Biofilms are prevalent in the living world, inhabiting sewer pipes, kitchen counters and even the surface of our teeth. A previous research study demonstrated that these biofilms employ sophisticated systems to communicate with one another, while another proved biofilms have a robust capacity for memory.

Süel’s laboratory, along with researchers at Stanford University and the Universitat Pompeu Fabra in Spain, has now found a feature of biofilms that reveal these communities as far more advanced than previously believed. Biological Sciences graduate student Kwang-Tao Chou, former Biological Sciences graduate student Daisy Lee, Süel and their colleagues discovered that biofilm cells are organized in elaborate patterns, a feature that previously only had been associated with higher-level organisms such as plants and animals. The findings, which describe the culmination of eight years of research, are published Jan. 6 in the journal Cell.

“We are seeing that biofilms are much more sophisticated than we thought,” said Süel, a UC San Diego professor in the Division of Biological Sciences’ Section of Molecular Biology, with affiliations in the San Diego Center for Systems Biology, BioCircuits Institute and Center for Microbiome Innovation. “From a biological perspective our results suggest that the concept of cell patterning during development is far more ancient than previously thought. Apparently, the ability of cells to segment themselves in space and time did not just emerge with plants and vertebrates, but may go back over a billion years.”

Biofilm communities are made up of cells of different types. Scientists previously had not thought that these disparate cells could be organized into regulated complex patterns. For the new study, the scientists developed experiments and a mathematical model that revealed the genetic basis for a “clock and wavefront” mechanism, previously only seen in highly evolved organisms ranging from plants to fruit flies to humans. As the biofilm expands and consumes nutrients, a “wave” of nutrient depletion moves across cells within the bacterial community and freezes a molecular clock inside each cell at a specific time and position, creating an intricate composite pattern of repeating segments of distinct cell types.

The breakthrough for the researchers was the ability to identify the genetic circuit underlying the biofilm’s ability to generate the biofilm community-wide concentric rings of gene expression patterns. The researchers were then able to model predictions showing that biofilms could inherently generate many segments.

“Our discovery demonstrates that bacterial biofilms employ a developmental patterning mechanism hitherto believed to be exclusive to vertebrates and plant systems,” the authors note in the Cell paper.

The study’s findings offer implications for a multitude of research areas. Because biofilms are pervasive in our lives, they are of interest in applications ranging from medicine to the food industry and even the military. Biofilms as systems with the capability to test how simple cell systems can organize themselves into complex patterns could be useful in developmental biology to investigate specific aspects of the clock and waveform mechanism that functions in vertebrates, as one example.

“We can see that bacterial communities are not just globs of cells,” said Süel, who envisions research collaborations offering bacteria as new paradigms for studying developmental patterns. “Having a bacterial system allows us to provide some answers that are difficult to obtain in vertebrate and plant systems because bacteria offer more experimentally accessible systems that could provide new insights for the field of development.”

Coauthors of the paper include: Kwang-Tao Chou (UC San Diego graduate student), Dong-yeon Lee (former UC San Diego graduate student, now a postdoctoral scholar at Stanford University), Jian-geng Chiou (UC San Diego postdoctoral scholar), Leticia Galera-Laporta (UC San Diego postdoctoral scholar), San Ly (former UC San Diego researcher), Jordi Garcia-Ojalvo (Universitat Pompeu Fabra Professor) and Gürol Süel (UC San Diego Professor).

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Materials provided by University of California – San Diego. Original written by Mario Aguilera. Note: Content may be edited for style and length.

The study published in Cell Stem Cell therefore establishes senescence as a potentially targetable mechanism for future treatment of Down syndrome, said Hiruy Meharena, a new assistant professor at the University of California San Diego who led the work as a Senior Alana Fellow in the Alana Down Syndrome Center at MIT.

“There is a cell-type specific genome-wide disruption that is independent of the gene dosage response,” Meharena said. “It’s a very similar phenomenon to what’s observed in senescence. This suggests that excessive senescence in the developing brain induced by the third copy of chromosome 21 could be a key reason for the neurodevelopmental abnormalities seen in Down syndrome.”

