Whether researchers at NYUAD's Center for Genomics and Systems Biology (CGSB) are conducting drug screening in nematodes, studying neurons in fruit flies, analyzing the genetic development of date palms, or investigating the use of algae as a source of biofuel, the fundamentals of the science are the same. "We all use the technique of DNA and RNA sequencing, or deep sequencing, to address questions that are important to each of us," said NYU New York Silver Professor of Biology Claude Desplan.
"The Center is a way of creating connections across disciplines," said Fabio Piano, NYUAD provost and founding director of the CGSB in New York. "It's a catalyst and hub of activity that brings to bear all the parts of the university on some important questions. And that kind of collaboration has proven to be really powerful."
The Genetic Diversity of the Date Palm
For the past decade, Michael Purugganan has studied the evolution and diversity of crops by analyzing their genomes. He has worked on grass species such as rice and corn, but recently he has taken on the date palm, the iconic crop of the UAE and the region.
Purugganan, who is NYUNY Dorothy Schiff Professor of Genomics and professor of Biology, was intrigued by the date palm because little work had been done on its evolution and cultivation. And with the 100 Dates! Project he leads at NYUAD, he hopes that genetic analysis will "tell us something about the history of the date palm: when people started to cultivate them, and how they spread from North Africa all the way to the Indian subcontinent."
Date palms are extremely diverse; thousands of varieties are scattered from Morocco to Pakistan. Some varieties produce fruit that is extremely sweet; others have fruit that is quite bitter. Dates can range from yellow to nearly black. Some date palms can survive on water with high salt content; others are resistant to disease.
"We're trying to understand the genetic basis for this variation, because that will tell us something about the history of the species and how it is evolving," Purugganan said.
Understanding the genetic mutations that help some date palms survive under difficult conditions could also help to improve cultivation. "We're finding that the water in many parts of the region is becoming more salty. So we're trying to understand how to cultivate date palms under increasing salinity levels," he said.
Not all of the work happens in the laboratory. Purugganan and members of his team try to glean information about varieties by speaking with farmers and vendors at markets in the region. Traditional knowledge can enhance the project, but it can also be confounding. For instance, just about every country has a variety called medjool. But is the UAE's medjool genetically the same as the medjool of Iraq? Testing in the lab can easily answer this question.
We're trying to understand the genetic basis for this [date palm] variation, because that will tell us something about the history of the species and how it is evolving.
Unlike corn and rice, Purugganan does not expect that his team will find a common wild ancestor of cultivated date palms. Therefore researchers will need to be more "creative" when analyzing genetic data. But with a large enough sample, the team will be able to determine the historical and genetic relationships among varieties.
Working in the UAE has provided benefits for Purugganan and his team: "We have partners in the UAE who are working closely with us to get samples from the emirates, and we have developed partnerships with people who have provided us with samples from Tunisia all the way to Pakistan."
Neuronal Specificity
A brain — even that of a tiny fruit fly — contains many kinds of neurons with different physiological functions. Motor neurons can extend from the brain all the way to an appendage; other neurons can be localized to a small region of the brain. What accounts for this differentiation? Why do some cells become motor neurons, while others become visual neurons? And how do they end up looking so different?
Claude Desplan and his team of researchers at the CGSB study the way neurons develop specificity. They are trying to figure out how visual neurons differ genetically from other neurons in the fruit fly brain. "All neurons, of course, share the same genetic information as other cells in the fruit fly, but not every cell expresses all of the genes," Desplan said.
Transcription factors play a critical role in specifying the fate of cells in the fruit fly brain. But Desplan and his team are trying to figure out just how this happens. (Transcription factors are proteins that attach to DNA and influence the transcription of DNA to messenger RNA, a process that is responsible for the expression of a gene.)
In other words, these researchers in Abu Dhabi are trying to correlate the characteristics of neurons with the genes they express.
Researchers begin by modifying the fruit fly so that visual neurons in the brain express Green Fluorescent Protein (GFP). Under a microscope, these neurons can be distinguished from other brain neurons.
Researchers then use old-fashioned dissection of the flies' brains and put the brain cells into a machine that separates the visual neurons that express the GFP from other neurons. "Once you have a few thousand of the cells that express the GFP, you can use modern technology for RNA sequencing, where you can sequence what genes are expressed in those specific cells," Desplan explained.
RNA sequencing provides researchers with a "total profile of gene expression" in the visual neurons, and allows them to learn every gene that is expressed in those cells in a very precise manner, Desplan said. "There will be some genes that are expressed in every cell, but there will be other genes that are expressed only in certain kinds of cells." Understanding the correlation between genes expressed specifically in one cell type and the properties of this cell type is important for understanding how cells gain their specificity.
Once you have a few thousand of the cells that express the Green Fluorescent Protein, you can use modern technology for RNA sequencing, where you can sequence what genes are expressed in those specific cells.
Scale is important. "If you can get the RNA expression profile for 50 or 60 neuron cell types, you will be able to make correlations between the gene and the characteristic of the neuron, which might help you understand the rules of the game," Desplan explained.
