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Clinical Trials, Research, Science, Stanford News

SPARK program helps researchers cross the “valley of death” between drug discovery and development

SPARK program helps researchers cross the “valley of death” between drug discovery and development

Mochly-RosenSeveral years ago, Stanford neuroscientist Craig Garner, PhD, found himself facing a common problem for researchers: figuring out how to cross the so-called “valley of death” between drug discovery and development. In his case, he wanted to get pharmaceutical companies interested in funding his lab’s promising new Down syndrome treatment.

The answer was SPARK, a hands-on training program that assists scientists in moving their discoveries from bench to bedside. The program was created by Daria Mochly-Rosen, PhD, after she experienced challenges in getting her own entrepreneurial venture off the ground. A story published in yesterday’s Inside Stanford Medicine explains how Mochly-Rosen and a group of industry experts search hundreds of patents submitted to the university’s Office of Technology Licensing and select projects, such as Garner’s, that could benefit from SPARK’s help. My colleague Ranjini Raghunath writes:

Since SPARK’S founding, 51 research teams have “graduated” from the program. More than half of its projects have been licensed or have advanced to clinical use, or both, in sharp contrast to the pharmaceutical industry’s own success rate of approximately five percent. With SPARK’s support, a research team led by dermatologist Alfred Lane, MD, has received a fund- able score on a food and Drug Administration orphan grant for phase-2 trials of a repurposed drug to treat lymphatic malformations that disfigure and disable children. Another team, led by immunologists William Robinson, MD, PhD, and Jeremy Sokolove, MD, is testing a combination of drugs to treat early stages of cartilage loss and joint degeneration in bone arthritis. findings of a third research team led by bioinformatics expert Atul Butte, MD, PhD, and Bruce Ling, PhD — biomarkers for detecting dangerously high blood pres- sure in pregnancy — have already been picked up for licensing by a start-up biotechnology company. Former SPARK beneficiaries, or “SPARKees,” have credited the program with helping them get research grants, publish papers in reputable journals and even land a tenure-track position, Mochly-Rosen said.

The piece goes on to note that universities around the world have launched, or are developing, their own SPARK programs. Mochly-Rosen’s overall goal for the program is to integrate Stanford and other institutions’ programs under one brand and use it to attract commercial investors to support early-stage research discoveries.

Previously: Director of NIH discusses accelerating translation of biomedical research into clinical applications, Re-engineering the drug-development process to speed medical advances, Why drug development is time consuming and expensive (hint: it’s hard) and A glimpse at the price of drugs: Why they cost what they cost
Photo of Daria Mochly-Rosen by Steve Gladfelter

Cancer, Research, Science, Stanford News, Stem Cells

Cellular culprit identified for invasive bladder cancer, according to Stanford study

Cellular culprit identified for invasive bladder cancer, according to Stanford study

Beachy image resizedInvasive bladder cancer is a grim disease that is expensive to treat and requires ongoing monitoring due to its high probability of recurrence. Stanford developmental biologist Philip Beachy, PhD, and urologist Michael Hsieh, MD, PhD, wanted to know how the cancer starts, and what makes it so intractable. Their research was published yesterday in Nature Cell Biology (subscription required).

As Beachy explained in the release I wrote:

We’ve learned that, at an intermediate stage during cancer progression, a single cancer stem cell and its progeny can quickly and completely replace the entire bladder lining. All of these cells have already taken several steps along the path to becoming an aggressive tumor. Thus, even when invasive carcinomas are successfully removed through surgery, this corrupted lining remains in place and has a high probability of progression.

In the photo above, the blue cells are progeny of just one cancer-initiating cell in the basal cell layer of the bladder lining. They’ve “elbowed out” their neighbors to take over the lining. The cells, and the cancers that arise, have a distinctive gene-expression profile. More from our release:

Although the cancer stem cells, and the precancerous lesions they form in the bladder lining, universally express an important signaling protein called sonic hedgehog, the cells of subsequent invasive cancers invariably do not — a critical switch that appears vital for invasion and metastasis. This switch may explain certain confusing aspects of previous studies on the cellular origins of bladder cancer in humans. It also pinpoints a possible weak link in cancer progression that could be targeted by therapies.

Hsieh, who has treated many patients with this type of bladder cancer, explained to me the significance of the finding:

This could be a game changer in terms of therapeutic and diagnostic approaches. Until now, it’s not been clear whether bladder cancers arise as the result of cancerous mutations in many cells in the bladder lining as the result of ongoing exposure to toxins excreted in the urine, or if it’s due instead to a defect in one cell or cell type. If we can better understand how bladder cancers begin and progress, we may be able to target the cancer stem cell, or to find molecular markers to enable earlier diagnosis and disease monitoring.

