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Applied Biotechnology, Clinical Trials, FDA, Public Health, Research, Stanford News

The best toxicology lab: a mouse with a human liver

The best toxicology lab: a mouse with a human liver

of mice and menA 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

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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Applied Biotechnology, Bioengineering, Global Health, In the News, Stanford News

Through his 50-cent microscope, Stanford engineer aims to “reach society in a very strong way”

Through his 50-cent microscope, Stanford engineer aims to "reach society in a very strong way"

Manu TED imageFoldscope, the ultra-low-cost paper microscope designed to aid disease diagnosis in developing regions, is back in the news. For a story appearing in today’s San Francisco Chronicle, writer Stephanie Lee talked with Stanford bioengineer Manu Prakash, PhD, and others about the invention:

“Manu Prakash is one of the most creative scientists and engineers and his invention is really original,” wrote Luke Lee, a bioengineering professor at UC Berkeley who works on global health problems, in an e-mail. “His elegant microscope is not only good for global health care, but also it will be a new educational tool to see the world.”

The Foldscope was two years in the making, starting with trips that Prakash and his graduate students took through India, Thailand, Uganda and Nigeria. The team met people who were suffering from infectious diseases but couldn’t afford conventional microscopes, which cost upward of $200, to diagnose their conditions.

“It was very clear that anything we came up with, if we can’t scale it to the cost it needs to be, it doesn’t really reach anywhere,” Prakash said.

Prakash went on to tell Lee, “This is not just an academic project. We happen to be in an academic setting, but we are trying to reach society in a very strong way.”

Previously: Free DIY microscope kits to citizen scientists with inspiring project ideas, Stanford bioengineer develops a 50-cent paper microscope, Stanford microscope inventor featured on TED Talk, Stanford bioengineer developing an “Electric Band-Aid Worm Test and Stanford bioengineers create an ultra-low-cost oral cancer screening tool
Photo by James Duncan Davidson/TED

Applied Biotechnology, Bioengineering, Global Health, Stanford News

Free DIY microscope kits to citizen scientists with inspiring project ideas

Free DIY microscope kits to citizen scientists with inspiring project ideas

foldscope-paper-microscope-620x406

Stanford bioengineer Manu Prakash, PhD, is giving away 10,000 build-your-own paper microscope kits to citizen scientists with the most inspiring ideas for things to do with this new invention.

This invention, called Foldscope, is a print-and-fold optical microscope that can be assembled from a flat sheet of paper. Although it costs less than a dollar in parts, it can magnify objects over 2,000 times and is small enough to fit in a pocket.

Prakash initiated The Ten Thousand Microscopes Project, funded by the Gordon and Betty Moore Foundation, as a way to open up the wonders of the microscopic world to future generations of scientists and engineers. Prakash, who entered and won science fairs as a child in India, clearly wishes that he had a tool like this when growing up.

“Many children around the world have never used a microscope, even in developed countries like the United States,” said Prakash. “A universal program providing a microscope for every child could foster deep interest in science at an early age.”

kid-sketches

Through this project, he and his team will assemble a crowd-sourced biology microscopy manual that includes examples of creative uses for his microscope, collected from the scientists, teachers, tinkerers, thinkers, hackers and kids who participate.

“So many times people use a tool for one specific purpose and don’t realize the rich potential for other uses,” said Prakash. “This online manual will inspire further explorations.”

To apply for a Foldscope kit, submit ideas on how you would use your microscope to signup (at) foldscope (dot) com. Recipients must pledge to document their experiments in a way that could be replicated by anyone. Submission details and sample proposals are posted at Foldscope.com. Kits will be shipped in August 2014 to the applicants with the best ideas.

“My dream is that someday, every kid will have a Foldscope in their back pocket,” said Prakash.

Previously: Stanford bioengineer develops a 50-cent paper microscope, Stanford microscope inventor featured on TED Talk, Stanford bioengineer developing an “Electric Band-Aid Worm Test and Stanford bioengineers create an ultra-low-cost oral cancer screening tool
Photos by TED and Prakash Lab

Applied Biotechnology, Bioengineering, Global Health, Stanford News, Videos

Stanford microscope inventor featured on TED Talk

Stanford microscope inventor featured on TED Talk

Earlier today I wrote about the 50-cent paper microscope developed by Stanford bioengineering professor Manu Prakash, PhD. You can now watch a video of him building and demonstrating the microscope on TED.com. This TED “Talk of Week” has already been viewed almost 300,000 times.

