to meat intake in one study.’

Additional research is needed to evaluate whether the differences in risk we observed in relation to meat intake reflect causal relationships, and if so the extent to which these diseases could be prevented by decreasing meat consumption. The result that meat consumption is associated with a lower risk of iron-deficiency anaemia, however, indicates that people who do not eat meat need to be careful that they obtain enough iron, through dietary sources or supplements.’

The World Cancer Research Fund recommends that people should limit red meat consumption to no more than three portions per week (around 350–500g cooked weight in total), and processed meat should be eaten rarely, if at all.

This study was based on 474,985 middle-aged adults, who were originally recruited into the UK Biobank study between 2006 and 2010, and were followed-up for this study until 2017. These participants were invited to complete a dietary questionnaire with 29 questions on diet, which assessed the consumption frequency of a range of foods. Participants were then categorised into subgroups based on their meat intake: 0-1 times/week; 2 times/week; 3-4 times/week and 5 or more times a week. The information on each participant’s meat intake was linked with hospital admission and mortality data from the NHS Central Registers.

Featured image: New study finds links between regular meat consumption and a wide range of common diseases. Image credit: Shutterstock


Reference: Papier, K., Fensom, G.K., Knuppel, A. et al. Meat consumption and risk of 25 common conditions: outcome-wide analyses in 475,000 men and women in the UK Biobank study. BMC Med 19, 53 (2021). https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-021-01922-9 https://doi.org/10.1186/s12916-021-01922-9


Provided by University of Oxford

Researchers Reveal New DNA-sensing Pathway in CD4+ T Cells and Regulatory Mechanism Mediating Aging-related Autoimmune Diseases (Medicine)

In a study published online in Immunity, Dr. XIAO Yichuan’s group at the Shanghai Institute of Nutrition and Health (SINH) of the Chinese Academy of Sciences (CAS), collaborating with Dr. ZHENG Mingyue’s group at the Shanghai Institute of Materia Medica of CAS, revealed that the KU complex mediated-DNA sensing in CD4+ T cells potentiates T cell activation and aging-related autoimmune diseases.   

For the elderly, although thymus atrophy causes a decrease in naive T cell output, the number of peripheral T cells does not decrease because of its homeostatic proliferation and activation under the aging state. However, the mechanism by which aging enhances homeostatic proliferation of T cells and thus promotes the development of autoimmune inflammation remains unknown. 

As expected, there is a huge accumulation of DNA in the cytoplasm of CD4+ T cells of aged mice and humans. The accumulated DNA enhances the proliferation and activation of TCR induced CD4+ T cells, suggesting DNA sensing can promote T cell functional activation. The researchers screened the proteins that bind to T cell cytoplasmic DNA by mass spectrometry and immunoblotting, and found that DNA in T cells does not bind to cGAS, but to KU complex (KU70/KU80).

Besides, they revealed that the KU complex was abundantly expressed in the cytoplasm of T cells and its recognition of DNA in CD4+ T cells promoted the activation of DNA-PKcs. This process in turn mediated the phosphorylation of ZAK at T169. The phosphorylated ZAK then activated the downstream AKT/mTOR pathway, enhancing the proliferation and activation of CD4+ T cells. Thus, activation of the KU complex-mediated DNA-sensing pathway in CD4+ T cells is a key mechanism leading to the development of autoimmune inflammation in aged mice. 

The discovery of the newly identified DNA-sensing pathway inspires the researchers to explore potential therapeutic strategies of aging-associated autoimmune inflammation.  

By using the Caloric Restriction (CR) or Fast-Mimicking Diet (FMD) mouse models, the researchers found that both modes of dieting significantly reduced DNA damage and cytoplasmic DNA accumulation in aged mouse CD4+ T cells, thereby inhibiting ZAK-T169 phosphorylation and activation of downstream AKT/mTOR signaling. The process ultimately suppressed CD4+ T cell activation and aging-associated autoimmune disease.   

Based on the identified key protein kinase ZAK in the DNA sensing pathway, the researchers applied deep learning combined with molecular simulation to screen a library of approximately 130,000 compounds and obtained iZAK2, a small molecule compound that specifically inhibits ZAK kinase activity. iZAK2 was found to effectively inhibit DNA-induced CD4+ T cell proliferation and activation, thereby alleviating the pathological symptoms of autoimmune disease in aged mice.  

