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Tiny ‘Organoids’ Promise Big Boost to Medical Care – NBCNews.com

Aug.18.2017 / 3:15 PM ET

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Tiny versions of human organs smaller than a pea are making a big splash around the world and for a good reason. Though the clusters of cells of brain, kidney, or liver arent much to look at, experts say these so-called organoids and organs-on-a-chip are poised to remake the way new drugs are brought to market.

Right now, drug development is notoriously slow and costly; bringing a new drug to market can take a dozen years and cost upward of $2 billion. Even after all that time and money have been spent, new drug candidates often prove to be ineffective or to have dangerous side effects.

A huge percentage of drugs fail even after hundreds of millions or billions of dollars of investment, says Dr. Donald Ingber, director of Harvard Universitys Wyss Institute for Biologically Inspired Engineering and a leader in organ-on-a-chip technology. In fact, only about one in 10 drugs that make it to human tests (after testing in the lab and in animals) wind up getting FDA approval.

Growing whole organs in the lab for drug testing is a long way off. But organoids promise to change the equation because they so closely mimic their fully formed counterparts inside living human bodies. They can be used to imitate diseased as well as healthy tissue and can even be linked together to create tiny bodies-on-a-chip.

This is not building a human bodythis is not Frankenstein science, Ingber says. This is really a sophisticated, minimalist approach to building models that can actually replace the use of animals and be much more accurate in terms of predicting how drugs or toxins would affect the human body.

In addition to making it possible to create better medicines at significantly lower cost, experts say organoids will help doctors customize medical treatments to individual patients and pinpoint the cause of genetic illness. With organoids, drug development should be speedier a particular benefit if new drugs are needed urgently to curb a pandemic or treat people affected by nuclear accidents or chemical or biological warfare.

And then theres this: experts say organoids for drug testing should reduce our reliance on animal testing.

Organoids are typically grown from cells taken from human skin and reprogrammed into a primitive state. With a little coaching to mimic the conditions found in an actual body, these jack-of-all-trades stem cells self-organize into the three-dimensional clumps.

The first organoids of brain and intestinal cells arrived in the mid-2000s. Since then, scientists have created organoids of many other tissues, including kidney, lung, and breast.

Though organoid science is in its infancy, its already helping patients.

Scientists in the Netherlands are using intestine organoids to help children suffering from cystic fibrosis. Scientists elsewhere are growing mini-livers with the hope that it might someday be possible to cure liver disease not by transplanting an entire liver (which, of course, must come from a donor) but instead by implanting thousands of tiny liver organoids grown from the patients own cells.

And then there are brain organoids, which might lead someday to new treatments for serious mental and neurological conditions. Still, Its a really far, far cry from an actual human brain, says Dr. Madeline Lancaster, a developmental biologist at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England.

As with all organoids, brain organoids lack certain key features of their inside-the-body counterparts, including blood vessels.

It would be wonderful if you had a three-dimensional brain tissue that was organized just like a real brain, and you could put in drugs and you could try to find something that would treat schizophrenia, Lancaster says, adding that is still a bit premature.

If organoids hold enormous promise for drug development, scientists say a mash-up of organoids and microchip technology commonly known as organs-on-a-chip, or simply organ chips, might be even better.

The chips are plastic wafers, typically about the size of a AA battery, that are laced with channels containing human organ and blood vessel cells. The devices make it possible for scientists to use electrical current, flowing air, and other physical phenomena to make, say, heart cells beat and lung cells respire.

These cues prompt the tissues to behave normally or respond realistically to disease. And scientists can use their microscopes to watch these physiological processes as they occur.

Its like a living cross-section to a part of an organ, Ingber says. We can see immune cells going back and forth, we can see tumor cells invadingits just visually quite amazing.

Ingber and other researchers have started to link multiple organ chips to form what theyre calling human-bodies-on-a-chip. By showing how a new drug might affect the whole body rather than just a particular organ, body chips could do even more to speed drug development.

