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Dave Jackson

Stem cell growth, required for kernel development, is controlled in corn by a set of genes called CLEs. But how these genes change the corn is complicated. Using CRISPR genome editing, CSHL researchers found they could change kernel yield and ear size by fine-tuning the activity of one of the CLE genes, ZmCLE7. In the image: an unmodified corn cob with normal ZmCLE7 gene activity (1) is packed with regular rows of kernels. Shutting off ZmCLE7 (2) shortened the cob, disrupted row patterns, and lowered kernel yield. However, decreasing the same gene’s activity (3) led to an increase in kernel yield, while increasing the gene’s activity (4) decreased the kernel yield. Jackson Lab/CSHL 2021

By Daniel Dunaief

The current signal works, but not as well as it might. No signal makes everything worse. Something in the middle, with a weak signal, is just right.

By using the gene-editing tool CRISPR, Cold Spring Harbor Laboratory Professor Dave Jackson has fine-tuned a developmental signal for maize, or corn, producing ears that have 15 to 26 percent more kernels. 

Dave Jackson. Photo from CSHL

Working with postdoctoral fellow Lei Liu in his lab, and Madelaine Bartlett, who is an Associate Professor at the University of Massachusetts Amherst, Jackson and his collaborators published their work earlier this week in the prestigious journal Nature Plants.

Jackson calls the ideal weakening of the CLE7 gene in the maize genome the “Goldilocks spot.” He also created a null allele (a nonfunctional variant of a gene caused by a genetic mutation) of a newly identified, partially redundant compensating CLE gene.

Indeed, the CLE7 gene is involved in a process that slows the growth of stem cells, which, in development, are cells that can become any type of cell. Jackson also mutated another CLE gene, CLE1E5.

Several members of the plant community praised the work, suggesting that it could lead to important advances with corn and other crops and might provide the kind of agricultural and technological tools that, down the road, reduce food shortages, particularly in developing nations.

“This paper provides the first example of using CRISPR to alter promoters in cereal crops,” Cristobal Uauy, Professor and Group Leader at the John Innes Centre in the United Kingdom, explained in an email. “The research is really fascinating and will be very impactful.”

While using CRISPR (whose co-creators won the Nobel Prize in Chemistry in October) has worked with tomatoes, the fact that it is possible and successful in cereal “means that it opens a new approach for the crops that provide over 60% of the world’s calories,” Uauy continued.

Uauy said he is following a similar approach in wheat, although for different target genes.

Recognizing the need to provide a subtle tweaking of the genes involved in the growth of corn that enabled this result, Uauy explained that the variation in these crops does not come from an on/off switch or a black and white trait, but rather from a gradient.

In Jackson’s research, turning off the CLE7 gene reduced the size of the cob and the overall amount of corn. Similarly, increasing the activity of that gene also reduced the yield. By lowering the gene’s activity, Jackson and his colleagues generated more kernels that were less rounded, narrower and deeper.

Uauy said that the plant genetics community will likely be intrigued by the methods, the biology uncovered and the possibility to use this approach to improve yield in cereals.

“I expect many researchers and breeders will be excited to read this paper,” he wrote.

In potentially extending this approach to other desirable characteristics, Uauy cautioned that multiple genes control traits such as drought, flood or disease resistance, which would mean that changes in the promoter of a few genes would likely improve these other traits.

“This approach will definitely have a huge role to play going forward, but it is important to state that some traits will still remain difficult to improve,” Uauy explained.

Jackson believes gene editing has considerable agricultural potential.

“The prospect of using CRISPR to improve agriculture will be a revolution,” Jackson said.

Other scientists recognized the benefits of fine-tuning gene expression.

“The most used type/ thought of mutation is deletion and therefore applied for gene knockout,” Kate Creasey Krainer, president and founder of Grow More Foundation, explained in an email. “Gene modulation is not what you expect.”

While Jackson said he was pleased with the results this time, he plans to continue to refine this technique, looking for smaller regions in the promoters of this gene as well as in other genes.

“The approach we used so far is a little like a hammer,” Jackson said. “We hope to go in with more of a scalpel to mutate specific regions of the promoters.”

Creasey Krainer, whose foundation hopes to develop capacity-building scientific resources in developing countries, believes this approach could save decades in creating viable crops to enhance food yield.

She wrote that this is “amazing and could be the green revolution for orphan staple crops.”

In the United States, the Food and Drug Administration is currently debating whether to classify food as a genetically modified organism, or GMO, if a food producer used CRISPR to alter one or more of its ingredients, rather than using genes from other species to enhance a particular trait.

To be sure, the corn Jackson used as a part of his research isn’t the same line as the elite breeding stock that the major agricultural businesses use to produce food and feedstock. In fact, the varieties they used were a part of breeding programs 20 or more years ago. It’s unclear what effect, if any, such gene editing changes might have on those crops, which companies have maximized for yield.

