Category: News Roundup

5 questions about designing coronavirus vaccines from our Reddit AMA

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.

This is a really complex question, and we’ll only be able to provide a partial answer. If you are curious about how vaccines and drugs are developed, here are a few other resources: https://www.sciencedirect.com/topics/medicine-and-dentistry/vaccine-development

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.

— Erin Yang

 

Volunteers rally to Rosetta@Home to stop COVID-19

Planetariums, businesses and more are now donating idle computing power to help advance biomedical research. Image: Frost Science

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.

 

Image: Frost Science

“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.

IPD Spinout PvP Biologics Acquired by Takeda

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.

Image by Vikram Mulligan

Today, PvP Biologics has announced it has been acquired by Takeda Pharmaceuticals following results from a Phase 1 study.

From the Press Release:

“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 launches to advance designer vaccines

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.


Read the full press release as well as coverage in GeekWire and EndPoints.

Neoleukin: from spinout to public company in 7 months

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.

To learn more about Neoleukin, visit: www.neoleukin.com

To learn more about their platform technology, see: https://www.nature.com/articles/s41586-018-0830-7

5 questions about LOCKR from our Reddit AMA

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


Who’s who:

BL: Bobby Langan, co-first author, UW
AN: Andrew Ng, co-first author, UCSF
HES: Hana El-Samad, co-senior author, UCSF

How synthetic biology could treat celiac disease

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.

Read her full report here: How Synthetic Biology Could Treat Celiac Disease

 

September IPD News Roundup

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RESEARCH

IPD Translational Investigator, Dr. Ingrid Pultz, published a paper in JACS  this month titled ‘Engineering of Kuma030: A Gliadin Peptidase That Rapidly Degrades Immunogenic Gliadin Peptides in Gastric Conditions‘.Kuma030 Using Rosetta to redesign the active site of the gliadin protease KumaMax – an enzyme computationally designed to break down gluten in the stomach – Dr. Pultz and collaborators show that the new variant Kuma030 degrades >99% of the gluten peptide that triggers inflammation in celiac disease patients. This work brings us even closer to arriving at an oral therapeutic for celiac disease.

IN THE NEWS

Dr. Pultz was interviewed by MyNorthwest.com on her work developing a pill that celiac patients can take before consuming gluten. Read and hear more at the link:

http://mynorthwest.com/874/2814454/A-gluten-fighting-pill-for-Celiac-disease-is-on-its-way-thanks-to-UW-Medicine-researchers

INSTITUTE

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”.

August IPD News Roundup

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RESEARCH

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 Science from 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.

Bale_improvedTetr

INSTITUTE

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 RosettaCON meeting 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.