ASCB Show Preview: The unhelpfulness of pigeonholes in cell biology

 

By Lloyd Dunlap

 

SAN DIEGO—The paradox of cell biology is that its methods of inquiry are forever changing while the fundamental questions being asked are forever the same, says Stanford University’s Julie Theriot, the program chair for the 55^th Annual Meeting of the American Society for Cell Biology (ASCB), being held Dec. 12-16 in San Diego.

 

“The reason cell biology is such a vital and exciting area of science to me is because nearly all the questions you might have about the nature of life or how life works have to be answered on the level of the cell,” says Theriot. “There is nothing more alive than a cell.”

 

The program that Theriot and her committee have assembled for San Diego showcases the new technologies and new concepts that are shaking up cell biology labs around the world. ASCB 2015 will feature big data, next-generation sequencing, CRISPR cas9 editing, limit-bending imaging, bioengineered cells and tissues, cells as self-organizing individuals and cells (and multicellular organisms) as self-organized collectives. Says Theriot, “As new technologies become available, the field takes those new approaches to ask the questions that have fascinated us for so many years—How do cells divide? How do they communicate? How do they move? How do they form new tissue?”

 

Every time some sort of new technology comes along, we get new kinds of probes that can give us more insight than we’ve ever had before, notes Theriot, adding: “This year, we’re celebrating big data as being a new way to look at these same questions. There’s also super-high-resolution microscopy and we have a symposium on that. And then there are the ways that fundamental concepts of cell biology now apply to other areas of inquiry.”

 

Tackling the broad issues in symposium sessions will be a line-up of big-name speakers. Co-winners of the 2014 Nobel Prize in Chemistry Eric Betzig and W.E. Moerner will lead off a panel with Harvard’s Xiaowei Zhuang on visualizing hidden biological processes. Coming at the self-organization question from a novel direction will be Stanford behavioral biologist Deborah M. Gordon, who is an expert on the collective and individual behavior of red harvester ants. And highlighting self-organization of a different kind will be Roberto Mayor, a developmental biologist from University College London. Mayor’s studies of neural crest cell development led him to his “chase and run” hypothesis of cell movement to explain metastasis.

 

CRISPR cas9, the hottest new gene-editing technology to hit cell biology in recent years, grew out of the discovery of an innate immunity mechanism in bacteria. One of its pioneers, Jennifer Doudna of the University of California, Berkeley—a Howard Hughes Medical Institute (HHMI) investigator—will bring the CRISPR story to a panel on “Bending Nature to Our Purposes.” That symposium also features Kristi Anseth of the University of Colorado, Boulder, and HHMI, who studies the molecular interface between cells and synthetic biomaterials, and Angela Belcher, a biomaterials engineer at MIT, whose lab, among other things, has demonstrated how viruses can be used to improve the efficiency of lithium-ion batteries.

 

All these and the other novel-concept symposia will stand on a robust foundation of classic and “classic plus novel variation” minisymposia. The topics here will cover cell biology’s greatest hits—cell cycle, membranes, organelles, cytoskeleton, signaling and differentiation plus sessions on the “real world” applications of cell biology and a new look at the cell biology of genetic information. Biology education is also on the minisymposia roster with a section entitled “Teaching How to Teach and Learn.”

Theriot is hoping that the 2015 annual meeting program’s combination of old questions and new technologies will draw cross-disciplinary newcomers and core-question cell biologists. Early reaction has been positive, she reports, including “fan mail” from a developmental biologist and longtime ASCB member who confessed that he hasn’t been to an annual meeting in some time. “He wrote to tell me how excited he was to see all these new directions in cell biology and how he’s definitely coming,” says Theriot.

 

 

ASCB 2015 features a pair of keynote speakers to address issues of biology on global, microscopic and political scales: Jane Lubchenco of Oregon State University and Sallie “Penny” Chisholm of MIT.

