QBI pioneers a collaborative and inclusive approach to scientific discovery

Nevan Krogan, PhD, has studied genes, proteins, and cells for 20 years, but he’d be the first to say he doesn’t have all the answers.

“Earlier this year, we came across a molecular pathway that was hijacked by Zika and dengue fever, leading to each disease, but we lacked any way to block it,” Krogan said. “It just so happened that Jack Taunton, PhD, down the hall, had an inhibitor of the same pathway that he was using in an anti-cancer clinical trial. We hypothesized that this drug might have an effect on dengue and Zika, so we tried it, and sure enough, it completely kills dengue and Zika.”

At many institutions, specialists in cancer and infectious disease might never interact, but as investigators for the Quantitative Biosciences Institute (QBI) at UC San Francisco, Krogan and Taunton regularly bounce ideas off one another, and even share the occasional experimental reagents, if need be.

This sort of multidisciplinary collaboration was exactly what Krogan and UCSF School of Pharmacy Dean B. Joseph Guglielmo, PharmD, had in mind when QBI evolved in 2016 from an existing Organized Research Unit (ORU) which now, like then, reports through the School of Pharmacy. ORUs are academic units in the University of California system that exist to strengthen interdisciplinary research.

QBI’s inclusive approach to science is already reaping dividends: it now counts over 100 research labs as affiliates, and it has earned over $70 million in federal research funding from the National Institutes of Health (NIH) for ambitious projects in fields as disparate as psychiatry and cancer.

Unique among UCSF’s handful of ORUs, QBI attracts investigators on the basis of the tools and techniques they employ, rather than the diseases they study. This structure encourages scientists in different fields to share their newly developed tools, allowing progress in one field, like proteomics, to rub off on others, like neuroscience.

“QBI is disease agnostic,” said Guglielmo. “If the right people want to partner, QBI has a template for collaboration that works, and they’re good at it.”

Under the leadership of Krogan, who is the director of QBI and a faculty member in the School of Medicine’s Department of Cellular and Molecular Pharmacology, the organization has pioneered new ways for scientists of all biomedical disciplines to find the support they need to tackle ambitious projects, whether it’s financial, technical, or professional.

“We created an infrastructure within UCSF to accelerate science,” said Guglielmo. “It’s working, and it’s here to stay.”

Building tools for discovery

Beyond catalyzing scientific connections, QBI has also founded three large-scale research initiatives, which pursue collaborative, multi-institution grants for high-risk, high-reward projects, a type of funding that is typically out of reach for individual labs.

The Psychiatric Cell Map Initiative (PCMI), which launched earlier this year, received nearly $20 million in September from the National Institute of Mental Health to investigate psychiatric disease. Founded with support from the UCSF Department of Psychiatry in collaboration with Jeremy Willsey, PhD, and Matt State, MD, PhD, PCMI is hunting for a new generation of treatments for everything from autism spectrum disorder to schizophrenia, drawing on the expertise of nearly a dozen experts ranging from biochemists to psychiatrists.

“We know very little about the underlying biology behind these psychiatric disorders,” said Krogan. “Only recently has it become apparent which sets of genes are mutated in autism or schizophrenia or Tourette’s syndrome, but we still do not understand how these mutations lead to disease. Anything we find has the potential to be groundbreaking.”

Like PCMI, QBI’s other major initiatives have themselves each earned multi-million-dollar grants from the NIH over the last two years. The Cancer Cell Map Initiative (CCMI), founded in collaboration with UC San Diego and Trey Ideker, PhD, was awarded $10 million from the National Cancer Institute in 2017, with the goal of mapping the molecular interactions that lead to cancer.

D. Berger, S. Seung, MIT; G. J. Lichtman, Harvard

3D reconstruction of neurons in the mouse brain, courtesy of Zeiss. PCMI aims to map the signaling pathways that give neurons their unique structures and functions for the purpose of understanding and fighting psychiatric disease.

Similarly, two awards under the umbrella of the Host-Pathogen Map Initiative (HPMI), founded in collaboration with UC Berkeley and Jeffrey Cox, PhD, were awarded a total of $33 million from the National Institutes of AIlergy and Infectious Diseases and the National Institute of General Medical Sciences to explore molecular mechanisms behind infectious diseases, including HIV and tuberculosis.

Over the past few years, scientists worldwide have become interested in cellular mapping, a broad approach that uses DNA or RNA sequencing to take a census of the body’s many cell types. With its own three cell mapping initiatives, QBI is taking this approach one step further, by mapping out the interactions between proteins that allow living cells to carry out their functions. Studying the resulting map of protein networks is akin to observing the construction of a building, instead of merely studying its blueprint.

“By focusing on these protein networks, we can now study the functional basis of disease,” said Krogan.

Intriguingly, early findings across the three initiatives appear to bind them together. “We’re starting to see that there’s overlap among the genes being mutated in autism and the genes we’re studying in cancer, HIV, tuberculosis, dengue, and Zika,” he said.

The observation suggests that many different diseases may result from problems with just a handful of important proteins, Krogan explains, which could open up new treatment possibilities for an array of seemingly disconnected diseases.

The discoveries are important, but the tools that QBI investigators are developing and improving on, like mass spectrometry techniques for identifying every protein in a cell, will be used by scientists around the world.

Extending opportunities to women

QBI has also made a concerted effort to support the work of female scientists, who have historically been underrepresented in leadership roles in the quantitative biosciences.

Jacqueline Fabius, the chief operating officer of QBI, who most recently managed development projects in Haiti for the United Nations, was the driving force behind the creation of QBI’s Scholarship for Women from Developing Nations in Biosciences, according to Krogan. The scholarship provides a year of funding to an early-career female scientist from a developing country.

QBI

From left: Jacqueline Kyosiimire-Lugemwa, PhD; Nevan Krogan, PhD; and Jacqueline Fabius. The three met in Uganda in 2017 to discuss Kyosiimire-Lugemwa’s interest in QBI’s Scholarship for Women from Developing Nations in Biosciences.

“In science, unlike politics, we have the privilege of ignoring borders,” said Fabius. “By empowering a woman scientist, we enable her to climb the difficult career ladder that is often found in male-dominated sectors in developing nations.”

The scholarship’s first recipient, Jacqueline Kyosiimire-Lugemwa, PhD, wasn’t even sure that she should continue to pursue her career in science when she applied for the QBI scholarship. As a post-doctoral researcher living in Uganda, her career was stagnating with no opportunities for advancement, and she was losing her drive.

Kyosiimire-Lugemwa arrived in San Francisco in January 2018, and with the help of QBI and the Krogan Lab, has found new inspiration for her work on “long-term non-progressors” with HIV, or people who seem to resist the progression of HIV into AIDS.

“Slowly but surely, through my experiences at QBI and UCSF, I am reviving my career in science. It takes hard work, but it’s achievable,” said Kyosiimire-Lugemwa.

QBI also provides professional opportunities for more-senior female scientists. Danielle Swaney, PhD, and Ruth Huttenhain, PhD, were each recently promoted to the position of assistant adjunct faculty members within Krogan’s lab as well as QBI. The role allows Swaney and Huttenhain to each lead a small research team and focus on their scientific ideas, while using the resources available in the Krogan lab, rather than having to build their own, independent labs.

“The structure here allows me to have independence as a professor but not all the risk of having my own lab,” said Swaney.

Gina Nguyen

Ruth Huttenhain, PhD (left), and Danielle Swaney, PhD (right), are jointly organizing the QBI UCSF Mass Spectrometry Symposium, seeking to attract a diverse array of speakers.

Swaney studies cancer under the auspices of CCMI, while Huttenhain works on neuroscience questions for PCMI. But their shared expertise in mass spectrometry, a technique that allows scientists to study all the proteins present in cells, has brought them together to organize the QBI Mass Spectrometry Symposium, slated for February 2019. One of their goals has been to draw speakers and attendees across the many sub-disciplines of mass spectrometry.

So far, they’ve also managed to attract a balanced roster of male and female speakers in mass spectrometry, a sign of how the profession is changing.

“Today, there’s much higher female representation in the next generation of leaders in mass spectrometry,” said Swaney. “These female scientists are well accepted in the field and they do fantastic science, and it has made recruiting stellar scientists easier while supporting diversity.”

A public mission to advance science

QBI is striving to not only change how science is done, but also to ensure that science makes an impact on the world at large. To that end, Krogan and Fabius have dedicated considerable time and effort toward QBI’s public outreach, which includes a robust online presence and a variety of live events.

Gina Nguyen, QBI’s communications specialist, is the personality behind QBI’s social media and events. “For our Instagram campaign, our summer intern interviewed 68 of our investigators, and we release these interviews each week to show the human side of the scientist,” she said. “When one of them wins an award, I interview them on the spot soon afterward. Sometimes all it takes is a human face and a little humor to show that QBI is a thriving community.”

Gina Nguyen

An example of QBI’s outreach on Twitter (@QBI_UCSF): “QBI staff scientist Manon Eckhardt of @CancerCellMap and @GladstoneInst @UCSF was featured on @medresearchnews for her research which revealed a number of interesting pathways impacted in #HPV-associated cancers: https://medicalresearch.com/cancer-_-oncol … #WomanCrushWednesday.”

Krogan and Fabius have even taken QBI to the dinner party as well. As part of its public outreach, QBI has partnered with Susan MacTavish Best, who hosts salon events in San Francisco, New York City, and Washington, DC, featuring leading thinkers. A CCMI salon held last year in the nation’s capital attracted journalists, those involved in politics, as well as program officers from the National Institutes of Health and the Defense Advanced Research Projects Agency, who are increasingly cognizant of the need to break down silos in science. The conversations that transpired ultimately opened the door for PCMI to earn its multi-million-dollar institutional grant, according to Fabius.

“Every scientist is familiar with the thrill of discovery, of solving a mystery,” said Krogan. “We want to share that excitement with the world and demonstrate the impact that basic science can have on modern medicine.”

More

• NIH Funds UCSF-led Initiative to Chart a Course Toward New Psychiatric Drugs (UCSF News Center)

• Cell mapping initiatives aim to uncover hidden pathways of disease (UCSF News Center)