Tag Archives: cell

BigBang

Pass the Nicotinamide Adenine Dinucleotide

NAD-moleculeFor those of us seeking to live another 100 years or more the news and/or hype over the last decade belonged to resveratrol. The molecule is believed to improve functioning of specific biochemical pathways in the cell, which may improve cell repair and hinder the aging process. Resveratrol is found — in trace amounts — in grape skin (and hence wine), blueberries and raspberries. While proof remains scarce, this has not stopped the public from consuming large quantities of wine and berries.

Ironically, one would need to ingest such large amounts of resveratrol to replicate the benefits found in mice studies, that the wine alone would probably cause irreversible liver damage before any health benefits appeared. Oh well.

So, on to the next big thing, since aging cannot wait. It’s called NAD or Nicotinamide Adenine Dinucleotide. NAD performs several critical roles in the cell, one of which is energy metabolism. As we age our cells show diminishing levels of NAD and this is, possibly, linked to mitochondrial deterioration. Mitochondria are the cells’ energy factories, so keeping our mitochondria humming along is critical. Thus, hordes of researchers are now experimenting with NAD and related substances to see if they hold promise in postponing cellular demise.

From Scientific American:

Whenever I see my 10-year-old daughter brimming over with so much energy that she jumps up in the middle of supper to run around the table, I think to myself, “those young mitochondria.”

Mitochondria are our cells’ energy dynamos. Descended from bacteria that colonized other cells about 2 billion years, they get flaky as we age. A prominent theory of aging holds that decaying of mitochondria is a key driver of aging. While it’s not clear why our mitochondria fade as we age, evidence suggests that it leads to everything from heart failure to neurodegeneration, as well as the complete absence of zipping around the supper table.

Recent research suggests it may be possible to reverse mitochondrial decay with dietary supplements that increase cellular levels of a molecule called NAD (nicotinamide adenine dinucleotide). But caution is due: While there’s promising test-tube data and animal research regarding NAD boosters, no human clinical results on them have been published.

NAD is a linchpin of energy metabolism, among other roles, and its diminishing level with age has been implicated in mitochondrial deterioration. Supplements containing nicotinamide riboside, or NR, a precursor to NAD that’s found in trace amounts in milk, might be able to boost NAD levels. In support of that idea, half a dozen Nobel laureates and other prominent scientists are working with two small companies offering NR supplements.

The NAD story took off toward the end of 2013 with a high-profile paper by Harvard’s David Sinclair and colleagues. Sinclair, recall, achieved fame in the mid-2000s for research on yeast and mice that suggested the red wine ingredient resveratrol mimics anti-aging effects of calorie restriction. This time his lab made headlines by reporting that the mitochondria in muscles of elderly mice were restored to a youthful state after just a week of injections with NMN (nicotinamide mononucleotide), a molecule that naturally occurs in cells and, like NR, boosts levels of NAD.

It should be noted, however, that muscle strength was not improved in the NMN-treated micethe researchers speculated that one week of treatment wasn’t enough to do that despite signs that their age-related mitochondrial deterioration was reversed.

NMN isn’t available as a consumer product. But Sinclair’s report sparked excitement about NR, which was already on the market as a supplement called Niagen. Niagen’s maker, ChromaDex, a publicly traded Irvine, Calif., company, sells it to various retailers, which market it under their own brand names. In the wake of Sinclair’s paper, Niagen was hailed in the media as a potential blockbuster.

In early February, Elysium Health, a startup cofounded by Sinclair’s former mentor, MIT biologist Lenny Guarente, jumped into the NAD game by unveiling another supplement with NR. Dubbed Basis, it’s only offered online by the company. Elysium is taking no chances when it comes to scientific credibility. Its website lists a dream team of advising scientists, including five Nobel laureates and other big names such as the Mayo Clinic’s Jim Kirkland, a leader in geroscience, and biotech pioneer Lee Hood. I can’t remember a startup with more stars in its firmament.

A few days later, ChromaDex reasserted its first-comer status in the NAD game by announcing that it had conducted a clinical trial demonstrating that a single dose of NR resulted in statistically significant increases in NAD in humansthe first evidence that supplements could really boost NAD levels in people. Details of the study won’t be out until it’s reported in a peer-reviewed journal, the company said. (ChromaDex also brandishes Nobel credentials: Roger Kornberg, a Stanford professor who won the Chemistry prize in 2006, chairs its scientific advisory board. Hes the son of Nobel laureate Arthur Kornberg, who, ChromaDex proudly notes, was among the first scientists to study NR some 60 years ago.)