Thse two keynote speakers will, in part, illustrate the increasing unhelpfulness of pigeonholes in science. Lubchenco and Chisholm could be lumped together as marine biologists, although this would explain little about the science they practice today. True, they both study ocean life, its mechanisms, its evolution to the present and its worrisome prospects for the future. And they both work at global and microscopic scales. For Lubchenco, a professor now and formerly administrator of the U.S. National Oceanic and Atmospheric Administration (NOAA), the main focus is a vast near-shore marine ecosystem along the U.S. Pacific Coast. For Chisholm, who is a professor at MIT with a joint appointment in biology and in civil and environmental engineering, it is a cyanobacterium so tiny that it was dismissed as “schmutz” by microbiologists for decades. Since its discovery in 1985, Prochlorococcus has turned out to be the smallest and most abundant photosynthetic organism on earth, a significant anchor of the oceanic food chain and, by its abundance and near ubiquitous range around the globe, a key player in the ocean carbon cycle and thus in regulating climate.

 

You could take the careers of both Lubchenco and Chisholm as indicators of where the biological sciences, on the smallest and largest scales, will be going in the mid-21^st century. For Chisholm, it was the world’s smallest photosynthetic organism that turned out to be gigantic. For Lubchenco, it was the highly dynamic, ecologically place-sensitive “rocky intertidal zone” at the ocean’s edge that first pulled her into environmental science and then to defend it, into the politics of science at the highest levels. At ASCB 2015, the two keynoters will talk about what drew them into their science and how cell biology can span their global and micro worlds.

 

 

Lubchenco found her scientific life’s work at a place familiar to cell biologists, the Marine Biological Laboratory (MBL) in the scientific beach town of Woods Hole, Mass. An undergraduate at Colorado College, Lubchenco left her native Rockies for a summer class in Invertebrate Zoology at MBL. While the cell biologists were indoors in their MBL labs, Lubchenco was up to her knees in an outdoor laboratory—the intertidal zone. Exposed in grad school to the tenets of a new kind of experimental and evolutionary ecology at the University of Washington, Lubchenco came to appreciate the intertidal zone as a living laboratory with steep physical and biological gradients, e.g., in temperature, kinetics, immersion time, ultraviolet levels, exposure to predators, herbivores or competitors—in short, a perfect system to test hypotheses about the relative importance of those factors in determining the distribution, abundance and diversity of species on the shore.

 

Earning a master’s degree in zoology from Washington and a Ph.D. from Harvard in marine ecology, Lubchenco then joined the Harvard faculty. After a few years, she and her husband, Bruce Menge, moved to Oregon State University in Corvallis to take a novel appointment—a full-time junior faculty position split into separate half-time but tenure-track positions so each of them could share caring for their children but still teach and do research. By the mid-1980s, the Lubchenco/Menge lab was going full bore pursuing “diverse but complementary interests.”

 

While continuing to pursue her science, Lubchenco was becoming increasingly aware of the disconnect between scientific knowledge and policy or management decisions on environmental issues. She realized that scientists were mostly talking to each other, not to the public or policy makers. Few scientists had the skills or support system to share their science to non-technical audiences, especially on controversial topics. Most scientists are ill-equipped for public outreach, she says, but for environmental scientists, it was critical. “It comes with the territory,” she says. “There weren’t that many ecologists who could talk about our science so I began doing more and more of that.”

 

Lubchenco also co-founded the Leopold Leadership Program, now at Stanford University, which trains mid-career academics in environmental fields on how to explain their science to the public, politicians, government administrators and business leaders. Then, as president of the AAAS in 1996-97, Lubchenco issued a call for all scientists to come out of their labs and explain the process of science to Americans. In 2009, the newly elected president Barack Obama named her as NOAA Administrator. She served four years and her term was productive and rewarding but stormy, literally.

 

“From 2009-2013, we had the most extreme weather of any four years in U.S. history,” Lubchenco recalls, including Hurricane Sandy. There was also the so-called “Climategate” email scandal and, most disastrously, the Deepwater Horizon oil platform blowout in the Gulf of Mexico. All of these disasters were fanned by a “dysfunctional, hyper-partisan, legislation-light Congress,” she says. “It was really intense and really hard but I’m very proud of everything we got done,” Lubchenco declares.

 

Lubchenco will bring her call for public engagement of scientists to ASCB 2015. Science has never been more powerful while the nature of evidence-based decision-making has never been so little understood or willfully ignored, she contends. And it’s not just climate change. Biologists have their own painful public issues—vaccination, stem cells or evolution.

