UCSF

Hunting for a cure for COVID-19: an insider’s story

As UCSF’s Quantitative Bioscience Institute mobilizes researchers to fight a global pandemic, QBI’s administrator shares the saga

Jacqueline Fabius is not a scientist. She doesn’t have a PhD in physics or computational biology or virology.

As the chief operating officer of the Quantitative Biosciences Institute (QBI) at UC San Francisco, what she does have is the administrative responsibility for enabling QBI to do what it does best—bring together scientists from diverse disciplines to tackle the most pressing problems that can only be solved by creative, dedicated teams.

And she has a unique vantage point from which to share a layperson’s observation of science in action.

With the COVID-19 pandemic unfolding and no treatment at hand, QBI’s penchant for team science and its expertise in quantitative research—which applies various methods to measure, analyze, and determine relationships among variables—has been in full swing for the past several weeks. The QBI Coronavirus Research Group, formed just weeks ago now has 22 research laboratories with hundreds of scientists pooling their expertise in biochemistry; virology; and structural, computational, chemical, and systems biology to understand how this novel virus hijacks human cells for its own replication.

Fabius recently shared the story of QBI’s ongoing COVID-19 research saga story with family and friends. Her insider's account follows.

For updates, jump below to


March 15, 2020

Dear family and friends:

It's been an intense few weeks!

I am going full nerd and even going to put in links. Get a glass of wine and get ready for a breathtaking read...

As of eight days ago in a completely unprecedented fashion, QBI gathered 22 of its top labs, comprising hundreds of scientists, who joined forces to try and find treatments for COVID-19. Systems, structural, computational, and chemical biologists have all come together to generate a map of how the virus hijacks human cells for its own replication and will use that knowledge to develop new treatments. This group is called the QCRG: QBI Coronavirus Research Group.

As immediate background, in case you did not know/remember, I am the COO at the Quantitative Biosciences Institute (QBI) within the University of California, San Francisco. The institute focuses on "disease agnostic" research of the molecular biology kind. It means that the research can be applied to any disease essentially: cancer, psychiatric disorders, neurological and infectious diseases.

The director of the institute, Nevan Krogan, and I run QBI. His research focuses on protein-protein interactions. I am going to explain this, because it plays a key role later in the story. Proteins are the functional building blocks of our cells, and it is when the proteins are affected or mutated that we have diseases. The director makes maps of cells both in healthy and diseases states. These maps help to inform the research.

The director's research looks at how proteins interact in cells and what clusters or networks they form. His research has shown that when you look at a network of proteins, you get more powerful information as to what causes a disease both upstream and downstream of a given network.

So, for instance, think of a city map. Think of yourself stuck in traffic at some point on some highway. You have no idea why you are stuck. However, if you look at the map of the area you are in, you can start seeing where some of the blockage happened and where it is causing the greatest trouble. If you were to free up a specific street of its blockage, you could potentially open the flow of normal traffic again. On the other hand, if you just looked at your stuck car, you would not be able to solve anything.

In the case of QBI, once we have a protein map, we need the expertise of other types of scientists for the next actions steps, hence the additional 21 labs.

This takes us to where we are today. As of three weeks ago, the director's lab (with about 38 scientists) started focusing on the coronavirus proteins to create a protein interaction map. The first step was to identify how many genes are in the coronavirus; there are 29. Thus far the lab has been able to clone 27 of those 29 genes. The genes are cloned so that scientists can do specific experiments with them. The process is the following (quick time travel back to 10th grade biology class!):

  • Identify the genes (the DNA strands) in the coronavirus
  • Clone the coronavirus genes in order to be able to study them in isolation
  • Tag the DNA strands (Put an identifier on them.)
  • Place the tagged DNA strands in human cells and allow for them to code themselves into proteins
  • Purify the proteins (Pull out the identified proteins one by one.)
  • Analyze each by mass spectrometry to identify which human proteins they interact with
  • Hand over the maps to our chemists to see if they can identify existing FDA-approved drugs that already target certain proteins in other diseases (This is called drug repurposing. A good example is Viagra, which was initially used to treat heart pain, but other, unexpected beneficial side effects were discovered.)
  • Hand over the identified interacting proteins to our structural scientists (those working with high-powered microscopes at a high resolution) to identify the structure of the networks, which lets us know where to attack the protein structure with treatment or drugs
  • Move to drug or treatment development

At this point the labs have been working tirelessly to finish the map and it should be completed by this coming Wednesday.

On the parts of the map that have already been completed, and with identified networks of human proteins that are interacting with the COVID-19, our chemistry specialists have already been identifying FDA-approved drugs that could potentially be used.

We do not have the live virus at UCSF, but two of our partners do: the Pasteur Institute in Paris and Mount Sinai in New York. Two days ago, amidst the panic of finding out that flights would stop between continents, we rushed to send the first set of compounds (compounds = drug structures…Think back to 11th grade chemistry now!), to both Paris and New York for our colleagues there to start testing our drug predictions against COVID-19 to see how it reacts.

We are looking (ideally) for something that would kill the virus, or at the very least would decrease its speed and potency. The latter would come in handy to "flatten out the curve," as you have been hearing in the news. Essentially if we could slow it down, or decrease its strength we would buy time for those in critical condition, and potentially have greater control on the outcome. For the less severe cases, we would make the virus less virulent and the infection faster to get over.