And understanding the rules of the game may provide Desplan and his team with insights about how specificity is achieved by cells in the fly brain, and perhaps in other cells, too.
Algae as a Source of Biofuel
Associate Professor of Biology Kourosh Salehi-Ashtiani's group studies genetic development in algae, with an eye to using algae as a source of biofuel. "One major motivation behind this project is to see the relationship between environment and evolution," he said.
The group analyzes terrestrial and marine algae, including strains from New York and the UAE. Algae that accumulate or secrete a lot of lipids could be useful as sources of biofuel, and the researchers have already found a marine algae that is doing just that.
The algae from New York and Abu Dhabi share similarities genetically, but they are quite different in their environmental requirements. The Abu Dhabi algae is limited in the kinds of nitrogen compounds it can utilize for nitrogen assimilation (the process by which algae convert nitrogen from the environment into useful compounds, such as amino acids). This makes sense, Salehi-Ashtiani said: "The soil here in Abu Dhabi is not very rich in nitrogen. So over time, these algae might have lost some of the genes or abilities to use nitrogen sources that they never see."
In addition to studying algae found in the environment, the team analyzes a model algae system, Chlamydomonas reinhardtii, which is interesting because it has genes that are plant-specific and others that are animal-specific. This encouraged Salehi-Ashtiani and his team to ask if these genes work together or separately; in other words, do these genes behave according to their evolutionary trajectories or are they transparent to that. The researchers discovered that if they removed one gene computationally from the organism, the deletion had little effect on development. But if you take out one gene and another related gene, the modification has a great effect. This leads Salehi-Ashtiani to think that there is synergy involved.
"When we look at the metabolic network topology, or the genes' placement on the network, as a subgroup, they are closer to each other. But when we look at other kinds of interaction, they are further apart," he explained. "So over the course of evolution, the network has evolved such that for related functions they make use of proteins that have different phylogenetic affinities. Chlamydomonas seem to 'like' diversity, when it comes to genes performing similar tasks."
Salehi-Ashtiani says that if you want to use algae as a source of biofuel, you want it to be able to grow well in the environment where it will be produced. The Abu Dhabi algae they have studied has a high heat tolerance, at least five degrees above that of the New York algae. It also helps if the algae grows fast and can withstand contamination from other algae or bacteria.
One major motivation behind this project is to see the relationship between environment and evolution.
The algae should also produce lots of lipids. "Our soil algae usually don't produce a lot of lipids, but they do grow fast, and you can induce them to make lipids if you starve them of nitrogen," Salehi-Ashtiani explained. "But pretty much all of our marine algae make a lot of oil. And we are working on finding conditions under which they can grow quickly."
Advanced Drug Screening
CGSB Founding Director Fabio Piano works alongside Kris Gunsalus, the program director for the chemical genomics group at CGSB. The group works with a model system called C. elegans, a nematode, or roundworm.
C. elegans are tiny — a millimeter long — and are excellent for genetic work because they have a lifecycle of less than three days, which allows researchers to study how the organism changes from generation to generation. They are also accommodating. "They feed happily on bacteria, and you can grow thousands, if not millions, in a lab," Piano said. And their clear skin makes it easy for researchers to observe every cell in the animal with a microscope.
At NYUAD, Gunsalus' team has built a lab specifically designed for studying C. elegans as a model system for drug screening. Thousands of worms are grown on 96-well plates. A robot handles the plates and photographs the worms at different stages of development. The robot can also algorithmically analyze the images.
To date, the lab has produced several million images of the C. elegans under a variety of conditions and at different stages of maturity. "The system has a quantitative ability to tell us how many objects of a particular kind it sees in a huge set of images. And it can do this very quickly," Gunsalus explained. "For instance, if I'm testing for a drug that kills C. elegans embryos, I'm looking for images of embryos that don't hatch after a drug has been applied to them. And I can tell the system to look for specific shapes that look like unhatched embryos."
Humans and C. elegans have the same insulin pathways. "So you can use mutations in the worms that mimic the kinds of problems that would be present in a human who didn't have insulin receptors," Gunsalus said. "We can then test drugs or drug combinations that could cure the worm of this defect." Those drugs might in turn be useful in finding new drugs that could be used to treat humans who have diabetes.
And though C. elegans are harmless to humans, their nematode cousins in the real world cause diseases that affect more than a billion people. With their platform, the team will be able to screen drugs that could potentially treat diseases — like elephantiasis and river blindness — caused by other nematodes.
Technology and Society
Genetic technology is developing rapidly. A human genome can now be sequenced in a couple days for a few thousand dollars. This diffusion of once very expensive technology can help people to get a better understanding of their diseases or the diseases of their children, Piano said. But just because you can sequence a genome does not mean you should. "There are a whole bunch of other questions that society will have to deal with," he said. "So now the question becomes: 'In what circumstances do you sequence a human genome? What kind of information is it going to give you?'"
This article originally appeared in NYUAD's 2013-14 Research Report (13MB PDF).