Van Andel Institute Trains Next Generation of Cryo-EM Structural Biologists

September 20, 2018 § 2 Comments

By George Van Den Driessche

Cryo-electron microscopy, or cryo-EM, is structural biology’s golden ticket these days. Since the game-changing technology won the 2017 chemistry Nobel Prize, it feels like there is no problem that cannot be solved by cryo-EM.

Do you have a large protein that won’t crystallize? Are you studying transporter channels or membrane signaling proteins and have no idea what the protein looks like?  Or are you designing new antiviral agents and need the viral capsid structure? Then, at least the current trend suggests, you should consider using cryo-EM, a technique that flash freezes proteins in liquid nitrogen and analyzes electron diffraction patterns to determine the molecular structure of proteins.

The Van Andel Institute, a nonprofit biomedical research facility in Grand Rapids, Michigan, invested more than $10 million dollars to install the David Van Andel Advanced Cryo-EM Suite in 2016. Last year, VAI celebrated the opening of its new facility with a conference about cryo-EM’s advancement of structural biology. This year, VAI hosted a special cryo-EM training workshop for graduate students, postdocs and new faculty. (Full disclosure: VAI awarded travel scholarships to workshop attendees, and I was one of them.)

Attendees at the Van Andel Research Institute’s cryo-EM training workshop this summer.
Van Andel Research Institute

Huilin Li, the VAI cryo-EM core director, designed the workshop so attendees could learn about cryo-EM theory and research advances on the first day and then spend the remaining time working with the microscopes, discussing protein-preparation techniques and reviewing image processing software. “This is a privately endowed research institute. We do research, collaboration, outreach and training. This workshop is part of the training,” Li said.

VAI assistant professor Juan Du, one of the presenters, studies TRPM4 channel proteins. TRPM4 is a calcium-activated nonselective (CAN) cation channel that monitors cellular charge by measuring calcium ion concentration. When the cell’s charge becomes too positive, calcium ions bind to TRPM4, and single-charged cations, such as sodium or potassium ions, flow through the channel. This process decreases the cell’s overall positive charge.

Du’s team determined the structure of TRPM4 and identified key calcium and modulator binding sites using single-particle cryo-EM. Their work appears in Nature. She advised attendees, “We are structural biologists, so we use all kinds of tools to solve problems, and very soon cryo-EM will be equal to X-ray crystallography, and, when that day comes, success will depend on who has a sample in hand. So, remember that biochemistry is the key to success.”

Keynote speaker Steve Ludtke, a professor of biochemistry and molecular biology at Baylor College of Medicine, presented his lab’s research streamlining cryo-electron tomography (cryo-ET) image annotation.

Cryo-ET allows researchers to see the dynamic interactions of frozen macromolecules and offers insight into the native environments of cells. Traditional cryo-EM requires protein purification, and this raises the possibility of disrupting a protein from its natural orientation.

Preparing grids for Titan Krios microscope: (left) loading grids prepared in liquid nitrogen, (top right) an unprepared grid, and (bottom right) the microscope
George Van Den Driessche

However, a major hurdle facing cryo-ET is the time required for image annotation. Image annotation is a task where scientists identify all the individual macromolecules by hand in a series images. A fully annotated cryo-ET image takes about a week to complete.

Ludkte is training deep learning models to overcome the image annotation time barrier. These models are capable of learning a wide-range of macromolecule features (such as distinguishing double-membrane mitochondria from single-membrane organelles) and require minimal training. Each model needs only 10 human annotated training images before the algorithm can begin recognizing patterns in the cryo-ET image.

Georgia Institute of Technology graduate student Kasahun Neselu said he enjoyed the hands-on training and was leaving feeling excited and filled with ideas to test on his own research projects.

Fatemeh Abbasi Yeganeh, a graduate student at Florida State University, said she enjoyed learning more about cryo-EM, meeting new people who share her passion for structural biology, and gaining confidence in the field.

“Currently, EM is the main focus of my Ph.D. project, and I take any opportunity to learn more and meet new people in the field,” Yeganeh said. “So, what can be better for a graduate student than attending a workshop that pays all your expenses, teaches you about your favorite field of study, and, also, gives you the opportunity to meet and talk to experts in the field?”

Top and side view of the TRPM4 calcium channel
George Van Den Driessche

George Van Den Driessche (gavanden@ncsu.edu) is a graduate research assistant in the Fourches lab at North Carolina State University.

The ‘What is a Germ?’ Challenge

December 7, 2012 § 2 Comments

A guest post by the American Society for Biochemistry and Molecular Biology‘s public outreach coordinator, Geoff Hunt:

Germs are everywhere. In the bathroom. On the subway. All over the kitchen. But what exactly is a germ? How does it make you sick? Is it alive? What does it look like?

Comb through the scientific literature, and you will find thousands of papers that can answer these questions. But those different answers are confusing to the general public.

That’s why ASBMB, in conjunction with the Cambridge Science Festival, is sponsoring the “What is a Germ?” challenge.  We’re looking for the most creative, insightful entries that can answer the simple question: What is a germ?

Here’s a chance for scientists to take their technical knowledge and boil it down to a simple, straightforward explanation, free of jargon, complications and caveats. Scientists can use any format for their responses but should be aware that they will have to impress a panel of tough judges — elementary and middle school students chosen from the Boston area.