Prakash, who grew up in the mega-cities of India without a refrigerator, is a leader in the frugal design movement. His lab is currently developing a number of global health solutions, leveraging the cost savings of emerging manufacturing techniques such as 3D printers, laser cutters and conductive ink printing.

Previously: Stanford bioengineer develops a 50-cent paper microscope, Stanford bioengineer developing an “Electric Band-Aid Worm Test and Stanford bioengineers create an ultra-low-cost oral cancer screening tool

Applied Biotechnology, Bioengineering, Global Health, Stanford News, Videos

Stanford bioengineer develops a 50-cent paper microscope

Stanford bioengineer develops a 50-cent paper microscope

UPDATE: A second blog entry, including a link to Prakash’s TED talk on this topic, can be found here. And this entry discusses Prakash’s plans to give away 10,000 build-your-own paper microscope kits to citizen scientists with the most inspiring ideas for things to do with this new invention.

***

When Manu Prakash, PhD, wants to impress lab visitors with the durability of his Origami-based paper microscope, he throws it off a three-story balcony, stomps on it with his foot and dunks it into a water-filled beaker. Miraculously, it still works.

Even more amazing is that this microscope — a bookmark-sized piece of layered cardstock with a micro-lens — only costs about 50 cents in materials to make.

In the video posted above, you can see his “Foldscope” being built in just a few minutes, then used to project giant images of plant tissue on the wall of a dark room.

Prakash’s dream is that this ultra-low-cost microscope will someday be distributed widely to detect dangerous blood-borne diseases like malaria, African sleeping sickness, schistosomiasis and Chagas.

“I wanted to make the best possible disease-detection instrument that we could almost distribute for free,” said Prakash. “What came out of this project is what we call use-and-throw microscopy.”

The Foldscope can be assembled in minutes, includes no mechanical moving parts, packs in a flat configuration, is extremely rugged and can be incinerated after use to safely dispose of infectious biological samples. With minor design modifications, it can be used for bright-field, multi-fluorescence or projection microscopy.

One of the unique design features of the microscope is the use of inexpensive spherical lenses rather than the precision-ground curved glass lenses used in traditional microscopes. These poppy-seed-sized lenses were originally mass produced in various sizes as an abrasive grit that was thrown into industrial tumblers to knock the rough edges off metal parts. In the simplest configuration of the Foldscope, one 17-cent lens is press-fit into a small hole in the center of the slide-mounting platform. Some of his more sophisticated versions use multiple lenses and filters.

To use a Foldscope, a sample is mounted on a microscope slide and wedged between the paper layers of the microscope. With a thumb and forefinger grasping each end of the layered paper strip, a user holds the micro-lens close enough to one eye that eyebrows touch the paper. Focusing and locating a target object are achieved by flexing and sliding the paper platform with the thumb and fingers.

microbes

Because of the unique optical physics of a spherical lens held close to the eye, samples can be magnified up to 2,000 times. (To the right are two disease-causing microbes, Giardia lamblia and Leishmania donovani, photographed through a Foldscope.)

The Foldscope can be customized for the detection of specific organisms by adding various combinations of colored LED lights powered by a watch battery, sample stains and fluorescent filters. It can also be configured to project images on the wall of a dark room.

In addition, Prakash is passionate about mass-producing the Foldscope for educational purposes, to inspire children — our future scientists — to explore and learn from the microscopic world.

In a recent Stanford bioengineering course, Prakash used the Foldscope to teach students about the physics of microscopy. He had the entire class build their own Foldscope. Then teams wrote reports on microscopic observations or designed Foldscope accessories, such a smartphone camera attachment.

For more on Foldscope optics, a materials list and construction details, read Prakash’s technical paper.

Previously: Stanford bioengineer developing an “Electric Band-Aid Worm TestStanford bioengineers create an ultra-low-cost oral cancer screening tool,
Related: Prakash wins Gates grant for paper microscope development

Applied Biotechnology, Bioengineering, Cardiovascular Medicine, Stanford News, Technology

Heart devices get a mobile makeover

Heart devices get a mobile makeover

AUM-close-up-chest560

Emerging diagnostic heart devices are going mobile. And by leveraging advances in smartphones and sensors, they’re able to perform their functions better, faster and cheaper than traditional heart monitoring equipment.

