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A systematic approach to melanoma mutations

jhalper — Tue, 27 Oct 2015 05:46:17 +0000

A systematic approach to melanoma mutations

Metastatic melanoma tumors. Left exhibits low or absent expression of RASA2 and reduced survival, typical of about 35% of patients. The sample on the right exhibits high RASA2 expression and increased survival

Rates of melanoma are increasing, even as the rates of other common cancers are decreasing. According to the Melanoma Research Alliance, it is the most common cancer diagnosis in young adults 25-29 years old in the United States, the second most common cancer in young people 15-29, and its incidence has tripled in the last 30 years.

What are we doing about it? The Weizmann Institute’s Prof. Yardena Samuels has a database of over 500 samples from melanoma patients, and she is using this information to figure out how mutations drive the cancer. This is easier said than done. The damage to our DNA from the sun’s radiation can be widespread – a single melanoma cell can have hundreds of mutations.

Samuels and her group are going about the process systematically: They looked within a particular subset of melanomas – a group that often has a poor prognosis – for a particular type of gene. The genes known as tumor-suppressors are often mutated or inactivated in cancer. When they work, they protect us from cancer by keeping the brakes on cell growth or telling a cell with cancerous mutations to commit suicide. When they don’t, they not only fail to prevent cancer from growing and spreading, they can be rooked into aiding the process.

The melanoma tumor-suppressor Samuels and her group found interacts with an oncogene that is common to the set of melanomas they were looking at – apparently regulating its activities.

How does one restore the function of a gene that is lost or mutated? That is the question that the group is now addressing. “Now that we have identified the tumor suppressor, we can work out its pathway in the cell and understand how it is meant to function. And that, we hope, may lead to some ideas for treating this subset of melanomas – up to 35 percent of the cases. Among other things, this work highlights the need for more personalized diagnoses and treatment protocols for cancers like melanoma,” says Samuels.

Prof. Yardena Samuels (front left, in white) and her group. Drs. Rand Arafeh and Nouar Qutob (standing to the right and left of Samuels, respectively) led the study

Also online today:

A link between the immune system and obesity: when certain rare immune cells are missing, mice gain weight, even on a regular diet.

A brake on plants' starch production machinery that turns it off at night -- but stays lightly depressed during the day too.

jhalper Tue, 10/27/2015 - 01:46

Tags

Biological networks

personalized medicine

genes

Guest Post: A time for everything – but speed it up, please!

jhalper — Mon, 12 Oct 2015 04:41:13 +0000

Guest Post: A time for everything – but speed it up, please!

Ziv Zwighaft

Ziv Zwighaft is a research student in the group of the Weizmann Institute’s Dr. Gad Asher. Their new findings reveal some intriguing connections between our circadian clocks – which tick according to cycles of day and night – metabolism and aging. Here is his description:

King Solomon said: “There is a time for everything, and a season for every activity under the heavens.”

Our research tries to take this insight into the condition of living creatures a few strides forward. How strictly does it apply? Our lives are regulated by a biological clock – it’s actually many clocks working in synergy, orchestrating our waking, sleeping and eating, our growth and life stages and, recent research suggests, our metabolism. So first and foremost, the new findings are strong support for the claim that our circadian clocks are strongly intertwined with our body’s metabolic activities. We showed that the daily changes in the levels of a group of essential metabolites called polyamines are regulated from two sides – both by eating times and by the ticking of the clock. Polyamines are naturally occurring metabolites that are known to play a role in various essential cellular processes, as well as pathologies. Our research shows that they also play an active role in setting the tempo of our internal timing. (The research revealed that polyamines both regulate and are regulated by a circadian clock. WSW)

Dysfunction in the clock can lead to a wide range of diseases, starting with sleep disorders and on to metabolic disorders like obesity and diabetes, and up to psychological illnesses.

One of the things I found most encouraging was our success in reproducing the results we obtained in tissue culture and raising them to the level of the whole animal. Here, a deviation from the natural polyamine levels translated into clock malfunction. For example, low levels of polyamines made the clock run slow, and this situation was reversible by enriching the diet with polyamines.

This phenomenon – a drop in polyamine levels and impairment in the clock’s accuracy – is typical of the process of aging. So by investigating the joins between two worlds – circadian clocks and metabolism – we able to demonstrate how to “rejuvenate” the internal pace of timekeeping in old mice.

This particular study is finished, but the work has not been completed. In these days we are continuing to look for additional connections between the circadian clocks and metabolic processes in the body; these connections may lead to new strategies in the war against age-related disease.

So bad news and good: On the one hand, polyamine levels of tend to drop as we age, and our internal clocks lose time. On the other hand, we get polyamines from food too. When the researchers added a polyamine supplement to the diets to old mice, their slow circadian clocks gained minutes.