The NAD findings tie into the ongoing story about enzymes called sirtuins, which Guarente, Sinclair and other researchers have implicated as key players in conferring the longevity and health benefits of calorie restriction. Resveratrol, the wine ingredient, is thought to rev up one of the sirtuins, SIRT1, which appears to help protect mice on high doses of resveratrol from the ill effects of high-fat diets. A slew of other health benefits have been attributed to SIRT1 activation in hundreds of studies, including several small human trials.

Here’s the NAD connection: In 2000, Guarente’s lab reported that NAD fuels the activity of sirtuins, including SIRT1the more NAD there is in cells, the more SIRT1 does beneficial things. One of those things is to induce formation of new mitochondria. NAD can also activate another sirtuin, SIRT3, which is thought to keep mitochondria running smoothly.

Read the entire article here.

Image: Structure of nicotinamide adenine dinucleotide, oxidized (NAD+). Courtesy of Wikipedia. Public Domain.

BigBang

Building a Liver

In yet another breakthrough for medical science, researchers have succeeded in growing a prototypical human liver in the lab.

From the New York Times:

Researchers in Japan have used human stem cells to create tiny human livers like those that arise early in fetal life. When the scientists transplanted the rudimentary livers into mice, the little organs grew, made human liver proteins, and metabolized drugs as human livers do.

They and others caution that these are early days and this is still very much basic research. The liver buds, as they are called, did not turn into complete livers, and the method would have to be scaled up enormously to make enough replacement liver buds to treat a patient. Even then, the investigators say, they expect to replace only 30 percent of a patient’s liver. What they are making is more like a patch than a full liver.

But the promise, in a field that has seen a great deal of dashed hopes, is immense, medical experts said.

“This is a major breakthrough of monumental significance,” said Dr. Hillel Tobias, director of transplantation at the New York University School of Medicine. Dr. Tobias is chairman of the American Liver Foundation’s national medical advisory committee.

“Very impressive,” said Eric Lagasse of the University of Pittsburgh, who studies cell transplantation and liver disease. “It’s novel and very exciting.”

The study was published on Wednesday in the journal Nature.

Although human studies are years away, said Dr. Leonard Zon, director of the stem cell research program at Boston Children’s Hospital, this, to his knowledge, is the first time anyone has used human stem cells, created from human skin cells, to make a functioning solid organ, like a liver, as opposed to bone marrow, a jellylike organ.

Ever since they discovered how to get human stem cells — first from embryos and now, more often, from skin cells — researchers have dreamed of using the cells for replacement tissues and organs. The stem cells can turn into any type of human cell, and so it seemed logical to simply turn them into liver cells, for example, and add them to livers to fill in dead or damaged areas.

But those studies did not succeed. Liver cells did not take up residence in the liver; they did not develop blood supplies or signaling systems. They were not a cure for disease.

Other researchers tried making livers or other organs by growing cells on scaffolds. But that did not work well either. Cells would fall off the scaffolds and die, and the result was never a functioning solid organ.

Researchers have made specialized human cells in petri dishes, but not three-dimensional structures, like a liver.

The investigators, led by Dr. Takanori Takebe of the Yokohama City University Graduate School of Medicine, began with human skin cells, turning them into stem cells. By adding various stimulators and drivers of cell growth, they then turned the stem cells into human liver cells and began trying to make replacement livers.

They say they stumbled upon their solution. When they grew the human liver cells in petri dishes along with blood vessel cells from human umbilical cords and human connective tissue, that mix of cells, to their surprise, spontaneously assembled itself into three-dimensional liver buds, resembling the liver at about five or six weeks of gestation in humans.

Then the researchers transplanted the liver buds into mice, putting them in two places: on the brain and into the abdomen. The brain site allowed them to watch the buds grow. The investigators covered the hole in each animal’s skull with transparent plastic, giving them a direct view of the developing liver buds. The buds grew and developed blood supplies, attaching themselves to the blood vessels of the mice.

The abdominal site allowed them to put more buds in — 12 buds in each of two places in the abdomen, compared with one bud in the brain — which let the investigators ask if the liver buds were functioning like human livers.

They were. They made human liver proteins and also metabolized drugs that human livers — but not mouse livers — metabolize.

