Dan Needleman’s name graces only one door in Harvard’s Northwest science building, but it appears on the websites of no fewer than four different entities within the university: the John A. Paulson School of Engineering and Applied Sciences (SEAS), the Department of Molecular and Cellular Biology (MCB), Biophysics, and the FAS Center for Systems Biology. It should come as no surprise then, that he has recently received tenure as the both Gordon McKay Professor of Applied Physics (SEAS) and Professor of Molecular and Cellular Biology (FAS). “The research my group does is interdisciplinary so, it gets cross-listed everywhere,” says Needleman in his rich baritone, one of his big, easy laughs reaching up to the corners of his blue eyes. The books that line the shelves of his light, airy office are similarly diverse, ranging from population genetics to theoretical physics to calculus. While the topic of each book is confined to the pages between its covers, Needleman set his sights on combining aspects of different scientific fields into a single career years before “interdisciplinary” became a buzzword touted by universities and corporations alike. Relaxed and affable, Needleman seems to have found the serenity that comes from achieving the ideal of finding something you like doing and doing it well, despite the fact that his “something” is a combination of some of the most intellectually challenging subjects around: active matter physics and cell biology.
Needleman credits his parents’ academic mindsets (his father is an engineering professor, his mother was a psychiatrist) with making him “interested in thinking about stuff” during his childhood in Providence, RI. Not exactly sure where to direct that thinking, he wandered through Economics, Chemistry, and Computer Science during his undergraduate years at Brandeis University before finding himself in the lab of physics professor (now emeritus) Bob Meyer. “I really liked the clear way he thought about problems; that really influenced me,” says Needleman. “He approached the challenge of understanding the world by using a combination of theory and quantitative experiments, which I found to be very logical and interesting.” Needleman’s interests were heavily leaning toward biology (he worked on ion channels with Chris Miller and neuroscience with Larry Abbott), but he wanted to use Meyer’s physics-driven approach to analyze and understand biological problems. “I decided to go forward academically with physics and then come back to biology later, because I felt that I had to really learn the principles of physics before I could effectively work at the intersection of those two fields,” he says.
Knowing that several years of physics was in his near future, Needleman took a year off from classes and worked in the lab of Terrence Sejnowski at the Salk Institute for Biological Studies in La Jolla, CA, investigating weakly electric fishes. He entered the University of California, Santa Barbara in 1999 and completed his PhD in Physics with Cyrus Safinya’s group in 2005. “It was a great lab, and I think working with Cyrus really taught how to be a scientist, but I was studying soft condensed matter physics with the motivation of understanding physics, whereas I really wanted to combine that with biology,” Needleman recalls. “There weren’t many labs doing that at the time, so I started looking for a postdoctoral position somewhere where I could have two advisors.” That search led him to Harvard, where he worked jointly in the labs of Tim Mitchison at Harvard Medical School and David Weitz in Applied Physics. But he was soon spending the majority of his time working with Mitchison on a tiny biological structure that would become the cornerstone of his own research: the mitotic spindle.
Unraveling the Spindle’s Mysteries
Spindles are complex structures made of DNA, microtubules, and associated proteins that form in dividing cells and separate the sister chromatids (i.e., matching pairs of duplicate chromosomes) to opposite ends of the cell so that the resulting daughter cells each have the proper number of chromosomes. In addition to being a crucial process for the survival of all eukaryotic organisms (cells with dysfunctional spindles usually die or have severely impaired function), spindles are a prime representation of the topic within biology that has most captivated Needleman since his undergraduate days: biological self-organization, the mechanisms by which simpler biological subunits (e.g., proteins) arrange themselves into more complex structures with their own unique characteristics (e.g., cellular structures like the spindle), seemingly without following any external guidelines or cues. Each microtubule within a spindle is composed of hundreds of subunit proteins that can attach to other proteins on chromosomes or the cellular membrane and “walk” chromatids to opposite sides of the cell. As complex as this orchestration of actions may seem, spindles have it down to, well, a science: they perform their intricate dance of cell division ~10 million times per second in the human body. Elucidating exactly how this happens has been the focus of Needleman’s research as a postdoc (2005-2008), Assistant Professor (2008-2012), Associate Professor (2012-2016) and, now, Tenured Professor. “We are excited that Dan Needleman is a member of the MCB family,” says MCB chair Alex Schier. “He is the poster child for how engineering and physics can inform investigations into fundamental biological questions.”
“One of the biggest differences in approaching molecules in biology versus in physics is that biological molecules aren’t ‘stupid;’ they actually use energy to do things,” says Needleman. Even when structures appear not to be moving, or are in a ‘steady state,’ they’re using energy.” Spindles are considered “non-equilibrium, steady-state” systems – they don’t exist in equilibrium because the molecules that make up a spindle are constantly using energy, but they’re steady-state because their overall structure can remain unchanged for hours. “The standard framework that physicists typically use for understanding matter doesn’t apply to these types of systems, because these molecules are active rather than passive; there’s a constant exchange of energy in the form of ATP and GTP hydrolysis. So, my group, and many others, are trying to develop a new framework that takes into account the energy flow inherent in biological systems to determine and predict the collective behavior of active molecules.” Small wonder, then, that his research spans so many different fields.
