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Cryogenic Electron Microscopy: A Leap Forward for UC Davis
Photo originally published in Structural Studies of the Giant Mimivirus. PLoS Biol 7(4): e1000092. doi:10.1371/journal.pbio.1000092. License: CC BY 2.5.
By Nathan Levinzon, Neurobiology, Physiology, and Behavior ‘23
Author’s Note: The purpose of this article is to inform the UC Davis community about the arrival and use of a groundbreaking technology to campus. I hope to have provided a comprehensive introduction to Cryo-EM, information on Cryo-EM at UC Davis, and an example of how the technology is already being used to solve problems in biology on campus. I also aim to share my excitement regarding this technology in the hope that I inspire others to pursue this interesting and advancing field of study.
Cryo-electron microscopy, often abbreviated as “Cryo-EM,” is a version of microscopy that uses beams of electrons instead of light to illuminate cryogenically frozen samples. Because the wavelength of an electron is much shorter than the wavelength of light, samples can be imaged at mind-boggling resolutions. After the sample is captured in many orientations, the images are compiled in software to finally resolve a three-dimensional image. “If you want to imagine what it’s like to use this technology,” UC Davis Professor Jawdat Al-Bassam explains in an interview for the College of Biological Sciences, “think about walking into a museum, looking at a statue, taking pictures of it, and figuring out how to put those pictures together to get a three-dimensional picture. In essence, that’s what we do with molecules. They are like small molecular statues, and we take images of them at a variety of angles and orientations. We combine these images to get a design plan for how these molecules are put together ” [1].
As a result of recent advances in technology and software, the progress in the resolution of Cryo-EM seems limitless. New microscopes on the market have brought the lowest resolution down to about two angstroms—twice the diameter of a hydrogen atom—with even higher resolutions yet to come. Before 2010, scientists could achieve maximum resolutions of about four angstroms. This incredible and exciting variant of microscopy stands to shape the future of biological sciences. Dean of Biological Sciences Mark Winey says that “Cryo-EM is certainly part of the portfolio of technology that any campus like UC Davis should have,” and it’s easy to see why [1].
One of the most advanced Cryo-EM microscopes on the market today is the newly released Glacios Cryo-Transmission Electron Microscope (TEM) by Thermo-Fisher. On the surface, the Glacios functions like any other TEM: A cryogenically frozen sample is prepared and shot with electrons that hit a camera in order to resolve a high-resolution, black and white image. What makes this microscope different, however, is its groundbreaking camera. The camera has a pixel size slightly smaller than the area that electrons interact with, which enables a high-speed electron detector to find the center of electron events with sub-pixel precision. The end result is a fourfold increase in resolution from older TEMs while simultaneously reducing aliasing, a sampling error caused by electron interference.
With this microscope, researchers can examine life at the molecular level better than ever before. The closed-system design of the microscope ensures a safe and robust pathway through every step of microscopy, from sample preparation and optimization to image acquisition and data processing of up to twelve samples [2]. Its massive throughput is as impressive as its small footprint, allowing for it to be installed in labs with pre-existing infrastructure. Autonomous sample loading and lense alignment have made Cryo-EM faster and easier for both the budding and seasoned scientist.
UC Davis has recently made a large investment of its own in Cryo-EM. On January 31, 2020, the College of Biological Sciences celebrated the ribbon-cutting for their own ThermoFisher Scientific Glacios Cryo-Transmission Electron Microscope, outfitted with a Gatan K3 direct detector camera. Festivities were short-lived, however, because labs were already in line to use this new machine. Researchers at Professor Al-Bassam’s lab were some of the first to use this microscope while studying kinesin, a motor protein found in eukaryotic cells. By utilizing Cryo-EM to resolve the structure of kinesin, they concluded that kinesin’s tails open a part of the motor that encapsulates ATP, slowing the movement of these motors and allowing kinesin to cluster and work together. With this new microscope in hand, these researchers are now able to unravel the functions of kinesin and how it interacts with other kinesin to move and group. The complete paper discussing the binding between kinesin tail and motor domains and its function in microtubule sliding can be found in the January 2020 edition of eLife [3].
Cryo-EM has never been easier, safer, and more accessible to use UC Davis. With the purchase of the Glacios, UC Davis has made itself ready to introduce a new generation of researchers to the field of modern biology. Resolutions that were thought impossible ten years ago are now a reality, and new advancements continue to push the bounds at which samples can be imaged at. With the quickening pace of advancements in Cryo-EM, there is no telling what mysteries researchers at UC Davis will uncover next.