The findings of this study reveal a novel DNA-sensing pathway in aged CD4+ T cells that is independent on cGAS/STING, which promotes T cell activation and proliferation and leads to the development of aging-associated autoimmune diseases. Further investigation and development of inhibitors that block DNA-sensing signaling in T cells may be beneficial for clinical treatment of aging-related autoimmune diseases. 

Aging of the immune system is a leading cause of chronic inflammation and autoimmune diseases of the elderly.  

Featured image: Schematic representation of the cartoon and mechanism of DNA sensing in aged CD4+ T cells promoting its activation and autoimmune inflammation. (Image by Dr. XIAO’s group)


Reference: Yan Wang, Zunyun Fu, Xutong Li et al., “Cytoplasmic DNA sensing by KU complex in aged CD4+ T cell potentiates T cell activation and aging-related autoimmune inflammation”, 2021. DOI: https://doi.org/10.1016/j.immuni.2021.02.003


Provided by Chinese Academy of Sciences

Invasive Weed May Help Treat Some Human Diseases, Researchers Find (Botany)

Native to the southeastern United States, a weedy grass has spread northward to Canada and also made its way to Australia and Japan. Andropogon virginicus grows densely packed and up to seven feet tall, disrupting growth patterns of other plants and competing for resources. When burned, it grows back stronger. There is no way to effectively remove the weed once it has invaded. But there might be a way to use it to human advantage.

An international team of researchers has found that A. virginicus extracts appear to be effective against several human diseases, including diabetes and cancer. The results were published on Dec. 31, 2020, in a special issue of Plants, titled “Biological Activities of Plant Extracts.”

A. virginicus is an invasive weed that seriously threatens agricultural production and economics worldwide,” said paper author Tran Dang Xuan, associate professor in the Transdisciplinary Science and Engineering Program in the Graduate School of Advanced Science and Engineering at Hiroshima University. “However, no solution efficiently utilizing and tackling this plant has been found yet. In this paper, we highlight the potential application of A. virginicus extracts in future medicinal production and therapeutics of chronic diseases such as type 2 diabetes and blood cancer, which can deal with both crop protection and human health concerns.”

Researchers found high levels of flavonoids in the samples they extracted from the weed. These plant chemicals have significant antioxidant and anti-inflammatory properties, according to Xuan. When tested against a variety of cell lines, the extracted plant chemicals bonded to free radicals, preventing damage to the cells. At skin level, this helps prevent age spots by inhibiting a protein called tyrosinase. Among other, deeper healthful actions, this bonding also helps prevent knock-on cellular actions that can lead to type 2 diabetes.

The team also specifically applied the extracted chemicals to a line of chronic myelogenous leukemia, a rare blood cancer. The extract appeared to kill off the cancer cells.

Xuan said the researchers plan to establish a comprehensive process to isolate and purify the compounds responsible for known biological properties, as well as work to identify new uses. They will further test the therapeutical effects of the compounds, with the eventual goal of preparing functional pharmaceuticals for human use.

“Although A. virginicus has been considered a harmful invasive species without economic value, its extracts are promising sources of antioxidant, anti-diabetic, anti-tyrosinase, and antitumor agents,” Xuan said.

Co-authors include La Hoang Anh, Nguyen Van Quan and Yu Iuchi, Transdisciplinary Science and Engineering Program in the Graduate School of Advanced Science and Engineering at Hiroshima University, Japan; Vu Quang Lam and Akiyoshi Takami, Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, Japan; and Rolf Teschke, Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Teaching Hospital of the Medical Faculty, Goethe University Frankfurt, Germany.

Featured image: (A) Bud stage; (B) Flowering stage; (C) Spikelets © Quan, Hiroshima University


Reference: Anh, La H.; Quan, Nguyen V.; Lam, Vu Q.; Iuchi, Yu; Takami, Akiyoshi; Teschke, Rolf; Xuan, Tran D. 2021. “Antioxidant, Anti-tyrosinase, Anti-α-amylase, and Cytotoxic Potentials of the Invasive Weed Andropogon virginicus” Plants 10, no. 1: 69. https://doi.org/10.3390/plants10010069


Provided by Hiroshima University

New Microcomb Could Help Discover Exoplanets and Detect Diseases (Material Science)

Tiny photonic devices could be used to find new exoplanets, monitor our health, and make the internet more energy efficient. Researchers from Chalmers University of Technology, Sweden, now present a game changing microcomb that could bring advanced applications closer to reality.

