The journal Science has selected artificial intelligence algorithms that predict the three-dimensional shapes of proteins — as well as the blizzard of protein structures they have revealed — as their 2021 Breakthrough of the Year. We are honored to have our work in this field recognized alongside that of the company DeepMind. As David Baker told Science, “all areas of computational and molecular biology will be transformed.”
Key to advancing any new scientific discovery is the ability for researchers to independently repeat the experiments that led to it. In science today, particularly biology, the lack of reproducibility between experiments is a major problem that slows scientific progress, wastes resources and time, and erodes the public’s trust in scientific research.
At the University of Washington, researchers have access to the UW Biofabrication Center, or BIOFAB, a unique facility located in the Nanoengineering and Sciences building in which scientific protocols are encoded as computer programs, allowing undergraduate lab technicians to execute experiments according to detailed instructions.
“The BIOFAB is unlike any other lab on campus,” says BIOFAB founder Eric Klavins, Professor and Chair of the UW Electrical and Computer Engineering Department. “In effect, we’ve been able to automate common protocols by using software to assist our student technicians. This ‘human-in-the-loop’ system goes a long way towards improving the replicability of biological research.”
In an effort to expand the lab’s automation capabilities, the BIOFAB has partnered with Agilent Technologies Inc., a life sciences development and manufacturing company based in California’s Silicon Valley. Using state-of-the-art research equipment from Agilent, the BIOFAB will develop high-throughput workflows for common tasks of interest to members of the synthetic biology community.
Programming the biology lab
Computer programmers write code to tell a computer what to do and how to do it. For a given program, the same inputs consistently result in the same outputs.
In contrast, two biology researchers can seemingly carry out the same experiment, but get different results. This is in part because instructions for how the experiment was conducted – whether documented in a lab notebook or published in a journal – are often vague or incomplete, leaving out details that the author may not have realized impacted the experimental outcome.
As a computer scientist turned synthetic biologist, Klavins realized what biologists needed was a more formal way – a programming language – to define how to conduct an experiment. This led to the development of Aquarium, a web-based software application that allows scientists to build executable protocols, design experimental workflows based on those protocols, manage the execution of protocols in the lab and automatically record the resulting data.
“Aquarium provides the means to specify, as precisely as possible, how to obtain a result,” said Klavins.
When it comes to engineering biology – reprogramming cells to produce chemicals or drugs, or perform complex functions like sensing toxic compounds in the environment – reproducibility is paramount. The BIOFAB uses Aquarium to standardize various scientific workflows, generating reliable and highly reproducible results. The BIOFAB is one of a growing number of labs known as biofoundries which are committed to efficiently engineering biological systems and workflows.
BIOFAB operations are overseen by two lab managers, with a dozen or so undergraduate students executing jobs for BIOFAB clients. BIOFAB technicians perform common molecular biology tasks like DNA assembly and purification as a fee-for-service to the scientific community. Since its founding in 2014, the BIOFAB has run over 30,000 jobs for 300+ different clients at the UW and beyond.
“The BIOFAB has been absolutely instrumental in establishing and executing robust Aquarium driven protocols for a major portion of our de novo design minibinder pipeline,” said Lance Stewart, Chief Strategy and Operations Officer at the UW’s Institute for Protein Design (IPD). IPD researchers use computers to design millions of minibinders – small, stable proteins that bind with high affinity to targets of interest – that must be produced and tested in the lab. IPD uses the BIOFAB to screen minibinder candidates for protein stability and protein:protein interactions, which involves constructing yeast libraries from chip synthesized oligonucleotide genes encoding minibinder designs and carrying out large scale fluorescence activated cell sorting and next generation DNA sequencing.
“By handing off time-consuming wet lab work to our technicians, BIOFAB clients like IPD can focus more on the design and data analysis aspects of their experiments,” said Klavins.
Learning by doing
On any given day, the BIOFAB is buzzing with undergraduate technicians working together in harmony to complete an assortment of experiments for BIOFAB clients. Most technicians start working in the BIOFAB as freshman or sophomores, and for many, it’s their first real lab experience.
Upon joining the lab, BIOFAB lab managers teach students basic lab skills, such as pipetting and sterile technique, and orient them to the lab. Armed with this foundational knowledge, BIOFAB technicians can begin executing a variety of different protocols by following the step-by-step instructions provided through Aquarium. Students become adept at performing complicated experimental workflows involving complex equipment through the process of doing them over and over again.
“Aquarium allows us to effectively train many students simultaneously and get them working in the lab relatively quickly,” said Aza Allen, a lab manager at the BIOFAB. “Aquarium’s technician interface makes it easy to get undergraduate students, who do not necessarily know much about molecular biology when they start, to perform experiments reliably.”
“I have learned so much beyond what could possibly be taught in a classroom setting,” said BIOFAB technician Nicole Roullier, a UW biochemistry senior. “Most undergraduates don’t have the opportunity to work with such sophisticated equipment and master advanced techniques like qPCR and next-generation sequencing (NGS). This hands-on training has built up my confidence in the lab in preparation for graduate school.”
A promising partnership
The BIOFAB provides critical automation and analytics infrastructure dedicated to enabling the rapid design, construction and testing of genetically reprogrammed organisms for biotechnology applications and research. Through its partnership with Agilent, the BIOFAB aims to offer new high-throughput capabilities that will further speed up and scale up synthetic biology research.
“We’re thrilled to be partnering with Agilent,” said Klavins. “Their support will not only accelerate the development of innovative technologies, but will help us educate students using cutting-edge equipment, bolstering our ability to prepare students for success in their own future research and career.”
“We think this is the start of an exciting collaboration,” said Kevin Meldrum, General Manager and Vice President of Genomics at Agilent. “We are pleased to be able to support researchers at the UW and the educational mission of the university through the BIOFAB. We see this as an investment in the future of our field.”
As a result of this partnership, the BIOFAB has acquired several valuable pieces of equipment, including Agilent’s state-of-the-art liquid-handling robot, the Bravo Automated Liquid Handling platform. While the Bravo can be used to automate sample preparation for a variety of different applications, the BIOFAB plans to initially use it to expedite its workflow for NGS. In addition to the Bravo, the BIOFAB has also acquired the AriaMx Real-Time PCR System, and the 5200 Fragment Analyzer System, a parallel capillary electrophoresis system.
“Library preparation for high-throughput NGS is a tedious, labor-intensive process,” said Klavins. “Agilent’s Bravo will help make this workflow more efficient and reduce pipetting errors that make results less consistent, while also freeing up time for our technicians to work on less repetitive tasks. We know that there are certainly other workflows that would benefit from the use of Bravo, and we plan to engage BIOFAB users to identify which ones to pursue. We are thrilled to be able to bring this resource to the UW community, and are excited to see the compelling science that comes out as a result.”
This report was written and translated into English by SK bioscience. (Image: SK bioscience)
SK bioscience (CEO Jae-yong Ahn) announced on November 4th that the company has confirmed a positive immune response and safety in the final analysis result of the phase I/II clinical trial of the COVID-19 vaccine candidate, ‘GBP510,’ co-developed with the Institute for Protein Design at the University of Washington in the U.S and adjuvanted with GlaxoSmithKline’s (GSK) pandemic adjuvant system.
SK bioscience enrolled 328 healthy adult participants to conduct the phase I/II clinical trial of GBP510 at 14 clinical institutions including Korea University Guro Hospital. As a result, the generation of the neutralizing antibodies against the COVID-19 virus has been confirmed in all participants receiving the adjuvanted vaccine, demonstrating a 99% seroconversion rate.
The observed neutralizing antibody titer after two weeks from the injection was about 6 times higher in a pseudovirion-based neutralization assay of the entire subject and about 3.6 times higher in a plaque reduction neutralization test of the subset compared to the serum panel of recovered COVID-19 patients. GBP510, which demonstrated a high level of neutralizing antibody induction in the phase I/II clinical trial, which included those over 65 years old whose antibody response rate is usually low, indicated a similar or higher level of immunogenicity compared to the current COVID-19 vaccines.
The result has been acquired by standardized analysis using international standard material and analytic methods established by the World Health Organization and the UK’s National Institute for Biological Standards and Control. The convalescent sera control is inclusive of the lowest to the highest levels of neutralizing antibody formation rates.
In terms of safety, no serious adverse events following immunization were detected in relation to GBP510 injection, demonstrating sufficient tolerability.
SK bioscience will submit the positive data of the phase I/II clinical trial to domestic and international regulatory agencies and plan to further accelerate the development of GBP510 based on the results.
SK bioscience is currently planning to initiate the global phase III clinical trial across the regions including Europe and Southeast Asia, followed by Vietnam where the trial is being already conducted, with the International Vaccine Institute this month. In South Korea, 14 clinical institutions including Korea University Guro Hospital are conducting the phase III clinical trial for GBP510 since August with enrolling about 500 participants, 5 times more population than originally planned.
Based on the data from the global phase III clinical trial targeting about 4,000 participants, SK bioscience will prepare to acquire an approval from South Korea’s Ministry of Food and Drug Safety. Also, the company plans to receive WHO Pre-qualification certification and emergency use authorization by individual countries based on the result of the phase III clinical trial.
GBP510 was the first COVID-19 vaccine candidate selected as a part of Wave 2, a project initiated by Coalition for Epidemic Preparedness Innovations (CEPI) in 2020 to support promising vaccine candidates. Following continued positive progress and market authorization, GBP510 will be made available to the COVAX Facility for procurement and equitable allocation worldwide. In addition, SK bioscience will supply GBP510 to the world, including Korea, by establishing its own distribution plans to individual countries through their approval process.
According to Our World in Data, a statistical site developed by a research team at Oxford University in the UK, only about 50% of the world’s population has received at least one dose of a COVID-19 vaccine, and the vaccination rate in low-income countries is only 3.7%, so the demand for vaccinations for COVID-19 is still high.
The synthetic antigen vaccine platform applied to the development of GBP510 allows it to be stored in normal refrigeration conditions under 2 to 8 degrees Celsius, so it can be distributed through the current vaccine logistics network and stored for a long time, securing wider accessibility.
SK bioscience CEO Jaeyong Ahn said, “We were able to successfully manage the phase I/II clinical trial with close cooperation of public health officials including the COVID-19 Pan-government Support Committee, MOHW, MFDS, and the KDCA, as well as global civil and public entities, such as CEPI, Bill and Melinda Gate Foundation, IVI, and GSK. As the phase 3 clinical trial is proceeding smoothly, we will develop GBP510 as quickly as possible to contribute to overcoming the pandemic and securing the right to human health.”
To better identify and prevent future pandemics, the University of Washington has become a partner in a five-year global, collaborative agreement with the U.S. Agency for International Development. The newly launched Discovery & Exploration of Emerging Pathogens – Viral Zoonoses, or DEEP VZN project, has approximately $125 million in anticipated funding and will be led by Washington State University.
The effort will build scientific capacity in partner countries to safely detect and characterize viruses which have the potential to spill over from wildlife and domestic animals to human populations.
“The DEEP VZN project provides an exciting chance to better understand why the world is experiencing more frequent and severe outbreaks of zoonotic infectious diseases transmitted between animals and people,” said Dr. Peter Rabinowitz, a co-principal investigator for USAID DEEP VZN and professor of environmental and occupational health sciences in the UW School of Public Health.
“This means gaining knowledge about new viruses that could cause problems in the future, and the ecosystem changes that appear to be driving the process of viruses jumping between species,” Rabinowitz added. “The hope is that this improved understanding will lead to prevention of future pandemics and more resilient ecosystems.”
The project plans to initially partner with five countries in Africa, Asia and Latin America to help local organizations carry out large-scale animal surveillance programs within their own countries safely and test samples for viruses using their own laboratory facilities. This will avoid the process of having to ship samples to other countries for testing and build an international network of laboratories capable of quickly responding to disease outbreaks.
“Since the vast majority of viruses that ignite pandemics have their origin in nonhuman animals, it is critical that we figure out which of the many new zoonotic viruses that we are now identifying are most likely to jump species into humans, spread easily from person to person and cause severe disease or death,” said Dr. Judith Wasserheit, a co-principal investigator in the project and chair of the UW Department of Global health.
“The UW Alliance for Pandemic Preparedness focuses on a proactive, integrated systems approach to pandemic preparedness that has brought together internationally recognized leaders in the kinds of laboratory methods that will make it possible for the DEEP VZN team to fully sequence and characterize novel viruses in unprecedented breadth and depth,” said Wasserheit, co-director of the Alliance. “In addition, the Alliance’s approach catalyzed collaborations between these lab-based scientists; One Health leaders working at the interface of human, animal and environmental health; and leaders in Global Health who will work with colleagues in focus countries to identify high-risk locations and subpopulations at the human-animal interface.”
The DEEP VZN project will focus on finding previously unknown pathogens from three viral families that have a large potential for viral spillover from animals to humans: coronaviruses, the family that includes SARS-CoV-2, the virus that causes COVID-19; filoviruses, like Ebola virus; and paramyxoviruses, such as Nipah virus. With 70% of new viral outbreaks in people originating from animals, understanding future threats helps protect the U.S. as well as the partner countries.
The goals are ambitious: to collect over 800,000 samples in the five years of the project, most of which will come from wildlife; then to detect whether known and novel viruses from the target families are present in the samples. When those are found, the researchers will determine their zoonotic potential, or the ability to be transmitted between animals and humans.
This process is expected to yield 8,000 to 12,000 novel viruses, which researchers will then screen and genome sequence for the ones that pose the most risk to animal and human health.
The UW Medicine laboratory effort, led by Dr. Alex Greninger, assistant professor of laboratory medicine and pathology at University of Washington School of Medicine, will use the cutting-edge research expertise of five internationally recognized UW Medicine laboratories to develop innovative techniques and provide reference and support activities for virus detection and characterization by in-country labs.
“It’s time to get to work and find some new viruses. We will be building capacity in other countries to be able to find new viruses and characterize them in hopes to better understand coronaviruses and other viruses circulating in the world,” said Greninger.
The UW Medicine labs:
The Greninger Labwill coordinate qRT-PCR and broad serology assay development and in-country training, viral genome recovery and viral glycoprotein characterization.
The David Baker Lab will model novel viral glycoproteins to determine risk potential based on in silico screens for potential human receptor affinity.
The David Veesler Lab has detailed mechanisms of viral attachment and entry for novel paramyxoviruses and coronaviruses and will extend these biochemical studies to novel viral glycoproteins discovered in DV.
The Michael Gale Jr. Lab will determine the degree and mechanisms of innate immunity evasion in human cells by novel viruses.
The Van Voorhis Lab will produce recombinant proteins for in-country serological analysis as it has done for SARS-CoV-2.
The UW Department of Global Health will apply its experience in more than 145 countries and expertise in capacity strengthening through the International Training and Education Center for Health, or I-TECH, to support sustainable sampling and strengthen in-country laboratory programs.
In addition to UW and WSU, USAID DEEP VZN includes virology expertise of The Washington University at St. Louis, as well as data management and in-country expertise of public health nonprofits PATH, based in Seattle, and FHI 360, based in North Carolina. These partners have extensive established presence and partners in countries in the target regions.
“To make sure the world is better prepared for these infectious disease events, which are likely to happen more frequently as wild areas become increasingly fragmented, we need to be ready,” said Felix Lankester, lead principal investigator for USAID DEEP VZN and associate professor with WSU’s Paul G. Allen School for Global Health. “We will work to not only detect viruses but also build capacity in other countries, so the United States can collaborate with them in carrying out this important work.”
Tadataka “Tachi” Yamada MD, KBE served as the Advisory Board Chair of our Institute since its founding almost ten years ago. His tremendous mentorship helped us in innumerable ways to grow from a single-PI Institute founded by David Baker to a group of five faculty and almost 200 scientists and staff.
Tachi also helped shepherd the IPD’s Translational Investigator Program, serving as the Chair of the Board of two of our spinouts, PvP and Icosavax. PvP was acquired in 2020 by Takeda, which continues to develop the Rosetta-designed enzyme Kumamax, invented by Dr. Ingrid Swanson Pultz in the Baker Lab, as an oral therapeutic for celiac disease. Icosavax, which completed their IPO last week, is developing nanoparticle vaccines invented in the King lab at the IPD and recently advanced a SARS-CoV-2 vaccine into human clinical trials.
From all of us at the Institute for Protein Design, we send our deepest condolences to Tachi’s family and especially to his wife, Leslie Yamada.
Tachi will be deeply missed. We thank him for his mentorship, leadership, service, and his gift of time in helping to create the IPD.
Two different candidate vaccines developed by researchers at the Institute for Protein Design recently entered human clinical trials. GBP510, a candidate COVID-19 vaccine, is undergoing a combined Phase 1/2 trial. Flu-Mos-v1, a candidate mosaic influenza vaccine, is undergoing Phase 1 testing.
Candidate COVID-19 vaccine
Our SARS-CoV-2 vaccine candidate was created with structure-based vaccine design techniques invented in the King lab the IPD. It is based on a computationally designed self-assembling protein nanoparticle that displays 60 copies of a key region of the viral Spike protein.
In preclinical studies reported last year in Cell, the vaccine produced high levels of virus-neutralizing antibodies at low doses. Compared to vaccination with the soluble SARS-CoV-2 Spike protein, on which many leading COVID-19 vaccine candidates are based, the nanoparticle vaccine produced 10 times more neutralizing antibodies in mice, even at a sixfold lower dose. When administered to a single nonhuman primate, it produced neutralizing antibodies targeting multiple different sites on the Spike protein. This may ensure protection against additional mutated strains of the virus, should they arise.
Further preclinical studies, published in Nature, also showed that the vaccine conferred robust protection and produced a strong B-cell response, which may improve how long the protective effects of the vaccine last.
Our lead COVID-19 nanoparticle vaccine candidate is being licensed non-exclusively and royalty-free during the pandemic by the University of Washington. One licensee, Icosavax, a Seattle biotechnology company co-founded in 2019 by King, is currently advancing studies to support regulatory filings and has initiated the U.S. Food and Drug Administration’s Good Manufacturing Practice. To accelerate progress by Icosavax to the clinic, Amgen has agreed to manufacture a key intermediate for these initial clinical studies.
Another licensee, SK bioscience of South Korea, is advancing its own studies to support clinical and further development. Lab studies conducted at SK bioscience offered additional evidence that the nanoparticle vaccine blocked proliferation of the COVID-19 virus.
SK bioscience is working toward commercialization within the first half of 2022 through an expedited approval process, such as an emergency use license. Their eventual goal would be to build up to a manufacturing scale of hundreds of millions of doses per year. GBP510, as SK has named the program, was selected for the first program of the Wave 2 (Next Generation COVID-19 Vaccine) project, which CEPI launched last year to support various COVID-19 vaccine candidates. If GBP510 proves safe and effective and becomes commercialized, it will be supplied globally through the COVAX Facility.
In addition to Neil King, head of vaccine design at the IPD and inventor of the computational design technology used in developing this COVID-19 nanoparticle vaccine candidate, other lead investigators are research scientists Alexandra Walls and Brooke Fiala, and David Veesler, associate professor, all in the University of Washington School of Medicine Department of Biochemistry, who conducted the work along with numerous collaborators.
Mosaic influenza vaccines
IPD researchers, together with collaborators at the National Institutes of Health, have developed experimental flu vaccines that protect animals from a wide variety of seasonal and pandemic influenza strains. The vaccine recently entered Phase 1 clinical testing. If proven safe and effective, these next-generation influenza vaccines may replace current seasonal options by providing protection against many more strains that current vaccines do not adequately cover.
A study detailing how the new flu vaccines were designed and how they protect mice, ferrets, and nonhuman primates was published in Nature. This work was led by researchers at the University of Washington School of Medicine and the Vaccine Research Center part of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health.
“Most flu shots available today are quadrivalent, meaning they are made from four different flu strains. Each year, the World Health Organization makes a bet on which four strains will be most prevalent, but those predictions can be more or less accurate. This is why we often end up with ‘mismatched’ flu shots that are still helpful but only partially effective,” said lead author Daniel Ellis, a research scientist in the King lab.
Dr. Anthony Fauci shared some news with Congress about our collaborative influenza vaccine research. Phase 1 trials are now underway!
— Institute for Protein Design (@UWproteindesign) May 28, 2021
To create improved influenza vaccines, the team attached hemagglutinin proteins from four different influenza viruses to custom protein nanoparticles. This approach enabled an unprecedented level of control over the molecular configuration of the resulting vaccine and yielded an improved immune response compared to conventional flu shots. The new nanoparticle vaccines, which contain the same four hemagglutinin proteins of commercially available quadrivalent influenza vaccines, elicited neutralizing antibody responses to vaccine-matched strains that were equivalent or superior to the commercial vaccines in mice, ferrets, and nonhuman primates. The nanoparticle vaccines—but not the commercial vaccines —also induced protective antibody responses to viruses not contained in the vaccine formulation. These include avian influenza viruses H5N1 and H7N9, which are considered pandemic threats.
“The responses that our vaccine gives against strain-matched viruses are really strong, and the additional coverage we saw against mismatched strains could lower the risk of a bad flu season,” said Ellis.
Initial clinical testing of the leading nanoparticle influenza vaccines is expected to take up to two years.
The field of protein structure prediction has greatly advanced in recent years thanks to increasingly accurate deep-learning methods. A new such method, called trRosetta developed at the Institute for Protein Design, has now made thousands of protein structures available via EMBL-EBI’s Pfam and InterPro data resource.
More than 6300 protein structures have been predicted in this way and are now available in Pfam, with more to follow.
“This is a big step forward because it gives the research community open access to thousands of new protein structures predicted using accurate computational models,” explains Alex Bateman, Senior Team Leader at EMBL-EBI. “This new dataset will enable researchers to explore proteins for which the structures remained hidden until now. And by exploring these protein structures, they can also start to gradually understand the protein functions.”
How does it work?
trRosetta is an algorithm for fast and accurate protein structure prediction. It uses the large, multiple sequence alignments available in Pfam and applies a deep learning model to predict the transformations and structure parameters for each protein. It then applies the Rosetta pipeline to predict the structure.
“We are delighted to work with the Pfam team to make our structure models widely available to the scientific community,” says David Baker, Director of the Institute for Protein Design at the University of Washington.
Pfam uses a quality score called the Local Distance Difference Test (lDDT). An IDDT score of 0.6 or greater is considered a reasonable model and scores above 0.8 are great models. The large majority of structural models obtained from rtRosetta are of good quality, with an lDDT score of over 0.7.
Pfam – the home of protein families
The Pfam database provides a complete and accurate classification of protein families and domains. Pfam is used by experimental biologists researching specific proteins, by structural biologists to identify new targets for structure determination, by computational biologists to organise sequences and by evolutionary biologists tracing the origins of proteins.
“It’s great to see so much progress in this field,” says Bateman. “Just 10 years ago, this kind of dataset was something we could only dream of, so to see it become a reality is amazing, and we hope many researchers will explore it and use it in their work.”
The work by the Pfam and InterPro groups was funded by BBSRC BBR grant BB/S020381/1.
Researchers from our vaccine design team recently participated in a Reddit ‘Ask Me Anything’ about our SARS-CoV-2 vaccine research. Reddit users asked over a hundred questions by the time the live event ended — we are sorry we could not address them all.
We were lucky to be joined by Lexi Walls, a postdoctoral scholar in the UW Veesler lab, who recently helped lead an effort to determine the structure of the SARS-CoV-2 spike protein by cyro-electron microscopy. “It was so wonderful to see such a broad audience pour in so many well-thought out questions about our research,” said Erin Yang, a Baker lab graduate student who helped organize the event.
Here is our pick for the top five vaccine-related questions from our Reddit AMA:
If a vaccine was created, and proven to work, how long would it take for it to be mass produced and for it to reach the general public?
The projections of 1 year to 18 months to have an FDA approved vaccine are probably accurate — if some of the vaccine candidates that [are] either in development or about to start clinical trials as of today do in fact provide protection (which we don’t know yet) and everything goes well.
Vaccines, like all medicines, have to be very safe. The safety bar for vaccines is very high as they are administered to large numbers of people. Much of the time that will be required to get a vaccine out will be devoted to ensuring that vaccine candidates are very safe, as well as effective.
— Lauren Carter
Is there a chance we’ll ever develop one day the technology to create and manufacture vaccines for new diseases, quickly enough to tackle their extremely damaging first wave (so essentially have a vaccine ready within 2, 3 months of a disease being discovered)?
Potentially. There will always be a need for safety trials, but new vaccine platforms that are modular (like ours) — once they have been proven in clinical trials — could be developed quickly for new indications. As an example, annual flu vaccines are manufactured relatively rapidly, but there is room for further improvement. — Lauren Carter
One long-term goal (which will not be ready for this pandemic) would be to create vaccines that could provide universal coverage against any family of viruses that has a high chance of causing a pandemic. For example, one could imagine having a single vaccine that protects against all possible coronaviruses, another vaccine that protects all possible flu viruses, etc. Based on what we know about how the immune system responds to flu, a universal flu vaccine does look possible as there are pieces of flu that are conserved between all flu viruses that infect humans. Coronaviruses are less studied in this regard. Hopefully greater study of them in the coming years will show that such a vaccine could be possible.
— Dan Ellis
What are we seeing in the human antibodies from recovered patients and how does that influence a potential vaccine? Are there other proteins we can target aside from the spike protein?
There are a variety of proteins present in coronaviruses, but the spike protein is the major vaccine and antibody target because it is present on the outside of virus and is the major protein that our immune systems target during natural infection. The spike protein is also the workhorse of viral entry — the spike protein’s role is to bind to host cells and fuse viral and host membranes to allow for infection. The spike is therefore the first target the immune system sees and acts against. This also means that if we can target antibodies to it, we could prevent viral entry into host cells completely and block infection (which is the ultimate goal!). The most promising target on the spike protein is called the receptor binding domain, the goal being to block the interaction with host (our) receptor. If this interaction is blocked, then the virus cannot enter cells and no infection can occur.
As for what we are seeing from human antibodies from infected patients… this is a pre-print (not yet peer-reviewed- a way to publicly post results early to allow for sharing of knowledge as fast as possible, but submitted to a scientific journal to go through that process) on just that topic!
— Lexi Walls
What makes creating a vaccine so hard? I genuinely want to understand the work and tech that goes behind creating something that kills a virus.
At a very basic level, making vaccines is hard because we don’t fully understand how the immune system perceives pathogens and most effectively marshals its forces (T cells, B cells, etc.) to eliminate pathogens. We know some things, like antibodies and T cells are important. So the job of vaccinologists is to make a thing that stimulates the immune system — which we do not fully understand — in just the right way. You want to raise the right flags for the immune system to see in order to identify the threat, but you don’t want to overwhelm the system or alert it to the wrong thing.
Another challenge in making vaccines is that they must be exceedingly safe. Vaccines are administered to large numbers of healthy people, so they must do no harm. Making a thing that provokes a potent, protective immune response but that is totally safe requires a lot of knowledge, skill, and operational excellence.
Finally, viruses and bacteria are experts at evading the immune system — they have developed lots of tricks to subvert or suppress immune responses. So you have to know enough about the bug (the virus or bacterium or whatever) to teach the immune system how to eliminate it, despite the tricks the bug tries to play.
— Neil King
How many vaccine candidates are there currently? Where are the trials being conducted?
A few different vaccine candidates from other groups have entered the earliest stage of clinical testing, and many others are racing to get there. A handful of patients have been injected in Seattle as part of one mRNA vaccine trial (Phase 1).
This is an incredible moment for science — all hands are on deck, moving quickly but safely.
As schools, museums, offices and stores shutter to slow the spread of the new coronavirus, millions of people are now finding themselves stuck at home. Fortunately, even in these trying times, there are are small steps that anyone can be take to help combat COVID-19.
One option is to donate to biomedical research — but doing so doesn’t necessarily require opening your wallet.
Rosetta@Home is a distributed computing project that relies on a network of volunteer computers. The goal of the project is to learn more about important biomolecules, including the proteins that comprise the new coronavirus. In doing so, scientists may discover how to create medicines and vaccines to stop it. Rosetta@Home operates on the Berkeley Open Infrastructure for Network Computing, or BOINC, which has existed since 2002. BOINC is open-source and funded primarily by the National Science Foundation.
In recent days, Rosetta@Home has seen a surge of new volunteers who are generously donating the use of their idle desktop, laptop and smartphone processors. The number of active users has doubled, and four of the project’s ten best compute days have occurred just in the last week. This giving is powering research on the new coronavirus at the UW Institute for Protein Design and at other universities.
New volunteers stepping up
To keep the public safe from the new coronavirus, the Phillip and Patricia Frost Museum of Science in Miami, Floria has had to temporarily close. The museum is home to a state-of-the-art planetarium, powered by the Frost Planetarium’s Dell PowerEdge 7910 servers, consisting of 168 processors. The Frost Museum just announced that it is generously donating its computer downtime to the Rosetta@Home project.
“As a leading scientific institution, we wanted to find a way to repurpose the powerful computing technology we had idle with our closure. We are now actively supporting groundbreaking research that will help us solve some of the world’s biggest challenges, such as COVID-19. Now more than ever, we need to work together and keep science and high quality research at the forefront of our thinking. We encourage others to join our Frost Science BOINC team and help make a difference, right from their homes” said Frank Steslow, Frost Science President & CEO.
Modus Create, a multi-national consulting firm, has also announced that it is donating all spare computer parts at its headquarters in Reston, Virginia to both Rosetta@Home and Folding@Home, a similar project. “Humanity’s ingenuity is often best demonstrated at times of crisis,” they write. Like many volunteers, Modus has also created a team on BOINC to organize their giving. Over 11,000 such teams have been formed, including many from universities, business and other institutions.
It is easy to join Rosetta@Home
Joining Rosetta@Home is simple. First, download the BOINC app on a compatible device (Windows, Mac, Linux or Android). Then, select Rosetta@Home as your preferred project. That’s it! Rosetta@Home is not for profit, operated by academics and will not collect any of your personal information. Follow the project on Twitter for updates: @RosettaAtHome
With Rosetta@Home running on your devices, you can contribute to science even as you sleep.
PvP Biologics is on a mission to develop a highly-effective therapeutic to reduce the burden of living with celiac disease. They are advancing an oral enzyme — TAK-062 — designed to break down gluten in the stomach. This exciting research, which began as an iGEM project in 2011, was matured at the Institute for Protein Design before being spun-out into a company in 2016.
Today, PvP Biologics has announced it has been acquired by Takeda Pharmaceuticals following results from a Phase 1 study.
“Many people living with celiac disease manage their symptoms by following a gluten-free diet, but there is no treatment for those who continue to experience severe symptoms,” said Asit Parikh M.D., Ph.D., Head, Gastroenterology Therapeutic Area Unit at Takeda. “PvP Biologics’ work demonstrated that TAK-062 is a highly targeted therapy that could change the standard of care in celiac disease. We are now applying our deep expertise in gastrointestinal diseases to advance the clinical study of TAK-062 and TAK-101, two programs with different modalities that have both demonstrated clinical proof of mechanism.”
Takeda exercised its option to acquire PvP Biologics for a pre-negotiated upfront payment as well as development and regulatory milestones totaling up to $330 million. Takeda and PvP Biologics previously entered into a development and option agreement, under which PvP Biologics was responsible for conducting research and development through the Phase 1 proof-of-mechanism study of TAK-062 in exchange for funding by Takeda related to a pre-defined development plan.
Icosavax, Inc. today announced its launch with a $51 million Series A financing. The company was founded on computationally designed self-assembling virus-like particle (VLP) technology developed here at the IPD (Cell 2019, Preview).
The proceeds of the financing will be used to advance the company’s first vaccine candidate, IVX-121, for respiratory syncytial virus (RSV) for older adults through Phase 1b clinical studies. Icosavax also announced today its leadership team, board of directors and key scientific advisors.
“Icosavax’s vaccine technology solves the problem of constructing and manufacturing VLPs displaying complex antigens by utilizing computationally designed proteins that separate the folding of individual protein subunits from the assembly of the final macromolecular structure. The individual proteins are expressed and purified using traditional recombinant technologies, and then self-assemble into VLPs when mixed together,” said Icosavax co-founder Neil King, Ph.D.
VLPs are known to induce superior immunological responses compared to traditional soluble antigens, eliciting protective immune responses while reducing the need for strong adjuvants, which in some instances have been associated with side effects.
The company’s RSV vaccine candidate, IVX-121, incorporates a stabilized prefusion F antigen licensed from NIAID/NIH (DS-Cav1; Science 2019). Extensive preclinical studies conducted at IPD and Icosavax suggest that IVX-121 could increase the protective immunogenicity of RSV F compared to the DS-Cav1 antigen alone.
IPD-spinout Neoleukin Therapeutics announced this week a merger with Aquinox Pharmaceuticals, a publicly traded company. The combined company will change its name to Neoleukin Therapeutics, and will continue to advance its Rosetta-designed protein platform for cancer, inflammation, and autoimmune diseases.
Neoleukin was spun out of the IPD Translational Investigator Program in January. As a result of this exciting merger, it will be the first publicly traded company in history with a de novo designed protein as its core technology. The new stock ticker will be NASDAQ:NLTX after the deal closes.
As part of the deal, Neoleukin has also gained access to $65 million in capitalization.
“The merger with Aquinox is transformational for our company,” said Neoleukin CEO Jonathan Drachman, MD. “We believe that cytokine mimetics, or Neoleukins, have the potential to offer enhanced therapeutic effects with fewer toxic side effects.”
Senior leadership at Neoleukin still includes three IPD-trainees: Daniel Silva, PhD as VP, Head of Research; Umut Ulge, MD, PhD as VP, Translational Medicine; and Carl Walkey, PhD as VP, Corporate Development. Aquinox’s former stockholders own approximately 61% of the combined company’s capital stock.
Researchers from the IPD and UCSF recently participated in a Reddit Ask Me Anything about LOCKR, our new de novo protein switch. Reddit users had dozens of fantastic questions — so many, in fact, that the team ran out of time before they could address them all.
“The questions were both insightful and interesting,” says Hana El-Samad, a co-senior author of the LOCKR reports. “I had so much fun answering them!”
Hana was joined by Bobby Langan from the IPD and Andrew Ng from UCSF, both co-first authors of the reports. Some participants asked pointed technical questions about concepts that our scientists are already grappling with. Others drew the lens back to ask about the medical and ethical ramifications of making proteins that can control the behavior of cells. (ICYMI: here’s the paper describing LOCKRs design, and here’s how the team turned it into a circuit for cellular feedback.)
Here is our pick for the top five LOCKR questions from our Reddit AMA:
1. How did you guys originally come up with the idea to design these proteins? Would a treatment using LOCKR still have side effects like drugs do? And you used the example of acute inflammation from a TBI; could these proteins be used for other kinds of inflammation as well, such as the chronic inflammation found in autoimmune diseases? – /u/raucous__raconteuse
The idea for LOCKR grew out of a 2016 paper (you may notice some authorship overlap 🙂 ) where we described how to create really well-behaved helical proteins. We wanted to add function into them, so after a couple whiteboard brainstorming sessions, we decided to try to get one part of the protein to switch in the way we published — and install function in such a modular way. Then, within the IPD and with Hana/Andrew, we developed the functions we’ve published and got it to work in living cells! There’s a lot of work still to do to determine if a cell that uses LOCKR will have any unintended side-effects. Of course, we are attempting to engineer the cells in a way to mitigate that in a predictable way.