Asher says that much more research will be needed before we can tell whether such food supplements will have an effect on aging in humans. In the meantime, however, it can’t hurt to stick to a healthy diet and add some extra edamame, peas or lentils to the menu.

jhalper Mon, 10/12/2015 - 00:41

Tags

biochemistry

circadian clocks

obesity

Hm?
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022763/
doi: 10.3402/fnr.v55i0.5572

"... On the other hand, the cell growth promoting effect may also be negative in relation to cancer development. It has been shown that increased polyamine levels are associated with increased cell proliferation as well as expression of genes affecting tumor invasion and metastasis (21)."

Dear Hank,

You are right, elevation in polyamine levels had been previously linked with cancer development. With that been said, in our research we restored the polyamine levels to basal levels and worked well inside the physiological range and far from the pathological concentrations. Like many things in life, too much or too little from something might hurt you...

Thank you for commenting, hope you enjoyed our project.

Ziv

The fact it can cause cancer is pretty scary.

The things one can do with light - and messages in the dark

jhalper — Tue, 01 Sep 2015 02:56:50 +0000

The things one can do with light - and messages in the dark

One day in the future, we may be treating our ailments with microbiotic combinations designed specifically to correct imbalances in our personal microbiomes. We’ll bring our prescriptions on rewritable paper and pay using shimmery optical chips embedded in our cell phone cases or maybe our jewelry. Or we’ll be waiting in our doctor’s office for a simple test of our microbiogenome to see if a light-based nanoparticle delivery treatment is working, while watching iridescent optical displays that change as we move...

These future scenarios (and many more) are all imaginary, but they are imminently feasible, given today’s new stories on basic research at the Weizmann Institute. These are about several things one can do with light, including a disappearing trick or two, and messages hidden in deep, dark places.

Dr. Rafal Klajn’s messages are written with light. Printed images on a unique surface disappear within a few minutes. This system, made of nanoparticles in a gel-like medium, can be rewritten over and over again, so it could, one day, be the basis of rewritable paper. Klajn’s innovation is to put light-sensitive molecules into the medium (rather than engineering the nanoparticles); light exposure turns the gel acidic and leads to a fairly simple chemical reaction with the nanoparticles that causes them to disperse. The molecules Klajn uses, by the way, were developed back in the day (1950s) at the Weizmann Institute, and they have been used, among other things for photosensitive coatings on glasses.

Lighting the medium causes nanoparticles to disperse. Image: lab of Dr. Rafal Klajn

A different trick of the light is that of a tiny marine creature commonly known as a sea sapphire. Only a millimeter or so in length, the males of several species flash in brilliant colors ranging from purple to green for a second or so, and in the next they appear to completely vanish from sight. Though we still don’t know if the colors are meant to attract females or warn other males, thanks to Profs. Lia Addadi, Steve Weiner and Dan Oron, and their students Dvir Gur and Ben Leshem, we now know exactly how they perform the trick. Thin, clear crystals on the sea sapphires’ backs are stacked in precise arrays with “spacers” of cellular material holding them in place. It is the tuning of the spaces between the crystals that cause light to be directed in very specific wavelengths. In some species, this creates a glitzy blue iridescence when the light hits them full-on, from above. But when the sea sapphire performs an evasive corkscrew maneuver in the water, the angles are foreshortened as it turns sideways and the reflected light is shifted into the ultraviolet – effectively creating a sort of temporary invisibility cloak.

The precise stacking of the crystals, say the researchers, could lead to the design of artificial nanophotonic structures that would have numerous applications.

[embed]https://youtu.be/26kus22RaTo[/embed]

Finally, a study that brings to light a signal hidden in a place that daylight never reaches – deep inside our intestinal tracts. We know by now that the thousands of different types of bacteria living there are writing their own messages, which our immune systems interpret to our benefit or detriment. Type 2 diabetes, for example, and inflammatory bowel disease are mediated by the mix of microorganisms in our guts. Today we can work out the makeup of a person’s gut microbiome, but its message is mostly still too faint to read.

Computer scientist Prof. Eran Segal and his research students, working together with the group of Dr. Eran Elinav, an immunologist, have come up with a way of identifying a sort of communiqué within the broad picture. The idea is to sequence all of the DNA in a single sample, a task that is already available today with advanced sequencing techniques. Such techniques break the DNA into pieces and then reassemble the short sequences into long ones. But the group showed that this information can tell you not just quantities each kind of bacterium, but how fast each is reproducing. That’s because many of them are in the process of copying out their genomes in preparation for splitting into daughter cells; thus an overall sequencing will turn up lots of partial genomes. Since each kind of bacterium conveniently starts copying at the same point in its circular genome, one can figure out the first and last sequences to be copied and compute the ratio between the two. That will tell you, from a single sample, how fast each is replicating.

And changes in growth rates, according to the team’s further analysis, is a better indicator of the above-mentioned disorders than any other attempt to read our microbiomic messages, so far.

