Cell Replacement by the Numbers (Biology)

Mapping cellular turnover sheds light on the balance between renewal and stability in our bodies

One of the earliest thought experiments in history asked whether the ship commanded by the legendary king Theseus could have its old timber replaced, piece by piece, and still remain the same ship. At some point would it actually be a new ship? Our bodies are something like Theseus’ ship, steadily turning over cells so that as we age, we can say that few of the original “planks” are left. In our bodies, some cells never get replaced, while others are exchanged on practically a daily basis. What does the overall picture of cell replacement look like? For biomedical research, that is more than a philosophical question, as it touches on numerous processes in the body, from metabolic health to cancer.

Prof. Ron Milo and research student Ron Sender of the Weizmann Institute of Science’s Plant and Environmental Sciences Department went about this issue using a biological census method developed in Milo’s group. Of the 30 trillion cells in an adult body, Milo and Sender first selected a number of the most prevalent, representative types, with red blood cells and the epithelial cells lining the intestinal tract at the high end of the turnover scale, the non-renewable brain cells and cardiac cells at the other extreme. Then, using the available statistics for each, they created comparative maps to show, at a glance, how many types, and how much of each type of the cells in the body die and get replaced over time – by numbers as well as by weight.

Roughly every 80 days our bodies produce a number of new cells roughly equal to the total number in the body

In the final tally, around 330 billion cells die and roughly the same number of new ones are born every day. By numbers, red and white blood cells – which live between one day and several months – are by far the largest portion, accounting for some 90%, of that turnover. Blood cells are quite light, so by mass, the daily total comes out to something a bit less than a hundred grams. Thus roughly every 80 days our bodies produce a number of new cells roughly equal to the total number in the body. However, in terms of mass, we create our weight in new cells every year and a half (not seven, as some have suggested).

When the cells are compared by the overall weight of cells that get turned over, blood cells still come out on top, but less so. Gut epithelial cells, which are much larger than blood cells, are a fair second, accounting for about 12% by numbers but 40%, by weight, and getting replaced, on average, every few days. By mass, fat cells and skin cells trail far behind, each accounting for around 4% of the total daily turnover, with lung cells making up only half a percent.

Because blood cells are light, they account for only around half of the mass © Weizmann Institute of Science

And the researchers did not forget another component of our body mass: The few hundred grams of gut bacteria we carry with us have an extremely high replacement rate of around 100 grams a day.

“These maps can now provide a baseline for a healthy adult,” says Milo. “We can, in the future, use them to explore, on the one hand, how the ratios change during growth and development and, on the other, how the balance between life and death in cell turnover is upset in cancer and many other diseases. In the future we might be able to develop diagnostic tests for determining unhealthy levels of turnover in certain cell types that could provide early signs of disease, or apply the findings to answering questions concerning the ways that cancer upsets this balance

”Our study gives a fresh quantitative perspective on the classic question of the ‘Theseus ship’ of the body, showing you can learn a lot by paying close attention to the numbers. Our body is both new and the same in a way we can now quantify, undergoing constant change through the process of cell turnover and yet keeping the same ratios of cells that preserve the same basic form and function.”

Video: Design: Itai Raveh | Animation: Oleg Fedorkov

Prof. Ron Milo is Head of the Mary and Tom Beck – Canadian Center for Alternative Energy Research; his research is also supported by the Zuckerman STEM Leadership Program; the Larson Charitable Foundation New Scientist Fund; the Ben B. and Joyce E. Eisenberg Foundation; the Yotam Project; the Ullmann Family Foundation; Dana and Yossie Hollander; Sonia T. Marschak; and the European Research Council. Prof. Milo is the incumbent of the Charles and Louise Gartner Professorial Chair.

