Tiny Brain Parts Teased from Stem Cells
Madeline A. Lancaster
A cross-section of an organoid showing development of different brain regions. All cells are in blue, neural stem cells in red and neurons in green.
Cambridge University Department of Engineering
When physicians run out of treatment options they look to a nascent field known as bioengineering. Specialized scientists apply engineering principles to biological systems, opening up the possibility of creating new human tissue, organs, blood and even corneas such as the one shown here. Waiting lists for organ transplants continue to be lengthy so the race to save lives with bioengineered body parts is on. Here’s a look at some of the most notable achievements in recent years.
Fraunhofer Institute for Interfacial Engineering and Biotechnology
Producing small amounts of artificial skin to graft on patients and use for toxicity testing has been possible for years. Human skin cells are cultivated in the lab and then embedded in a collagen scaffold. In 2011, the Fraunhofer Institute for Interfacial Engineering and Biotechnology introduced a system that can rapidly manufacture two-layer artificial skin models. Their Tissue Factory has the capacity to make 5,000 skin sheets in a month.
Princeton University / Frank Wojciechowski
Reproducing 3-D biological structures, particularly the complex human ear, presents significant challenges for bioengineers. A team at Princeton University led by mechanical and aerospace engineering associate professor Michael McAlpine used 3-D printing technology to make a functional ear from calf cells and electronic materials. The ear that debuted in May 2013 is no mere replacement -- it can pick up radio frequencies well beyond the range that human ears normally detect.
Popular Science via Getty Images
Surgeon Anthony Atala directs the Wake Forest Institute for Regenerative Medicine and is known for growing new human cells, tissues and organs -- particularly ones that advance urology. Atala and his team’s bioengineered bladders succeeded in clinical trials. The bladders were constructed from patients’ cells that were grown over two months on a biodegradable scaffold and then implanted. Patients included children with spina bifida who risked kidney failure. It’s been several years since then and the results are positive. “These constructs appear to be doing well as patients get older and grow,” Atala told the NIH Record.
Massachusetts General Hospital/PNAS
Being able to make blood vessels in the lab from a patient’s own cells could mean better treatments for cardiovascular disease, kidney disease and diabetes. In 2011, the head of California-based Cytograft Tissue Engineering reported progress in a study where three end-stage kidney disease patients were implanted with blood vessels bioengineered in the lab. After eight months the grafts continued to work well, easing access to dialysis. Then this month a team at Massachusetts General Hospital found a way to encourage stem-like cells to develop into vascular precursor cells, a key step on the way to becoming blood vessel cells. They generated long-lasting blood vessels in living mice.
Ott Lab / Massachusetts General Hospital
Artificial heart devices have been surgically implanted since the 1980s, but no device has been able to replace the human heart as effectively as a healthy biological one. After all, a human heart pumps 35 million times in a single year. Recently scientists have made advances in adding more biological material to artificial heart devices. In May the French company Carmat prepared to test an artificial device containing cow heart tissue. At Massachusetts General Hospital, surgeon Harald C. Ott and his team are working on a bioartificial heart scaffold while MIT researchers recently printed functional heart tissue from rodent cells.
Wake Forest University Baptist Medical Center
Bioengineers are working on it, but the liver is one of the largest, most challenging organs to recreate. In 2010 bioengineers at Wake Forest University Baptist Medical Center grew miniature livers in the lab using decellularized animal livers for the structure and human cells. This month, a team from the Yokohama City University Graduate School of Medicine published results of a study where they reprogrammed human adult skin cells, added other cell types, and got them to grow into early-stage liver “buds.” Currently the scientists can produce about 100 of them, but the study’s lead author Takanori Takebe told the Wall Street Journal that even a partial liver would require tens of thousands.
Harvard Apparatus Regenerative Technology
In April, after an international team of surgeons spent nine hours operating on her at Children's Hospital of Illinois in Peoria, 32-month old Hannah Warren became the youngest patient to ever receive a bioengineered organ. Scientists had made a windpipe for her using her own bone marrow cells. Born without a trachea, she needed help breathing, eating, drinking and talking. Harvard Bioscience created the custom scaffold and bioreactor for the experimental procedure. Sadly Hannah died on July 7 due to complications from a more recent surgery on her esophagus. Despite the high risks, bioengineers say they will continue to move ahead.
When a ruptured or degenerating disc causes chronic back pain, treatment is limited. At worst, patients undergo surgery to fuse vertebrae together and then have limited flexibility. Over the past several years artificial discs have emerged as an alternative, but they can wear out as they work. In 2011, a research team from Cornell University bioengineered implants using gel and collagen seeded with rat cells that were then successfully placed into rat spines. This summer Duke bioengineers took things further, coming up with a gel mixture they think can help regenerate tissue when injected into the space between discs.