The study’s finding that neural progenitor cells (NPCs), which develop into major cells in the brain including neurons, have a senescent character is remarkable and novel, said senior author Li-Huei Tsai, but it is substantiated by the team’s extensive work to elucidate the underlying mechanism of the effects of abnormal chromosome number, or aneupoloidy, within the nucleus of the cells.

“This study illustrates the importance of asking fundamental questions about the underlying mechanisms of neurological disorders,” said Tsai, Picower Professor of Neuroscience, director of the Alana Center, and of The Picower Institute for Learning and Memory at MIT. “We didn’t begin this work expecting to see senescence as a translationally relevant feature of Down syndrome, but the data emerged from asking how the presence of an extra chromosome affects the architecture of all of a cell’s chromosomes during development.”

Genomewide changes

Meharena and co-authors spent years measuring distinctions between human cell cultures that differed only by whether they had a third copy of chromosome 21. Stem cells derived from volunteers were cultured to turn into NPCs. In both the stem cells and the NPCs, the team examined 3D chromosome architecture, several metrics of DNA structure and interaction, gene accessibility and transcription, and gene expression. They also looked at the consequences of the gene expression differences on important functions of these developmental cells, such as how well they proliferated and migrated in 3D brain tissue cultures. Stem cells were not particularly different, but NPCs were substantially affected by the third copy of chromosome 21.

Overall, the picture that emerged in NPCs was that the presence of a third copy causes all the other chromosomes to squish inward, not unlike when people in a crowded elevator must narrow their stance when one more person squeezes in. The main effects of this “chromosomal introversion,” meticulously quantified in the study, are more genetic interactions within each chromosome and less interactions among them. These changes and differences in DNA conformation within the cell nucleus lead to changes in how genes are transcribed and therefore expressed, causing important differences in cell function that affect brain development.

Treated as senescence

For the first couple of years as these data emerged, Meharena said, the full significance of the genomic changes were not apparent, but then he read a paper showing very similar genomic rearrangement and transcriptional alterations in senescent cells.

After validating that the Down syndrome cells indeed bore such a similar signature of transcriptional differences, the team decided to test whether anti-senolytic drugs could undo the effects. They tested a combination of two: dasatinib and quercetin. The medications improved not only gene accessibility and transcription, but also the migration and proliferation of cells.

That said, the drugs have very significant side effects — dasatinib is only given to cancer patients when other treatments have not done enough — so they are not appropriate for attempting to intervene in brain development amid Down syndrome, Meharena said. Instead an outcome of the study could be to inspire a search for medications that could have anti-senolytic effects with a safer profile.

Senescence is a stress response of cells. At the same time, years of research by former MIT biology professor Angelika Amon, who co-directed the Alana Center with Tsai, has shown that aneuploidy is a source of considerable stress for cells. A question raised by the new findings, therefore, is whether the senescence-like character of Down syndrome NPCs is indeed the result of an aneuploidy induced stress and if so, exactly what that stress is.

Another implication of the findings is how excessive senescence among brain cells might affect people with Down syndrome later in life. The risk of Alzheimer’s disease is much higher at a substantially earlier age in the Down syndrome population than among people in general. In large part this is believed to be because a key Alzheimer’s risk gene, APP, is on chromosome 21, but the newly identified inclination for senescence may also accelerate Alzheimer’s development.

The Alana Foundation, the LuMind Foundation, Burroughs Wellcome Fund, UNCF-Merck and the National Institutes of Health funded the research.

“People may wonder why our team is working on fingerprints,” says Sijia Wang, a geneticist at the Shanghai Institute of Nutrition and Health, of Chinese Academy of Sciences, and co-senior author on the paper. “We started the work purely out of curiosity. But later it turns out fingerprint pattern is associated with genes for limb growth, which are critical for fetal development. This provides another classic example of pleiotropy, when multiple phenotypes are interrelated to each other and are affected by the same genes.”

While fingerprints are unique to individuals, they are generally categorized into three types: arch, loop, and whorl. These furrows and ridges begin to form on a fetus’ fingers and toes after the third month of pregnancy. Scientists have suspected that fingerprints have potentially evolved to help grab objects and sense their textures, but exactly how these patterns are formed remains unknown.

Wang and colleagues scanned the DNA of more than 23,000 people across ethnic groups and found that at least 43 regions on the genome are associated with fingerprint patterns. One of the most influential regions appeared to be regulating the expression of a gene called EVI1, which is known for its role in embryonic limb development.

