Tiny Human Esophagus Grown in the Lab—Here's Why 09-27

Here’s something to digest: Scientists in Cincinnati have grown miniature versions of an esophagus, the organ responsible for guiding your food to your stomach. And in a first, they did it entirely using human stem cells.

Called organoids, these tiny balls of lab-grown tissue resemble a real human esophagus, the researchers report today in the journal Cell Stem Cell. Previously, scientists succeeded in growing all sorts of organoids—stomachs, kidneys, brains, and even an esophagus made using mature patient tissue as the starting material. (Here’s how one team used a spinach leaf to create a mini beating heart.)

These tiny organs-in-a-dish help scientists study how organs develop normally, and they’re used to figure out how these body parts go wrong, giving rise to cancer and other disorders.

“Three-dimensional laboratory models of human esophagus are badly needed, especially since the mouse anatomy is fundamentally different to a human’s,” says Rebecca Fitzgerald, an esophageal cancer researcher at the University of Cambridge who wasn’t involved in the study.

And since organoids act as a kind of stand-in for the real thing, they can also be used to test drugs to better predict how patients might respond to different treatments. (For instance, artificial wombs may help with premature births.)

“Because they grow in a petri dish, we can poke and prod them all we want,” says James Wells, senior author on the new study and chief scientific officer of the Cincinnati Children's Center for Stem Cell and Organoid Medicine.

Follow the Recipe

Wells and his colleagues started with induced pluripotent stem cells, a kind of “master” cell that has the ability to become any other cell in the body. To make them turn into specialized esophagus cells, investigators added a mixture of chemicals and proteins to the stem cells.

“These act as cues or signals that help to guide those pluripotent stem cells into specifically forming esophageal tissues,” Wells says. “It’s like following a recipe.”

One key step in this recipe was the gene Sox2 and its associated protein, which have been linked to esophageal conditions. The team found that this gene plays a central role in helping the esophagus develop in a human embryo. It took about two months to grow the tiny blobs—each about a millimeter wide—in the lab. (Other researchers have used human stem cells to grow sheep-human hybrids to help with organ regeneration.)

Wells and his Cincinnati team are already growing a few organoids to help diagnose patients who have medical conditions that affect the esophagus, like congenital birth defects. It’s part of the hospital’s bigger effort to create personalized mini-organs from pediatric patients with gastrointestinal disorders.

“So let’s just say, in the clinic they’ve done everything they can to figure out what’s wrong with the patient using all the standard clinical tests,” Wells explains.

The patient gets put into a custom-made MRI machine, which renders a 3-D image of the child’s organs. That image is sent to a team of surgeons, who will try to figure out if the organs can be surgically repaired. Meanwhile, doctors take a tiny piece of tissue from the patient and send it off to Wells’ lab, which makes stem cells from the tissue sample and then grows the organoids. Being able to examine these mini-organs up close, outside of a patient, can lead to a diagnosis.

Opening Up Possibilities

In the future, Wells hopes to be able to grow organoids that could be transplanted back into patients born with unhealthy or missing esophagus tissue. He says this could also work in adults who have had parts of their esophagus removed due to cancer.

“In the long term, we want to make tissue to help the surgeons reconstruct the esophagus in cases where there’s too much missing for the surgeon to correct,” Well says. But that’s likely several years away.

Using stem cells as a starting material “may be a major plus, since some patients may lack healthy esophageal tissue from which to try to engineer a new esophagus,” says Paul Knoepfler, a stem cell biologist at the University of California, Davis, School of Medicine.

It’s also possible that esophageal organoids made from stem cells rather than patient tissue may grow bigger or produce more types of cells that occur naturally in the esophagus, he says. One thing that was missing from the esophagus-in-a-dish, for instance: The open space where food and liquids would go, called the lumen.

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Why diagnosing Alzheimer’s today is so difficult—and how we can do better 07-17

Shyam's take....

Bill Gates's next investment in Alzheimer’s research is in a new fund called Diagnostics Accelerator. This project of the Alzheimer’s Drug Discovery Foundation (ADDF) aims to accelerate bold new ideas for earlier and better diagnosis of the disease. Bill Gates is planning to invest more than 30 million for this cause. 