For example, the CADence, shown above, detects blocked arteries from the surface of the chest by identifying the noisy signals of blood turbulence associated with blockages.

The Zio Patch, on the right, is a sensor that can be worn on the chest for up to 14 days to detect intermittent, irregular heartbeats, called arrhythmias. ZIO-150-90

Both of these amazing devices reveal the mysteries of the heart non invasively, and they provide more potentially life-saving heart data to physicians than conventional equipment.

Yet despite these advantages, adoption into the medical system has been slow.

In the new issue of Stanford Medicine magazine on cardiovascular health, I interview the entrepreneurs behind these inventions — the heart gadgeteers — and let them describe the hurdles that add years to the process of launching new medical devices into the marketplace.

Previously: Mysteries of the heart: Stanford Medicine magazine answers cardiovascular questions, New Johnson & Johnson CEO discusses medical device futures at Stanford eventStanford physician-entrepreneur discusses need to change FDA approval process and Is the United States losing ground as a leader of medical innovation?
Photos courtesy of AUM Cardiovascular, iRhythm Technologies

Applied Biotechnology, Ethics, Events, Genetics, Stanford News

Coming soon: A genome test that costs less than a new pair of shoes

Coming soon: A genome test that costs less than a new pair of shoes

Air JordansScarcely a week ago, a leading genomics company, Illumina, announced it could sequence a human genome for the new, low price of $1,000. This week attendees at a personalized medicine conference heard a Silicon Valley startup say it would get the price down to $100.

Either price is a steep drop from the $2 million it cost in 2007 to sequence the genome of DNA discoverer James Watson, PhD. Illumina, a San Diego-based company (and one of Stanford’s partner  in a just-funded stem cell genomics center), claimed the $1,000 price in a Jan. 14 announcement on its latest sequencer model. CEO Jay Flatley said the achievement shows that science has “broken the sound barrier” in the race to make genome sequencing affordable for medical care.

Speaking Monday at the sixth annual Personalized Medicine World Conference in Mountain View, Calif., Flatley predicted that genome sequencing would one day become so widely used in bedside medical care that it would be regarded as a “molecular stethoscope.”

Skeptics at the conference questioned whether a $1,000 genome test could include all the interpretation and analysis necessary to make the raw data useful for patients. But within minutes of the question, another company stepped up to say it was already working on a test that would lower the cost even more to $100.

“At $100, you get to be really competitive,” said Stefan Roever, CEO of Genia Technologies, a startup based in Mountain View, during a panel presentation at the conference. Genia is using a different method, called nanopore-based sequencing. The start-up was part of a consortium with Harvard Medical School and Columbia University that won a $5.25 million grant in September from the National Human Genome Research Institute to develop the technology.

The PMWC conference was a mix of academic researchers, companies commercializing the genomics, and venture capitalists checking out the new crop of start-ups. Stanford was represented by Stephen Quake, PhD, professor of bioengineering; George Sledge, MD, professor of medicine; and a multitude of others. Also making presentations were LeRoy Hood, MD, PhD, head of the Institute for Systems Biology in Seattle, and Eric Green, MD, PhD, director of the National Human Genome Research Institute.

Amir Dan Rubin, president and CEO of Stanford Hospital & Clinics, gave a keynote talk at the start of the conference. Stanford Hospital & Clinics was one of the cosponsors of the conference, held Jan. 27-28 at the Computer History Museum in Mountain View.

Donna Alvarado is a Bay Area-based writer and editor who volunteers at the Stanford Health Library and finds inspiration in medical and health topics.

Previously: Stanford researchers work to translate genetic discoveries into widespread personalized medicineWhole-genome fetal sequencing recognized as one of the year’s “10 Breakthrough Technologies”New recommendations for genetic disclosure released and Ask Stanford Med: Genetics chair answers your questions on genomics and personalized medicine
Photo by rondostar

Applied Biotechnology, Genetics, Research, Science, Stanford News

RNA Rosetta stone? Molecules’ second, structural language predicted from their first, linear one

RNA Rosetta stone? Molecules' second, structural language predicted from their first, linear one

Rosetta stoneThe RNA whisperer is at it again.