Our New York partners received the compounds on Friday, and started working on them. Our Pasteur partners will receive their box on Monday.

As I sit here writing to you, my email is binging every few minutes. As information comes out of the mass spectrometer, identifying connections on the map, we update the map. As the map is updated in real time, the chemists on the team of 22 labs are immediately at work, and that part of the team is having an active back and forth dialogue on what they know about specific compounds. Once deemed safe, we are getting the next shipment ready for New York and Paris.

It's hard for me to emphasize the lightning pace at which all of this is moving. We are at such an advanced stage of technology, that we are able to move faster than ever have before during an epidemic.

The energy at the institute, which is almost empty due to the State of Emergency, and the fact that almost everyone is sheltering in place and working from home, is incredible. In the past week we had meetings with the essential scientists, first to gauge who was voluntarily willing to come to the lab (following safety protocols, of course). We have essentially set up a 24-hour shift situation. Key people were identified, shifts set, and even people in self-quarantine at home are working remotely all day, all night.

At the same time, we have been dealing with the science and organizing our work among the 22 labs, we have been pitching our story to the media to bring about both awareness and desperately needed fundraising around this research. Unlike Harvard, etc., we are public.

At this time the New York Times and Good Morning America are interested, and all of a sudden, other media outlets have heard about our work and want to cover what is going on as well. Tonight I am going to try my hand at a piece for The Conversation, which we hope will post sometime next week. Long live the Comp Lit degree!

Given what is going on with international shutdowns, we are also working directly with the French Consulate in San Francisco, exploring diplomatic transport routes for the compounds to reach Paris. Who could have possibly predicted the importance of our first annual joint symposium between QBI and the Pasteur Institute on Infectious Diseases a year ago? The idea behind that, and all the international efforts we have been putting into the institute, is to facilitate collaborations worldwide. We have (obviously) had to cancel our second annual meeting, which was meant to be taking place this coming week in Paris.

Fabius in lab.

Jacqueline Fabius looks at mass spectrometer.

How the world has changed in such a short time. Did any of us ever even remotely imagine we would see anything like this in our lifetimes?

As horrific as all of this is for the world, I am excited and inspired to be part of this team at this time in history. It is hard for me to believe on a daily basis that I am working with people, both men and women, (There are some kick-ass women on this team! We are going to do some specific features on them.), who are so intelligent, dedicated, and the right people to be seeking solutions. The energy in the room (when we still gathered in a large group) was palpable. The energy and 24-hour response, on email, text, and phone calls is equally riveting. To get on a call with Paris, to have a relationship with these game changers is incredible. We are hoping that we can find something that helps with this virus.

I hope I have conveyed the level of work, intensity, and speed at which we are moving. We have been showing up before sunrise, and leaving long after sundown. Adrenaline...

Xu working in lab.

Jiewei Xu, MS

As I mentioned, the map should be done by Wednesday. I can give you a further and shorter update if you like then! Of course, I will be sharing links etc., with you. We have been ultra-focused on the science, people moving to work remotely, and we are slightly behind on website updates. I will send you that later, which will have the profiles of all these cool people. That said, if you have any questions, please feel free to send them to me, and I will run them by our scientists. As you know, there are so many unknowns with this virus, which makes it unlike the flu or others in close virus families. There will not be answers to all questions at this time.

I took the pictures yesterday. Jiewei Xu is one of our most skilled technicians who took today's afternoon shift. The other picture is me trying to look like a scientist at the mass spectrometer. 

That's right, this is the life you all imagined me moving into after the hut in Haiti...

OK! That's my very lengthy report for now!

Much love,

Jacqueline

Update March 22, 2020

QBI’s COVID-19 team of collaborators released to the global science community on March 22 results of the team’s hunt for promising drug candidates to treat COVID-19. Some of the 69 compounds the team identified have already been approved as medicines to fight other diseases. If these existing drugs prove to be effective against COVID-19, they could be deployed against the virus much more quickly than the time it would take to discover, develop, test, and approve a new drug.

The results, published on the website bioRxiv were covered by The New York Times.

The team’s collaborators at the Icahn School of Medicine at Mount Sinai in New York and the Pasteur Institute in Paris have started testing 22 of the other compounds on the list against live coronavirus grown in their laboratories; they’re waiting for results.

Update March 20, 2020

QBI scientists have initially identified 50 promising drug candidates, and collaborators across the globe are now testing 10 of them against COVID-19 in the laboratory. If any of these already FDA-approved medications are found to be effective against the virus, a treatment could be available in months instead of years. The COVID-19 work under way by QBI has now been covered in The New York Times, ABC News and Scientific American.

QBI’s director, Nevan Krogan, PhD, has used computational approaches to move research forward on the world’s biggest communicable disease threats, such as Zika, dengue, and Ebola.


About the School: The UCSF School of Pharmacy is a premier graduate-level academic organization dedicated to improving health through precise therapeutics. It succeeds through innovative research, by educating PharmD health professional and PhD science students, and by caring for the therapeutics needs of patients while exploring innovative new models of patient care. The School was founded in 1872 as the first pharmacy school in the American West. It is an integral part of UC San Francisco, a leading university dedicated to promoting health worldwide.