A microcomb is a photonic device capable of generating a myriad of optical frequencies – colours – on a tiny cavity known as microresonator. These colours are uniformly distributed so the microcomb behaves like a ‘ruler made of light’. The device can be used to measure or generate frequencies with extreme precision.

In a recent article in the journal Nature Photonics, eight Chalmers researchers describe a new kind of microcomb on a chip, based on two microresonators. The new microcomb is a coherent, tunable and reproducible device with up to ten times higher net conversion efficiency than the current state of the art.

“The reason why the results are important is that they represent a unique combination of characteristics, in terms of efficiency, low-power operation, and control, that are unprecedented in the field,” says Óskar Bjarki Helgason, a PhD student at the Department of Microtechnology and Nanoscience at Chalmers, and first author of the new article.  

The Chalmers researchers are not the first to demonstrate a microcomb on a chip, but they have developed a method that overcomes several well-known limitations in the field. The key factor is the use of two optical cavities – microresonators – instead of one. This arrangement results in the unique physical characteristics.

Placed on a chip, the newly developed microcomb is so small that it would fit on the end of a human hair. The gaps between the teeth of the comb are very wide, which opens great opportunities for both researchers and engineers.

A wide range of potential applications

Since almost any measurement can be linked to frequency, the microcombs offer a wide range of potential applications. They could, for example, radically decrease the power consumption in optical communication systems, with tens of lasers being replaced by a single chip-scale microcomb in data centre interconnects. They could also be used in lidar for autonomous driving vehicles, for measuring distances.

Associate Professor and research leader of the project, Department of Microtechnology and Nanoscience, Chalmers University of Technology, Sweden. © Photo: Michael Nystås /Chalmers

Another exciting area where microcombs could be utilised is for the calibration of the spectrographs used in astronomical observatories devoted to the discovery of Earth-like exoplanets.

Extremely accurate optical clocks and health-monitoring apps for our mobile phones are further possibilities. By analysing the composition of our exhaled air, one could potentially diagnose diseases at earlier stages.

Providing answers to questions not yet asked

“For the technology to be practical and find its use outside the lab, we need to co-integrate additional elements with the microresonators, such as lasers, modulators and control electronics. This is a huge challenge, that requires maybe 5-10 years and an investment in engineering research. But I am convinced that it will happen,” says Victor Torres Company, who leads the research project at Chalmers. He continues:

“The most interesting advances and applications are the ones that we have not even conceived of yet. This will likely be enabled by the possibility of having multiple microcombs on the same chip. What could we achieve with tens of microcombs that we cannot do with one?”

Read the article Dissipative solitons in photonic molecules in Nature Photonics

  • The paper is written by Óskar B. Helgason, Francisco R. Arteaga-Sierra, Zhichao Ye, Krishna Twayana, Peter A. Andrekson, Magnus Karlsson, Jochen Schröder and Victor Torres Company at the Department of Microtechnology and Nanoscience at Chalmers.
     
  • All the research, including modelling, theoretical and experimental work and nanofabrication, has been carried out at Chalmers University of Technology. The research has been funded by the European Research Council, through Victor Torres Company’s ERC Consolidator Grant, and by the Swedish Research Council.
Researchers at Chalmers University of Technology, Sweden, present a microcomb on a chip – based on two microresonators instead of one. It is a coherent, tunable and reproducible device with up to ten times higher net conversion efficiency than the current state of the art. © Illustration: Yen Strandqvist /Chalmers

More about: Frequency combs and microcombs

  • A frequency comb is a special laser where the emission frequencies are evenly spaced. It functions as a ruler made of light, where the markers set the frequency scale across a portion of the electromagnetic spectrum, from the ultraviolet to the mid infrared. The location of the markers can be linked to a known reference. This was achieved in the late 90s, and it signified a revolution in precision metrology – an achievement recognised by the Nobel Prize in Physics in 2005.
  • A microcomb is a modern technology, alternative to mode-locked lasers, that can generate repetitive pulses of light at astonishing rates. They are generated by sending laser light to a tiny optical cavity called a microresonator. Thus, microcombs have two important attributes that make them extremely attractive for practical purposes: the frequency spacing between markers is very large (typically between 10 – 1,000 GHz), that is much higher than the spacing in mode-locked laser frequency combs, and they can be implemented with photonic integration technology. The compatibility with photonic integration brings benefits in terms of reduction of size, power consumption and the possibility to reach mass-market applications. The large spacing between teeth means that microcombs can be used for novel applications, such as light sources for fiber-optic communication systems or for the synthesis of pure microwave electromagnetic radiation.
  • The key to the new enhanced microcomb from Chalmers is that the researchers have used two microresonators instead of one. The microresonators interact with each other, similar to how atoms bind together when forming a diatomic molecule. This arrangement is known as a photonic molecule and has unique physical characteristics.