Emulate, a Wyss Institute spinoff, plans to begin selling organs-on-chips and the tech to run them within the next six months. The FDA recently started evaluating how well Emulates liver chips mimic human reactions to food and foodborne illnesses. The company is also working with Johnson & Johnson, the Michael J. Fox Foundation, and Merck to use organ chips to advance treatments for blood clots, Parkinsons disease, and asthma.

Meanwhile, German competitor TissUse plans to offer humans-on-a-chip packed with more than 10 organs next year, CNBC reported.

Someday you might even be able to safeguard your health with the help of bodies-on-a-chip created from your own cells: doctors could scrape off a few skin cells and use them to create body chips that theyd use to determine which drugs would be most effective should you be stricken by cancer or another serious illness.

Meanwhile, Ingber and other researchers are using their bodies-on-chips to examine how body tissue is affected by nuclear radiation, chemical weapons, and deadly germs.

There are a lot of things out there that we just dont know how to treat becauseyou cant test them in humans, says Dr. Anthony Atala, director of the Wake Forest Institute for Regenerative Medicine in Winston-Salem, North Carolina, who is also developing bodies-on-a-chip. But, of course, these deadly forces can be tested on body chips.

The FDA has awarded a contract to Ingber and his team to use their technology to investigate possible treatments for radiation sickness. Eventually, the chips could help us be better prepared for accidents similar to Japans 2011 Fukushima nuclear disaster.

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Bio-inspired materials give boost to regenerative medicine – Medical Xpress

August 18, 2017 In a new studyin Nature Communications, Stephanopoulos and his colleague Ronit Freeman successfully demonstrated the ability to dynamically control the environment around stem cells, to guide their behavior in new and powerful ways. Credit: Northwestern University

What if one day, we could teach our bodies to self-heal like a lizard's tail, and make severe injury or disease no more threatening than a paper cut?

Or heal tissues by coaxing cells to multiply, repair or replace damaged regions in loved ones whose lives have been ravaged by stroke, Alzheimer's or Parkinson's disease?

Such is the vision, promise and excitement in the burgeoning field of regenerative medicine, now a major ASU initiative to boost 21st-century medical research discoveries.

ASU Biodesign Institute researcher Nick Stephanopoulos is one of several rising stars in regenerative medicine. In 2015, Stephanopoulos, along with Alex Green and Jeremy Mills, were recruited to the Biodesign Institute's Center for Molecular Design and Biomimetics (CMDB), directed by Hao Yan, a world-recognized leader in nanotechnology.

"One of the things that that attracted me most to the ASU and the Biodesign CMDB was Hao's vision to build a group of researchers that use biological molecules and design principles to make new materials that can mimic, and one day surpass, the most complex functions of biology," Stephanopoulos said.

"I have always been fascinated by using biological building blocks like proteins, peptides and DNA to construct self-assembled structures, devices and materials, and the interdisciplinary and highly collaborative team in the CMDB is the ideal place to put this vision into practice."

Yan's research center uses DNA and other basic building blocks to build their nanotechnology structuresonly at a scale 1,000 times smaller than the width of a human hair.

They've already used nanotechnology to build containers to specially deliver drugs to tissues, build robots to navigate a maze or nanowires for electronics.

To build a manufacturing industry at that tiny scale, their bricks and mortar use a colorful assortment of molecular Legos. Just combine the ingredients, and these building blocks can self-assemble in a seemingly infinite number of ways only limited by the laws of chemistry and physicsand the creative imaginations of these budding nano-architects.

Learning from nature

"The goal of the Center for Molecular Design and Biomimetics is to use nature's design rules as an inspiration in advancing biomedical, energy and electronics innovation through self-assembling molecules to create intelligent materials for better component control and for synthesis into higher-order systems," said Yan, who also holds the Milton Glick Chair in Chemistry and Biochemistry.