To achieve this ambitious goal, the eleven-person Needleman lab follows an approach that pays homage to Needleman’s original inspiration, Bob Meyer at Brandeis, using a close interplay of quantitative experiments and theory to study how spindles assemble, position themselves, and segregate chromosomes in a variety of organisms [C. elegans (nematode) embryos, Xenopus frog egg extracts, mouse oocytes and embryos, human tissue culture cells and oocytes], and they are developing new methods to produce the data they need if existing methods are insufficient. His group has developed a technique they call “a massively parallel form of fluorescence correlation spectroscopy” which, unlike standard fluorescence fluctuation spectroscopy (used to evaluate molecules at one discrete point at one precise moment in time), allows them to evaluate the movement of soluble molecules at hundreds of different points simultaneously – a crucial ability when trying to study spatial organization. They use this and other tools to explore several different facets of spindles, including how microtubules interact with each other, attach to chromosomes, and how spindles vary across individuals and different species (some organisms’ spindles have ten microtubules, while others’ have over a hundred thousand).
The implications of Needleman’s research reach beyond the satisfaction of being able to describe biological phenomena with physical processes: in addition to elucidating how spindles are structured and assemble, the group is applying their work to help solve a very real human health problem: infertility. Needleman says, “A significant portion of spontaneously aborted embryos have severe errors in chromosome segregation during mitosis and meiosis. It’s not clear what causes these errors, but some people think they could be due to mitochondria ‘going bad,’ which deprives spindles of the energy they need to function correctly, leading to improper cell division.” One of his lab’s projects is focused on improving in vitro fertilization (IVF) success rates (currently ~30%) by developing a way to noninvasively measure the mitochondrial function of egg cells, which could offer an effective technique to separate “good” eggs from “bad” ones and minimize the heavy financial, physical, and emotional burden carried by infertile people who want children.
A Gentleman and a Scholar
Upon his achievement of tenure, Needleman is most excited about the potential for more synergy between traditionally distinct disciplines to enhance humanity’s understanding of the complex processes that underlie our very existence. “We are trying to better understand the physics of active matter, use such approaches from physics to learn how biological processes work, how and why they vary across species and individuals, and how and why their breakdown can cause disease. It’s really a combination of physics, evolutionary biology, and medical science, all applied to cellular biology,” he says simply, as if mixing those fields together to form a career were as easy as pouring ingredients into a blender and pressing “On.” In reality, it takes time, intensive study, and deep thinking to put such disparate elements together in a way that produces meaningful results, just like making a great soufflé requires much more than the presence of butter, flour, and eggs. The difficulty of that feat is perhaps best understood and appreciated by the students and postdocs in his lab, nearly all of whose pre-graduate training was in Physics. “A lot of physicists who transition to biology don’t really recognize or understand all the work that’s been done previously in that field; they come up with a problem that they think is cool and work on it, but it isn’t really relevant or helpful for biology as a whole,” says Bryan Kaye, a fifth-year graduate student. “The questions that Dan asks are often, fundamentally, molecular cell biology questions. His fearlessness in jumping into a completely new field and learning it from the ground up has really inspired and helped me in my own work, because as a physicist I hadn’t even touched a pipet until I got to Dan’s lab.”
It would be easy for a lab full of physicists learning how to do cell biology to become a stressful work environment, as Needleman’s scientific standards are very high. “He’ll never accept ‘Because somebody said it’ or ‘Because it was in a paper’ as evidence that an idea is correct. You have to support any statement with the logic and research on which your assumptions are based,” says Kaye. But if his expectations of intellectual work are exacting and rigid, Needleman himself is quite the opposite, his students affectionately referring to him as “The Dude” from The Big Lebowski for his relaxed and friendly demeanor (and long, blond hair). “He’s just the nicest guy, super laid back and friendly, and that was one of the major reasons I came to Harvard,” says Kaye. “Even though first-year students are expected to rotate through a few labs, the three of us who joined in 2011 stayed because we liked working with Dan so much. He’s always present but doesn’t micromanage, and asks questions like ‘Well, couldn’t you think about it this way?’ instead of chastising us when we’re wrong.”
Needleman also has his students’ best interests at heart, despite the research and publication pressures inherent to academic labs. “Professors at some universities just push their lab members to churn out as much research and as many papers they can, without really caring about their students’ careers” explains Kaye. “The best thing about working with Dan is that he gives us the luxury of taking the time to do really good work, even if that means taking a class we’re interested in at the expense of some research hours. Being treated well is my biggest motivator, because I want to give back to someone who has invested so much time and energy into my own well-being.” Tae Yeon Yoo, another fifth-year student in the lab, agrees: “Dan never pushes us to work too hard, but his excitement about our work always motivates us to get new data. He is very open-minded and supportive, and will often talk to lab members for hours about their own research. Thanks to conversations with Dan, I’ve decided to continue my career in quantitative biology research.”
Blazing new trails across challenging, disparate disciplines and ensuring the success of the next generation of physics-turned-biologists while maintaining a reputation as a genuinely great person is a tall order, but Dan Needleman continues to deliver. “Dan’s laid-back attitude and genuine passion for science set the tone for the lab,” says Peter Foster, the third of the trifecta of grad students who joined the lab in 2011. “He focuses on doing good science, and lets the rest follow. It’s all about asking the right underlying question, and taking whatever approach is necessary to answer it.” In the case of Needleman’s research, that approach requires a level of ingenuity and outside-the-box thinking that is perfectly suited to SEAS, which itself eschews traditional academic departments and encourages the cross-pollination of ideas. “Dan embodies the true spirit and power of Harvard Engineering and Applied Sciences – his work spans Molecular Biology, Applied Physics, Physics, and Applied Mathematics,” says SEAS dean Frank Doyle. “It defies classification into any traditional ‘silo,’ but rather is truly multi-disciplinary and, as a result, truly powerful.”
Author: Lindsay Brownell