Featured image: PhD Student Óskar Bjarki Helgason demonstrates the chip and the experimental setup for generating the game changing microcomb. © Photo: Mia Halleröd Palmgren, Collage: Yen Strandqvist /Chalmers


Provided by Chalmers University of Technology

New Technology Enables Predictive Design of Engineered Human Cells (Biology)

Capability could accelerate the development of new treatments for diseases

Northwestern University synthetic biologist Joshua Leonard used to build devices when he was a child using electronic kits. Now he and his team have developed a design-driven process that uses parts from a very different kind of toolkit to build complex genetic circuits for cellular engineering.

One of the most exciting frontiers in medicine is the use of living cells as therapies. Using this approach to treat cancer, for example, many patients have been cured of previously untreatable disease. These advances employ the approaches of synthetic biology, a growing field that blends tools and concepts from biology and engineering.

The new Northwestern technology uses computational modeling to more efficiently identify useful genetic designs before building them in the lab. Faced with myriad possibilities, modeling points researchers to designs that offer real opportunity.

“To engineer a cell, we first encode a desired biological function in a piece of DNA, and that DNA program is then delivered to a human cell to guide its execution of the desired function, such as activating a gene only in response to certain signals in the cell’s environment,” Leonard said. He led a team of researchers from Northwestern in collaboration with Neda Bagheri from the University of Washington for this study.

Leonard is an associate professor of chemical and biological engineering in the McCormick School of Engineering and a leading faculty member within Northwestern’s Center for Synthetic Biology. His lab is focused on using this kind of programming capability to build therapies such as engineered cells that activate the immune system, to treat cancer.

Bagheri is an associate professor of biology and chemical engineering and a Washington Research Foundation Investigator at the University of Washington Seattle. Her lab uses computational models to better understand — and subsequently control — cell decisions. Leonard and Bagheri co-advised Joseph Muldoon, a recent doctoral student and the paper’s first author.

“Model-guided design has been explored in cell types such as bacteria and yeast, but this approach is relatively new in mammalian cells,” Muldoon said.

The study, in which dozens of genetic circuits were designed and tested, will be published Feb. 19 in the journal Science Advances. Like other synthetic biology technologies, a key feature of this approach is that it is intended to be readily adopted by other bioengineering groups.

To date, it remains difficult and time-consuming to develop genetic programs when relying upon trial and error. It is also challenging to implement biological functions beyond relatively simple ones. The research team used a “toolkit” of genetic parts invented in Leonard’s lab and paired these parts with computational tools for simulating many potential genetic programs before conducting experiments. They found that a wide variety of genetic programs, each of which carries out a desired and useful function in a human cell, can be constructed such that each program works as predicted. Not only that, but the designs worked the first time.

“In my experience, nothing works like that in science; nothing works the first time. We usually spend a lot of time debugging and refining any new genetic design before it works as desired,” Leonard said. “If each design works as expected, we are no longer limited to building by trial and error. Instead, we can spend our time evaluating ideas that might be useful in order to hone in on the really great ideas.”

“Robust representative models can have disruptive scientific and translational impact,” Bagheri added. “This development is just the tip of the iceberg.”

The genetic circuits developed and implemented in this study are also more complex than the previous state of the art. This advance creates the opportunity to engineer cells to perform more sophisticated functions and to make therapies safer and more effective.

“With this new capability, we have taken a big step in being able to truly engineer biology,” Leonard said.

The research was supported by the National Institute of Biomedical Imaging and Bioengineering (award number 1R01EB026510), the National Institute of General Medical Sciences (award number T32GM008152) and the National Cancer Institute (award number F30CA203325).

The title of the paper is “Model-guided design of mammalian genetic programs.”