Submit your entry today to germchallenge2013@gmail.com! The deadline for submission is Friday, March 1.

For more information, go to www.asbmb.org/germ. Finalists will get to present their entries during the Cambridge Science Festival’s “Curiosity Challenge” on Sunday, April 21.

The value of a Ph.D.

May 3, 2012 § 6 Comments

How long do you need to spend in the company of these to be professionally successful? Image by http://www.flickr.com/photos/codonaug/6464583867/

Do you need a Ph.D.? A Nature article and responses to it have gotten me thinking about the value of a Ph.D. Paula Stephan at Georgia State University wrote a piece in Nature a month ago questioning the economic wisdom of the current Ph.D. training system. In a nutshell, Stephan thinks there are way too many folks with a Ph.D.  She argued, “Research institutes, by producing fewer PhDs, lead to a better balance between supply and the limited number of research jobs. Abstinence, after all, is the most effective form of birth control.” (She does make research institutions sound like puppy mills, doesn’t she?)

Her article understandably provoked some responses. One was from Henrik G. Dohlman at the University of North Carolina, Chapel Hill. He raised the good point that getting a Ph.D. doesn’t mean you must go into the academic career path. There are other careers out there that benefit from the skills and expertise gained in doing science Ph.D.s.

Take my career choice, for example. Science writing has many paths, and one of them is through a Ph.D. program in the sciences and engineering.

I have no regrets in getting my Ph.D. in biochemistry and molecular biology. Yes, it was astoundingly hard work and a long slog with lots of soul searching, but it was an important time of my life. I learned to ask the right questions, find the correct sources of information, and to be persistent until I got an answer that made sense. I realized what a science writer does is what a scientist does but in different spheres — and that my temperament and innate skills are better suited for science writing than for research. My Ph.D. let me land a job right out of graduate school because a magazine was searching for someone with a science background and the zest for science communication.

Dohlman’s response to Stephan’s article could raise a question: How do you know whether or not you need a Ph.D. to be professionally successful? I certainly was clueless how my Ph.D. would be useful when I was starting out in graduate school. I thought it was going to immediately lead me into a top-notch job in industry or academia and perhaps put me in line for the Nobel Prize.

Graduate school quickly cured me of my naïveté. It taught me that scientists don’t live in a rapid succession of “Eureka!” moments. They keeping hacking away at a question or a problem until they have a plausible answer. There are a lot of failures, but the occasional successes are gratifying and sweet.

So I would say Dohlman has a good point. A Ph.D. is useful for more than just launching careers in academic or industry research. It teaches graduate students persistence, hard work, critical thinking and, most importantly, an appreciation of the ebb and flow of research.  If graduate students choose something other than research as a career path, you can  think of them as ambassadors of the scientific research enterprise.

But Stephan’s point is also well worth considering. Times are economically tough, to say the least. It costs money to train Ph.D.s. I sometimes have wondered if I would have been equally successful in life had I done a master’s degree in biochemistry. But I don’t know the answer because I haven’t done the experiment.

So I turn to my readers to ask what are the options for gainful employment these days for graduates with master’s, or even bachelor’s, degrees in the biosciences. In my day, the only feasible career I saw with a bachelor’s degree in biochemistry was to be a laboratory technician, which seemed to have limited professional development. But that was over a decade ago. Do you have a story to share about your professional success withouth a Ph.D.?

Khan Academy takes on biochemistry and molecular biology

March 22, 2012 § Leave a comment

Salman Khan has made a big splash with his take on educating kids. In 2004, he got the idea of using short videos, about 15 minutes long, to teach his then-preteen niece the fundamentals of mathematics. In uploading his videos onto YouTube, Khan (he goes by “Sal”)  discovered that there was a whole world, not just his niece, hungry for the kind of teaching videos he was creating.

Khan’s work has won the backing of Bill Gates, who said he uses Khan’s videos. Khan Academy is a nonprofit organization that Khan has established, and it has received donations from the Bill & Melinda Gates Foundation and won Google’s Project 10 to the 100 of ideas to change the world.

These days, Khan Academy is not just about mathematics. It tackles a broad range of subjects, from art history to . . . you guessed it . . . biochemistry and molecular biology. I counted at least 12 videos on topics that I encountered during undergraduate courses. The videos, all recorded by Khan, cover respiration, glycolysis, photosynthesis, neurotransmission, bits of physiology and some genetics.

The videos are aimed at novices who want to learn the foundations of a subject. Khan starts at the very beginning, describing, for instance, how glucose gets turned into pyruvate during the Krebs Cycle.

Because Khan is writing out his explanations as he speaks, his explanations go at a slow and steady pace, which allows students to take notes (and gives me a flashback to a professor I had as an undergrad who had premade slides and whizzed through the entire chapter on metabolism in 7.5 minutes). And because it’s a video, you can always pause and rewind to to the parts you missed or didn’t quite comprehend.

The Khan Academy last week launched its iPad app so you now don’t have to be tethered to a computer to do your learning.

I think those of you who teach high school or undergraduate courses in molecular biology and biochemistry might find these videos as useful supplements. Let me know how it goes!

Enjoy!

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