Prior to joining ASU, Stephanopoulos trained with experts in biological nanomaterials, obtaining his doctorate with the University of California Berkeley's Matthew Francis, and completed postdoctoral studies with Samuel Stupp at Northwestern University. At Northwestern, he was part of a team that developed a new category of quilt-like, self-assembling peptide and peptide-DNA biomaterials for regenerative medicine, with an emphasis in neural tissue engineering.

"We've learned from nature many of the rules behind materials that can self-assemble. Some of the most elegant complex and adaptable examples of self-assembly are found in biological systems," Stephanopoulos said.

Because they are built from the ground-up using molecules found in nature, these materials are also biocompatible and biodegradable, opening up brand-new vistas for regenerative medicine.

Stephanopoulos' tool kit includes using proteins, peptides, lipids and nucleic acids like DNA that have a rich biological lexicon of self-assembly.

"DNA possesses great potential for the construction of self-assembled biomaterials due to its highly programmable nature; any two strands of DNA can be coaxed to assemble to make nanoscale constructs and devices with exquisite precision and complexity," Stephanopoulos said.

Proof all in the design

During his time at Northwestern, Stephanopoulos worked on a number of projects and developed proof-of-concept technologies for spinal cord injury, bone regeneration and nanomaterials to guide stem cell differentiation.

Now, more recently, in a new study in Nature Communications, Stephanopoulos and his colleague Ronit Freeman in the Stupp laboratory successfully demonstrated the ability to dynamically control the environment around stem cells, to guide their behavior in new and powerful ways.

In the new technology, materials are first chemically decorated with different strands of DNA, each with a unique code for a different signal to cells.

To activate signals within the cells, soluble molecules containing complementary DNA strands are coupled to short protein fragments, called peptides, and added to the material to create DNA double helices displaying the signal.

By adding a few drops of the DNA-peptide mixture, the material effectively gives a green light to stem cells to reproduce and generate more cells. In order to dynamically tune the signal presentation, the surface is exposed to a soluble single-stranded DNA molecule designed to "grab" the signal-containing strand of the duplex and form a new DNA double helix, displacing the old signal from the surface.

This new duplex can then be washed away, turning the signal "off." To turn the signal back on, all that is needed is to now introduce a new copy of single-stranded DNA bearing a signal that will reattach to the material's surface.

One of the findings of this work is the possibility of using the synthetic material to signal neural stem cells to proliferate, then at a specific time selected by the scientist, trigger their differentiation into neurons for a while, before returning the stem cells to a proliferative state on demand.

One potential use of the new technology to manipulate cells could help cure a patient with neurodegenerative conditions like Parkinson's disease.

The patient's own skin cells could be converted to stem cells using existing techniques. The new technology could help expand the newly converted stem cells back in the laband then direct their growth into specific dopamine-producing neurons before transplantation back to the patient.

"People would love to have cell therapies that utilize stem cells derived from their own bodies to regenerate tissue," Stupp said. "In principle, this will eventually be possible, but one needs procedures that are effective at expanding and differentiating cells in order to do so. Our technology does that."

In the future, it might be possible to perform this process entirely within the body. The stem cells would be implanted in the clinic, encapsulated in the type of material described in the new work, and injected into a particular spot. Then the soluble peptide-DNA molecules would be given to the patient to bind to the material and manipulate the proliferation and differentiation of transplanted cells.

Scaling the barriers

One of the future challenges in this area will be to develop materials that can respond better to external stimuli and reconfigure their physical or chemical properties accordingly.

"Biological systems are complex, and treating injury or disease will in many cases necessitate a material that can mimic the complex spatiotemporal dynamics of the tissues they are used to treat," Stephanopoulos said.

It is likely that hybrid systems that combine multiple chemical elements will be necessary; some components may provide structure, others biological signaling and yet others a switchable element to imbue dynamic ability to the material.

A second challenge, and opportunity, for regenerative medicine lies in creating nanostructures that can organize material across multiple length scales. Biological systems themselves are hierarchically organized: from molecules to cells to tissues, and up to entire organisms.