Featured image: Synthetic biologists achieve a breakthrough in the design of living cells © Justin Muir


Provided by Northwestern University

The Cause Of Genetic Diseases Can Also Be Found In “Gene Deserts” (Biology)

Large parts of the human genome do not contain protein-coding genes. Now, however, a research team with participation from the University of Basel has discovered the cause of a severe hereditary defect in such a “gene desert”. The study in the scientific journal Nature shows that a single genetic change in the “junk DNA” long thought to be useless can have serious consequences.

An interdisciplinary research team from Lausanne, Berlin and Basel has uncovered a new mechanism for inherited diseases. The findings, published in the journal Nature, have far-reaching implications for the entire field of medical genetics. The study involved researchers from the Institute of Molecular and Clinical Ophthalmology (IOB) at the University of Basel, the University and University Hospital of Lausanne (CHUV), the Max Planck Institute and the University of Berlin.

“When we realized the importance of our findings, we were really stunned,“ says Professor Andrea Superti-Furga from the University Lausanne and CHUV. Even the most sophisticated diagnostic tests, such as whole genome sequencing, provide an accurate diagnosis of the genetic defect in only half of the cases in which a genetic cause for a disease is suspected. The new results suggest that some of the undiagnosed cases may be due to changes in “empty” regions of the genome.

“Although we knew that some of these regions – originally believed to contain inessential sequences and referred to as “junk” DNA – could have a function, we never imagined that they could be responsible for important genetic diseases,” Superti-Furga states.

Puzzling hereditary defect

The study focused on severe limb malformations in four unrelated newborns, behind which a genetic defect was suspected. Surprisingly, no variant was found in any of the genes already identified in the human genome that could have explained the malformations.

In their search for the genetic cause, the team benefited from the technical expertise that Professor Carlo Rivolta and his team at the IOB of the University of Basel have accumulated on genetic diseases of the eye. “We identified the genomic event that was responsible for this invalidating condition according to the same bioinformatic and molecular protocols we would have used for a rare and recessive form of retinal degeneration, and we were successful”, Rivolta explains.

According to the study, the cause for the malformations lies in the loss of a small section in the genetic material that is located in the middle of a so-called “gene desert”, far away from the next known gene. A bioinformatic analysis of this apparently informationless section of the genome indicated that the missing DNA segment contained a so-called “long non-coding RNA” (lncRNA). This is a section of the genome that is transcribed to RNA, but the transcript is not used as a template for making a protein. Instead, the RNA molecule itself serves as an element involved in the regulation of cellular processes.

Further experiments revealed that this previously unknown lncRNA was indeed necessary to activate the nearest gene called EN1. Although the EN1 gene itself was intact, the lack of activation of this gene was responsible for the malformations.

Important information hidden in the “junk DNA”

Today, about 8000 different genetic disorders and diseases are known, and the discovery of a new one, while important for affected individuals and their families, is no longer exceptional. However, the current study shows that such a disease, triggered by a single genetic alteration, can be caused not only by defects in one of the approximately 20,000 known genes that lead to a protein product. The cause may also lie in alterations in elements that are far removed from a gene and yet important for its activation and regulation.

The majority of such elements are still unknown, as was the lncRNA now identified in a section of the genome considered “empty.” Thus, while the known protein-coding genes, which make up only 2 % of the human genome, are the basic functional elements for the life of a cell and an organism, single changes in the remaining 98 % of the genome may also have consequences for human health.

Featured image: Even in regions of the genome that do not code for proteins, changes in the DNA sequence can have far-reaching consequences. (Symbolic image: MIKI Yoshihito, flickr CC BY 2.0)


Reference: Lila Allou et al.
Noncoding deletions identify Maenli IncRNA as a limb-specific En1regulator
Nature (2021), doi: 10.1038/s41586-021-03208-9


Provided by University of Basel

Cancer Research Reveals How Different Mutations in One Gene Can Cause Different Types of Diseases (Medicine)

Leading cancer experts at the University of Birmingham have solved a long-standing question of how various types of mutations in just one gene cause different types of diseases.

Generic laboratory image © University of Birmingham

A team of scientists at the University’s Institute of Cancer and Genomic Sciences, led by Professor Constanze Bonifer, studied a gene known as RUNX1, which is responsible for providing instructions for the development of all blood cells and is frequently mutated in blood cancers.

