Multi-institutional collaboration brings advanced microscopy training to scientists in Africa

The African continent carries the highest disease burden in the world, disproportionately affected by HIV, malaria, and Ebola, among other diseases. Modern scientific techniques hold a lot of promise for developing new medicines and vaccines, and African scientists have made major contributions to infectious disease research, genomics, and public health. Access to some advanced technologies, such as cryogenic electron microscopy, or cryo-EM, remains limited, so researchers often rely on international collaborations to perform projects abroad. And some diseases are never studied at all because their impact and sometimes even their names, like schistosomiasis, are far from the minds of the researchers deciding which scientific questions to answer.

“There are a lot of neglected diseases that are a huge burden to Africa, some of which many people have never even heard of,” said Emmanuel Nji, CEO of BioStruct-Africa.  The grassroots nonprofit organization works to build and sustain infrastructure and an expert scientific workforce in Africa, creating a network of researchers and expanding access to structural biology, the study of the three-dimensional architectures of biological molecules like proteins and DNA. “We need to start addressing these questions in African facilities,” said Nji. It has to be fair.”

A new collaboration between Stanford University, Belmont University, and BioStruct-Africa will help train African scientists in cryo-EM, an advanced technique that allows scientists to better understand disease and design new therapeutics and vaccines. The two-year program, which is funded by the Gates Foundation, will include hands-on workshops for scientists to learn how to prepare samples for analysis, use the cryo-EM, and interpret data. It will also include immersive training in the lab of Christopher Barnes, assistant professor of biology in the School of Humanities and Sciences (H&S) and institute scholar of Sarafan ChEM-H at Stanford University. The researchers embedded in his lab will use cryo-EM to investigate HIV and schistosomiasis, a disease caused by parasitic worms present in contaminated water.

“The people who go through this program are going to learn techniques and generate knowledge, and then return to their home institutions and train others in those techniques. Our goal isn’t simply to train individual scientists, but to empower and invest in future leaders who will establish a sustainable cryo-EM community across Africa,” said Barnes, who is leading this program along with Nji and Jamaine Davis, associate professor of biochemistry and assistant dean, Scholarly Productivity & Innovation, Thomas F. Frist, Jr. College of Medicine at Belmont University.

“Cryo-EM has revolutionized our ability to look at proteins and understand biology, already leading to new discoveries and new therapeutics,” said Carolyn Bertozzi, the Anne T. and Robert M. Bass Professor in H&S and the Baker Family Director of Sarafan ChEM-H. “I am delighted that Sarafan ChEM-H can play a role in expanding cryo-EM training and research in Africa and grateful for Christopher’s brilliant leadership.”

Painting protein pictures with cryo-EM

Viruses and other pathogens have surfaces studded with proteins. Some of these proteins, known as antigens, are uniquely identified by the immune system; antibodies, a class of proteins themselves, stick to these antigens and start a cascade of actions that leads to the immune system neutralizing the invader. Understanding antigens, antibodies, and other proteins is key to preventing and treating infections.

Structural biology is particularly effective in infectious disease research. By charting the hills and valleys on a protein’s surface, scientists can design better vaccines and antiviral medicines.

One of the most powerful methods for determining the structure of proteins is cryo-EM. In their natural state, proteins are dynamic. They roll, bend, and stretch, opening and closing as they work. To prepare a sample for cryo-EM, a protein tumbling through a liquid is flash-frozen at super cold temperatures and then analyzed using a high-resolution microscope. One sample might contain hundreds to millions of individual protein molecules, each captured mid-motion. Each frozen protein molecule represents a single snapshot in time. By combining these snapshots, scientists can build detailed three-dimensional structures and sometimes reveal the different shapes proteins adopt as they carry out their functions.

Cryo-EM is a powerful method. It is also expensive. So expensive, in fact, that historically, African researchers seeking cryo-EM studies have relied on international facilities, making access to the technology limited.

“You don’t ever want a technology that is inaccessible to a huge swath of the world,” said Barnes.

Cryo-EM camp

To help overcome the access limitations that have historically slowed researchers’ cryo-EM studies on the continent, there is broad interest in establishing more cryo-EM instruments in Africa in the future. Barnes, Nji, and Davis developed this multi-institution program, which is funded by the Gates Foundation, to help ensure that African scientists are trained in cryo-EM techniques.

Through the program, 10-15 scholars will attend three week-long intensive bootcamps, each designed to give scientists a crash course in a key step in cryo-EM research: from making and purifying a protein, to preparing the sample for the microscope, to analyzing the data. A smaller group of 3-5 scientists will come to Stanford to learn from and work alongside Barnes and the members of his group for eight weeks. During the program, participants will work to determine the structures of proteins that are important in HIV and schistosomiasis. Equipped with the skills they learned, the researchers will be able to tackle a variety of other diseases.

“We need the stakeholders who are most impacted by these diseases to come to the table. More diverse perspectives and the commitment from those affected are going to make the biggest impact,” said Davis. “Building capacity while also working to eradicate these diseases is a win-win situation.”

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Barnes is also an assistant professor, by courtesy, of structural biology and a member of Stanford Bio-X. Bertozzi is also a professor of chemistry and, by courtesy, of chemical and systems biology, a member of Stanford Bio-X, the Wu Tsai Human Performance Alliance, the Maternal & Child Health Research Institute, the Stanford Cancer Institute, and the Wu Tsai Neurosciences Institute, and a Howard Hughes Medical Institute investigator.