A team of scientists from the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA has been awarded a $4.7 million grant from the National Institutes of Health to investigate how genomic variation influences the production of induced pluripotent stem cells, or iPS cells.

The five-year grant to researchers Brunilda Balliu, Jason Ernst, Chongyuan Luo, Kathrin Plath, Roy Wollman and Noah Zaitlen is one of 25 announced today as part of the NIH’s new Impact of Genomic Variation on Function (IGVF) Consortium.

To create human iPS cells, scientists take skin, blood or other tissue-specific cells and reprogram them back to a stem-like state. These reprogrammed cells can make unlimited copies of themselves and can be coaxed to differentiate into any cell type found in the body, making them an attractive potential source for cell therapies for a range of diseases and injuries.

However, because each person has slight differences in the sequence of their DNA — genomic variations — iPS cells derived from various donors respond differently to the techniques used in reprogramming and differentiation.

To begin to understand precisely why and how this happens, the researchers will study iPS cells derived from 100 individuals from a range of ethnic and racial backgrounds with the goal of connecting the cells’ genomic variations to differences in their reprogramming and differentiation capacities.

“Induced pluripotent stem cells are the foundation of regenerative medicine, but before we can realize their full potential, we need to understand them more deeply,” said Luo, the project’s leader and an assistant professor of human genetics at the David Geffen School of Medicine at UCLA.

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Nandita Garud, assistant professor of ecology and evolutionary biology, has been named a 2021-2022 UCLA Hellman fellow and is a recipient of a microbiome, neurobiology and disease award from Scialog. Both distinctions recognize Garud for her research on methods of quantifying genomic data in the microbiome.

In early 2020, the Hellman fellows fund provided an endowment to UCLA to establish the UCLA Society of Hellman Fellows, which provides research support for assistant professors who show capacity for great distinction in their research.

The inaugural Scialog microbiome, neurobiology and disease initiative brought together more than 50 scientists from a variety of disciplines to propose research to help transform understanding of the gut-brain axis at the chemical, microbial and immunological level.

Garud, along with her collaborator Will Ludington, a biology professor at the Carnegie Institution for Science, received one of the six awards given to multidisciplinary teams from the United States and Canada. Garud will receive $55,000 from the Research Corporation for Science Advancement, the Paul G. Allen Frontiers Group and the Frederick Gardner Cottrell Foundation for winning the Scialog award.

The body’s immune cells naturally fight off viral and bacterial microbes and other invaders, but they can also be reprogrammed or “trained” to respond even more aggressively and potently to such threats, report UCLA scientists who have discovered the fundamental rule underlying this process in a particular class of cells.

In a study published June 18 in the journal Science, the researchers identified a key molecular mechanism within macrophages, infection-fighting cells of the innate immune system, that determines whether — and how well — the cells can be trained. Their findings could help pave the way for future targeted strategies to enhance the function of the immune system.

“Like a soldier or an athlete, innate immune cells can be trained by past experiences to become better at fighting infections,” said lead author Quen Cheng, an assistant clinical professor of infectious diseases at UCLA’s David Geffen School of Medicine. However, he noted, the researchers had previously observed that some experiences seemed to be better than others for immune training. “This surprising finding motivated us to better understand the rules that govern this process.”

Whether immune training occurs depends on how the DNA of the cell is wrapped. In human cells, for instance, more than 6 feet of DNA must fit into the cell’s nucleus, which is so small that it is not visible to the naked eye. To achieve this feat, the DNA is tightly wrapped into chromosomes.

Only selected regions of the DNA are exposed and accessible, and only the genes in those accessible regions are able to respond and fight infection, said senior author Alexander Hoffmann, UCLA’s Thomas M. Asher Professor of Microbiology and director of the Institute for Quantitative and Computational Biosciences.

However, by introducing a stimulus to a macrophage — for example, a substance derived from a microbe or pathogen, as in the case of a vaccine — previously compacted DNA regions can be unwrapped. This unwrapping exposes new genes that will enable the cell to respond more aggressively, in essence training it to fight the next infection, Hoffmann said.

The new research reveals that the precise dynamics of a key immune signaling molecule in macrophages, called NFκB, determine whether or not this unwrapping and exposing of genes occurs. Moreover, the researchers report, the dynamic activity of NFκB itself is determined by the precise type of extracellular stimulus introduced to the macrophage.

“Importantly, our study shows that innate immune cells can be trained to become more aggressive only by some stimuli and not others,” Cheng said. “This specificity is critical to human health because proper training is important for effectively fighting infection, but improper training may result in too much inflammation and autoimmunity, which can cause significant damage.”