It is not for the first time, that research in Alzheimer disease management or prevention research has received attention or funding. However, when a person like Bill Gates devotes time and funds for a cause, the cause itself receives widespread attention from people all over the world. The awareness for the cause increases manifold. It gives direction to many philanthropists as to which cause they should invest. It simultaneously encourages the devoted scientists, researchers and the medical professionals working for this cause. These people not only find light at the end of the tunnel, they feel the entire tunnel has brightened up. This way Bill Gates involvement, more than the investment proves to be driver and huge catalyst. For me, his devoting time for the cause, is more important than his investment. I also like his idea of  venture philanthropy, it could mean that research could at least fund itself partially and the end product could bring back some returns for the investors or help create a corpus, that could fund further research.  Kudos Mr. Gates.

Now please read the article.....

When I announced that I was investing in Alzheimer’s research for the first time last fall, I thought I knew what to expect. I knew I would get to engage more deeply with the brilliant scientists and advocates working to stop Alzheimer’s—and I haven’t been disappointed. The things I’ve seen over the last seven months make me more hopeful than ever.

What I didn’t see coming was the amazing response I got from the Alzheimer’s community at large. Because my family didn’t talk publicly about my dad’s diagnosis before the announcement, I had yet to experience how remarkable the support community is. So many of you have shared your personal experiences with me, both in person and online (including here on TGN). It helps to hear from others who are going through the same thing.

Alzheimer’s research is a frontier where we can dramatically improve human life—both the lives of people who have the disease and their loved ones. I’m optimistic that we can substantially alter the course of Alzheimer’s if we make progress in several key areas. One of the biggest things we could do right now is develop a reliable, affordable, and accessible diagnostic.

The process of getting diagnosed with Alzheimer’s today is less than ideal. It starts with a cognitive test. If you don’t perform well, your doctor needs to rule out all other possible causes for memory loss, like stroke or a nutritional deficiency. Then your doctor can order a spinal tap or PET scan to confirm you have Alzheimer’s. Although these tests are fairly accurate, the only way to diagnose the disease definitively is through an autopsy after death.

There are two big problems with this process. First, it can be expensive and invasive. Most insurance plans in the United States won’t reimburse tests for Alzheimer’s. Patients often pay thousands of dollars out of their own pockets. Meanwhile, spinal taps can be scary and uncomfortable, and PET scans require the patient to stay perfectly still for up to 40 minutes. That’s difficult for anyone to do—but especially someone with Alzheimer’s.

Second, patients aren’t being tested for the disease until they start showing cognitive decline. The more we understand about Alzheimer’s, the clearer it becomes that the disease begins much earlier than we previously thought. Research suggests Alzheimer’s starts damaging the brain more than a decade before symptoms start showing. That’s probably when we need to start treating people to have the best shot at an effective drug.

This delay is a huge problem in the quest for a scientific breakthrough. It’s currently so difficult to find enough eligible patients for a clinical trial that it can take longer to enroll participants than to conduct the study. We need a better way of diagnosing Alzheimer’s—like a simple blood test or eye exam—before we’re able to slow the progression of the disease.  

It’s a bit of a chicken and egg problem. It’s hard to come up with a game changing new drug without a cheaper and less invasive way to diagnose patients earlier. But most people don’t want to find out if they have the disease earlier when there’s no way to treat it. The commercial market for Alzheimer’s diagnostics simply isn’t there. There’s promising research being done, but very few companies are looking at how to turn that research into a usable product.

That’s why my next investment in Alzheimer’s research is in a new fund called Diagnostics Accelerator. This project of the Alzheimer’s Drug Discovery Foundation (ADDF) aims to accelerate bold new ideas for earlier and better diagnosis of the disease. Today I’m joining Leonard Lauder, ADDF, the Dolby family, the Charles and Helen Schwab Foundation, and other donors in committing more than $30 million to help launch Diagnostics Accelerator.

Diagnostics Accelerator is a venture philanthropy vehicle, which means it’s different from most funds. Investments from governments or charitable organizations are fantastic at generating new ideas and cutting-edge research—but they’re not always great at creating usable products, since no one stands to make a profit at the end of the day. Venture capital, on the other end of the spectrum, is more likely to develop a test that will actually reach patients, but its financial model favors projects that will earn big returns for investors.

Venture philanthropy splits the difference. It incentivizes a bold, risk-taking approach to research with an end goal of a real product for real patients. If any of the projects backed by Diagnostics Accelerator succeed, our share of the financial windfall goes right back into the fund.