The approach makes sense, said Kenneth Zaret, a professor of cellular and developmental biology at the University of Pennsylvania. His research helped establish that blood and connective tissue cells promote dramatic liver growth early in development and help livers establish their own blood supply. On their own, without those other types of cells, liver cells do not develop or form organs.

Read the entire article here.

Image: Diagram of the human liver. Courtesy of Encyclopedia Britannica.

BigBang

From RNA Chemistry to Cell Biology

Each day we inch towards a better scientific understanding of how life is thought to have begun on our planet. Over the last decade researchers have shown how molecules like the nucleotides that make up complex chains of RNA (ribonucleic acid) and DNA (deoxyribonucleic acid) may have formed in the primaeval chemical soup of the early Earth. But it’s altogether a much greater leap to get from RNA (or DNA) to even a simple biological cell. Some recent work sheds more light and suggests that the chemical to biological chasm between long-strands of RNA and a complex cell may not be as wide to cross as once thought.

From ars technica:

Origin of life researchers have made impressive progress in recent years, showing that simple chemicals can combine to make nucleotides, the building blocks of DNA and RNA. Given the right conditions, these nucleotides can combine into ever-longer stretches of RNA. A lot of work has demonstrated that RNAs can perform all sorts of interesting chemistry, specifically binding other molecules and catalyzing reactions.

So the case for life getting its start in an RNA world has gotten very strong in the past decade, but the difference between a collection of interesting RNAs and anything like a primitive cell—surrounded by membranes, filled with both RNA and proteins, and running a simple metabolism—remains a very wide chasm. Or so it seems. A set of papers that came out in the past several days suggest that the chasm might not be as large as we’d tend to think.

Ironing out metabolism

A lot of the basic chemistry that drives the cell is based on electron transport, typically involving proteins that contain an iron atom. These reactions not only create some of the basic chemicals that are necessary for life, they’re also essential to powering the cell. Both photosynthesis and the breakdown of sugars involve the transfer of electrons to and from proteins that contain an iron atom.

DNA and RNA tend to have nothing to do with iron, interacting with magnesium instead. But some researchers at Georgia Tech have considered that fact a historical accident. Since photosynthesis put so much oxygen into the atmosphere, most of the iron has been oxidized into a state where it’s not soluble in water. If you go back to before photosynthesis was around, the oceans were filled with dissolved iron. Previously, the group had shown that, in oxygen-free and iron rich conditions, RNAs would happily work with iron instead and that its presence could speed up their catalytic activity.

Now the group is back with a new paper showing that if you put a bunch of random RNAs into the same conditions, some of them can catalyze electron transfer reactions. By “random,” I mean RNAs that are currently used by cells to do completely unrelated things (specifically, ribosomal and transfer RNAs). The reactions they catalyze are very simple, but remember: these RNAs don’t normally function as a catalyst at all. It wouldn’t surprise me if, after a number of rounds of evolutionary selection, an iron-RNA combination could be found that catalyzes a reaction that’s a lot closer to modern metabolism.

All of which suggests that the basics of a metabolism could have gotten started without proteins around.

Proteins build membranes

Clearly, proteins showed up at some point. They certainly didn’t look much like the proteins we see today, which may have hundreds or thousands of amino acids linked together. In fact, they may not have looked much like proteins at all, if a paper from Jack Szostak’s group is any indication. Szostak’s found that just two amino acids linked together may have catalytic activity. Some of that activity can help them engage in competition over another key element of the first cells: membrane material.

The work starts with a two amino acid long chemical called a peptide. If that peptide happens to be serine linked to histidine (two amino acids in use by life today), it has an interesting chemical activity: very slowly and poorly, it links other amino acids together to form more peptides. This weak activity is especially true if the amino acids are phenylalanine and leucine, two water-hating chemicals. Once they’re linked, they will precipitate out of a water solution.

The authors added a fatty acid membrane, figuring that it would soak up the reaction product. That definitely worked, with the catalytic efficiency of serine-histidine going up as a result. But something else happened as well: membranes that incorporated the reaction product started growing. It turns out that its presence in the membrane made it an efficient scrounger of other membrane material. As they grew, these membranes extended as long filaments that would break up into smaller parts with a gentle agitation and then start growing all over again.

In fact, the authors could set up a bit of a Darwinian competition between membranes based on how much starting catalyst each had. All of which suggests that proteins might have found their way into the cell as very simple chemicals that, at least initially, weren’t in any way connected to genetic and biochemical functions performed by RNA. But any cell-like things that evolved an RNA that made short proteins could have a big advantage over its competition.

Read the entire article here.