Featured image: By numbers, blood cells make up 90% of those replaced each day © Weizmann Institute of Science


Reference: Sender, R., Milo, R. The distribution of cellular turnover in the human body. Nat Med 27, 45–48 (2021). https://www.nature.com/articles/s41591-020-01182-9 https://doi.org/10.1038/s41591-020-01182-9


Provided by Weizmann Institute of Science

Stress Response Protein Links Inflammatory Disease to Colon Cancer (Medicine)

The findings might help identify those at extra risk of this cancer and develop means of prevention

Inflammation promotes some of the deadliest cancers. In the colon, inflammatory bowel disease is well known to be associated with higher-than-average rates of malignancy. Nevertheless, the developing tumor is commonly diagnosed only when it has already advanced or even metastasized, possibly because the early symptoms of malignancy are often mistakenly ascribed to a flare-up of intestinal inflammation. Weizmann Institute of Science researchers have now revealed a molecular missing link between chronic gut inflammation and cancer. This revelation may help develop ways of preventing colon cancers in people with inflammatory diseases of the intestines.

Dr. Ruth Scherz-Shouval of the Biomolecular Sciences Department hypothesized that the path from chronic bowel disease to cancer winds through the stress response to inflammation within the intestinal cells. She focused on heat shock factor 1, or HSF1, a protein that triggers cellular changes in just such instances of stress and strain on the cells. In earlier work she had found that HSF1 causes supporting cells called fibroblasts to start assisting the progression of cancer in their vicinity. In the new research, Scherz-Shouval and her team asked whether this process begins even before cancer is seen – in colon inflammation that eventually leads to colon cancer.

Doctoral student Oshrat Levi-Galibov led a series of experiments in which the scientists observed changes in mice that exhibited symptoms of chronic inflammation of the gut, resulting some two months later in colon tumors. At different stages in the course of the inflammatory disease, the researchers examined the gut tissue of the mice, using advanced two-photon microscopy, and analyzed the protein composition of this tissue, using mass spectrometry and other methods. They found that starting in the early stages of inflammation, the extra-cellular matrix that is generated by fibroblasts – the network of collagen and other large molecules providing support to surrounding cells – underwent abnormal changes that later facilitated cancerous growth.

To ascertain whether these changes had been triggered by HSF1, they silenced this protein in mice through genetic engineering. The fibroblasts then created a normal extracellular matrix, and the mice failed to develop chronic inflammation and did not grow colon tumors.

(l-r) Hagar Lavon, Dr. Ruth Scherz-Shouval and Oshrat Levi-Galibov © Weizmann Institute of Science

Next, the researchers established that their findings were relevant to human disease by examining tissue samples from patients who had been treated for inflammation-related colon cancer at the Sheba Medical Center in Tel HaShomer and at Memorial Sloan Kettering Cancer Center in New York City. HSF1 was found to be activated in the tissues of these patients, and their extracellular matrix and protein composition had undergone abnormal changes similar to those observed in mice in the Weizmann study.

Finally, the scientists experimented with a small molecule that blocks HSF1 activity. When they exposed fibroblasts isolated from inflamed tissue to this molecule, these cells failed to create an extracellular matrix. In other words, the molecule put an end to the fibroblasts’ cancer-facilitating activity.

HSF1 was found to be activated in the tissues of these patients

In the future, these findings may lead to a drug that will help prevent inflammation-related colon cancer by selectively blocking the effects of HSF1 on fibroblasts. This research may also one day make it possible to identify people among those with inflammatory bowel disease who are at an increased risk of colon cancer, so that these high-risk individuals can receive the preventive treatment long before the cancer gets a chance to form.

Study participants included Hagar Lavon, Dr. Rina Wassermann-Dozorets, Dr. Meirav Pevsner-Fischer, Shimrit Mayer, Yaniv Stein, Gil Friedman and Dr. Reinat Nevo of Weizmann’s Biomolecular Sciences Department; Dr. Esther Wershof and Prof. Erik Sahai of the Francis Crick Institute, London; Dr. Lauren E. Brown, Dr. Wenhan Zhang and Prof. John A. Porco of Boston University; Ofra Golani of Weizmann’s Life Sciences Core Facilities Department; Dr. Lior H. Katz, Dr. Ido Laish and Dr. Dror S. Shouval of Sheba Medical Center; and Dr. Rona Yaeger and Dr. David Kelsen of Memorial Sloan Kettering Cancer Center.