My hope is that this investment builds a bridge from academic research to a reliable, affordable, and accessible diagnostic. I expect to see lots of new players come to the table, who have innovative new ideas but might not have previously had the resources to explore them. If you think you’re one of these bold thinkers, we want to hear your great ideas. I encourage you to apply for funding on the new Diagnostics Accelerator website here.

Imagine a world where diagnosing Alzheimer’s disease is as simple as getting your blood tested during your annual physical. Research suggests that future isn’t that far off, and Diagnostics Accelerator moves us one step closer.

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A Chink in Bacteria's Armor 04-22

Building the bacterial wall: The blue balls are wall-making proteins. The yellow represents a newly synthesized bacterial cell wall. The green color represents "scaffolding" proteins. Video: Janet Iwasa for Harvard Medical School..

The wall that surrounds bacteria to shield them from external assaults has long been a tantalizing target for drug therapies. Indeed, some of modern medicine’s most reliable antibiotics disarm harmful bacteria by disrupting the proteins that build their protective armor. 

For decades, scientists knew of only one wall-making protein family. Then, in 2016, a team of Harvard Medical School scientists discovered that a previously unsuspected family of proteins that regulate cell division and cell shape had a secret skill: building bacterial walls.

Now, in another scientific first described March 28 in Nature, members of the same research team have revealed the molecular building blocks—and a structural weak spot—of a key member of that family.

“Our latest findings reveal the molecular structure of RodA and identify targetable spots where new antibacterial drugs could bind and subvert its work,” said study senior investigator Andrew Kruse, associate professor of biological chemistry and molecular pharmacology at Harvard Medical School.

The newly profiled protein, RodA, belongs to a family collectively known as SEDS proteins, present in nearly all bacteria. SEDS” near-ubiquity renders these proteins ideal targets for the development of broad-spectrum antibiotics to disrupt their structure and function, effectively neutralizing a range of harmful bacteria.

A weak link

In their earlier work, the scientists showed that RodA builds the cellular wall by knitting together large sugar molecules with clusters of amino acids. Once constructed, the wall encircles the bacterium, keeping it structurally intact, while repelling toxins, drugs and viruses.

The latest findings, however, go a step further and pinpoint a potential weak link in the protein’s makeup.

Specifically, the protein’s molecular profile reveals structural features reminiscent of other proteins whose architecture Kruse has disassembled. Among them, the cell receptors for the neurotransmitters acetylcholine and adrenaline, which are successfully targeted by medications that boost or stem the levels of these nerve-signaling chemicals to treat a range of conditions, including cardiac and respiratory diseases.

One particular feature caught the scientists’ attention—a pocket-like cavity facing the outer surface of the protein. The size and shape of the cavity, along with the fact that it is accessible from the outside, make it a particularly appealing drug target, the researchers said.

“What makes us excited is that this protein has a fairly discrete pocket that looks like it could be easily and effectively targeted with a drug that binds to it and interferes with the protein’s ability to do its job,” said study co-senior author David Rudner, professor of microbiology and immunobiology at Harvard Medical School.

In a set of experiments, researchers altered the structure of RodA in two bacterial species—the textbook representatives of the two broad classes that make up most of disease-causing bacteria. One of them was Escherichia coli, which belongs to a class of organisms with a double-cell membrane known as gram-negative bacteria, so named due to a reaction to staining test used in microbiology. The other bacterium was Bacillus subtilis, a single-membrane organism that belongs to so-called gram-positive bacteria.

When researchers induced even mild alterations to the structure of RodA’s cavity, the protein lost its ability to perform its work. E. coli and B. subtilis cells with disrupted RodA structure rapidly enlarged and became misshapen, eventually bursting and leaking their contents.

“A chemical compound—an inhibitor—that binds to this pocket would interfere with the protein’s ability to synthesize and maintain the bacterial wall,” Rudner said. “That would, in essence, crack the wall, weaken the cell and set off a cascade that eventually causes it to die.”

Additionally, because the protein is highly conserved across all bacterial species, the discovery of an inhibiting compound means that, at least in theory, a drug could work against many kinds of harmful bacteria.