References
- Slipher, David, et al. “CRYO EM: Unleashing the Future of Biology at UC Davis.” UC Davis College of Biological Sciences, 31 Jan. 2020, biology.ucdavis.edu/cryo-em. Accessed 23 Mar. 2020.
- “Cryo TEM: Cryo-EM.” Thermo Fisher Scientific – US, www.thermofisher.com/us/en/home/electron-microscopy/products/transmission-electron-microscopes/glacios-cryo-tem.html.
- Bodrug, Tatyana, et al. “The Kinesin-5 Tail Domain Directly Modulates the Mechanochemical Cycle of the Motor Domain for Anti-Parallel Microtubule Sliding.” ELife, vol. 9, 2020, doi:10.7554/elife.51131.
Merging Amputees with their Prostheses
By Brooke B., Computer Science/Design ’22
Author’s Note: As a computer science major, I have always been interested in the concept of an algorithm that can communicate with the brain through manufactured nerve signals. I read about this research in the news and I thought it was a great example of the marriage of biology and computer science, as well as how the two together can improve lives. I wrote this news article in hopes to reach more of the general public to shed light on the strides we’re making in prosthetic technology.
New research was published early October 2019 in Science Translational Medicine with the first prosthesis augmented by sensory feedback for above-the-knee amputees.¹ The findings have helped amputees achieve greater control over their prosthetic limbs. One participant in the clinical study reported feeling as if their prosthesis was their real leg again: “After all of these years, I could feel my leg and foot again, as if it were my own leg,” Djurica Resanovic said, “You don’t need to look at where your leg is to avoid falling.”
Swiss companies ETH Zurich and SensArs Neuroprosthetics developed the sensory feedback technology to improve prosthetic devices. Seven sensors detect signals along the foot of the artificial leg prototype, and one sensor detects the angle of flexion from the knee. These communicate via Bluetooth to an electric conductor, called an electrode, surgically implanted into the stump’s tibial nerve. Co-author of the publication and SensArs Neuroprosthetics co-founder Silvestro Micera has found the approach of piercing an electrode through the nerve rather than wrapping around it to be efficient in other studies performed for bionic hands. The sensors on the limb receive spatial information when moved, which are translated into biosignals by the team’s new algorithm. The electrode implanted to the neuron receives the signals and sends the information through the nervous system to be received at the brain for processing. The better integration of the prosthesis to the body depends on the accuracy of these electrical signals, and how closely they resemble those a real leg would have produced.
Three amputees participated in a clinical trial over a period of three months to test the new technology. “We showed that less mental effort is needed to control the bionic leg because the amputee feels as though their prosthetic limb belongs to their own body,” explained Stanisa Raspopovic, an ETH professor who led the study. “…the feedback is crucial for relieving the mental burden of wearing a prosthetic limb which, in turn, leads to improved performance and ease of use.”
Even blindfolded and wearing earplugs, participants were able to feel their prosthetic prototype. With the improved awareness of the limb in space, navigating through obstacles required less effort and as a result, subjects fell less. With no stimulation in the limb, the average ratio of falls to obstacles was 39 percent, as opposed to the ratio of eight percent with the stimulated prosthesis. On a test with stairs where subjects were tasked with completing laps, the average amount completed with the new technology was 2.28, as opposed to an average of 1.67 laps without it. Additionally, the brain appeared to be less burdened by the prosthesis, exhibiting lower amplitudes in acoustic event-related potentials tests.² These tests pick up small voltages the brain gives off in response to stimuli, thus a lower reading would indicate less mental stimulation involved in maneuvering with the prosthesis.³ Consequently, more focus can be devoted towards other tasks within the amputee’s life.
Silvestro Micera believes the intraneural electrodes implemented in this research hold vast prospects in neuroprosthetic applications. “We believe [they] are key for delivering bio-compatible information to the nervous system… Translation to the market is just around the corner.”
References
- Ecole Polytechnique Fédérale de Lausanne. “Amputees merge with their bionic leg.” ScienceDaily. ScienceDaily, 2 October 2019. <www.sciencedaily.com/releases/2019/10/191002144243.htm>.
- Francesco Maria Petrini, Giacomo Valle, Marko Bumbasirevic, Federica Barberi, Dario Bortolotti, Paul Cvancara, Arthur Hiairrassary, Pavle Mijovic, Atli Örn Sverrisson, Alessandra Pedrocchi, Jean-Louis Divoux, Igor Popovic, Knut Lechler, Bogdan Mijovic, David Guiraud, Thomas Stieglitz, Asgeir Alexandersson, Silvestro Micera, Aleksandar Lesic and Stanisa Raspopovic. Enhancing functional abilities and cognitive integration of the lower limb prosthesis. Science Translational Medicine, 2019 DOI: 10.1126/scitranslmed.aav8939
- Sur, S., & Sinha, V. K. (2009). Event-related potential: An overview. Industrial psychiatry journal, 18(1), 70–73. doi:10.4103/0972-6748.57865
Robot-Assisted Surgeries
By Neha Madugala, Cognitive Science, ‘22
Author’s Note:
I came across an article detailing the future of surgery. What initially seems like science fiction may be becoming a reality as more and more surgeries are being administered by robots. Through my research, however, I found that robot-assisted surgeries may have the initial appeal of lowering human error, but there are still various issues that must be resolved before they can fully take over in the surgical room.
Robot-assisted surgeries boast the potential of shorter recovery time, less pain and blood, and fewer scars and infections. They have been on the market for a little less than twenty years, and have been used in cancer procedures for about the past fifteen years. While the FDA has approved these devices for other procedures, robot-assisted surgeries have not officially been approved for cancer treatments. Regardless, surgeons have been and continue to perform robot-assisted surgery for cancer-related procedures due to their benefits and increased efficiency.
Robot-assisted surgeries mainly contrast from traditional surgeries because they can be performed through small cuts in the patient’s body. As a result, they are minimally invasive. There are three robotic arms, allowing for multiple angles for improved accuracy, which perform the incisions. According to The New York Times, the robotic arms are controlled by a computer and software that replicates the operating surgeon’s movements. This occurs as the operating surgeon performs the movements while looking at a magnified and high-definition screen of the surgical site captured by a camera attached to the robot. While the device requires limited retraining for surgeons, as of now, there is only one company actually offering this device. Interestingly, the device requires less precision and attention by the surgeon due to the magnification and the actual incisions being performed by the robot.
In 2000, the FDA approved for one of the first robot-assisted systems to be brought to the market. The system, called the da Vinci Surgical System promised to improve the efficiency and effectiveness of medical surgeries, not just cancer-related surgeries. In order to bring the system to the market quickly, the robotic surgery system went through “premarket notification,” allowing the company to skip the rigorous safety and efficacy trials. Essentially, “premarket notification” is supposed to ensure that a device is safe and this notation helps quicken a device’s journey to the market. The FDA said that this decision was based only on short-term data and a spokesperson stated that the decision was made “based on evaluation of the device as a surgical tool and did not include evaluation of outcomes related to the treatment of cancer.” The device promises more successful surgeries with limited retraining and a smooth transition from a humancentric to robot-assisted surgery. These prospects posed limited risks and the evident benefit of improving the success rate of these surgeries; as a result, the device was approved without a thorough and holistic evaluation.
While this system has only been approved for some urological and gynecological procedures, these devices are used for a vast array of other unapproved procedures. The FDA can assess the safety of these devices for certain procedures, but they cannot prevent these systems from being used in unapproved settings in the medical field. As a result, medical professionals may still use these systems for procedures that have not been approved by the FDA.
At the beginning of March, the FDA released a statement reminding the public that robot-assisted surgeries have not been approved for mastectomy or cancer-related surgeries, two procedures for which the device is frequently used. Dr. Terri Cornelison, who works for the FDA’s Center for Devices and Radiological Health, has stated, “We are warning patients and providers that the use of robotically-assisted surgical devices for any cancer-related surgery has not been granted marketing authorization by the agency. The survival benefits to patients when compared to traditional surgery have not been established.” The FDA has claimed that there is no supporting evidence that robot-assisted surgeries are better than traditional surgeries and they have further claimed that robot-assisted surgeries result in more problems for patients receiving treatment for cervical cancer. Cornelison further states, “We want doctors and patients to be aware of the lack of evidence of safety and effectiveness for these uses so they can make better informed decisions about their cancer treatment and care.”
The FDA cited two studies that warn against the danger of robot-assisted surgery. Both studies were published by the New England Journal of Medicine. Both studies analyzed the difference between robot-assisted and traditional procedures for cervical cancer in women. The first study found that women who received surgery with robotic methods faced four times as many cancer recurrences and six times as many deaths. It should be noted that the procedure – radical hysterectomy – is considered to be a relatively safe procedure when performed correctly that can cure patients of cervical cancer. Furthermore, in the second study, 9.1% of the sample group died after minimally invasive surgeries, or in other words robot-assisted surgeries, and 5.3% died in open surgeries, which involve no robotic mechanisms.
It is not clear why robot-assisted surgeries have had worse results for cervical cancers. Dr. Pedro T. Ramirez, a surgical researcher at the Anderson Cancer Center in Houston, believes that these results may be due to the device or because carbon dioxide, which is used to provide a working and viewing space for the surgeon, may increase the spread of cancer during the procedure.
These findings by the FDA encourage patients to question their medical professionals about what type of procedures they will receive and to know the facts about different methods for surgery. In order to ensure that they receive the best care, it is important that patients have a say in the procedure they will receive by accurately weighing the risks and benefits. While the FDA cannot stop the use of these tools in the medical field, increased interest and probing of the mechanics of these systems are helping raise awareness about what is actually happening in the operation room.
The Effect of Trastuzumab on HER2-Signaling in Breast Cancers to Induce Cardiotoxicity
By Karissa Cruz, B.S. Biochemistry and Molecular Biology, Spring ‘19
Author’s Note: I wrote this piece as part of my UWP 104F assignments and ended up becoming really interested in what I wrote about. I specifically chose this topic because I think breast cancer is a smart, complex disease, and the treatment can change day-to-day. I wanted to shed light on a widely accepted breast cancer treatment that is now under review after discovering that it can cause cardiac dysfunction.
Epigenetic Approach Sheds Light on Potential New Therapeutic Strategy for Alzheimer’s Disease
By Rachel Hull, Biochemistry & Molecular Biology, ’19
Author’s note: I first learned about this news through an article on Big Think that provided few details about the science behind the breakthrough. Reading the original research paper clarified both how this research had been conducted and what was so noteworthy about it. Given the prevalence of Alzheimer’s disease, this new study may yet prove to be instrumental in the disorder’s treatment.
New Drug “Sponge” Absorbs Chemo Side Effects
By Brooke B., Neurology, Physiology, and Behavior, ‘22
Author’s Note: I heard about this device on the news, and I was immediately intrigued by the concept. I decided to research it further, upon which I was surprised how logical and efficient the device worked with such substantial results. I wanted to share what I believe to be a huge breakthrough in cancer research.
Cause of Seizures in Individuals with Angelman Syndrome
By Neha Madugala, Cognitive Science, ‘22
Author’s Note
While browsing recent scientific achievements and breaking news in the scientific community, I came across an article declaring that the 125-year-old neuroscience mystery surrounding perineuronal nets (PNNs) is finally resolved. PNNs have stumped neuroscientists for decades, yet their importance is undeniable. To understand the extent of this discovery, I read more about PNNs and found that they have a key connection to Angelman syndrome, which causes severe epileptic seizures in children. The new findings from the Philpot Lab identifying the purpose of PNNs draw a connection between PNNs and seizures, and this information can lead to improved medications and therapeutic treatment methods.
As Hot as a Davis Summer: A Review and Analysis of Ecstasy-Induced Hyperthermia
By Ruby Nguyen, Music and Neurobiology, Physiology, and Behavior, ‘19
Author’s note: I wrote this literature review for UWP104F, Writing for Health Professions. The assignment was to write a literature review on a health-related topic of our choosing. I decided to write this literature review on ecstasy-induced hyperthermia, the primary cause of death in ecstasy overdoses. I want to inform researchers on potential drug options or treatments that could be further explored for use in treating ecstasy-using patients. I also want to reveal areas for further consideration. My hope is that this literature review will spark greater interest on the topic and guide future research into exploring new treatment options for ecstasy-induced hyperthermia.
RoboBees: The Future of Food and Society?
By Tannavee Kumar, Genetics & Genomics, ’20
Author’s Note
Going into my research on fully automated and autonomous bee swarms, I was aware that there was much controversy on how we as a society should address and work to solve the problem of the drastically declining honeybee population. Upon coming across the large initiative that a team at Harvard University is spearheading, I was interested whether robotic bees are the future of agriculture and moreover part of the tidal wave of automation.