Little by little, bioengineered intestines are being grown in the lab to diagnose digestive disorders and to help patients born without a piece of intestine. In 2011, Cornell biological and environmental engineering assistant professor John March began collaborating with Pittsburgh-based pediatric surgeon David Hackam on a small artificial intestine using collagen and stem cells. Then last year in Switzerland, EPFL professor Martin Gijs led a project in the Laboratory of Microsystems to create a miniature intestinal wall from cultured epithelial cells and electronics called NutriChip to identify foods that cause inflammation. Scientists at Harvard’s Wyss Institute also made a “gut-on-a chip” to mimic the real thing using intestinal cells in a tiny silicon polymer device.
University of California, San Francisco
One in 10 American adults will have some level of chronic kidney disease, according to the Centers for Disease Control and Prevention. Currently around 600,000 patients in the U.S. have chronic kidney failure. Most rely on dialysis while a fraction of them actually get transplants. Scientists from the University of California, San Francisco are on a mission to create a sophisticated artificial kidney device made with human kidney cells, silicon nanofilters and powered by blood pressure. The project, led by UCSF nephrologist William Fissell and bioengineering professor Shuvo Roy, aims to begin testing the kidney device in 2017.
A team of European scientists has grown parts of a human brain in tissue culture from stem cells. Their work could help scientists understand the origins of schizophrenia or autism and lead to drugs to treat them, said Juergen Knoblich, deputy scientific director at the Institute of Molecular Biotechnology of the Austrian Academy of Science and one of the paper's co-authors.
The advance could also eliminate the need for conducting experiments on animals, whose brains are not a perfect model for humans.
To grow the brain structures, called organoids, the scientists used stem cells, which can develop into any other kind of cell in the body. They put the stem cells into a special solution designed to promote the growth of neural cells. Bits of gel interspersed throughout the solution gave the cells a three-dimensional structure to grown upon. In eight to ten days the stem cells turned into brain cells. After 20 days to a month, the cells matured into a size between three and four millimeters, representing specific brain regions, such as the cortex and the hindbrain.
Growing brain tissue this way marks a major advancement because the lab-grown brain cells self-organized, and took on growth patterns seen in a developing, fetal brain.
Currently, the organoids are limited to how big they can get because they do not have a circulatory system to move around nutrients.
Knoblich's team didn't stop of growing the brain organoids, though. They went a step further and used the developing tissue to study microcephaly, a condition in which the brain stops growing. Microcephalic patients are born with smaller brains, and impaired cognitive development. Studying microcephaly in mice doesn't help because human and mouse brains are too different.
A cross-section of an organoid showing development of different brain regions. All cells are in blue, neural stem cells in red and neurons in green. Madeline A. Lancaster
For this part of the study, the researchers used stem cells from a microcephalic patient and grew neurons in a culture. They found that in normal brains have progenitor stem cells that make neurons, and can do so repeatedly. In microcephalic brains, the progenitor cells differentiate into neurons earlier, said Madeline A. Lancaster, the study's lead author. The brain doesn't make as many neurons and a child is born with a much smaller brain volume.
Yoshiki Sasai, a stem-cell biologist at the RIKEN Center for Developmental Biology in Kobe, Japan, garnered headlines last year by growing the precursors to a human eye. "The most important advancement is that they combined this self-organization culture with disease-specific cells to model a genetic disease of human brain malformation," he said.
"Everything we have done with other organs starts with this stage," said Anthony Atala, M.D., the director of the Wake Forest Institute for Regenerative Medicine, who has done yeara of research into using 3-D printers to build organs. Atala was not involved in this study, but he noted that before he could build organs he needed to grow the pieces -- to get the cells to differentiate in just the right way. So though it's unlikely anyone will print brains the way he did a kidney, this kind of experiment is where organ regeneration starts.
Knoblich said the next step is studying other brain disorders, but it will take some time to grow enough brain tissue. One factor is maximum size and how far the brain can develop in the culture. Brain cells develop in layers, and there are several by the time a baby is born. The cortical cells Knoblich's team grew only had one such layer. Another factor is getting blood vessels inside the tissue. That problem could be solved sometime in the future, though he said he couldn't predict when.
It is tempting to think one day there will be whole brains in vats, but that isn't likely to happen. "Aside from the severe ethical problem, I do not think this will be possible," Knoblich said. To form actual functioning neural circuits, a brain needs sensory input. "Without any sensory input the proper organization may not happen."
The results of the study appear today in the journal Nature.