May lead to new personalized treatments for lung diseases

In Boston, using a combination of pluripotent stem cells (cells that can potentially produce any cell or tissue type) and machine learning (artificial intelligence that allows supercomputers to learn automatically), researchers have improved how they generate lung cells.

Using this technique, cells can be grown in a laboratory and stored for more than one year without losing their lung identity and used to model lung diseases thereby finding better treatments and cures for lung diseases in the future.

Induced pluripotent stem (iPS) cells are derived from the donated skin or blood cells of adults and, with the reactivation of four genes, are reprogrammed back to an embryonic stem cell-like state. iPS cells can be differentiated toward any cell type in the body and do not require the use of embryos.

{module INSIDE STORY} Building on previous work from the Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center, researchers in the CReM, working together with investigators from Carnegie Mellon University (CMU), reprogrammed blood from adults into iPS cells. They then treated these stem cells with growth factors over a period of one month until they became cells that were very similar to adult lung cells.

According to the researchers, often when this type of experiment is performed the resulting cells are not a pure collection of the cell that they aimed to create (target cell) and they do not keep the characteristics of the target cell for prolonged periods of time.

"Therefore, we developed a combination of techniques that examines the gene expression of thousands of single cells combined with DNA barcoding of each individual cell and machine learning to build up a dynamic picture of what factors favor cells that go on to be lung cells in our system. Using this knowledge we were able to improve our methods for generating lung cells so that we can now create more relevant cells that keep their cell identity in a dish for more than one year," explained Killian Hurley, MD, PhD, researcher at the Royal College of Surgeons in Ireland, who co-authored the study with Jun Ding, PhD, a post-doctoral fellow at CMU.

The researchers believe this study will improve their ability to model lung disease and treatments in the laboratory for diseases including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), alpha-1 antitrypsin deficiency and neonatal respiratory distress or early-onset interstitial lung disease.

Millions of people in the United States and around the world have severe lung diseases, often without good treatments or cure. Some of these diseases may even require lung transplantation which is a complex and high-risk surgery with the need for donor organs always exceeding the supply.

"The machine learning methods we developed for this study can also be applied to studies of other tissues and organs," said Ding. "We hope that our newly developed techniques for generating a pure, unlimited supply of cells using patients-derived stem cells can make possible new treatments or cures for diseases. These developments would prolong lives and improve the quality of those lives."

"The key hurdle to understanding what goes wrong with an individual patient's lung cells has been our inability to access those cells or to grow them in the laboratory. This approach allows us to now engineer from any individual patient those very finicky cells and to introduce bar codes into those cells that allow us to track and understand each cell and all their progeny over time in the laboratory dish. The result is an inexhaustible source of new lung cells that can be prepared from any patient of any age," added co-corresponding author Darrell Kotton, MD, David C. Seldin Professor of Medicine and Director, CReM, who led the work together with Ziv Bar-Joseph, PhD, the FORE Systems Professor of Computer Science at CMU.

Researchers from the Moscow Institute of Physics and Technology have discovered an additional component in ATP synthase, a molecular machine that produces the energy-conserving compound in all cellular organisms. 

In order to store energy, living cells rely on a molecule called ATP. It is produced by ATP synthase, a molecular-scale motor comprised of a rotor and a stator. Such machines are nested in the inner membranes of mitochondria and chloroplasts in most organisms, including animals, plants, and bacteria. The rotor component resembles a barrel embedded into a biological membrane. This "barrel," or C-ring, is made of between eight and 17 so-called protomers. Their exact number depends on the organism.

MIPT researchers and their colleagues from Grenoble, France, have obtained a first-ever high-resolution structure of the C ring from spinach chloroplasts. As the supercomputer model of the C ring was taking shape, the biophysicists spotted something peculiar. The new unique features of the ATP synthase structure are described in detail in a paper in an educational journal. {module INSIDE STORY}

"We noticed additional circle-shaped elements inside the C ring," said MIPT doctoral student Alexey Vlasov from the Institute's Research Center for Molecular Mechanisms of Aging and Age-Related Diseases. "At first we thought that was an artifact. But when we looked through the C ring structures obtained by other scientists for various organisms, the circles turned up again, time after time."

It came as a surprise for the researchers that previous studies did not pay attention to the circles inside C rings. Up until now, their nature remained unexplained.

"This study speaks to the fact that no minor detail is negligible in science. Even a subtle feature, spotted in due course, might lead to a breakthrough discovery," noted Valentin Gordeliy, who heads research groups at the Institute of Structural Biology in Grenoble (France) and Jülich Research Center (Germany) and is the scientific coordinator of the MIPT Research Center for Molecular Mechanisms of Aging and Age-Related Diseases.

The biophysicists from MIPT set out to solve the C ring puzzle. Supercomputer modeling and biochemical experiments indicated that the ring contained quinone molecules. They act as electron carriers in biological systems. Some of the examples are plastoquinone, found in chloroplasts, and the coenzyme Q in mitochondria.

Biologists have long known that the C ring of ATP synthase does not have a "hole" in it. So while some molecules were expected to exist on the inside, no one was sure which exactly. The finding proved unexpected: quinones.

While the discovery is interesting in and of itself, researchers have yet to determine why the C ring hosts quinones and how they get there. One theory suggests C rings can function as pores in mitochondrial membranes. Such a pore might open when the cell death process is initiated. Can the quinones in a C ring kill a cell? This is a question for the MIPT biologists to address in their further research.