Three different studies – all basic research – in departments ranging from physics to computer science to chemistry and biology. The future possibilities are endless.

jhalper Mon, 08/31/2015 - 22:56

Tags

Chemical communication

personalized medicine

inflammatory syndrome

A Mutation in the "Library" Bodes a Litany of Ills

jhalper — Wed, 17 Jun 2015 03:07:50 +0000

A Mutation in the "Library" Bodes a Litany of Ills

When Dr. Jakub Abramson was a 14-year-old boy in the former Czechoslovakia, he asked his father what was the best place to do science. His father took the question seriously and, after some consideration, answered “the Weizmann Institute of

Dr. Jakub Abramson

Science.” Since that day, says Abramson, he knew he was bound for the Institute. “It’s just that the science I was interested in back then involved blowing things up,” he says.

Today, Abramson is more interested in exploding the common wisdom about autoimmune diseases. His lab at the Weizmann Institute has produced two new papers – one of them showing that an autoimmune disease so rare that most people have never heard of it has a more common form that could affect one in 1,000 people or more. Abramson’s lab worked together with that of Dr. Eystein S. Husebye in Norway. Husebye, a leading endocrinologist, had a patient whose symptoms pointed to the rare disease, which is recessive – caused by mutations in both copies of a particular gene called AIRE. But genetic testing showed that the patient had only one mutated copy of the AIRE gene. This surprising finding led the team to also check the patient’s family members, uncovering evidence for a milder disease associated with just one mutation. Subsequent studies led by the Norwegian and Weizmann scientists helped to elucidate the mode of action of these dominant mutations, as well as to demonstrate that they are significantly over-represented in patients suffering from various autoimmune syndromes.

This finding suggests that several autoimmune disorders for which the genetic cause was unknown may actually be caused by a specific mutation in one copy of the AIRE gene.

AIRE stands for AutoImmune REgulator. One mutation can cause a range of different symptoms because the autoimmune attack can affect pretty much any organ in the body. Abramson began investigating this gene in his postdoctoral research at Harvard Medical School, and his current research has led him to believe that it may be the key to various (but not all) autoimmune diseases for which the genetic factor has remained elusive.

The AIRE gene is only expressed in one organ – the thymus – and in one relatively rare type of cell, called mTEC. But every one of the immune system T cells must pass inspection by an mTEC before it is allowed out of the thymus and into the body. “Of course, the thymus does not have a brain,” says Abramson, “but the mTEC is a library of sorts – containing a comprehensive repository of self-antigens. That is, almost every one of the body’s genes is expressed in this cell. The process is one of negative selection – any T cell that is attracted to a self-antigen in the mTEC library gets eliminated in the thymus. So a slip-up at this stage could open the door to all sorts of autoimmune diseases.”

In the other paper, Abramson and his team identified a gene that regulates the AIRE master regulator. This gene, called Sirtuin 1 (Sirt1), is expressed in massive quantities in the mTEC cells – its levels are hundreds of times the norm – where it operates as an “on” switch for AIRE. This gene, interestingly enough, has previously been described as controlling diverse biological processes, including fertility, metabolism, stress responses and aging.

“We have uncovered yet another critical function for Sirt1 – the establishment of immunological self-tolerance in the thymus,” says Abramson. “We hope that this finding will provide an important basis for diagnosing all sorts of autoimmune syndromes for which the genetic cause is unknown. In the future, this may be very instrumental in designing new, 'personalized' strategies for treating these disorders. Indeed there is evidence that specific Sirt1 mutations are found in certain patients suffering from type1 diabetes." Whether Sirt1 mutations are also associated with other types of autoimmune disorders is currently under investigation by the Abramson-Husebye teams in follow up studies.

jhalper Tue, 06/16/2015 - 23:07

Tags

autoimmune disease

Gene expression profiles

genes

immunology

personalized medicine

The puzzle of chemotherapy resistance

jhalper — Wed, 03 Jun 2015 05:12:14 +0000

The puzzle of chemotherapy resistance

What is a breakthrough in cancer research? It is a new piece of a puzzle made up of a million pieces. It may, however, be a piece that allows a picture to start emerging – one that lets us see the shape of the next piece needed to fill in more of the puzzle, or start making changes to rearrange the picture from one of cancerous growth to one of normalcy.

The Institute’s Prof. Yosef Yarden’s recent research provides a vital piece for the puzzle of resistance – how cancer cells, especially those in recurring cancers, stop responding to chemotherapy. His answer is specific to a kind of lung cancer, one that has a certain mutation in the gene for a growth receptor on the cell’s outer membrane. So his findings point to the need for both a personalized approach to treating cancer and a new general approach to understanding the lengths that certain cancer cells will go to in order to keep dividing and spreading.

The particular puzzle was that the chemotherapy used to treat these lung cancers almost always sends them into what appears to be complete remission. But they invariably come back, often with a second mutation in the same receptor; and the new cancer is not only resistant to the original chemotherapy, it is also resistant to a second drug that should, by all scientific reckoning, block the re-mutated growth receptor and thus stop the cancer’s spread.