Previously: Is the worm turning? Early stages of schistosomiasis bladder infection charted, Mathematical technique used to identify bladder cancer marker and Bladder infections–How does your body repair the damage?
Photo by Kunyoo Shin, PhD

Science, Technology

Survey says: Americans split on the future of science

Mechanics of Time TravelIf you’re feeling sciencey, check out a Pew Research Center survey completed with Smithsonian Magazine and released yesterday. You’ll see the percentage of Americans surveyed who would welcome or dismiss personal robots servants, driverless cars or other futuristic possibilities, given the options.

piece published on the blog re/code reports:

Asked what inventions they most want to take advantage of themselves, participants repeatedly landed on three themes: Medical strides that extend human longevity, flying cars or personal space crafts, and time travel.

On the other hand, nearer realities like robot caregivers, face computers, genetic engineering and drones seem to give a lot of people the heebie-jeebies. Among the findings:

  • 65 percent think it would be a change for the worse if lifelike robots become the primary caregivers for the elderly and people in poor health.
  • 63 percent think it would be a change for the worse if personal and commercial drones are given permission to fly through most U.S. airspace.
  • 53 percent think it would be a change for the worse if most people wear implants or other devices that constantly show them information about the world around them.

What do you think?

Previously: Using personal robots to overstep disabilityHelping the public make sense of scientific research and Hey, president-to-be: What are your views on science?
Via Kara Swisher
Photo by Bob Owen

Research, Science, Stanford News

Getting a glimpse of the shape molecules actually take in the cell

Getting a glimpse of the shape molecules actually take in the cell

Working at a medical school, every day I talk to scientists who are discovering ever more intricately detailed information about our bodies and our cells. With these daily amazements about what we do know, it’s always good to be reminded of how much is still unknown.

Case in point, I recently talked with Xuesong Shi, PhD, a postdoctoral fellow in the lab of biochemist Dan Herschlag, PhD. He has been trying to understand the many configurations and structures molecules and complexes of molecules take on. This may seem a bit abstract, but what the molecules look like – how many different shapes they fold into and how they interact with each other – can provide information that explains both how molecules behave normally, and also why they fail to work properly in some diseases.

For a long time now most of the information we have about the shape and structure of molecules came from turning those molecules into crystals of rigidly packed, identical structures. That’s a technique called X-ray crystallography, which people at Stanford carry out using the powerful X-ray beams at SLAC.

Herschlag points out that X-ray crystallography has been extremely valuable for helping scientists understand the molecules that make up our cells. But the crystals don’t necessarily give the whole picture. For example, molecules are thought to take on many different shapes when forming complexes, not just the single shaped found in a crystal. “The idea is that molecules have many forms in solution,” Shi said. Some molecules also don’t form crystals well.

Shi has been tackling this problem using an X-ray interferometry technique developed in the lab of biochemist Pehr Harbury, PhD, who collaborated with Herschlag and Shi on the work. It involves attaching tiny gold particles to known locations on molecules – in this case a snippet of DNA. Then, by using X-rays to look at where the gold particles are in relation to each other, scientists can piece together the myriad shapes the molecules take on when freed from a crystal lattice.

Shi was first author on a paper published online March 31 in the Proceedings of the National Academy of Sciences describing this technique. He told me that although that paper investigated the structure of DNA, he hopes to use the technique to better understand a variety of molecules where knowing the myriad shapes the molecule takes on is essential for understanding its function.

Applied Biotechnology, Bioengineering, Global Health, Microbiology, Science

The pied piper of cool science tools

The pied piper of cool science tools

Kid-scopeWhen Stanford bioengineer Manu Prakash, PhD, and his students set out to solve a challenging global health problem, the first order of business is to have fun.

“We’re a curiosity-driven lab,” says Prakash, as he sits in his office overflowing with toys, gadgets, seashells and insect exoskeletons.

In the last month, Prakash introduced two new cool science tools — a 50-cent paper microscope and a $5 programmable kid’s chemistry set. The response from fellow science lovers, compiled on this Storify page, has been amazing.

Already, 10,000 kids, teachers, health workers and small thinkers from around the globe have signed up to receive build-your-own-microscope kits. Thousands more have sent us e-mails describing the creative ways they’d use a microscope that they could carry around in their back pockets.