 

“And the narrative that’s out there is that science is aloof and impenetrable. Environmental science is all about doom and gloom. Cellular and molecular biology is scary and they (biologists) are playing God. And all that scientists want is more money to do their own thing. That’s the narrative. I believe it’s incumbent on the scientific community to help change that,” she notes.

 

Scientists have to become bilingual, she says, speaking the language of science and the language of lay people; however, “This doesn’t mean that all scientists need to become adept at communicating, but we need the whole community to support those who do. Some scientists may not wish to be more public; others won’t be good at it, but they all need to support their colleagues who are willing and able.”

 

One of the key lessons environmental scientists learned was the need for intellectual backup from other scientists in the field to stand behind their more public colleagues, protecting them from ad hominem attacks, vouching for their professional integrity and validating their science. Lubchenco says. “We need to change the culture of academia so that public engagement and public scholarship are valued, rewarded and supported.”

 

Environmental scientists have also learned the importance of being helpful, not just harbingers of bad news. Lubchenco says, “We also need to focus on solutions, not just problems. We need to provide good news as well as bad. It’s all not hopeless.” That and more will be on Lubchenco’s agenda for ASCB 2015.

 

 

Giving the latest description of her science as “cross-scale systems biology,” Chisholm offers up the example of Prochlorococcus, the marine cyanobacterium she had a hand in discovering in 1985 and which she has been grooming as a laboratory model system and studying as an extraordinarily diverse wild type. “The beauty of Prochlorococcus is that you can study it both in the lab and in the wild,” Chisholm believes. “You always know where you can find it, find it in great numbers and find examples of its extraordinary diversity. This makes it possible not only to understand its machinery—how the cell works— but also the planetary forces that shaped that machinery and all of its variants over evolutionary time.”

 

With Prochlorococcus, she says, “You can study the organism on all scales from the genome or the transcriptome up to the global biosphere. My hope is that it will serve as a model in all facets of an organism—its evolution, its physiology, its ecology and then its genomic and molecular biology.”

 

Out at sea on an oceanographic survey vessel, Chisholm and her former postdoc, Rob Olson, were actually studying another larger (1.5μ /microns) cyanobacterium, Synechococcus, which fluoresces an unmistakable orange. But on one cruise Olson noticed red flashes from something even smaller—under 0.8μ /microns. “It’s barely visible through normal light microcopy and even with epifluorescence or phase contrast, you won’t see it unless you know what you’re looking for,” says Chisholm. “If people saw it before, they just thought it was busted up cells.”

 

It slowly dawned on Chisholm and Olson that the red flashes that kept popping up were not broken bits of something else but a free-living single-cell organism. Going back through the literature, Chisholm realized, “It turns out that it had been discovered two times; once an electron micrograph of it was dismissed as a Synechococcus variant, and another time its tell-tale pigments were thought to be degradation products in seawater. Looking backward and putting all these pieces together, we were able to say this is a different beast.”

 

And there were a lot of them. Prochlorococcus is so far the most abundant photosynthetic organism on earth. While Prochloroccus is commonly referred to as a species, its genetic diversity upends classic taxonomic definitions. In a recent paper in Science, the Chisholm lab reported on extensive single-cell genomic studies of Prochlorococcus samples that revealed hundreds of genetically stable—and genetically ancient—subpopulations co-existing within meters of each other, if not within the same drop of seawater. “It changes the way you think about what’s an organism,” says Chisholm. “Prochlorococcus would have been considered a separate species by traditional microbial standards, and yet it embodies enormous genetic and physiological diversity.” So what is a floating mid-ocean Prochlorococcus bloom? “I’d call it a collective or a federation,” Chisholm says.

 

Living largely in the nutrient-poor tropical and sub-tropical open ocean waters, at different depths and different light levels, these subpopulations appear to stabilize the total population by containing strains adapted to varied conditions. Still Prochlorococcus raises questions, in Chisholm’s mind, about the Darwinian concept of competition as a driver of evolution. “The more we study it, the more I let go of the word, competition. I’m not saying that the Darwinian framework is wrong but is competition really driving and shaping the system? This seems to say that there’s much more to it.” Yet Chisholm shrugs off any notion of a new grand synthesis on her part based on Prochlorococcus. “I don’t have a formal theory for the way we’re thinking about it. We just keep studying it. We leave it to others to use our observations about Prochlorococcus to support the growing belief that nature operates as a finely tuned co-evolved collective, rather than a tooth-and-claw world in which only the ‘fittest’ survive.”

