2018–2019 Highlights

The Beckman Center has enjoyed an exciting and productive year of scientific achievement. This year’s highlights include:

Paul Berg 2018 Commencement Speaker for the Stanford University School of Medicine Paul Berg, Ph.D., the Robert W. and Vivian K. Cahill Professor of Cancer Research, Emeritus, and the founding director of the Beckman Center for Molecular and Genetic Medicine, gave the keynote address at the Stanford School of Medicine’s 110th Commencement on June 16, 2018.

A world renowned biochemist, educator and advocate for scientific freedom, Berg shared the 1980 Nobel Prize in Chemistry for his work creating the first recombinant DNA molecule. During his talk to the Class of 2018, Berg emphasized the indispensable role of investigation and charged the graduates to, “aim high and keep learning, be skeptical of accepted certainty and stay fast in the belief that facts matter.”

2018 (Fall) Beckman Symposium This year’s annual symposium took place on September 10, 2018. Titled, “The Revolution in Diagnostics,” it attracted a large audience. Research presentations were made by some of the world’s leading scientists on topics such as single cell DNA sequencing, liquid biopsies for cancer and fetal DNA, implantable devices, state-of-the-art imaging technologies and other technological breakthroughs that are opening up whole new worlds of diagnostic possibility.

Speakers included Ash Alizadeh, M.D., Ph.D. (Stanford University), Euan Ashley, M.D., Ph.D. (Stanford University), Joseph DeRisi, Ph.D. (UCSF), Sanjiv “Sam” Gambhir, M.D., Ph.D. (Stanford University), Kari Nadeau, M.D., Ph.D. (Stanford University), Stephen Oesterle, M.D. (New Enterprise Associates), and Stephen Quake, D.Phil. (Stanford University). Drs. Stephen Quake and Lucy Shapiro served as hosts. The symposium dinner was hosted by former Secretary of State George Shultz at his campus home.

New Technology Development Grants Awarded The Beckman Center awarded five new interdisciplinary Technology Development Grants in the Biomedical Sciences. The grants will support the development of new and improved instruments or devices, or the development of new methodologies to be used in biomedical research. Each seed grant provides funding of $100,000 per year for a two-year period.

Applicants to the Technology Development Grant Program were encouraged to submit proposals that had a disease focus, involved collaboration between basic and physician scientists, and had a translational medicine (bench-to-bedside) emphasis.

Twenty-six outstanding grant applications were submitted from 62 faculty members representing 37 separate disciplines drawn from the Schools of Medicine, Engineering, and Humanities and Sciences. The selection committee was composed of Beckman Center Advisory Board members.

Beckman Faculty Member Finds Hidden DNA Sequences Tied to Schizophrenia, Bipolar Risk Dr. David Kingsley, professor of developmental biology, and a Howard Hughes Medical Institute investigator, has discovered that a series of repeated DNA sequences unique to humans may be linked to the development of schizophrenia and bipolar disorder.

The finding suggests that the rapid evolutionary changes that led to the extraordinary complexity of the human brain may have predisposed our species to psychiatric diseases not found in other animals.

Although the sequences exist within a small stretch of DNA that has been previously linked to schizophrenia and bipolar disorder, they represent a kind of genomic stutter that is particularly difficult to detect using conventional sequencing methods.

“The human genome reference sequence shows only 10 repeats of this 30-nucleotide sequence, but we’ve found that individuals actually have from 100 to 1,000 repeats, and that the sequence itself can vary,” said Kingsley. “In contract, chimpanzees and other primates have just one repeat of the sequence, indicating that the region has greatly expanded during human evolution. Some of the sequence variants now found in people are also closely associated with the development of schizophrenia and bipolar disorder.”

The study also outlines a possible way to one day identify people at risk for, and ways to intervene in, these disorders.

Beckman Faculty Member Finds That in Apoptosis, Cell Death Spreads Through Perpetuating Waves Dr. James Ferrell, professor of biochemistry and of chemical and systems biology, and his research group, have found that inside a cell, death (apoptosis) often occurs like the wave at a baseball game. This kind of a rolling surge, spurred by the activity of one or a few things, is known as a trigger wave.

Once cell death is initiated, by way of disease or something else, specific killer proteins in the cell, called caspases, activate. These proteins then float to other caspases and activate them; those follow suit until the entire cell is destroyed. To see how death takes over a single cell, Ferrell and his group used Xenopus frog eggs. One egg is a single cell and as cells go, these are enormous, making them a prime candidate to observe how death spreads from one end of the cell to the other, which can be done with the naked eye.

By using a fluorescent technique linked to the activation of apoptosis, Ferrell could watch as the bright green glow moved its way down the tube at a constant speed, indicating that apoptosis was spreading via trigger waves, as opposed to some other more rudimentary mechanism, such as diffusion, which slows down as it moves.

Now, they’re asking whether trigger waves might be responsible for how our innate immune response spreads from cell to cell.