For the love of science, here are a few of these inspirational e-mails:

I would love to have one. I’m only in 6th grade but I love science. I hope to visit the moon one day. — Raul

I am an electrical engineer from Kenya and have never used a microscope in all my life. But what I would really like to do is to avail the foldscope to students in a primary school that I am involved in mentoring. This apart from hopefully inspiring them in the wonders of science, would enable the students see the structure of the mosquito proboscis, a malaria-spreading agent in this part of the world. I would also like to look at the roots of mangrove trees and see the structure that enables them to keep sea water salts out. — Macharia Wanyoike

This is brilliant! I am in science and nanotechnology education and my wish is for South African rural children, Namibia, Zimbabwe, Botswana to all have these microscopes! It will be amazing. — Professor Sanette Brits, University of Limpopo, South Africa

waterbearI am studying how magnetic fields at different frequencies affect water bears. They are very difficult to find and it would be great if I had a tool to help me find them that is  portable while searching for them. I have digital motic microscope phase contrast and darkfield microscopes but nothing portable. — Edward W. Verner (Water bear shown to the left.)

I could use it to check if patients have scabies. Or if I were visiting remote monasteries in the Himalayas where they have outbreaks. I’d definitely pack it. For myself I’d use it on nature walks. GREAT ACCOMPLISHMENT for mankind. Congratulations. — Linda Laueeano, RN

Hi! I am a high school student from South Korea. While I was searching for interesting project, I saw your video. It was very amazing and I can’t believe that only one dollar can save hundreds and thousands people who were suffering from malaria and other diseases that can be found by your “foldscope”. I really love to study about your project and I had already read your thesis. Truly, it was hard to understand everything, but I really tried hard and I discussed this issue for more than a week with my science club. We are group of 10 people and we are eager to do this project. Also I really appreciate you to do this wonderful thing for poor kids in many other countries. Thanks. — Joung Yeon Park

I am assisting a K-12 community school with creating a STEAM Innovation Knowledge HUB, as they are trying to move their Common Core Curriculum into a STEM to STEAM driven program. It would be great to receive several Foldscopes or be able to purchase. Please contact me ASAP. Congratulations on a great new support product and great innovation. Thank you, smile. — Dr. Dion N. Johnson, Wayne State University

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Cardiovascular Medicine, Nutrition, Science

What’s not to love? Chocolate’s feel-good chemicals

Cabdury2Spring is here and symbols of new life abound. If Cadbury Cream Eggs (yes, gross, but I love them anyway) and Mini Eggs on drugstore shelves have you, too, thinking about chocolate, check out this piece in the Washington Post on the history and chemistry of the “feel-good” components of the stuff, including “the world’s most widely consumed psychoactive drug,” caffeine.

Chemist Simon Cotton, PhD, writes:

Another chocolate molecule believed to be important was discovered less than 20 years ago: anandamide. This binds to receptors in the brain known as cannabinoid receptors. These receptors were originally found to be sensitive to the most important psychoactive molecule in cannabis, Δ9-THC. Likewise, anandamide and similar molecules found in chocolate are also thought to affect mood.

Phenylethylamine, another family of chemicals, is found in chocolate in very small amounts. It is a naturally occurring substance with a structure that is closely related to synthetic amphetamines, which of course, are also stimulants. It is often said that our brain produces phenylethylamine when we fall in love. It acts by producing endorphins, the brain’s natural “feel-good” molecules. The bad news, however, is that eating chocolate is probably not the best way of getting our hands on phenylethylamine as enzymes in our liver degrade it before it can reach the brain.

There are other molecules in chocolate – especially in dark chocolate – such as flavonoids, which some scientists think may help improve cardiovascular health. But chocolate manufacturers have been known to remove bitter flavanols from dark chocolate.

One last feel-good factor, which isn’t a molecule: the melt-in-your mouth sensation. The fatty triglycerides in cocoa butter can stack together in six different ways, each resulting in a different melting point. Only one of these forms has the right melting point of about 34 degrees, so that it “melts in your mouth, not in your hand.” Getting the chocolate to crystallize to give this form is the product of very careful chocolate engineering.

I’m curious to know what kinds of chemicals give the sugary “whites” and “yolks” of the cream eggs their appeal, though maybe it’s better kept a foil-wrapped secret.