The extracellular matrix (red) in the colon of regular mice (top left) was disrupted by inflammation (top, center and right), whereas mice lacking HSF1 (bottom left) failed to develop inflammation under the same conditions, and their matrix remained normal over time (bottom, center and right) © Weizmann Institute of Science

Dr. Ruth Scherz-Shouval’s research is supported by the Moross Integrated Cancer Center; the Dr. Barry Sherman Institute for Medicinal Chemistry; the Laura Gurwin Flug Family Fund; the Rising Tide Foundation; the Elsie and Marvin Dekelboum Family Foundation; the Sklare Family Foundation; and the estate of Aliza Yemini. Dr. Scherz-Shouval is the incumbent of the Ernst and Kaethe Ascher Career Development Chair in Life Sciences. 

Featured image: Lining of mouse gut under a microscope. That of regular mice (top left) becomes disorganized as chronic inflammation progresses (top, second and third from left), facilitating the development of cancer (top right). In mice lacking HSF1 (bottom left), inflammation fails to develop (bottom, second and third from left, and right)


Reference: Levi-Galibov, O., Lavon, H., Wassermann-Dozorets, R. et al. Heat Shock Factor 1-dependent extracellular matrix remodeling mediates the transition from chronic intestinal inflammation to colon cancer. Nat Commun 11, 6245 (2020). https://www.nature.com/articles/s41467-020-20054-x https://doi.org/10.1038/s41467-020-20054-x


Provided by Weizmann Institute of Science

Precise Mapping Shows How Brain Injuries Inflict Long-term Damage (Neuroscience)

Researchers have shown how forces acting on the brain during traumatic injury are linked to damage seen years after the initial trauma.

The findings, from a cross-disciplinary team at Imperial College London, could be used to predict the severity of brain injuries and help design more effective helmets for a range of sports and activities. 

Understanding the link between (initial injury and ongoing effects) is crucial for predicting who is at risk for long-term damage, and how protection may be better designed to prevent this damage.

— Dr Mazdak Ghajari, Dyson School of Design Engineering

Traumatic brain injury (TBI) results from a sudden impact or jolt to the head, such as during a road traffic accident or bomb blast, or during sports like rugby and American football. Immediate impacts of TBI can include bleeding and unconsciousness, but it can also result in changes to regions of the brain that lead to symptoms like memory loss, mood and personality changes, and lack of concentration, sometimes many years after the initial injury. 

However, the link between the mechanical forces that act on the brain during TBI and the resulting long-term changes is poorly understood. 

Now, researchers from the Faculties of Engineering and Medicine at Imperial, including the teams of Dr Mazdak GhajariProfessor David Sharp and Dr Magdalena Sastre, have shown a clear link  between the forces acting on the brain during TBI and its associated long-term changes. The research, which is published in Brain, combined a computational model of brain injury with experimental studies on rat brains. 

Dr Mazdak Ghajari, from the Dyson School of Design Engineering at Imperial, said: “The initial damage during a traumatic brain injury takes only milliseconds to occur, but it triggers many changes that result in ongoing effects which can be felt years later. Understanding the link between the two is crucial for predicting who is at risk for long-term damage, and how protection may be better designed to prevent this damage.”

The shear stresses on the brain correlated with markers of brain inflammation.

— Dr Magdalena Sastre, Department of Brain Sciences

Previously, the team had built a human computer model to predict the location of long-term brain damage following TBI, focusing on the ‘white matter’ of the brain. The white matter contains nerve fibres called axons: extensions of neurons which help connect them. Axons play a large role in the brain networks that are altered in long-term brain damage.  

Now, they have tested this modelling approach to see if it can accurately predict the pattern of white matter damage in rats given mild or moderate TBI. They simulated the rats’ brains during injury, revealing the location and duration of mechanical forces linked to damage. Using a precise experimental model, this damage was induced in the rat brain and followed up after several weeks, which correlates to years of changes in a human brain. 

They found that the effect of shear stresses on the white matter helped to predict the location of long-term damage. Shear stresses push two parts of the same object, in this case the brain, in different directions. 