The results of their research has shown that the balance of cells types in the blood is affected much earlier than previously thought, which is particularly important for families that carry the mutant gene.

The research, published in Life Science Alliance, opens up the possibility of identifying early changes in cells of patients carrying the mutation even before any disease manifests itself – increasing their chances of survival.

The study, the culmination of four years of research, showed that whilst some types of RUNX1 mutations directly changed how other genes behaved in blood cells, not all did. In particular, the mutations that are inherited through families do not immediately affect the cells but instead change the roadmap they follow to become other cell types, such as platelets and white blood cells.

Lead author Professor Constanze Bonifer said: “The most important results we found came from studying mutations that run in families which predisposes their members to diseases such as Familial Platelet Disorder (FPD) and Acute Myeloid Leukaemia (AML).

“AML is an aggressive cancer of the white blood cells, whereas in FPD, the ability to produce blood clots which is required to stop bleeding is impaired. Prior to this study, it was completely unclear why changes in just one gene cause so many different diseases.”

Co-corresponding author Dr Sophie Kellaway said: “We used a cell culture system capable of generating blood cells in vitro, then induced the mutant forms of RUNX1 in these cells and immediately examined the effect on cellular behaviour and gene activity.

“We found that every RUNX1 mutation changed cells in a different way and had a different impact on how genes responded.

“What we have been able to demonstrate is that different genetic alterations in RUNX1 can send cells towards alternate paths of malignancy.”

This work was funded by grants from the Kay Kendall Leukaemia Fund, the Biotechnology and Biological Sciences Research Council, and Blood Cancer UK.

Rachel Kahn, Research Communications Manager at Blood Cancer UK said: “This detailed research shows that it’s not only a mutation that’s important in deciphering whether or not someone will develop a disease, but it’s precisely where the mutation occurs that can alter how blood cells develop and lead to disease.

“Many blood cancers are difficult to treat and have a poor prognosis. This is particularly the case for AML, which was studied in this research. Understanding more about what specific changes lead to the disease will help us to tailor treatments in the future, giving everyone the best possible chance of survival.”

The research results demonstrate that different classes of mutant RUNX1 proteins use unique multifactorial mechanisms to cause disease and so development of novel treatments will require an individual approach.

The team now plans to work with clinicians and families carrying mutant RUNX1 proteins, to examine patient blood cells to see whether their findings in cultured cells can also be seen in patient blood cells, in particular, before they develop any symptoms. They will then examine whether they can find ways to restore normal blood cell development.

Reference: Kellaway et al (Jan, 2021). Different mutant RUNX1 oncoproteins program alternate haematopoietic differentiation trajectories. Life Science Alliance. DOI: 10.26508/lsa.202000864

Provided by University of Birmingham

Researchers Identify Nanoparticles That Could Deliver Therapeutic mRNA Before Birth (Medicine / Nanotechnology)

Study demonstrates the efficacy and therapeutic potential of select ionizable lipid nanoparticles for delivering mRNA to treat genetic diseases before birth.

Researchers at Children’s Hospital of Philadelphia and the School of Engineering and Applied Science at the University of Pennsylvania have identified ionizable lipid nanoparticles that could be used to deliver mRNA as part of fetal therapy. The proof-of-concept study, published today in Science Advances, engineered and screened a number of lipid nanoparticle formulations for targeting mouse fetal organs and has laid the groundwork for testing potential therapies to treat genetic diseases before birth.

Dr. William H. Peranteau, senior author of the paper. © Children’s Hospital of Philadelphia

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

Michael J. Mitchell, Skirkanich Assistant Professor of Innovation in Penn Engineering’s Department of Bioengineering, is the other co-senior author of the study.

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

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

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

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

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

Reference: Riley RS, Kashyap MV, Billingsley MM, White B, Alameh MG, Bose SK, Zoltick PW, Li H, Zhang R, Cheng AY, Weissman D, Peranteau WH, Mitchell MJ. “Ionizable Lipid Nanoparticles for In Utero mRNA Delivery,” Science Advances, 7(3), January 13, 2021, DOI: 10.1126/sciadv.aba1028 https://advances.sciencemag.org/content/7/3/eaba1028

Provided by Childrens Hospital of Philadelphia

About Children’s Hospital of Philadelphia:

Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, Children’s Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 595-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu