A few years ago, Stanford pharmacogenomic expert Gary Peltz, MD, PhD, collaborating with researchers in Japan, developed a line of bioengineered mice whose livers were largely replaced with human liver cells that recapitulate the architecture and function of a human liver. Now, in a recent study published in PLoS Medicine, Peltz’s team has shown that routine use of this altered lab mouse in standard toxicology tests preceding clinical trials would save human lives.

Among the liver’s numerous other job responsibilities, one of the most important is chemically modifying drugs in various ways to make them easier for the body to get rid of. But some of those chemical products, or metabolites, can themselves be quite toxic if they reach high levels before they’ve been excreted.

The Food and Drug Administration requires that prior to human testing, a drug’s toxicological potential be assessed in at least two mammalian species. But we humans metabolize things differently from other mammals, because our livers are different. That can make for nasty surprises. All too often, drugs showing tremendous promise in preclinical animal assessments fail in human trials due to unforeseen liver toxicity, said Peltz, a former pharmaceutical executive who is intimately familiar with established preclinical testing procedures in the industry.

That’s what happened in 1993 when, after a short safety trial of a drug called FIAU concluded without incident, the comp0und was placed in a phase-2 clinical trial of a drug for hepatitis B. FIAU belongs to a class of drugs that can interfere with viral replication, so it was considered a great candidate for treating virally induced infections such as hepatitis B.

As I wrote in my release about the new study:

“FIAU was supposed to be a revolutionary drug,” Peltz said. “It looked very promising in preclinical tests. In phase 1, when the drug was administered to subjects for a short period of time, the human subjects seemed to do fairly well.” But the phase-2 trial was stopped after 13 weeks, when it became clear that FIAU was destroying patients’ livers.

In fact, nearly half the patients treated with FIAU in that trial died from complications of liver damage. Yet, before advancing to clinical trials FIAU had been tested for as long as six months in mice, rats, dogs and monkeys without any trace of toxicity. An investigation conducted by the National Academy of Sciences later determined that the drug had shown no signs of being dangerous during those rigorous preclinical toxicology tests.

In Peltz’s new study, though, FIAU caused unmistakable early signs of  severe liver toxicity in the bioengineered mice with human livers. This observation would have served as a bright red stop signal that would have prevented the drug from being administered to people.

Bonus item: Using bioengineered mice with human livers instead of mice with murine ones would no doubt result in the clinical and commercial success of some drugs that never got to the human-testing stage because they caused liver toxicity in mice.

Previously: Fortune teller: Mice with ‘humanized’ livers predict HCV drug candidate’s behavior in humans, Alchemy: From liposuction fluid to new liver cells and Immunology escapes from the mouse trap
Photo by erjkprunczyk

In an effort to spark collaboration among thought leaders across industry, government and academia, Stanford’s upcoming Big Data in Biomedicine conference is hosting a technical showcase where attendees can browse displays and demos highlighting public and private companies’ innovations related to big data.

Conference organizers are continuing to develop the program, but the current roster of companies committed to participating in the showcase range from industry giants to smaller ventures. Among the participants are multinationals firms, such as Samsung, SAP and General Electric Co. and emerging startups ClusterK, a cloud computing platform; StationX, a developer of software for scientists and clinicians working with genomics data; and Syapse, which aims to bring molecular profiling into standard medical use.

Part networking opportunity and part show-and-tell, the event is a new addition to this year’s conference and will be held on May 21 under a tent on the lawn of the medical school’s Li Ka Shing Center for Learning and Knowledge. Conference-goers will have a chance to watch demos of biomedical analytical tools and large computing solutions for big data, as well as relevant ontologies that make for very effective information organization and retrieval.

Previously: Euan Ashley discusses harnessing big data to drive innovation for a healthier world, Registration opens for Big Data in Biomedicine conference at Stanford, Grant from Li Ka Shing Foundation to fund big data initiative and conference at Stanford and Big laughs at Stanford’s Big Data in Biomedicine Conference
Photo by Saul Bromberger

When Stanford professor John Ioannidis, MD, DSc, discusses ideas on how METRICS might improve research quality, he points to the wealth of statistics within any newspaper’s sports section.

“Science needs as many ways to measure performance as sports do,” says Ioannidis. “More important, we need to find efficient approaches for enhancing this performance. There are many ideas on how to improve the efficiency of setting a research agenda, prioritizing research questions, optimizing study design, maximizing accuracy of information, minimizing biases, enhancing reporting of research, and aligning incentives and rewards so that research efforts become more successful. Possibly we can do better on all of these fronts.”

The center’s other co-director is Steven Goodman, MD, MHS, PhD, professor of medicine and of health research and policy.

METRICS’s core group of interdisciplinary scholars will be working on various aspects of meta-research, from methodologies to processes to policy. The center will also provide educational funding for students and scholars; organize collaborative working groups that include academics, policymakers, research funders and the public; and help establish similar initiatives worldwide.

You can learn more about “meta-research” and METRICS’s mission in the short interview above and in this release. Ioannidis discusses the center’s short- and long-term goals in the video clip below.

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 in featured-entry box by Norbert Von Der Groeben

SMS (“Stanford Medical School”) Unplugged was recently launched as a forum for students to chronicle their experiences in medical school. The student-penned entries appear on Scope once a week; the entire blog series can be found in the SMS Unplugged category.

“Why do you go to medical school?” My little sister frowned, angry that I was leaving again after just a week.

“Why don’t you come with me?” I responded, and ran towards her with my arms outstretched. With a squeal she turned to run up the stairs. So began our last game of chase until I see her again in six months.

My sister’s question followed me on the plane ride back to California. For the last four years, my decisions have been based on the desire to help people through medicine. Every step of the way I’ve become more sure that this is for me.

It all started with shadowing a neurologist. I was a freshman in college and was trying to decide whether to pursue my interest in psychology or medicine. Little did I know that this neurologist monitors peripheral nerves during neurosurgery, and I soon found myself clad in green scrubs, cap and mask, entering the OR for the first time.

The words craniectomy for microvascular decompression floated my way. When I looked them up later, I learned that this means an artery had come too close to a nerve and every time the heart beat, the artery expanded, hitting the nerve and causing the patient great pain.

Watching the neurosurgeon and his resident move an artery inside the patient’s brain, a sense of belonging washed over me. I felt that I was finally in the right place. The thrill of scrubbing into the OR, the intellectual fascination of seeing the neurosurgeon cut open the patient’s brain and the sense that this person’s life was in his hands tipped the scale on my decision to pursue medicine. It’s the moment I look back on when I need to reassure myself that I chose the right path.

Now toward the end of my first year as a med student, I know what things like craniectomy for microvascular decompression mean without having to look them up. And I just got my badge to shadow in the neurosurgery OR again.

I wonder how I’ll feel shadowing neurosurgery this time. Part of me really hopes that it’s nothing exceptional so that I can gravitate toward a specialty where I get to see my little sister more than twice a year. Part of me really hopes that I get the feeling again that I’ve found my calling. And I stall a little bit, wondering which one I’d prefer.

Several 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

During finals, one of my college roommates would ritualistically sit in silence and knit an entire hat before she could begin studying. The steady, repetitive action calmed her down and cleared her mind. (Before less stressful exams, she baked.)

I thought of her when coming across a recent post on The Checkup that points to evidence, including previous research in seniors with mild cognitive impairment, that the health benefits experienced by people who engage in activities such as knitting and crocheting might be more than anecdotal. More from the piece:

In one study, 38 women hospitalized for anorexia were given a questionnaire about their psychological state after being taught to knit.

After an average of one hour and 20 minutes of knitting a day for an average of three weeks, 74 percent of them reported less fear and preoccupation with their eating disorder, the same percentage reported that knitting had a calming effect, and just over half said knitting gave them a sense of pride, satisfaction and accomplishment.

…

The rhythmic movements of knitting offer many of the same kinds of benefits as meditation, says Carrie Barron, [MD,] an assistant clinical professor of psychiatry at Columbia University in New York and co-author of the book “The Creativity Cure: How to Build Happiness With Your Own Two Hands.” In addition, she says, seeing a project take shape provides a deep sense of satisfaction.

That might have been why Pee-wee Herman found the unsolved mystery of his stolen bike so unnerving: “It’s like you’re unraveling a big cable-knit sweater that someone keeps knitting and knitting and knitting…” he said in the 1985 film Pee Wee’s Big Adventure.

Previously: Image of the Week: Personalized brain activity scarves, Image of the Week: aKNITomy, Study shows meditation may alter areas of the brain associated with psychiatric disorders and Ommmmm… Mindfulness therapy appears to help prevent depression relapse
Photo by Merete Veian

Rockefeller University neurobiologist Cori Bargmann, PhD, is quoted in today’s New York Times as saying optogenetics is “the most revolutionary thing that has happened in neuroscience in the past couple of decades.” The article is a profile piece of Karl Deisseroth, MD, PhD, the Stanford researcher who helped create the field of optogenetics, and it reveals how a clinical rotation in psychiatry led him to this line of work:

It was eye-opening, he said, “to sit and talk to a person whose reality is different from yours” — to be face to face with the effects of bipolar disorder, “exuberance, charisma, love of life, and yet, how destructive”; of depression, “crushing — it can’t be reasoned with”; of an eating disorder literally killing a young, intelligent person, “as if there’s a conceptual cancer in the brain.”

He saw patient after patient suffering terribly, with no cure in sight. “It was not as if we had the right tools or the right understanding.” But, he said, that such tools were desperately needed made it more interesting to him as a specialty. He stayed with psychiatry, but adjusted his research course, getting in on the ground floor in a new bioengineering department at Stanford. He is now a professor of both bioengineering and psychiatry.

Previously: A federal push to further brain research, An in-depth look at the career of Stanford’s Karl Deisseroth, “a major name in science”, Lightning strikes twice: Optogenetics pioneer Karl Deisseroth’s newest technique renders tissues transparent, yet structurally intact, The “rock star” work of Stanford’s Karl Deisseroth and Nature Methods names optogenetics its “Method of the Year
Related: Head lights
Photo in featured-entry box by Linda Cicero/Stanford News Service

When I talk to neuroscientists about how they study the brain I get a lesson (usually filled with acronyms) in the various ways scientists go about trying to read minds. Some of the tools they use can detect when general regions of the brain are active, but can’t detect individual nerves. Others record the activity of individual nerves, one nerve at a time, but can’t detect networks of nerves firing together. Still another tool can report the afterglow of a signal that has been sent across networks of neurons.

There hasn’t been any one way of seeing when a nerve fires and which neighbors in connects to.

I wrote recently about a new tool to do just that, developed by bioengineer Michael Lin, MD, PhD, and biologist and applied physicist Mark Schnitzer, PhD. They’ve both come up with proteins that light up when a nerve sends a signal. They can put their proteins in a group of nerves in one part of the brain then watch those signals spread across the network of neurons as they interact.

In my story I quote Lin: “You want to know which neurons are firing, how they link together and how they represent information. A good probe to do that has been on the wish list for decades.”

The proteins could be widely used to better understand the brain or develop drugs:

With these tools scientists can study how we learn, remember, navigate or any other activity that requires networks of nerves working together. The tools can also help scientists understand what happens when those processes don’t work properly, as in Alzheimer’s or Parkinson’s diseases, or other disorders of the brain.

The proteins could also be inserted in neurons in a lab dish. Scientists developing drugs, for example, could expose human nerves in a dish to a drug and watch in real time to see if the drug changes the way the nerve fires. If those neurons in the dish represent a disease, like Parkinson’s disease, a scientist could look for drugs that cause those cells to fire more normally.

Now that I’ve written about the invention of this new tool I’m looking forward to hearing more about how scientists start using it to understand our brain or develop drugs.

3D rendered illustration of a nerve cell by Sebastian Kaulitzki/Shutterstock

Invasive 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

Many people are deeply skeptical of foreign aid, believing that these monies often wind up in the pockets of corrupt leaders or never make it down the chain of bureaucracy to the people who really need it. But a new Stanford analysis of both government and private aid programs shows that health aid has been extremely effective not only in extending the lives of people in developing countries but also saving the lives of children under age 5.

Lead researcher Eran Bendavid, MD, said foreign aid programs had their biggest impact between 2000 and 2010, when investments in health reached their peak. During that time, the U.S. government launched its hugely successful initiative, the President’s Emergency Plan for AIDS Relief (PEPFAR), while other private groups, such as the Gates Foundation, stepped up investments in health as well.

During that time, low-income countries receiving aid saw a dramatic decline – between 26 and 34 percent – in the number of children who died before their 5th birthday. With just a 4 percent increase in aid, or $1 billion, foreign aid could continue to have a major impact on child mortality, Bendavid said.

“If health aid continues to be as effective as it has been, we estimate there will be 364,800 fewer deaths in children under 5,” Bendavid said. “We are talking about $1 billion, which is a relatively small commitment for developed countries.”

He said many people may find the results surprising. “But for me, it fits with other evidence of the incredible success of public health promotion in developing countries,” he said. For instance, he did a study in 2012 which found that more than 740,000 lives were saved between 2004 and 2008 in nine countries as a result of the PEPFAR program. Other technologies, such as diphtheria, tetanus, measles and polio vaccines for children and insecticide-treated bed nets to prevent malaria, all have contributed to better health among adults and children in low-income countries.

He and colleague Jay Bhattacharya, MD, PhD, also found that aid programs had a lasting impact. The signs of aid’s impact on child mortality were measurable for three years after aid was distributed, while the link between aid and longer life expectancy was detectable five years after aid was made available, the researchers reported.

Previously: Stanford study: South Africa could save millions of lives through HIV prevention and PEPFAR has saved lives – and not just from HIV/AIDS, Stanford study finds
Photo by Karen Ande