“This highlights the beauty of super-basic scientific discovery,” said co-investigator Thomas Bernhardt, professor of microbiology and immunobiology at Harvard Medical School. “You get to the most fundamental level of things that are found across all species, and when something works in one of them, chances are it will work across the board.”

Solving for X

To determine RodA’s structure, scientists used a visualization technique known as X-ray crystallography, which reveals the molecular architecture of protein crystals based on a pattern of scattered X-ray beams. The technique requires two variables—the intensity of scattered X-rays and a so-called “phase angle,” a property related to the configuration of the atoms in a protein. The latter is measured indirectly, typically by using a closely related protein as a substitute to calculate the variable.

In this case, however, the team had on its hands a never-before-described protein with no known molecular siblings.

“In most cases you can use a related structure and bootstrap to a solution,” Kruse said. “In this case, we couldn’t do that. We had to predict what RodA looked like without any prior information about it.”

They needed a new way to solve for X.

In a creative twist, researchers turned to evolution and predictive analytics. Working with Debora Marks, assistant professor of systems biology at Harvard Medical School, they constructed a virtual model of the RodA’s folding pattern by analyzing the sequences of its closest evolutionary cousins.

The success of this “roundabout” approach, researchers said, circumvents a significant hurdle in field of structural biology and can open the doors toward defining the structures of many more newly discovered proteins.

“These insights underscore the importance of creative crosspollination among scientists from multiple disciplines and departments,” said study first author Megan Sjodt, a research fellow in biological chemistry and molecular pharmacology at Harvard Medical School. “We believe our results set the stage for subsequent work toward the discovery and optimization of new classes of antibiotics.”

The work was supported by National Institutes of Health grant U19AI109764.

Co-investigators included Kelly Brock, Genevieve Dobihal, Patricia Rohs, Anna Green, Thomas Hopf, Alexander Meeske, Veerasak Srisuknimit, Daniel Kahne and Suzanne Walker, all from Harvard. 

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The Healing Power of Stem Cells 01-24

What Are Stem Cells?

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They are cells that maintain a state of “open-mindedness” thoughout the life of the individual from fetal life senescence, to enable them to participate in repair, replacement and regeneration of the tissue they happen to be in, in addition to affecting tissues in other parts of the body by migration and by producing growth factors and cytokines. They are regarded as undifferentiated and are found in different tissues of the body, throughout life. The early fetal stem cells are “pluripotent’ with a vast potential; while non-embryonic adult mesenchymal stem cells are “multipotent.” This means they are less versatile than those of the fetus, but non-the-less can turn into several different kinds of cells within any tissue type.

Where Are Stem Cells Found?

Undifferentiated, non-embryonic adult mesenchymal stem cells are found everywhere in the body, in all tissues, but especially in fat tissue, bone marrow and blood- in that order.  The stem cells found in blood and bone marrow are hematopoietic stem cells because, under normal circumstances, they are destined to form red blood cells (RBCs), white blood cells (WBCs), and platelets; and those stem cells that are found in fat (adipose) tissue, among fat cells, are called adipose stem cells.

GCSC&RMC uses adipose stem cells because they are approximately 2,500 times as abundant as hematopoietic stem cells, per a given mass of tissue. Furthermore, no organs are hurt or disturbed in the process of harvesting adipose tissue, which only requires local anesthesia.

How Are Stem Cells Used?

Stem cells have the potential to repair human tissue and certain internal organs by forming new cells and producing substances to regenerate cartilage, bone, ligaments, tendons, nerve, fat, muscle, and blood vessels. Stem cells are being investigated and researched as an innovative therapy option for more than 70 major diseases and conditions that affect millions of people worldwide. These include diabetes mellitus, Parkinson’s, Alzheimer’s, multiple sclerosis, ALS (Lou Gehrig’s Disease), spinal cord injuries, various eye conditions, and HIV/AIDS.

The GCSC&RMC Process

Gulf Coast Stem Cell & RMC has a specific SVF harvest and injection protocol. First, a couple of ounces of fat are harvested from the love handle areas of the back, under surgically sterile conditions and local anesthesia, by minimally-invasive mini-liposuction. This procedure lasts a mere 20 minutes; and this small amount of fat yields millions of stem cells (at least half a million per ml of fat). In fact, it is possible to obtain well over 50 million cells from a single harvest.