Lung cancer cells (green) cultured together with normal lung cells (red). The triple-antibody combination EGFR, HER2 and HER3 strongly impairs the survival of tumor cells while sparing normal cells. Modified confocal microscopy image: Maicol Mancini, lab of Prof. Yosef Yarden

Yarden and his group found that the resistant cancer cells had actually rewired a main internal communications line, ultimately putting several “sibling” receptors on the cell’s outer surface. These siblings can take in the growth signal but are impervious to the drugs that block the original signal.

With this piece of the puzzle in hand, he and his team were able to design antibodies to block the two other receptors, and they applied these together with the original antibody that “should have worked.” This “triple treatment” was very effective against resistant lung cancers – in lab dishes and in mice.

Since lung cancer is the leading cause of cancer death, worldwide, this is a little piece of the puzzle that could, conceivably, have pretty large implications in the future. But not just for lung cancer: The emerging picture, say Yarden, is one in which drugs that target just one receptor, for example, the cancer cell’s growth receptor, can activate a chain reaction that turns the cell resistant and possibly even more ready to divide and spread than before. Yarden had previously shown in collaboration with Prof. Michael Sela of the Institute, that certain breast cancers arising from specific mutations can be treated with a combination of receptor-blocking drugs. In other words, this mechanism of chemotherapy resistance is likely to be present in many cancers, suggesting that more than a few more pieces of the puzzle might now be within reach.

jhalper Wed, 06/03/2015 - 01:12

Tags

chemotherapy resistance

growth factor receptor

Michael Sela

Yosef Yarden

breast cancer

I’m surprised at the title and substance of this article, especially for this website.
I’m puzzled by the eight uses of the word “puzzle”.

There is NO “puzzle.”
You ALREADY KNOW what the answer is: Chemotherapy resistance EVOLVED.
As with all of evolution theory, the rest is just details to be worked out later. I mean to be theorized later.

See Noeve, if you go back to the article this links to, you will see that the resistance did not evolve in the way they thought it would. Believe it or not, there are still a lot of puzzles out there.

Basic chemistry might keep brain cells healthy

jhalper — Wed, 27 May 2015 04:34:38 +0000

Basic chemistry might keep brain cells healthy

“Inclusion bodies – those clumps of protein that are found in the brain cells of Alzheimer’s patients – are, sadly, a product of aging,” says Dr. Maya Schuldiner. “They can form naturally in practically all cells, but when these cells get old, the mechanism for clearing them away starts to fail.”

That is not great news for those of us who are already seeing signs of incipient dementia every time we forget a name or misplace our keys. But of course there is good news too. Schuldiner has discovered a “detergent” that cells make to wash away those nasty protein clumps. And she believes that, in the future, this detergent could provide the basis of drugs to treat neurodegenerative diseases, among them Alzheimer’s and Parkinson’s.

We put the word “detergent” in quote marks, but the truth is that the basic chemistry is pretty much the same as that of laundry soap: The two-part molecules have a fatty, water-repelling end and a water-loving end. The fatty end can attach to molecules of grease or protein; the water-loving ends latch on to the nearest water molecules to whisk the “dirt” away. In scientific terms, the proteins in the inclusion body become soluble.

"Laundry soap" in human cells: The Inclusion bodies are in red, lipid droplets in green

Schuldiner and her team realized this detergent was being produced when they saw lipid droplets – “little lard balls,” in Schuldiner’s words – tethered to the inclusion bodies they were investigating in yeast cells. These little lard balls turn out to be a bit more complex than they look. They produce a special kind of fat that is similar to a sterol (related to cholesterol) – when and only when there is an inclusion body in the cell. This sterol is what forms the detergent.

She says that she and her team were amazed to find evidence of detergents inside a cell. Since detergent molecules are basically indiscriminate in their actions – capable of clearing away all sorts of proteins and fats – the cell would need to produce them carefully and deliberately in place. Hence the physical tethering.

Her lab mostly works with yeast cells, which have, says Schuldiner, “the same inclusion body issues as human cells. They contain a protein that is nearly identical to the human one for tethering the lipid droplets. And, like the human ones, they suck at the removal process once they get old.” The group did repeat their experiments on human cells in lab dishes, finding similar results to their yeast cell studies. And Schuldiner points out that other studies have noted the lipid droplets around inclusions in the nerve cells of Alzheimer’s patients, but mostly ignored the deceptive little “lard balls.”

What gives her hope for treatment is that the detergent production is really “basic chemistry.” Clearly any potential drugs based on her group’s findings are, for now, in the speculation stage, but we can all hope for rapid advances in this area.

jhalper Wed, 05/27/2015 - 00:34

Tags

A bacterium's sense of self explained

jhalper — Mon, 27 Apr 2015 03:52:55 +0000

A bacterium's sense of self explained

Foreigner or native-born? Your immune system discriminates between them, as do those of bacteria. Yes indeed, bacteria do have immune systems – pretty complex ones at that. And like any useful immune system, the bacterial ones must have a good technique for distinguishing “foreign” from “self.”