To test their finding, the team modified the DNA of mice so their expression of EVI1 was turned down. They found that mice with downregulated EVI1 developed abnormal skin patterns on their digits compared with wild-type mice.

Analysis of human data revealed that fingerprint patterns are genetically correlated with finger length. For example, people with whorl-shaped fingerprints on both of their little fingers tend to have longer little fingers than those who do not, and this correlation is strongly linked to genes involved ini limb development.

“We don’t know exactly how the genes shape fingerprint patterns, but it could be determined by the amount of strength from growth that’s put on an embryonic tissue called volar pads that plays an important role in the formation of different patterns of fingerprint,” says Jinxi Li, a geneticist at the Human Phenome Institute at Fudan University in Shanghai, and a co-first author on the paper. She explains that as a fetus’ hands grow, the palms and fingers would stretch and elongate. These forces could turn a whorl into a loop, for example.

Notably, previous research has suggested that EVI1 is linked to risk of leukemia, and some studies have observed that people with more whorl patterns are more susceptible to the disease,” Wang says.

“Many congenital genetic disorders are related to different dermatoglyphic patterns, such as fingerprints,” he says. For example, children with Down’s syndrome are more likely to have a single crease running across the palm of their hands. “Our study suggests that dermatoglyphic patterns are affected by crucial development genes, which provides a strong theoretical basis for this kind of pleiotropy.”

The research is part of the International Human Phenome Project led by Fudan University in Shanghai that aims to map how the human phenotypical traits are correlated with each other. Next, the team plans to conduct more research on how dermatoglyphic patterns are related to diseases and the underlying pleiotropic mechanism.

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HGT is the movement of genetic material between disparate groups of organisms, rather than by the “vertical” transmission of DNA from parent to offspring. Previous studies have looked at HGT between bacteria and their viruses and have shown that it plays a major role in the movement of genes between bacterial species. However the new study, published in Nature Microbiology, looks at interactions between viruses and eukaryotes, which include animals, plants, fungi, protists and most algae.

“We knew from individual examples that viral genes have played a role in the evolution of eukaryotes. Even humans have viral genes, which are important for our development and brain function,” said the study’s lead author, Dr. Nicholas Irwin, a Junior Research Fellow at Merton College, University of Oxford, and former PhD student at the University of British Columbia (UBC). “We wanted to understand more broadly how HGT has affected viruses and eukaryotes from across the tree of life.”

To tackle this problem, the authors examined viral-eukaryotic gene transfer in the genomes of hundreds of eukaryotic species and thousands of viruses. They identified many genes that had been transferred and found that HGT from eukaryotes to viruses was twice as frequent as the reverse direction.

“We were interested to find that certain groups of viruses, especially those that infect single-celled eukaryotes, acquire a lot of genes from their hosts,” said the study’s senior author, Dr. Patrick Keeling, a professor in the Department of Botany at UBC. “By studying the function of these genes we were able to make predictions about how these viruses affect their hosts during infection.”

In contrast to viruses, eukaryotic organisms retained fewer viral genes, although the ones that were kept appear to have had a major impact on host biology over evolutionary time.

“Many of these viral-derived genes appear to have repeatedly affected the structure and form of different organisms, from the cell walls of algae to the tissues of animals,” said Dr. Irwin. “This suggests that host-virus interactions may have played an important role in driving the diversity of life we see today.”

“These transfers not only have evolutionary consequences for both virus and host, but could have important health implications,” Dr. Keeling said.

HGT allows genes to jump between species including viruses and their hosts. If the gene does something useful, it can sweep through the population and become a feature of that species. This can lead to a rapid emergence of new abilities, as opposed to the more incremental changes that result from smaller mutations.

Although viruses such as Zika and coronaviruses do not appear to participate in these gene transfers, they often manipulate similar genes in their hosts through complex mechanisms. Future research into these transferred genes may therefore provide a novel approach for understanding the infection processes of these and other viruses which could be important for drug discovery.

“The past two years have clearly demonstrated the destructive potential of viruses, but we think that this work serves as an interesting reminder that viruses have also contributed to the evolution of life on Earth,” said Dr. Irwin.

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Materials provided by University of British Columbia. Note: Content may be edited for style and length.