In a study just published in Nature, Stanford’s Howard Chang, MD, PhD – an expert in all things RNA – and his colleagues detail how they were able to translate from one language spoken by this versatile biomolecule to another, more obscure but important one.

RNA is best known as the intermediate material in classic protein production. A so-called “messenger RNA” molecule serves as a mobile, short-lived copy of its more durable lookalike, DNA, the stuff genes are made of. Gene-reading machines in a cell’s nucleus produce RNA copies of protein-coding genes. Unlike a gene, which is a sequence of chemical letters situated somewhere on a big, bulky chromosome, a messenger RNA molecule can float out of the nucleus to the cell’s watery cytoplasm where proteins get made, and transmit a gene’s instructions to the protein-making machinery.

But RNA does more than simply specify which proteins are going to get made. A messenger RNA molecule’s 3-dimensional shape, for example, conveys bountiful information telling the cell’s protein-producing proletariat where to bring it, what to do with it when it gets there, and when and and how much protein to make from it.

DNA is famously double-stranded. That’s because, of its four component chemical “letters,” two in particular share a strong mutual attraction, biophysically speaking. Happily, the other two letters have a chemical crush on one another as well. So, when the letters composing one DNA strand are complementary to those on a closely opposed strand (and they virtually always are), the two strands lock in a lasting embrace to form a stable double helix.

RNA molecules are strings of four different chemical letters almost identical to those constituting DNA. But unlike DNA, an RNA molecule typically travels solo, as a single-stranded chain of those four chemical letters. It is thus a rather playful, floppy molecule. Nonetheless, the same alphabetical affinities that produce DNA’s double helix are at work in an RNA molecule, albeit in a more fleeting form: Small sequences of chemical letters along an RNA molecule find themselves attracted to complementary sequences elsewhere on the same molecule, causing it to fold into so-called secondary structures featuring pinched double-stranded sections alternating with bulges and loops, hairpins and hinges.

Chang’s gang has figured out how to predict, based on an RNA molecule’s linear chemical sequence, the way it will fold up into its secondary structure. They were able to do this for  thousands of differently shaped RNA molecules found in one type of human cell – about a thousandfold increase over the number of such structures that had been laboriously determined to date, Chang told me. That has consequences for understanding disease mechanisms and, potentially, for drug discovery as well.

Looks like RNA research is shaping up.

Previously: Night of the living dead gene: Pseudogene wakes up, puts chill on inflammation, New job description for RNA, oldest professional biomolecule and iPhone app shows 2D structures of thousands of RNA molecules
Photo by OliBac

Aging, Applied Biotechnology, Technology

Treating common forms of blindness using tissue generated with ink-jet printing technology

Treating common forms of blindness using tissue generated with ink-jet printing technology

eyes_011414The possibility of printing organs or tissues to treat a range of medical conditions is one that continually fascinates me. So I was interested to read about a new approach using a standard ink-jet printer to build tissue for repairing retinal damage.

Technology Review reports on why printing eye cells could be more effective than the conventional method of generating cells:

Scientists can grow single layers of cells in cultures, but printing may be a more effective way to engineer new tissues and organs, which are made of multiple different cell types positioned in intricate three-dimensional orientations. The retina, for example, is a highly organized, multilayered structure composed of various types of neurons and non-neuronal cells. The new ink-jet technique makes it possible to place retinal cells in “very precise and special arrangements,” says [University of Cambridge professor Keith Martin, who led the research].

Rebuilding the retina is an extremely difficult challenge, because “you have to reconstruct what is basically a small computer” whose function arises from a very complicated architecture in which multiple cell layers are connected in a number of different ways, says Joel Schuman, chairman of the department of ophthalmology at the University of Pittsburgh. If this architecture could be re-created using a printer, “you would be so many steps ahead of trying to grow the layers individually and then put them together,” he says.

The piece goes on to explain how printed eye cells could be used in treating common forms of blindness including macular degeneration, which is the leading cause of blindness.

Previously: Stanford researchers develop solar-powered, wireless retinal implantAustralian scientists implant early prototype of a “bionic eye” into a patient, Stanford-developed retinal prosthesis uses near-infrared light to transmit images and Developing a prosthetic eye to treat blindness
Photo by Scinern

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