You may even have heard of the bacterial immune system: It’s called CRISPR, and it’s used in biology research around the world for DNA engineering and genome editing. CRISPR normally inserts short DNA sequences taken from phages – viruses that invade bacteria – into special slots called spacers within its genome. These bits of DNA form an “immune memory” – the record of past infection that helps fight the next one. The phage sequences are used as a template to create “antisense” RNA-protein complexes that can identify and take out further phages that try to sneak into the cell. This kind of immunity is adaptive and, until recently, scientists did not think that bacteria had something so sophisticated as an adaptive immune system.

bacteria cell and phages. Wikimedia commons

Within less than a decade of its discovery, researchers had revealed how CRISPR works and even found how to use it for other purposes, but there were still some fairly big open questions -- especially how it discriminates between foreign and self. How can it look at two sequences of DNA and know that one belongs to a phage, the other to its own genome? For a bacterium, this is quite critical: Mistakenly inserting a bit of self-DNA could cause a fatal “autoimmune” attack. But if the cell misidentifies the phage DNA as self, the results could be no less deadly. And the ID system must be nimble, as well, since most environments are home to many more phages than bacteria.

Prof. Rotem Sorek and his group, working with researchers at Tel Aviv University, “infected” bacterial cells with round bits of DNA called plasmids and then recorded some 38 million separate immunization events to see how and where the selection occurs. (That’s no mistake: They really have data from 38 million events.)

The CRISPR foreign-self discrimination mechanisms they discovered astonish and delight because they are clever and efficient, and they use the bacteria’s DNA copying machinery to do the job. Extra DNA stuck in the genome – say from a virus that wants to get replicated – will gum up the machinery as the DNA double strand is being unwound in preparation for copying. A stall in the process brings in the repair enzyme; this enzyme, along with several CRISPR-associated proteins, checks out the sequence.

In the end, it all comes down to differences in replication: Viral DNA, which pretty much exists to reproduce, will have a lot of genetic bits that replicate at high rates. What it won’t have much of is another sequence that is found all over that bacterial genome, which tells the copying machinery to stop. So if the repair machinery finds lots of one and doesn’t run into the other, it can “assume” the DNA comes from a phage.

Why should we care about a bacterial immune mechanism? In truth, many think we need to start taking more of an “ecosystem” approach to the whole subject of bacteria and viruses – our world is teeming with them. So, for example, if we want to use phages, as some have suggested, as antibiotics, we might have to understand how the bacteria could develop resistance. On the other hand, some of the first to investigate the commercial use of CRISPR have been the yogurt producers, who can lose their bacterial cultures to phages. Phages can also live symbiotically inside bacteria, and in the case of certain hosts, cause harmless bacteria to become pathogenic. And, of course, phages are part of your personal ecosystem – present in and alongside the microbiota that live in your gut and on your skin.

Sorek is now looking for other bacterial immune systems – CRISPR is found in only around half of all bacteria, so there are sure to be others. And that, he says, will open up a whole new set of questions about discrimination on the microscopic scale.

jhalper Sun, 04/26/2015 - 23:52

Guest post: Dr. Gabriele D’Uva: How to Grow New Heart Cells

jhalper — Mon, 13 Apr 2015 06:10:12 +0000

Guest post: Dr. Gabriele D’Uva: How to Grow New Heart Cells

Dr. Gabriele D'Uva is finishing up his postdoctoral research at the Weizmann Institute. Here is his account of three years of highly successful research on regenerating heart cells after injury. Among other things, it is the story of the way that different ideas from vastly different research areas can, over the dinner table or in casual conversation, provide the inspiration for outstanding research:

Three years ago, when I joined the lab of Prof. Eldad Tzahor, the emerging field of cardiac regeneration was totally obscure to me. My scientific track at that time was mainly focused on normal and cancer stem cells: cells that build our bodies during development and adulthood. The deregulation of these cells can lead to cancer. I have to admit that I didn’t know even the shape of a cardiac cell when my postdoc journey started…

Eldad’s lab was also switching fields -- well, not drastically, like me, but still it was a transition from a basic research on the development of the heart to the challenge of heart regeneration during adult life.

Two neonatal cardiomyocytes (staining in red) undergoing cell division after treatment with NRG1

In contrast to most tissues in our body, which renew themselves throughout life using our pools of stem cells, the renewal of heart cells in adulthood is extremely low; it almost doesn’t exist. Just to give an approximate picture of renewal and regeneration processes: Every day we produce billions of new blood cells that completely replace the old ones in a few months. In contrast, heart cells renewal is so low that, many cardiac cells remain with us for our entire life, from birth to death! Consequently, heart injuries cannot be truly repaired, leading to (often lethal) cardiovascular diseases. This might appear somewhat nonsensical, since the heart is our most vital organ: No (heart) “beat” no life.

Hence a challenge for many scientists is to understand how to induce heart regeneration Scientists have been trying different strategies, for example, the injection of stem cells. We decided to adopt a different strategy – one that mimics the natural regenerative process of healing the heart in such “regenerative” organisms as amphibians and fish, and even newly-born mice. In all these cases the regeneration of the heart involves the proliferation of heart muscle cells called cardiomyocytes. Therefore the challenge before us was: “How can we push cardiomyocytes to divide?”