 

Chisholm does have ambitions for Prochlorococcus. She believes that Prochlorococcus could become a gold-standard organism for ecology and evolution in general. “Just as studies of E. coli revolutionized molecular biology, studies of Prochlorococcus—in all its dimensions— could change the way we think about the forces that shape the broader dimensions of life on earth,” she says.

 

It’s not an easy organism to culture but the Chisholm lab has developed reliable protocols, keeping clonal strains going for decades at MIT. “It’s a temperamental bug and it’s not fully tamed,” she admits. It doesn’t like being isolated in pure cultures because it has evolved to rely on “co-bacteria,” separate species that are fulfilling certain functions that Prochlorococcus doesn’t do well for itself. Defining these relationships is difficult, she says. It’s not an obligate relationship because Prochlorococcus survives in pure culture. Nor is the relationship symbiotic or parasitic. Mutualistic is the closest term but Chisholm is not happy with that term either.

 

 

 

The title of the upcoming Symposium at ASCB 2015 is okay, says Jennifer Doudna. A Howard Hughes Medical Institute (HHMI) investigator and a professor of biochemistry, biophysics, and structural biology at the University of California, Berkeley, Doudna is, most prominently, a key player in the discovery and development of CRISPR Cas9, the hottest new gene editing technique in cell biology today. “Bending Nature to Our Purposes” will be the sign at the symposium door in San Diego on December 15, but Doudna says that she thinks of her work less as “bending nature” and more as “learning from nature” what is possible. “It’s trying to figure out how Nature does things and every now and then realizing that I might harness this for another purpose,” she says.

Doudna will be joined at the podium in San Diego by two noted biology repurposers: Angela Belcher, a biomaterials engineer at MIT, whose lab has demonstrated, among other things, how viruses can be used to improve the efficiency of lithium-ion batteries, and Kristi Anseth, University of Colorado, Boulder, and HHMI, whose lab is developing biomaterial scaffolds for multiple purposes including assembly in situ of “cell carriers” by polymerization inside patients.

 

CRISPR/Cas9, though, is the biotechnology of the hour, and Doudna has reached that rare status in cell science—she is becoming well known outside cell science. The news media have come calling. Last year, Doudna and her early collaborator Emmanuelle Charpentier, now at the Helmholtz Center for Infection Research in Germany, each won a $3-million Breakthrough Prize in Life Sciences. Doudna reports that there is already a tremendous amount of curiosity about CRISPR/Cas9 among the general public. Does the public get it?

 

“Mostly they don’t,” she laughs. “I’d love to change that. People are fascinated with this idea. I do think that scientists have to explain technology well enough so that society can make informed decisions.”

 

Doudna says she’s also been struck by the number of people who have contacted her from the “creative” community—writers, artists, screenwriters and television producers. “I got invited to speak at the Science Fiction Writers of America meeting. Unfortunately I couldn’t do it but CRISPR seems to inspire people well beyond the scientific community.” The fascination is not about her personally, Doudna says, but about how a discovery like CRISPR can change societal thinking. “More broadly, it makes people think about what’s possible and about how we as humans can employ this kind of technology to do things that were not even thinkable in the recent past.”

 

Doudna says that CRISPR demonstrates both the value and the unpredictability of basic research. CRISPR began for Doudna with a request from a Berkeley colleague, geomicrobiologist Jill Banfield, to sequence a bacterium sampled from the highly acidic wastewater of a mine in northern California. Recently Doudna told Andrew Pollack of the New York Times, “I remember thinking this is probably the most obscure thing I ever worked on.” Genomic sequencing revealed “clustered regularly interspaced short palindromic repeats” or CRISPR, that turned out to be a fundamental bacterial mechanism for tailoring innate immunity to counter viral intruders. Working with Charpentier, Doudna harnessed CRISPR to a gene now called Cas9 to come up with an amazingly accurate way for scientists to edit genomes.