After the cells are harvested, the stem cells are separated from the fat cells and are ready for deployment within 90 minutes or less from harvest. They can then be injected into a vein to reach wider targets throughout the entire body, and directly into target areas like the spinal space, joints and specific tissues.

Orthopedic

Stem cell therapy is a minimally invasive, low-risk option that may help patients who suffer from the daily discomforts of orthopedic conditions such as osteoarthritis, rheumatoid arthritis, sports-related injuries, spine disease, and general problems with shoulders, elbows, hands/wrists, hips, knees, or ankles. Research indicates that most orthopedic issues are fundamentally caused by inflammatory, autoimmune, or degenerative processes. Stem cells have the potential to reduce discomfort by decreasing inflammation, modulating autoimmunity, and repairing or replacing bone, tendons, and ligaments that have deteriorated due to injury or a degenerative joint disease. This investigational therapy could benefit the near 350 million people worldwide who are afflicted by arthritis, about 50 million of whom live in the United States, including over a quarter million children.

Neurological

Over one billion people worldwide suffer from neurological diseases. In universities and medical research centers around the world, stem cells are being explored for their regenerative potential. We at GCSC&RMC have research protocols for many neurological conditions, including multiple sclerosis, peripheral neuropathy, Parkinson’s disease, muscular dystrophy, spinal cord injuries, and more. Beyond their ability to become different kinds of cells, stem cells are able to cross the blood-brain barrier, aided by hygroscopic molecules like Mannitol. This potential for transmigration, or crossing the barrier, means that stem cells can reach broader areas of brain tissue that have been affected by injuries or degenerative diseases. This has been shown to be the case in a rat model. Subtle differences in brain function can affect mood, balance, thought processes, and other areas that have significant impacts on a patient’s overall quality of life.

Cardiac & Pulmonary Diseases

Cardiac disease is the most common killer in the United States. Every day, 2,200 people die from cardiovascular diseases—that’s 1 in every 3 deaths. Stem cell therapy has the potential to help with cardiac and pulmonary conditions such as a heart attacks, myocardial infarctions, congestive heart failure, ischemic heart disease, COPD, and pulmonary fibrosis. The purpose of our research protocols is to target inflammation, reducing it; regenerating cells lost in cardiac ischemia, replacing damaged or diseased heart-muscle cells, and promoting the development of new coronary artery branches. The latter can be effected through the production of substances like the angiogenesis factor. When an intravenous dose of SVF or stem cells is given, the infused molecules and cells pass through the heart to the vast capillary network of the lungs, where a significant proportion of the cells stay. There they participate in various repair processes, which, according to published results and our own, often improve gaseous exchange and may result clinical improvement.

Autoimmune Diseases

Autoimmune diseases happen when the body’s immune system turns against itself and starts mistakenly attacking healthy cells. Many disease processes are considered autoimmune, and many of those conditions have shown response to research protocols using stem cell therapy, including lupus, hepatitis, Crohn’s disease, rheumatoid arthritis, scleroderma, myasthenia neuropathy, CIDP, and ulcerative colitis. Deploying stem cells in these diseases may reduce inflammation of affected organs and tissues, regenerate damaged cells and tissue, and help modulate the immune response by possibly block compliment reactions.

UroGenital & Skin

Intersticial Cystitis (IC) and Lichen Sclerosis are among the most distressing, chronic conditions that can afflict women and men, although they are much commoner in women. There are an estimated 108 million people suffering from lichen sclerosis around the world. When women are afflicted, the labia may fuse together, adding to the distress. Our research findings, as well as those of others in our group (CSN), indicate that SVF deployment may help both women and men who suffer with those conditions. Furthermore, according to our research findings, patients who had local injections of filtered fat (nanofat) into the labia and surrounding skin, in addition to the SVF  appeared to have better outcomes. Clearly, in those who benefit the stem cells as well as growth factors and cytokines re-direct the atrophic, inflammatory process towards healing and resolution.

Erectile Dysfunction may be a very distressing entity to those afflicted and the condition afflicts approximately 50% of men over 40, to some degree. Naturally the causes may be multifactorial, but research results indicate that combining pressure wave therapy with SVF may result in significant improvement in over 60-70% of men.  In those who benefit, stem cells may have the potential to stimulate the growth of the smooth muscle lining of vessels and improve endothelial function, repair and rejuvenate damaged and effete cells and boost blood flow to erectile tissues.

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