Previously: When caffeine dependence affects quality of lifeDo you (heart) chocolate? Evaluating the cocoa “prescription” for cardiac health and Mapping the DNA of wild strawberries and fine chocolate
Photo by Joel Kramer

Cancer, Genetics, Patient Care, Research, Science, Stanford News

Blood will tell: In Stanford study, tiny bits of circulating tumor DNA betray hidden cancers

Blood will tell: In Stanford study, tiny bits of circulating tumor DNA betray hidden cancers

5507073256_36387f3df9_zBlood is a remarkable liquid. Not only does it carry red blood cells to deliver oxygen, it also transports cells of the immune system to protect us from infection. But there’s another, hidden payload: bits of genetic material derived from dying cells throughout the body. In a patient with cancer, a tiny fraction of this circulating DNA comes from tumor cells.

Now researchers in the laboratories of Stanford radiation oncologist Maximilian Diehn, MD, PhD, and hematologist and oncologist Ash Alizadeh, MD, PhD, have found a way to read these genetic messages and use them to diagnose lung tumors and monitor how they respond (or don’t) to treatment. The technique is highly sensitive and should be broadly applicable to many types of solid tumors. It also bypasses some of the more fussy patient-optimization steps that have previously been required.

From our release:

“We set out to develop a method that overcomes two major hurdles in the circulating tumor DNA field,” said [Diehn]. “First, the technique needs to be very sensitive to detect the very small amounts of tumor DNA present in the blood. Second, to be clinically useful it’s necessary to have a test that works off the shelf for the majority of patients with a given cancer.”

“We’re trying to develop a general method to detect and measure disease burden,” said Alizadeh, a hematologist and oncologist. “Blood cancers like leukemias can be easier to monitor than solid tumors through ease of access to the blood. By developing a general method for monitoring circulating tumor DNA, we’re in effect trying to transform solid tumors into liquid tumors that can be detected and tracked more easily.”

Using their technique, the researchers were able to identify 50 percent of patients with Stage I cancers, and all patients with more advanced disease. The research was published Sunday in Nature Medicine.

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Clinical Trials, Nutrition, Science, Stanford News

Bad news for pill poppers? Little clear evidence for Vitamin D efficacy, says Stanford’s John Ioannidis

Bad news for pill poppers? Little clear evidence for Vitamin D efficacy, says Stanford's John Ioannidis

Vitamin DVitamin D is a darling of the supplementation world. Deficiencies in the vitamin have been blamed for all manner of ailments, including diseases of the skeletal system, autoimmunity, infections and cancer.

Now researchers from the University of Edinburgh, Imperial College London and the University of Ioannina School of Medicine in Greece have analyzed 107 systematic literature reviews and 161 meta-analyses regarding vitamin D supplementation or levels in blood plasma and the occurrence of 137 various medical outcomes. They’ve published their findings in today’s issue of the British Medical Journal, where they wrote:

In conclusion, although vitamin D has been extensively studied in relation to a range of outcomes and some indications exist that low plasma vitamin D concentrations might be linked to several diseases, firm universal conclusions about its benefits cannot be drawn.

In particular, the researchers found that the evidence does not support a role for vitamin D in increasing bone mineral density or reducing the risk of falls and fractures in older people. As senior author and Stanford study design expert John Ioannidis, MD, DSc, explained to me in an e-mail:

Vitamin D has been evaluated in thousands of studies in terms of its relationship to at least 137 health outcomes. We hope that systematic consideration of the available evidence will help avoid hot debate about health decisions involving vitamin D  that have mostly depended on speculations rather than evidence to-date.

Rather than writing off vitamin D altogether, the researchers note that additional, well-designed studies and trials are necessary before any firm conclusions can be drawn about its efficacy. The paper is accompanied by a second from researchers at the University of Cambridge analyzing relationships between vitamin D levels and the risk of mortality from several causes, as well as an editorial declaring that, despite much study, vitamin D is “no magic bullet.”

Previously: The Lancet documents waste in research, proposes solutions, “US effect” leads to publication of biased research, says Stanford’s John Ioannidis and Shaky evidence moves animal studies to humans, according to Stanford-led study
Photo by Colin Carmichael

Genetics, In the News, Research, Science, Stanford News, Technology

Policing the editor: Stanford scientists devise way to monitor CRISPR effectiveness

Policing the editor: Stanford scientists devise way to monitor CRISPR effectiveness

edited paperAs a writer, I think a lot about editing. Will this sentence work here? Maybe I should change this word. Argh – a typo! But I’m not alone. Biologists also appreciate the power of editing, particularly when it comes to modifying genes in cells or organisms.

Recently a powerful new technology has emerged (called CRISPR) that allows researchers to make small, precise and permanent changes in the DNA of animal and human cells. It builds on the concept of genome editing that is key to generating cells, cell lines or even whole animals such as laboratory mice, containing specific genetic changes for study. With CRISPR, however, researchers can generate in days or weeks experimental models that usually take months or years. As a result, they can quickly assess the effect of a particular gene by deleting it entirely, or experiment with repeated, tiny changes to its DNA sequence.

According to a recent New York Times article, scientists roundly agree that CRISPR is revolutionary. At least three companies have been launched in the mere 18 months since the first results were reported by researchers at the University of California, Berkeley and Umea University in Sweden, and more than 100 research papers based on the technique have been published. But, although it’s highly specific, it’s (sadly) not perfect. According to the New York Times piece:

Quick is not always accurate, however. While Crispr is generally precise, it can have off-target effects, cutting DNA at places where the sequence is similar but not identical to that of the guide RNA.

Obviously it’s important to know when (and how frequently) this happens. Unfortunately, that’s been difficult to assess.

Enter researchers in the laboratory of pediatric cancer biologist Matthew Porteus, MD, PhD. Porteus’s lab is interested in (among other things) learning how to a particular type of genome editing called homologous recombination to treat diseases like sickle cell anemia, thalassemia, hemophilia and HIV. They’ve devised a way to monitor the efficiency of genome editing by CRISPR (as well as other more-traditional genome editing technologies) that could be widely helpful to researchers worldwide. Their technique was published today in Cell Reports. As postdoctoral researcher Ayal Hendel, PhD, told me:

We have developed a novel method for quantifying individual genome editing outcomes at any site of interest using single-molecule real-time (also known as SMRT) DNA sequencing. This approach works regardless of the editing technique used, and in any type of cell from any species.

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Events, Science, Stanford News

A day in the lab: Stanford scientists share their stories, what fuels their work

A day in the lab: Stanford scientists share their stories, what fuels their work

Lab Crawl - smallRecently a notable group of Stanford faculty and students working in the basic sciences – where fundamental questions such as how we exist, how cells divide, and how the brain thinks – opened up their labs to a small group of visitors eager to learn more about their work.

Guests, including a number of aspiring young scientists, toured the labs and gained a rare, hands-on perspective of what it’s like to travel the journey of a basic scientist, a journey of sometimes unknown destination. Faculty, graduate, and post-doctoral students shared stories of how they came to do this type of work and what attracted them to the exploratory and collaborative nature of Stanford. Many spoke of frustration with the current trend of investing primarily in research with “proven outcomes” vs. the more fundamental, high-risk, high-reward work being done in labs like theirs.

A highlight of the day was a lunchtime talk by Adam de la Zerda, PhD. Adam is a talented young scientist who came to Stanford to study engineering but, spurred by a personal experience, he instead went on to bridge the gap between engineering and medicine to develop and patent a technology that converts light waves into ultrasound waves using nanoparticles. Called photoacoustic molecular imaging, the process generates images with unprecedented resolution compared to current methods such as computed tomography or magnetic resonance imaging. The technology, soon entering the human-trial phase, has the potential to revolutionize tumor detection and removal. Adam credits his success to the freedom he was given at Stanford to pursue his passion, thanks to early supporters and mentors who were willing to take a risk on his yet-unproven work and talents.

Lab Crawl2 - smallOther faculty members and students who shared their research that day were working on a wide variety of innovative projects, including developing new approaches to gene therapy, genetics, and deep sequencing; analyzing DNA breaks to anticipate disease; better understanding touch, the least understood of the five senses; and analyzing the effects of salmonella to more effectively prevent and fight the disease in developing areas.

Hosting the day was Dan Herschlag, PhD, senior associate dean of graduate education and postdoctoral affairs at Stanford, who told the visitors, “It’s this kind of research, focused on innovative but unproven avenues of investigation and disruptive ideas, that will bring us to places we’ve never known before, help launch new industries, and usher forth new drugs and therapies to treat the most intractable illnesses.”

Eileen DiFranco is director of communications and media in the Office of Medical Center Development at Stanford.

Previously: The lure of research: How Nobel winner Thomas Südhof came to work in the basic sciences, The “sky’s the limit” for young Stanford structural biologist, Funding basic science leads to clinical discoveries, eventually and Why basic research is the venture capital of the biomedical world
Photos by Steve Fisch

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