We adopted a team strategy. Cancer turned out to be a somewhat useful model for a “strategy.” After all, the hallmark of this disease is continuous self-renewal and cell proliferation. Starting from this thought, Prof. Yossi Yarden, a leading expert in the cancer field, suggested: “Why don’t you try an oncogene, such as ERBB2, whose deregulation can lead to uncontrolled cellular growth and tumour development?” The idea was that cardiomyocytes could be pushed into a proliferative state by this cancer-promoting agent. To Eldad, this was a nice “life” circle closing, since Eldad, when he was a PhD student in Yossi’s lab, focused exactly on the ERBB2 mechanism of action in cancer progression. I must admit, the idea sounded very intriguing and I really liked it.

Eldad, as a developmental biologist, had a different approach. Based on his field of expertise, his tactic was to apply proliferative (and regenerative) strategies learned from the embryos, when heart cells normally proliferate to form a functional organ. It turned out that a key player in driving embryonic heart growth is again… ERBB2!

So, Yossi and Eldad, from different fields of expertise, had the same idea: Look to ERBB2, which is a receptor on the cell surface that amplifies and transmits growth factor signals. It looked, back then, like a challenging idea; I was very happy to take the dare.

So this is exactly how my three and half years of post doc research started. At that stage, ERBB2 looked like a perfect candidate for cardiac regeneration. The idea to bring together cancer and developmental knowledge doubled the percentage of our success. The odds were on my side!

A first rule to starting a project regarding the role of any protein is to check for its expression. Therefore I started to analyse the kinetic of expression of ERBB2 in a normal heart during post-natal development. Interestingly, I noticed a dramatic reduction in ERBB2 levels in the heart during the first week of post-natal life. I have to mention that mouse cardiomyocytes stop dividing soon after birth, in about a week. It’s probably a residual proliferative ability of their embryonic life. My initial results revealed a strong reduction in ERBB2 expression, exactly coincident with the period in which heart cells lose their proliferative and regenerative capabilities.

I was very intrigued by this result, which immediately opened a very important question: “Is the loss of the regenerative ability of the heart in mice due to the decline of ERBB2 expression after birth?” After hundreds of experiments I can confidently answer: Yes. ERBB2 levels are reduced in cardiomyocytes shortly after birth, and this down-regulation limits the proliferative and regenerative ability of cardiac muscle cells.

To prove that, we first generated mice in which we deleted the Erbb2 gene specifically in heart cells. Loss of the ERBB2 gene (and protein) led to reduced cardiomyocyte proliferation and consequently to a very thin and poorly contracting heart. In the absence of ERBB2, the heart at birth was so weak that it could not tolerate the blood pressure and became dilated, a cardiac disease in humans known as dilated cardiomyopathy. The conclusion was that EBB22 is required for proper proliferation and growth of heart during embryonic development and its expression is physiologically reduced soon after birth to allow maturation of the cardiomyocytes.

Cardiomegaly (giant heart) in adult mice upon induction of Erbb2 (heart on the right) compared to normal mice (heart on the left)

Because of its major role in cancer, the only way to study ERBB2 involvement during heart regeneration was to search for a sophisticated system to finely, and transiently, increase its levels in the heart, within defined time windows. For this, we generated mice in which we could switch ERBB2 ON or OFF in cardiomyocytes. The results were amazing. Persistent ERBB2 induction led to a giant heart, two to three times bigger than normal in just a week or two. The analysis of the mechanism demonstrated that ERBB2 gets muscle cell to “rejuvenate” to an earlier stage (a phenomenon called “dedifferentiation”) and to reacquire the ability to proliferate -- similar to what happens during embryonic development. In addition, ERBB2 increases the size of the cardiomyocytes (a phenomenon called “hypertrophy”).

Thus far, the project had been proceeding in the right direction. However we soon realized that a bigger team could improve the project’s success. A very talented master’s student, Alla Aharonov, joined me in this effort. Alla’s help was precious in many ways. In particular, she contributed to our resolving the specific molecular pathways that are mediated by ERBB2 activation. Precious help in the analyses of cardiac functions were obtained from the lab of Profs. Jonathan Leor and Michal Neeman. Very important were also the “dinner discussions” with my wife, Mattia Lauriola (who was conducting a parallel postdoc in Yossi Yarden’s lab), in addition to Yossi’s scientific support and help from the beginning of the project. At certain point Eldad also involved Prof. Richard Harvey, a good friend of his and a leading scientist in heart development, whose suggestions turned out to be very effective. The project and the team were blooming.