TBI is an initial indication, but the field of engineering therapeutic cells — especially using LOCKR — is so new that working on other kinds of inflammation and autoimmune diseases is certainly on the table. What indications would you like to see researchers like us work on? – BL
2. Do you guys know yet when LOCKR could be in commercial use? Even a ballpark guestimation would be interesting. – /u/JustTheBP
There is a lot of work that still needs to be done to use LOCKR in a commercially viable product, and that work is starting! Since the biotech/FDA pipeline is (necessarily) long and rigorous, it’ll be many years before something using LOCKR is ready for use in humans. -BL
3. It sounds like the target for the artificial protein is different protein domains. Is there any risk of off-target binding? Does the “key” protein that allows the activity of the artificial protein need to be endogenous? I imagine there could be a situation where it would be desirable to have the artificial protein activated by a pharmaceutical, is that an area of interest for the research or is the focus more on utilizing existing pathways within the cell? – /u/senojsenoj
Because cells are like burritos where everything is mixed together, there is always a risk for off-target interaction, but part of the beauty of LOCKR is that since these proteins were completely designed in a computer, they will be far less likely to interact with other proteins in the cell compared to other engineered proteins that are directly taken from nature. Currently, the Key that activates the Switch is also a designer protein, but many others are interested in designing proteins that are activated by or interact with endogenous proteins. Designing proteins that can be activated by small molecules is also extremely useful, and many others are working on this! -AN
4. What advice do you have for an undergrad, looking to change the world someday? Have any living trials been conducted yet? Will there be any applications in an orthopedic surgical setting, like with joint replacements, to reduce post-op swelling? What about for chronic joint inflammation? Can this also be used in place of immuno suppressants after an organ transplant? – /u/whiskerbizkits
First piece of advice — keep up your passion for changing the world. Second, pursue studies in science and engineering, and think about engaging actively in research (ask professors what research opportunities are available). As to your questions about applications, we believe that live cell therapies (the ability to take cells out of a patient, engineer them and put them back to be “living medicine”) hold great promise for all the areas you mention. For these cells to be safe, effective and robust, they need to be “smart,” which means they need to be able to detect their local environment and react to it. We need to program them to do so. This is where LOCKR (and other synthetic proteins) and synthetic biology in general can help! And btw, these therapeutic cells could also be programmed to shut themselves off once their job is done, so this is not engineering the genetic code of a human, but rather giving them the equivalent of smarter “pills”! –HES
5. How many other names for the protein did you all consider? Did you have to stretch a bit to land on one as cool as LOCKR, or was that just totally serendipitous? – /u/DrColossusOfRhodes
I knew someone would comment on the name! Scott (another co-first author on this paper) and I went through several iterations over the span of a week — he came up with LOCK then I added the R from pRotein considering other, trendy, names in tech right now (CRISPR, tumblr, flickr, grindr, etc). I get a laugh every time I present the acronym. It’s a little stretched… but it works 🙂 -BL
BL: Bobby Langan, co-first author, UW
AN: Andrew Ng, co-first author, UCSF
HES: Hana El-Samad, co-senior author, UCSF
Dr. Ingrid Pultz, an IPD Translational Investigator and Chief Scientific Officer at PvP Biologics, has written a special report for the American Council on Science and Health about how protein design is being used to help fight celiac disease. Pultz describes how an international competition, a video game, and venture capital all aligned to help enable this exciting work.
The IPD hosted its second Scientific Council meeting this month, chaired by David Urdal, PhD, MS. The council is made up of UW and Fred Hutch faculty from a variety of departments (Oncology, Genome Sciences, Immunology, Allergy & Infectious Diseases, Biochemistry, and Pharmacology). The goal of the IPD Scientific Council is threefold:
1. Identify new opportunities, targets, and applications to which protein design can be applied
2. To strategize on how best to balance core technology development with translational projects of value today and translational projects with important impacts 5 to 10 years down the road
3. Provide feedback on current projects
IPD Director Dr. David Baker was the Keynote speaker at the 13th Annual NanoDDS (International Nanomedicine and Drug Delivery) symposium, held at the UW this year. Dr. Baker gave a talk entitled ‘Engineering Protein Nanocarriers: Deisgn of protein interaction inhibitors and self-assembling nanocages’.
Dr. Baker also spoke on a panel at the Washington State Academy of Sciences 8th Annual Symposium on “Accelerating Science’s Impact: Translating Discoveries Into Solutions”. Held at the Museum of Flight, the panel was moderated by UW CoMotion Executive Director Vikram Jandhlaya and panelists discussed various topics under the theme of “Translational Science for Health and Disease Barriers and Solutions”.
Following the groundbreaking 2014 Nature paper describing the development of a computational method to design multi-component coassembling protein nanoparticles, comes a publication in Protein Sciencefrom Baker lab graduate student Jacob Bale and collaborators. Titled “Structure of a designed tetrahedral protein assembly variant engineered to have improved soluble expression“, the paper reports a variant of a previously low yielding tetrahedral designed material for which structure determination was difficult. The new variant described in the paper had a much improved yield after redesign and the structure obtained agreed with the computational model with high atomic-level accuracy. The methods used here to improve soluble protein yield will be generally applicable to improving the yield of many designed protein nanomaterials.
Congratulations to newly minted PhDs and graduates of the Baker lab Dr. Shawn Yu and Dr. Ray Wang! Both defended their dissertations this month. Dr. Yu gave a talk on “Computational design of interleukin-2 mimetics” and Dr. Wang spoke about “Protein structure determination from cryoEM density maps”. We wish them the best of the luck in their next steps!
The annual RosettaCONmeeting was held July 29-Aug1 at the beautiful Sleeping Lady Mountain Resort in Leavenworth, WA. Many IPD scientists attended the conference, heard talks from researchers in Rosetta labs across the country, presented posters on their own research, and socialized with the larger Rosetta community.