Nonetheless, as a proof of concept, the research Jackson’s team conducted will open the door to additional scientific efforts and, down the road, to agricultural opportunities.

“There will undoubtedly be equivalent regions which can be engineered in a whole set of crops,” Uauy wrote. “We are pursuing other genes using this methodology and are very excited by the prospect it holds to improve crop yields across diverse environments.”

Dave Jackson. Photo from CSHL

By Daniel Dunaief

Just as humans have competing impulses — should we eat or exercise, should we wait outside in the rain to meet a potential date or seek shelter, should we invest in a Spanish tutor or a lacrosse coach — so, too, do plants, albeit not through the same deliberate abstract process.

Working with corn, Dave Jackson, a professor at Cold Spring Harbor Laboratory, has discovered that the gene Gß, (pronounced Gee-Beta,) balances between the competing need to grow and to defend itself against myriad potential threats.

By looking at variations in the gene, Jackson and his postdoctoral fellows, including Qingyu Wu and Fang Xu, have found that some changes in Gß can lead to corn ears with more kernels. The results of this work, which were published in the Proceedings of the National Academy of Sciences last month, suggest that altering this gene may eventually increase the productivity of agricultural crops.

Indeed, the study of this gene included an analysis of why some mutations are lethal. An overactive Gß gene turns the corn brown and kills it. This occurs because the gene cranks up the immune system, causing the plant to attack itself.

Other scientists have found mutations in this gene in plants including arabodopsis and rice.

“We are the first to figure out why the mutations are lethal in corn,” Jackson said. “That’s also true in rice. Rice mutations were made over a decade ago and they also caused the plants to die. Nobody knew why. The main puzzle was solved.”

Dialing back this immune response, however, can encourage the plant to dedicate more resources to growth, although Jackson cautions that the research hasn’t reached the point where scientists or farmers could fine tune the balance between growth and defense.

“We are not there yet,” he said. “That’s what would be possible, based on this knowledge.”

Even in the safer environment of an agricultural field, however, plants can’t abandon all efforts at defense.

“Plants need some defense, but probably much less than if they were growing in the wild,” he said.

By altering the balance toward growth, Jackson is looking at mutations that make more stem cells, which can produce flowers and, eventually kernels. The next steps in this research will not likely include scientists in Jackson’s lab. Qingyu Wu plans to move on to a research position in China. 

Penelope Lindsay. Photo by Patricia Waldron

A prolific plant scientist and mentor, Jackson has seen several of his lab members leave CSHL to pursue other opportunities. Recently, he has added three new postdoctoral researchers to his team: Thu Tran, Jae Hyung Lee and Penelope Lindsay.

Jackson plans to use single-cell sequencing in his future research. Using this technique, scientists can find regulatory relationships between genes and monitor cell lineages in development. Jackson described this approach as an “amazing new technology” that’s only been around for a few years. He hopes to use this technique to find new leads into genes that control growth.

Lindsay, who is joining the lab this month, would like to build on her experience as a plant biologist by adding computational expertise. A graduate of the Boyce Thompson Institute in upstate Ithaca, where she was working on the symbiotic relationship between some plants and a specific type of fungi in the soil, Lindsay would also like to work on single-cell sequencing. She plans to continue to study “how specific genotypes produce a phenotype” or how its genes affect what it becomes.

Jackson’s lab’s focus on the undifferentiated cells of the meristem appealed to Lindsay.

Lindsay first met Jackson a few years ago, when he was giving a talk at Cornell University. It was there, fittingly enough, that she had learned about the work that led to the current paper in the Proceedings of the National Academy of Sciences about growth versus defense.

“I was really impressed with the techniques and with the connection to basic research,” Lindsay said. She was excited to learn how Jackson and his students took biochemical approaches to understand how this signaling pathway affected development.

Cold Spring Harbor Laboratory also intrigued Lindsay, who was interested to join a facility that encouraged collaborations among labs.

Born in New York City, Lindsay spent some of her time in upstate New York before moving to Florida, where she also attended college.

Surrounded by family members who have found outlets for their creativity through art — her mother, Michelle Cartaya, is an artist who takes nature photos and her father, Ned Lindsay, remodels homes — she initially attended New College of Florida in Sarasota expecting to pursue a degree in English. Once in college, however, she found excellent scientific mentors, who encouraged her to pursue research.

As a graduate student, Lindsay was greatly intrigued by the signaling pathway between plants and the symbiotic relationship with arbuscular mycorrhizal fungi. During her graduate work, she studied a mutated version of a plant that lacked a signaling protein that encourages this collaboration. When she added considerable amount of the protein to the plant, she expected to restore the symbiosis, but she found the exact opposite.

“The amount of the protein is critical,” she said. “If you have too much, that’s a bad thing. If you don’t have enough, it’s also bad. It’s like Goldilocks.”

A new resident of Huntington, Lindsay, who was a disc jockey for a community radio station in Ithaca and makes electronic music using synthesizers and computers, is looking forward to starting her work at Cold Spring Harbor Laboratory and to living near New York City.