The main findings, which we are happy to report, are that transient activation of ERBB2 (ranging from 10 days to 3 weeks) can trigger cardiomyocyte dedifferentiation and proliferation. These two processes in turn are critical to achieving cardiac regeneration after the injury that we had induced in mice to mimic human heart attacks. (termed myocardial infarction). Therefore, the activation of ERBB2 is one strategy to promote heart regeneration. It’s important to mention that one of the therapies currently being tested in clinical trials is a growth factor stimulus called Neuregulin1 (NRG1), which activates ERBB2 signalling. However, since we uncovered the fact that that ERBB2 levels are very low in adult mouse cardiomyocytes, we suggest that the efficacy of NRG1 therapy might be limited in adulthood. Further experiments in cardiomyocytes derived from human patients could answer this question.

The good news is that, according to our results, heart patients will definitely improve if we can, in the future, find a way to fine-tune ERBB2 levels. We need to find a way to control the expression of this receptor, or its signalling partners, for a short time to repair the damaged heart. How? That’s the next challenge; but it which could help millions patients worldwide!

Our findings point to a central role of ERBB2 in cardiomyocyte cell division and regeneration.

jhalper Mon, 04/13/2015 - 02:10

Tags

Cancer Research

Embryonic development

heart disease

dedifferrntiation

Eldad Tzahor

Gabriele D'Uva

growth factor receptor

heart cell regenertation

This was such an interesting read! I am amazed by the continuous progress being made under the radar. Is it possible to manipulate the heart from birth to ensure that levels of ERBB2 never decrease? I am looking forward to see how these results will alter the treatment of heart conditions.

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What are the chances of succeeding in finding a way to fine-tune ERBB2 levels and a way to control the expression of this receptor, or its signalling partners, for a short time to repair the damaged heart in the future?and is it guaranteed that when you succeed in these findings heart patients will improve?

Wow that is amazing! More research should definitely be done on the subject. I am confident that these findings will help to ensure that heart diseases will be treated easily and that people with weak hearts will have a chance to live a normal life. (15001548)

what is the difference between cardiac and tissue cell that give rise the high frequent renewal of the tissue cells but extremely low to the cardiac cell?

That is excelent work indeed.I claim with no doubt that these findings can extend to other interesting researches about the heart.

I find this research ground-breaking and indicates that science is one step closer to finding the life-saving therapy and treatment that patients with cardiovascular disease need. It is enlightening to also know how heart cell stop regenerating from birth which highlights the importance not taking one's heart health for granted. It would be great if similar research can be done on the regeneration of neuron cells in the body which like this research, will cure other various degenerative diseases.

I find this research very remarkable and proves that science is one step closer to finding a cure for patients suffering from various cardiovascular diseases. Can the same approach be used to treat other damaged tissues such as the in the brain when a patient has suffered a stroke?

It is incredible to turn something negative into something positive. Can the same cancer growth idea be used for other organs as well? I would love to see how this idea can be used in the brain or nervous system to cure auto immune degenerative diseases. It is unbelievable to imagine where the medical research will be in 20 years from now. The life expectancy can increase drastically.

with such groundbreaking studies it would now seem that soon the world would be populated by older and older people. Is there no possible way of programming the heart cells to function like those of the liver?

i would pose the same question as you danielle, can it also be used for other organs? so that finally we can get a cure for cancer not a guarantee of losing a loved as soon as they have cancer, this would help a lot of people in different ways.Excelent work being down by our scientist and physicians

excellent work being done by our scientist and physicians i meant

The fact that this discovery has been made could have unlimited possibilities! would it be possible to synthesize ERBB2 that is might be possible in humans to utilize it when it is needed, for example in patients with failing hearts? Or perhaps a way unto which the production of ERBB2 could be increased to an extent that humans continue to produce it only to regenerate heart cells without the side effect of an enlarged heart as seen by the mouse heart three times the size of a normal mouse heart. Very interesting read though and cannot wait for further advancements in this field. u15016677

If these ERBB2 cells are known to stimulate growth, could it not also be used in other areas of the body where for example there is a cell deficiency, or maybe with diabetes where there is a low production of the necessary components. There should be a way to use ERBB2 in other areas of the body as well.

I find this research very interesting, I can even see myself doing perhaps something similar in the future. This research not only have the potential to change the way we look at the human heart but also the way we look at various degenerative diseases. It will change the medical world drastically. One thing I am wondering about is why the heart has such a low renewal rate?

Well done on the research conducted and progress made in the field of cardiac regeneration. It truly made for a very informative read and it was interesting to note about the almost non-existing renewal of heart cells. The research provides hope that damaged hearts could be repaired in the near future. Keep up the good work! (04648685)

It is amazing! More research ought to certainly be done on the subject. I am certain that these discoveries will help to guarantee that heart sicknesses will be dealt with effectively and that individuals with frail hearts will have an opportunity to carry on with a typical life

This is amazing, to think that researchers has come this far in a matter of a few years. The regeneration of heart cells is maybe one of the most important medical fields to explore to ensure that people with heart damage can live a full life despite their condition.
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Since ERBB2 seems to be triggered in all the cardiac tissue, leading to hypertrophy, which in itself is potentially fatal, how would one limit its action or generation to specific areas affected by myocardial infarction, which are necrotic? Put another way, how would one achieve a patch effect?