 

Confronted with her “obscure” quote, Doudna explains, “I guess my point there is that for all of us in science who are doing basic research, we don’t set out with a practical goal in mind beyond the goal of understanding how things work. That was certainly true here. For me and for my lab, the idea of working on a bacterial immune system and studying how bacteria deal with viral infection was a fun, fascinating project that I certainly never anticipated would lead to something like this.”

 

Doudna continues, “But that’s such an important thing for people, particularly for non-scientists, to appreciate. That’s the nature of science. It’s about looking under the proverbial rocks and every now and then you find something. By just paying attention, you’ve found something that has broader implications.”

 

It’s a message she intends to stress at ASCB 2015. “This to me underscores the importance of funding basic research. For ASCB, this is preaching to the choir but it’s such an important message for all scientists to put across to the outside world. I don’t think anybody at ASCB would argue with the value of funding basic research. This is clearly an organization that is front and center in that.”

 

In San Diego, Doudna may also touch on the unintended consequences of CRISPR, including the possibility of its premature and, in her opinion, dangerous use at this time in human genetic engineering. “I’m trying to lead a conversation about the responsible use of this technology. I certainly don’t advocate anything that inhibits legitimate research,” says Doudna. Still, she believes that the basic science of CRISPR is not ready for clinical applications, particularly for any use on human germ line cells where changes would be inheritable. “Especially if you’re talking about making changes in the (human) germ line, changes that can be passed on to subsequent generations,” says Doudna, “that is a profound thing and something we need to study.”

 

Doudna is not against the eventual clinical development and commercialization of CRISPR/Cas9. The reality is that funding for basic research is likely to remain problematic for the short and long term, Doudna believes. “We, as scientists, have to do a better job at thinking creatively about ways to fund research. We need a better model for cooperating with drug, technology or commercial developers.”

 

Over the years, Doudna says, “I have had productive collaborations with big companies and small ones. When you get it right, it’s really fun and exciting. I’ve learned more from some of these collaborations than from anything else. The problem is, how to do it. Sometimes we in academia get distracted. We need to bring our expertise to bear on real-world problems. In many of these diseases, people are suffering and we need to solve this.”

 

Doudna notes that her sudden fame has been anything but sudden. She has run her own lab for 25 years, she says, and there were times when things were not turning out as expected and the next step was not obvious. “I always say that you have to take the long view. This is not a sprint. It’s a marathon. Somehow I’ve always kept going by thinking that there’s something around the corner that’s going to be interesting. So far, that’s worked for me,” says Doudna.

 

---

Recognizing that modern research in cell biology relies increasingly on quantitative analysis of large data sets, ASCB wants to give meeting attendees (particularly graduate students and postdoctoral fellows) direct and useful exposure to these important topics. Each workshop, offering practical skills training to analyze large data sets, will begin with a one-hour introduction to the topic open to all attendees, followed by a hands-on, two-and-half-hour workshop (preregistration is required for the hands-on portion).

 

Presenters: Manuel Garber and Alper Kucukural, UMass Medical School

Sunday, Dec. 13

3 p.m.-6:30 p.m.

 

Presenters: John Albeck and Michael Pargett, University of California, Davis

Monday, Dec. 14

3 p.m.-6:30 p.m.

 

Presenters: Mark Bray and Anne Carpenter, Broad Institute of Harvard and MIT

Tuesday, Dec. 15

3 p.m.-6:30 p.m.

 

Presenters: Manuel Garber and Alper Kucukural, UMass Medical School

Sunday, Dec. 13

3 p.m.-6:30 p.m.

 

Fifteen member-organized special interest subgroup sessions will be presented on Saturday, Dec. 12, from 1 p.m. to 5 p.m. One subgroup will be presented on Tuesday, Dec. 15, from 3 p.m.-6:30 p.m., having been promoted to a minisymposium time slot. That would be Subgroup P: The Cellular and Molecular Basis of Invasive Metastatic Cancer (Room 32B), with organizers Mark A. McNiven of the Mayo Clinic; Laura M. Machesky of the Beatson Institute, Cancer Research UK; and Alissa M. Weaver of Vanderbilt University.