NFκB helps immune cells to identify incoming threats. When receptors on immune cells detect threatening external stimuli, they activate the NFκB molecule inside the cell. The dynamics of NFκB — how it behaves over time — form a language similar to Morse code by which it communicates the identity of the external threat to the DNA and tells it which genes to ready for battle.

The specific “word” of this code that NFκB uses to tell DNA to unwrap is dependent on whether NFκB is oscillatory or steady over eight or more hours after encountering a stimulus. Oscillating NFκB builds up in a macrophage’s nucleus, then moves into the cytoplasm, then returns to the nucleus in cycles, much like a swinging pendulum. Non-oscillating, or steady, NFκB moves into the nucleus and stays there for several hours.

Using advanced microscopy, the researchers followed the activity of NFκB in macrophages derived from the bone marrow of healthy mice, tracking how the molecule’s dynamics changed in response to several different stimuli. They discovered that NFκB was successful at training macrophages — unwrapping DNA and exposing new infection-fighting genes — only when the stimulus induced non-oscillating NFκB activity.

“For a long time, we’ve known intuitively that whether NFκB oscillates or not of must be important but had simply not been able to figure out how,” Cheng said. “These results are a real breakthrough for understanding the language of immune cells, and knowing the language will help us ‘hack’ the system to improve immune function.”

The researchers were also able to simulate this training process with a mathematical model, and the predictive understanding they gleaned may allow for future precision-targeted engineering of trained immunity, Hoffmann said. Mathematical modeling of immune regulatory systems is a key goal of his laboratory, in order to use predictive simulations for precision medicine.

Cheng earned his Ph.D. under Hoffmann’s guidance through UCLA’s Specialty Training and Advanced Research, or STAR, program for physician scientists.

Hoffmann and Cheng expect this research to inspire a wide range of additional studies, including investigations into human diseases caused by immune cells that are improperly trained, strategies to optimize immune training to fight infection and ways to complement existing vaccine approaches.

“This study shows how collaborations between researchers in the UCLA College and David Geffen School of Medicine can produce innovative and impactful science that benefits human health,” Hoffmann said.

The study’s co-lead author is Sho Ohta, an assistant professor at the University of Tokyo and a former postdoctoral scholar in Hoffmann’s UCLA laboratory. Other co-authors are UCLA M.D.–Ph.D. student Katherine Sheu; Roberto Spreafico, a former postdoctoral scholar in Hoffmann’s laboratory; Adewunmi Adelaja, who earned his Ph.D. in Hoffmann’s laboratory and is now working toward his M.D. at UCLA; and Brooks Taylor, a former UCLA doctoral student in Hoffmann’s laboratory.

The study was funded by the National Institutes of Health and the UCLA Department of Medicine’s STAR program.

UCLA life scientists have identified six “words” that specific immune cells use to call up immune defense genes — an important step toward understanding the language the body uses to marshal responses to threats.

In addition, they discovered that the incorrect use of two of these words can activate the wrong genes, resulting in the autoimmune disease known as Sjögren’s syndrome. The research, conducted in mice, is published this week in the peer-reviewed journal Immunity (Cell Press).

“Cells have evolved an immune response code, or language,” said senior author Alexander Hoffmann, the Thomas M. Asher Professor of Microbiology and director of the Institute for Quantitative and Computational Biosciences at UCLA. “We have identified some words in that language, and we know these words are important because of what happens when they are misused. Now we need to understand the meaning of the words, and we are making rapid progress. It’s as exciting as when archaeologists discovered the Rosetta stone and could begin to read Egyptian hieroglyphs.”

Immune cells in the body constantly assess their environment and coordinate their defense functions by using words — or signaling codons, in scientific parlance — to tell the cell’s nucleus which genes to turn on in response to invaders like pathogenic bacteria and viruses. Each signaling codon consists of several successive actions of a DNA binding protein that, when combined, elicit the proper gene activation, in much the same way that successive electrical signals through a telephone wire combine to produce the words of a conversation.

The researchers focused on words used by macrophages, specialized immune cells that rid the body of potentially harmful particles, bacteria and dead cells. Using advanced microscopy techniques, they “listened” to macrophages in healthy mice and identified six specific codon–words that correlated to immune threats. They then did the same with macrophages from mice that contained a mutation akin to Sjögren’s syndrome in humans to determine whether this disease results from the defective use of these words.

“Indeed, we found defects in the use of two of these words,” Hoffmann said. “It’s as if instead of saying, ‘Respond to attacker down the street,’ the cells are incorrectly saying, ‘Respond to attacker in the house.’”

The findings, the researchers say, suggest that Sjögren’s doesn’t result from chronic inflammation, as long thought, but from a codon–word confusion that leads to inappropriate gene activation, causing the body to attack itself. The next step will be to find ways of correcting the confused word choices.