This research is so inspirational and very interesting. I can't wait to see how damaged hearts will be repaired in the future. It is amazing how medical science has improved.

Well done to medical science! It is amazing how the world of medicine has improved.

This is very interesting. I can not wait to see how damaged heart will be repaired in the future. This is outstanding work done by scientists and physicians. Science just keep improving our lives day by day.

I found this article not only interesting but inspiring, To take the concept and idea of what cancer does to the cell, then to apply it to an organ where regenerative capabilities are needed?. My only question is are we able to control ERBB2 receptors and the growth of the heart cells? and as asked in comment #8 can this be applied to other internal organs??

What are the chances of cardiac regeneration in baby's born with holes in their hearts,especially baby's born with down syndrome? Will this research project be of any help to them?

This is truly fascinating. I had no idea that heart cells could not be renewed or repaired. An interesting point to acknowledge however is why try to repair an organ that is destined to fail at some point? Why not replace the organ with a more reliable, longer lasting piece of equipment? I believe further studies should be focused on cybertronics.
u15001319

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I'm really impressed with this research and hope to one day partake in this exciting search to cure the heart!!!

WOW hopefully by the time my heart gives in this research would have been completed and my heart saved ;)

To all you South African commenters: sorry if your comments did not appear immediately. I was on vacation, but tried to get them up as soon as I could.

Please keep up your interest in this site and in science!

Artificial Sweeteners, Your Gut Bacteria and You

jhalper — Wed, 17 Sep 2014 15:08:37 +0000

Artificial Sweeteners, Your Gut Bacteria and You

Could artificial sweeteners be helping cause the very thing they are supposed to prevent? They may well do so, and you can probably blame your microbiota – those masses of mostly-friendly bacteria that live in your gut. According to a paper by Weizmann Institute scientists that appeared today in Nature, artificial sweeteners not only encourage the wrong kind of bacteria to expand their numbers, they also induce mix-ups in the cross-communication between these bacteria and your body. Those mix-ups can lead to glucose intolerance – the first step toward metabolic syndrome and diabetes. So, ironically enough, if you consume the recommended amounts of zero-calorie drinks, you could begin developing glucose intolerance in just a week. That is what happened to human volunteers who consumed artificially sweetened food and drink for the experiment.

The Weizmann Institute’s Dr. Eran Elinav, who conducted the research together with Prof. Eran Segal, says that this is not really a surprising finding. Your body does not absorb artificial sweeteners – they pass right through you. Even if it did, the human body could not yet have evolved tolerance to the sweeteners – substances that have only existed for about a century. Your gut bacteria, on the other hand, evolve rapidly, and they pretty much eat what you eat, including those zero-calorie drinks.

We have known for a while that the composition of your internal population of bacteria can, among other things, affect your tendency to gain weight, and that diet has an effect on this composition. But this knowledge is still fairly vague: No one can tell you, yet, just what to eat for the most healthful microbiome, or what, exactly, that mix of bacteria will do for you. So the Nature paper makes a pretty strong statement: Your gut microbiota cannot be ignored any longer. Their intimate relationship with your body is vital; its consequences for your health are critical.

Gut microbiota -- treat them right, and they'll treat you right

The researchers worked with both mouse and human subjects. The mouse research was pretty damning on its own: Mice fed artificial sweeteners (in FDA-permitted doses) developed glucose intolerance while those that had been treated with antibiotics to eliminate their gut bacteria did not. In the meantime, sterile mice that had the microbiota from glucose intolerant mice implanted in their guts quickly developed the same glucose intolerance. Even gut bacteria grown in a lab dish with artificial sweeteners and then implanted in mice could induce glucose intolerance.

The human research was, as is usually the case, a bit more complicated. The findings suggest that some people may not be affected either way by artificial sweeteners, while for many others the effect will be negative. The difference is, again, in the makeup of their gut microbiota. The researchers first discovered these two different patterns in a large trial they have been conducting called the Personalized Nutrition Project (www.personalnutrition.org). The trial, in which hundreds have already participated, aims to figure out how each individual’s mix of heredity, habits and gut microbiota come together to determine how their food will affect them. The ultimate goal of this project, says Segal, is to give people the knowledge they need to avoid such diet-related diseases as obesity, metabolic syndrome, hypertension and atherosclerosis.

The human volunteer experiment backed up these findings. As with the mice, the composition of their gut microbiota changed with that one change in their diets, and for many, this led to the onset (thankfully reversible) of glucose intolerance.

Elinav believes that the widespread use of artificial sweeteners may even be contributing to the global obesity epidemic. In the not so distant future, a personalized nutrition evaluation – including a check of one’s gut microbiota – might be used to recommend the proper diet for avoiding such health problems as artificial-sweetener-induced glucose intolerance.

In the meantime, they suggest you drink water!

Here is a nice video they made at the Wall Street Journal:

jhalper Wed, 09/17/2014 - 11:08

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Biomatics