Beckman Faculty Member Discovers New Algorithm That Could Improve Diagnosis of Rare Diseases Today, diagnosing rare genetic diseases requires a slow process of educated guesswork. Dr. Gill Bejerano, associate professor of developmental biology and of computer science, is working to speed it up.

Bejerano and his research group have developed an algorithm that automates the most labor-intensive part of genetic diagnosis: that of matching a patient’s genetic sequence and symptoms to a disease described in the scientific literature. Without computer help, this match-up process takes 20-40 hours per patient.

The algorithm developed by Bejerano’s team cuts the time needed by 90%. The algorithm also holds potential for helping doctors identify new genetic diseases, Bejerano said. For example, if a patient’s symptoms can’t be matched to any known human diseases, the algorithm could check for clues in a broader knowledge base.

Beckman Faculty Member Able to Predict Osteoporosis, Fracture Risk with Genetic Screen A new genetic screen developed by Dr. Stuart Kim, emeritus professor of developmental biology, may predict a person’s future risk of osteoporosis and bone fracture.

Specifically, the study, one of the largest of its kind, identified 899 regions in the human genome associated with low bone-mineral density, 613 of which have never before been identified.

People deemed to be at high risk – about 2% of those tested – were about 17 times more likely than others to develop osteoporosis and about twice as likely to experience a bone fracture in their lifetimes. In comparison, about 0.2% of women tested will have a cancer-associated mutation in the BRCA2 gene, which increases their risk of breast cancer to about six times that of a woman without a BRCA2 mutation.

Early identification of people with an increased genetic risk for osteoporosis could be an important way to prevent or reduce the incidence of bone fracture, which according to the National Osteoporosis Foundation affects 2 million people each year and accounts for $19 billion in annual health care costs.

“There are lots of ways to reduce the risk of a stress fracture,” said Kim. “But currently there is no protocol to predict in one’s 20s or 30s who is likely to be at higher risk, and who should pursue these interventions before any sign of bone weakening. A test like this could be an important clinical tool.”

Beckman Faculty Member Deploys Worms to Investigate How Neurological Drugs Work There are drugs derived from plans to treat epilepsy, to prevent migraines and to halt manic episodes in people with bipolar disorder. But in many cases, no one knows exactly how those and other neurological drugs work – what chemical processes in the brain those drugs alter, or sometimes even what the active ingredients are.

Dr. Miriam Goodman, professor of molecular and cellular physiology, along with her collaborators Sue Rhee, Ph.D., and Thomas Clandinin, Ph.D., propose to use a tiny roundworm called Caenorhabditis elegans as the perfect platform for studying these questions. C. elegans are much simpler than humans, but have a lot of genetic similarities.

The team will start with a large collection of C. elegans worms containing a range of genetic mutations and a plant called valerian, extracts of which are now used in drugs to treat epilepsy and which have been used for thousands of years to treat mild anxiety.

When the team exposes their worms to valerian extracts they’ll watch to see which ones wiggle closer and which flee, as they sort themselves according to their genetically encoded responses. The researchers will then look to see which genes are responsible for that behavior.

The hope is to use these experiments not just to understand the genetic and neural pathways through which plant extracts and plant-derived drugs work, but also to discover new drugs.

Beckman Faculty Member Teams Up with Colleagues to Fight Common Viral Infection in Kidney Transplant Recipients Dr. Mark Davis, professor of microbiology and immunology, and Howard Hughes Medical Institute investigator, along with his colleagues, Olivia Martinez, Ph.D., and Stephan Busque, M.D., have joined forces to learn how immune cells in some kidney transplant patients fight a common virus.

The work could lead to a test to predict who is at risk for potentially deadly infections like cytomegalovirus (CMV), and possibly develop new treatments.

The researchers plan to examine special immune cells, called T cells, in two groups of transplant patients – one with CMV disease and one without. To find out why T cells aren’t always successful in controlling viral infection, the team will analyze T cells in blood samples taken from one group of transplant recipients in whom the virus is under control, and another group in whom CMV is reactivated. The researchers will sequence the proteins that dot the outside of T cells and recognize infections – there are billions of such sequences – in order to find combinations that are present in one group of patients, but not the other.

Results from the study will not only help develop better tools for identifying transplant patients at risk of CMV disease, but give researchers a better understanding of basic characteristics of viral immunity and vaccine design.

Beckman Faculty Member Reveals the Molecular Mechanism Underlying Hypertrophic Cardiomyopathy About 1 in every 500 people is born with hypertrophic cardiomyopathy, a genetic disease caused by any one of numerous mutations that, mysteriously, cause heart muscle to contract with too much force. Now, researchers led by Dr. James Spudich, professor of biochemistry, have discovered the mechanism behind this workaholic heart.

The protein myosin is a motor of sorts, whose dynamic action contributes to the overall contraction of a muscle. But it only works part-time, spending much of its existence in a posture akin to that of a sleeping flamingo, with its head tucked tightly into its torso. This is typical of normal heart function.

Spudich and his colleagues discovered that many mutations associated with hypertrophic cardiomyopathy, although they occur at different points along the myosin gene’s sequence, often wind up affecting the amino acids on the same surface of the folded protein’s outer edge, altering the myosin molecule in ways that coax it out of its sleeping flamingo posture.

The changed postural preference, in turn, keeps the myosin molecule from spending enough time snoozing on the job, collectively causing constant overdrive in the heart muscle’s power output.

Beckman Faculty Member Uncovers Puzzle of a Mutated Gene Lurking Behind Many Parkinson’s Cases Genetic mutations affecting a single gene play an outsized role in Parkinson’s disease. The mutations are generally responsible for the mass die-off of a set of dopamine-secreting, or dopaminergic, nerve cells in the brain involved in physical movement.

The pathogenic variants of the gene, LRRK2, share a common tendency: they cause the protein it encodes to run in constant overdrive, upsetting the delicate balance of a healthy cell.

Dr. Suzanne Pfeffer, professor of biochemistry, and her colleagues, have previously reported that mutant LRRK2 renders some classes of nerve cells deficient in their ability to create an important subcellular structure called the primary cilium. In the new study, Pfeffer and her research team discovered that cells lacking primary cilia are unable to respond to a powerful chemical messenger known as sonic hedgehog. Secondly, the scientists learned, the types of cells that can’t make a decent primary cilium when their LRRK2 protein is in overdrive include a set of cholinergic nerve cells. And these cholinergic cells have a close working relationship with the dopaminergic cells implicated in Parkinson’s disease.

So an LRRK2 protein in overdrive leads to no primary cilia, which leads to no response to the sonic hedgehog signal, which leads to no chemical help for the dopaminergic cells and therefore, to their death.

Could the breakdown of that support system underlie the unrelenting loss of dopaminergic cells in Parkinson’s? Pfeffer’s lab is now studying that very question.

The Cell Sciences Imaging Facility (CSIF) Dr. Joanna Wysocka, the Lorry Lokey Professor in the School of Medicine, professor of developmental biology, and of chemical and systems biology, and Howard Hughes Medical Institute investigator, received an HHMI grant award in the amount of $972,126 for the purchase of an Intelligent Imaging Innovations (3i) V2 Lattice Light Sheet Microscope (LLSM), that facilitates high spatiotemporal resolution live-cell imaging with minimal photo damage.

The instrument will be housed in the CSIF and available to researchers across the Stanford campus.

The LLSM technology delivers much lower light dosage while achieving signal-to-noise ratios that are equal to or higher than other conventional live-cell imaging modalities. It has the advantage of 1) minimizing photobleaching of the fluorophores and thus lowers the requirement of extensive optimization of fluorophores used for labeling, and 2) it greatly minimizes phototoxicity and thus extends typical imaging time by at least an order of magnitude with uncompromised frame rates.

The School of Medicine’s Dean’s Office is contributing startup funding to staff the services provided on this new instrument. Installation is scheduled for summer 2019.

With financial support from the Beckman Center, the School of Medicine’s Dean’s Office and the Stanford Cancer Institute, the CSIF has purchased a CODEX, highly multiplexed imaging platform together with an epifluorescence microscope and analysis workstation. This combined instrument will allow automated, highly multiplexed, antibody localizations of potentially an unlimited number of proteins on tissue sections or tissue arrays, with cellular level of resolution. The CODEX instrument will provide greatly increased throughput and analysis of multiple cancer, neurological and other tissue specific markers which will allow phenotypic cluster analysis of different cell types within their spatial context. The facility will provide image analysis and pipeline development support, as well as, develop and validate antibody panels for research groups. The CSIF’s CODEX service will start in early 2019.

In collaboration with the Otolaryngology Department at the Medical School, the CSIF has purchased a Leica ICE High Pressure Freezer (HPF) with the capacity to do optogenetic light and electrical stimulation. This new HPF will allow larger, thicker sample loading for ice-free vitreous ice freezing, the gold-standard for cell preservation than previously available and will be used for advanced ultrastructural and immuno- EM localization studies in the EM lab. This new instrument was installed in December 2018.

Fluorescence Activated Cell Sorting (FACS) Facility The FACS Facility has continued to grow at a rapid pace and has continued to add instruments to provide the latest technologies and easy access for researchers.

Using funds provided by the Beckman Foundation, the facility has added a spectral analyzer. This instrument measures fluorescence using the full emission spectra rather than each dye’s peak spectra.

Using this approach, this new instrumentation offers unique flexibility in the reagent combinations that can be used simultaneously. In its current iteration, the spectral cytometer enables 20+ colors excited by only 3 lasers. Two additional lasers are already slated for further upgrade of this instrument in 2019.

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2018–2019 Highlights

The Beckman Center has enjoyed an exciting and productive year of scientific achievement. This year’s highlights include:

Highlights from Previous Years

2017 - 2018

2016 - 2017