Consider that for all of us, life starts simple, with just a single cell. By the time we reach adulthood, every adult human body is its own universe of cells, with recent estimates of 37 trillion or so. The human brain alone has 100 billion cells or about the same number of cells as stars in the Milky Way galaxy.

But over the course of a life, or by disease, whole constellations of cells are lost due to the ravages of time or the genetic blueprints going awry.

Collaborative DNA

To overcome these obstacles, much more research funding and recruitment of additional talent to ASU will be needed to build the necessary regenerative medicine workforce.

Last year, Stephanopoulos' research received a boost with funding from the U.S. Air Force's Young Investigator Research Program (YIP).

"The Air Force Office of Scientific Research YIP award will facilitate Nick's research agenda in this direction, and is a significant recognition of his creativity and track record at the early stage of his careers," Yan said.

They'll need this and more to meet the ultimate challenge in the development of self-assembled biomaterials and translation to clinical applications.

Buoyed by the funding, during the next research steps, Stephanopoulos wants to further expand horizons with collaborations from other ASU colleagues to take his research team's efforts one step closer to the clinic.

"ASU and the Biodesign Institute also offer world-class researchers in engineering, physics and biology for collaborations, not to mention close ties with the Mayo Clinic or a number of Phoenix-area institutes so we can translate our materials to medically relevant applications," Stephanopoulos said.

There is growing recognition that regenerative medicine in the Valley could be a win-win for the area, in delivering new cures to patients and building, person by person, a brand-new medicinal manufacturing industry.

Explore further: New technology to manipulate cells could help treat Parkinson's, arthritis, other diseases

More information: Ronit Freeman et al. Instructing cells with programmable peptide DNA hybrids, Nature Communications (2017). DOI: 10.1038/ncomms15982

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Two-step process leads to cell immortalization and cancer – UC Berkeley

A mutation that helps make cells immortal is critical to the development of a tumor, but new research at UC Berkeley suggests that becoming immortal is a more complicated process than originally thought.

The key to immortalization is an enzyme called telomerase, which keeps chromosomes healthy in cells that divide frequently. The enzyme lengthens the caps, or telomeres, on the ends of chromosomes, which wear off during each cell division.

This skin section shows a benign mole or nevus that is transitioning into a melanoma, the most serious type of skin cancer. New experiments by UC Berkeley and UCSF researchers suggest that immortalization of skin cells, which is essential to turning them cancerous, is a two-step process: a mutation in nevus cells slightly raises levels of telomerase, which keep the cells alive long enough for a second change, still unknown, that up-regulates telomerase to make the cells immortal and malignant. (Image by Dirk Hockemeyer/UC Berkeley and Boris Bastian/UCSF)

When the telomeres get too short, the ends stick to one another, wreaking havoc when the cell divides and in most cases killing the cell. The discovery of telomerase and its role in replenishing the caps on the ends of the chromosomes, made by Elizabeth Blackburn and Carol Greider at UC Berkeley and John Szostak at Harvard University in the 1980s, earned them a Nobel Prize in Physiology or Medicine in 2009.

Because telomeres get shorter as cells age, scientists theorized that cancer cells which never age become immortalized by turning on production of telomerase in cells that normally dont produce it, allowing these cells to keep their long telomeres indefinitely. An estimated 90 percent of all malignant tumors use telomerase to achieve immortality, and various proposed cancer therapies focus on turning down the production of telomerase in tumors.

The new research, which studied the immortalization process using genome-engineered cells in culture and also tracked skin cells as they progressed from a mole into a malignant melanoma, suggests that telomerase plays a more complex role in cancer.

Our findings have implications for how to think about the earliest processes that drive cancer and telomerase as a therapeutic target. It also means that the role of telomere biology at a very early step of cancer development is vastly under-appreciated, said senior author Dirk Hockemeyer, a UC Berkeley assistant professor of molecular and cell biology. It is very likely that what we find in melanoma is true for other cancer types as well, which would warrant that people look more carefully at the role of early telomere shortening as a tumor-suppressing mechanism for cancer.

The results were reported online August 17 as a first release publication from the journal Science.