Many diseases are related to miscommunication in cells, but this study, the scientists say, is the first to recognize that immune cells employ a language, to identify words in that language and to demonstrate what can happen when word choice goes awry. Hoffman hopes the team’s discovery will serve as a guide to the discovery of words related to other diseases.

The immune system at war: Words and codes

How are immune cells so effective at mounting a response that is specific and appropriate to each pathogen? The answer, Hoffman says, lies in “signaling pathways,” the communication channels that link immune cells’ receptor molecules — which sense the presence of pathogens — with different kinds of defense genes. The transcription factor NFκB is one of these signaling pathways and is recognized as a central regulator of immune cell responses to pathogen threats.

“The macrophage is capable of responding to different types of pathogens and mounting different kinds of defenses. The defense units — army, navy, air force, special operations — are mediated by groups of genes,” he said. “For each immune threat, the right groups of genes must be mobilized. That requires precise and reliable communication with those units about the nature of the threat. NFκB dynamics provide the communication code. We identified the words in this code, but we don’t yet fully understand how each defense unit interprets the various combinations of the codon–words.”

And of course, calling up the wrong unit is not only ineffective, Hoffmann notes, but may do damage, as vehicles destroy roads, accidents happen and worse, as in the case of Sjogren’s and, possibly, other diseases.

Algorithms, computers and calculus: Identifying the six words

For the study, the scientists analyzed how more than 12,000 cells communicate in response to 27 immune threat conditions. Based on the possible arrangement of temporal NFκB dynamics, they generated a list of more than 900 potential “words” — analogous to all combinations of three-letter words with a vowel for the second letter.

Then, using an algorithm originally developed in the 1940s for the telecommunications industry, they monitored which of the potential words tended to show up when macrophages responded to a stimulus, such as a pathogen-derived substance. They discovered that six specific dynamical features, or “words,” were most frequently correlated with that response.

An analogy would be listening to someone in a conversation and finding that certain three-letter words tend to be used, such as “the,” “boy,” “toy,” and “get,” but not “biy” or “bey,” said lead author Adewunmi Adelaja, who earned his Ph.D. in Hoffmann’s laboratory and is now working toward his M.D. at UCLA.

The team then used a machine learning algorithm to model the immune response of macrophages. If they taught a computer the six words, they asked, would it be able to recognize the stimulus when computerized versions of cells were “talking?” They confirmed that it could. Drilling down further, they explored what would happen if the computer only had five words available. They found that the computer made more mistakes in recognizing the stimulus, leading the team to conclude that all six words are required for reliable cellular communication.

The scientists also used calculus to study the biochemical molecular interactions inside the immune cells that produce the words.

Hoffmann and his colleagues revealed in the journal Science in 2014 how and why the immune system’s B cells respond only to true threats. In a study published in Cell in 2013, his team showed for the first time that it was possible to correct a cellular miscommunication involving the connection of receptors to genes during inflammation without severe side effects.

Hoffmann’s research is supported by the National Institutes of Health.

Other co-authors of the current research are UCLA M.D.–Ph.D. student Katherine Sheu, UCLA postdoctoral researchers Yi Liu and Stefanie Luecke, and Brooks Taylor, a former UCLA doctoral student who initiated the research. All of them work or have worked in Hoffmann’s laboratory.

Eran Halperin, professor of computer science, human genetics, computational medicine and anesthesiology, has been elected as a fellow of the International Society for Computational Biology, a leading professional organization for computational biology and bioinformatics.

The society announced its 2021 class of fellows on March 2 and recognized Halperin for his “transformative work in the field of computational genomics through novel algorithms and theory that has enabled large-scale studies of genetic variation data.” Halperin is one of 13 new honorees who will be formally introduced at the joint Intelligent Systems for Molecular Biology conference/European Conference on Computational Biology, which will be held virtually in July.

In addition to his appointments at the UCLA Samueli School of Engineering and the David Geffin School of Medicine at UCLA, Halperin is the associate director of informatics at the Institute of Precision Health, the co-director of the Computational Genomics Summer Institute and the director of the Artificial Intelligence in Medicine program at UCLA Computational Medicine. He also leads the Big Data Genomics Laboratory, which focuses on the development of computational tools for the analysis of genetic and epigenetic data.

Methods and software programs developed by Halperin’s research group have been used by hundreds of researchers worldwide to better understand the genetic causes of illnesses, such as cardiovascular diseases, non-Hodgkin’s lymphoma and breast cancer.

Halperin joined UCLA in 2016 from Tel Aviv University in Israel. He has published more than 100 peer-reviewed articles across different disciplines such as human genetics, computational biology and theoretical computer science. He has received various honors for academic achievements, including the Rothschild Fellowship, the Technion-Juludan prize and the Krill Prize.