Lindsay continues to find plants fascinating because they “get everything they need” while living in one place their entire lives. “They have so many sophisticated biochemical pathways to protect themselves,” she said.

From left, Zachary Lippman and Dave Jackson, professors at CSHL who are working on ways to alter promoter regions of genes to control traits in tomato and corn. Photo by Ullas Pedmale

By Daniel Dunaief

He works with tomatoes, but what he’s discovered could have applications to food and fuel crops, including corn, rice and wheat.

Using the latest gene editing technique called CRISPR, Zachary Lippman, a professor at Cold Spring Harbor Laboratory, developed ways to fine-tune traits for fruit size, branching architecture and plant shape. Called quantitative variation, these genetic changes act as a dimmer switch, potentially increasing or decreasing specific traits. This could help meet specific agricultural needs. Looking at the so-called promoter region of genes, Lippman was able to “use those genes as proof of principal” for a technique that may enable the fine-tuning of several traits.

For decades, plant breeders have been looking for naturally occurring mutations that allow them to breed those desirable traits, such as a larger fruit on a tomato or more branches on a plant. In some cases, genetic mutations have occurred naturally, altering the cell’s directions. At other times, breeders have sought ways to encourage mutations by treating their seeds with a specific mutagenic agent, like a chemical.

In an article in the journal Cell, Lippman said the results reflect a road map that other researchers or agricultural companies can use to create desirable traits. This article provides a way to “create a new, raw material for breeders to have access to tools they never had before,” he said. Lippman has taken a chunk of the DNA in the promoter region, typically on the order of 2,000 to 4,000 base pairs, and let the CRISPR scissors alter this part of the genetic code. Then, he and his scientific team chose which cuts from the scissors and subsequent repairs by the cell’s machinery gave the desired modifications to the traits they were studying.

Invented only five years ago, CRISPR is a genetic editing technique that uses tools bacteria have developed to fight off viral infections. Once a bacteria is attacked by a virus, it inserts a small piece of the viral gene into its own sequence. If a similar virus attacks again, the bacteria immediately recognizes the invader and cuts the sequence away.

Scientists sometimes use these molecular scissors to trim specific gene sequences in a process called a deletion. They are also working toward ways to take another genetic code and insert a replacement. “Replacement technology is only now starting to become efficient,” Lippman said. Clinical researchers are especially excited about the potential for this technique in treating genetic conditions, potentially removing and replacing an ineffective sequence.

In Lippman’s case, he used the scissors to cut in several places in the promoter regions of the tomato plant. Rather than targeting specific genes, he directed those scissors to change the genome at several places. When he planted the new seeds, he explored their phenotype, or the physical manifestation of their genetic instructions. These phenotypes varied along a continuum, depending on the changes in their genes.

By going backward and then comparing the genes of the altered plants to the original, he could then hone in on the precise changes in the genetic code that enabled that variation. This technique allows for a finer manipulation than turning on or off specific genes in which an organism, in this case a plant, would either follow specific instructions or would go on a transcriptional break, halting production until it was turned on again.

At this point, Lippman has worked with each trait individually but hasn’t done quantitative variation for more than one at a time. “The next question,” he said, “is to do this multitargeting.” He will also use the tool to study how genes are instructed to turn on and off during growth, including exploring the levels and location of expression.

Lippman is talking with agricultural and scientific collaborators and hopes to go beyond the tomato to exploring the application of this approach to other crops. He is working with Dave Jackson, who is also a professor at Cold Spring Harbor Laboratory, on applying this model to corn.

The scientific duo has known each other for 20 years. Jackson taught his collaborator when Lippman was a graduate student at Cold Spring Harbor Laboratory and Jackson was chair of his thesis committee.

They have worked together on and off since Lippman became a faculty member about nine years ago. Last year, the two received a National Science Foundation genome grant to work on using CRISPR to study the effect of changes in promoter regions in their respective plant specialties.

“Unfortunately for us, tomato has a faster life cycle than corn, but we hope to have some results in corn this fall,” Jackson explained in an email. Lippman hopes to continue on the path toward understanding how regulatory DNA is controlling complex traits. “We can use this tool to dissect critical regulatory regions,” he said. “When we create this variation, we can look at how that translates to a phenotypic variation.”

Lippman said he is especially excited about the fundamental biological questions related to plant growth and development. When other scientists or agricultural companies attempt to use this approach, they may run into some challenges, he said. Some plants are “not transformable [genetically] easily.” These plants can be recalcitrant to plant transformation, a step sometimes needed for CRISPR gene editing. Still, it is “likely that CRISPR will work in all organisms,” he said.

Lippman hopes others discuss this technique and see the potential for a system that could help to customize plants. “My hope and my anticipation is that people all over the world will look at this paper and say, ‘Let’s start to try this out in our own systems.’ Hopefully, there will be a grass roots effort to import this tool.”