From nevus to cancer Hockemeyer and his UC Berkeley colleagues, in collaboration with dermatopathologist Boris Bastian and his colleagues at UCSF, found that immortalization is a two-step process, driven initially by a mutation that turns telomerase on, but at a very low level. That mutation is in a promoter, a region upstream of the telomerase gene referred to as TERT that regulates how much telomerase is produced. Four years ago, researchers reported that some 70 percent of malignant melanomas have this identical mutation in the TERT promoter.

The TERT promoter mutation does not generate enough telomerase to immortalize the pre-cancerous cells, but does delay normal cellular aging, Hockemeyer said, allowing more time for additional changes that turn telomerase up. He suspects that the telomerase levels are sufficient to lengthen the shortest telomeres, but not to keep them all long and healthy.

If cells fail to turn up telomerase, they also fail to immortalize, and eventually die from short telomeres because chromosomes stick together and then shatter when the cell divides. Cells with the TERT promoter mutation are more likely to up-regulate telomerase, which allows them to continue to grow despite very short telomeres. The marginal levels of telomerase in the cell, Hockemeyer said, result is some unprotected chromosome ends in the surviving mutant cells, which could cause mutations and further fuel tumor formation.

Before our paper, people could have assumed that the acquisition of just this one mutation in the TERT promoter was sufficient to immortalize a cell; that any time when that happens, the telomere shortening is taken out of the equation, Hockemeyer said. We are showing that the TERT promoter mutation is not immediately sufficient to stop telomeres from shortening.

It is still unclear, however, what causes the eventual up-regulation of telomerase that immortalizes the cell. Hockemeyer says that its unlikely to be another mutation, but rather an epigenetic change that affects expression of the telomerase gene, or a change in the expression of a transcription factor or other regulatory proteins that bind to the promoter upstream of the telomerase gene.

Nevertheless, we have evidence that the second step has to happen, and that the second step is initiated by or is occurring at a time when telomeres are critically short and when telomeres can be dysfunctional and drive genomic instability, he said.

In retrospect, not a surprise Though most cancers seem to require telomerase to become immortal, only some 10 to 20 percent of cancers are known to have a single-nucleotide change in the promoter upstream of the telomerase gene. However, these include about 70 percent of all melanomas and 50 percent of all liver and bladder cancers.

Hockemeyer said that the evidence supporting the theory that the TERT promoter mutation up-regulated telomerase has always been conflicting: Cancer cells tend to have chromosomes with short telomeres, yet have higher levels of telomerase, which should produce longer telomeres.

According to the new theory, the telomeres are short in precancerous cells because telomerase is turned on just enough to maintain but not lengthen the telomeres.

Our paper reconciles contradictory information about the cancers that carry these mutations, Hockemeyer said.

The finding also resolves another recent counterintuitive finding: that people with shorter telomeres are more resistant to melanoma. The reason, he said, is that if a TERT promoter mutation arises to push a precancerous lesion the mole or nevus toward a melanoma, the chances are greater in someone with short telomeres that the cell will die before it up-regulates telomerase and immortalizes the cells.

The study also involved engineering TERT promoter mutations in cells differentiated from human pluripotent stem cells and following their progression toward cellular immortality. The results were identical to the progression seen in human skin lesions obtained from patients in UCSFs Helen Diller Family Comprehensive Cancer Center and examined in the Clinical Cancer Genomics Laboratory, which Bastian directs.

Other co-authors of the Science paper are UC Berkeley graduate students Kunitoshi Chiba and Franziska Lorbeer, who contributed equally to the research, Hunter Shain of UCSF, David McSwiggen, Eva Schruf and Xavier Darzacq of UC Berkeley, and Areum Oh and Jekwan Ryu of the Santa Clara firm Optical Biosystems. The work was supported by the Siebel Stem Cell Institute, California Institute of Regenerative Medicine and National Institutes of Health. RELATED INFORMATION

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Two-step process leads to cell immortalization and cancer - UC Berkeley