Dr Magdalena Sastre, from the Department of Brain Sciences at Imperial, said: “The shear stresses on the brain correlated with markers of brain inflammation, which is associated with memory loss and other future functional cognitive alterations.”

Development of injury after moderate impact © Imperial College London

We are also looking at how the type of impacts experienced by American football players affects whether they lose consciousness, and whether new helmet designs might protect soldiers from the effects of blast waves following explosions.

— Professor David Sharp, Department of Brain Sciences

The brain is jelly-like in consistency, so when it received a jolt, it shakes in a similar way, causing shear between adjacent parts. The intensity of the shear at different locations caused by different impacts, for example what angle they come from, predicts where the most severe white matter damage will occur. This could potentially help doctors predict the likely long-term effects in patients who have suffered a TBI. 

Dr Ghajari said: “Different types of injuries will cause different kinds of shear. With this new model we can now more accurately predict which injuries will cause severe, long-term damage, and potentially avert it. For example, motorbike accidents involve a lot of rotational movement, which causes lots of shear. We are studying dozens of bike helmets to see which best protect against excess rotation.” 

Now the team’s computational model has been validated in real rat brains, they can use it to ask a range of research questions by modelling different kinds of TBI. 

Professor David Sharp, also from the Department of Brain Sciences, added: “We are also looking at how the type of impacts experienced by American football players affects whether they lose consciousness, and whether new helmet designs might protect soldiers from the effects of blast waves following explosions. These types of studies can also help explain whether repeated small impacts, such as heading the ball in football, could lead to similar long-term brain injury.”

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The research comes out of a long-term collaboration between engineers, medics and biologists at Imperial, a partnership Dr Ghajari describes as “requiring lots of patience and energy, but producing extremely rewarding results.” 

Researchers come from the Department of Brain Sciences, the Biological Imaging Centre, the Dyson School of Design Engineering, the Centre for Blast Injury Studies, and the UK Dementia Research Institute at Imperial, as well as colleagues at King’s College London. 

The work was funded by the Wellcome Trust and the Royal British Legion at the Centre for Blast Injury Studies. 

From biomechanics to pathology: predicting axonal injury from patterns of strain after traumatic brain injury,’ by Cornelius K. Donat, Maria Yanez Lopez et al. is published in Brain

Featured image: Imaging and computational models depicting the development of brain injury after a mild impact on rat brains © Imperial College London


Provided by Imperial College London

Application of Potassium to Forage Grass Used as Cover Crop Guarantees Higher-quality Cotton (Botany)

The use of cover crops between cotton harvests protects the soil, conserves water, and reduces the risk of erosion. Researchers at the University of Western São Paulo (UNOESTE) and São Paulo State University (UNESP) in Brazil found that application of potassium (K) to a grass cover crop grown before cotton in sandy soil lowered production cost and resulted in cotton with a higher market value. 

“The dynamics of early application of potassium to grass planted as a cover crop before cotton results in more resistant fibers and a smaller proportion of short fibers than when the conventional method of applying the nutrient to the cotton crop is used. In addition to the improvement in quality, the technique reduces production cost for the farmer because of its impact on operational dynamics. The farmer can apply potassium once instead of twice. The technique saves labor and diesel oil, as well as optimizing operational logistics. In the long run, it’s also expected to reduce fertilizer use,” said Fábio Echer, a professor at UNOESTE and lead author of an article on the study published in Scientific Reports.

The two-year study, which was conducted on UNOESTE’s experimental farm, compared the conventional method of fertilizing cotton directly with two other methods, both involving early application of potassium. It also evaluated cotton growing without fertilizer and without a cover crop.

The research was funded by a master’s scholarship awarded by FAPESP to Vinicius José Souza Peres. The São Paulo State Cotton Growers Association (APPA) and Fundação Agrisus also collaborated on the project.

Quantitative and qualitative analysis of fiber

In one of the treatments, the researchers applied potassium to the grass cover crop in two doses (70 kg per hectare each). They compared this with application to the cover crop of a single dose of 140 kg per hectare and split application, with half going to the cover crop and the other half to the cotton. The results in terms of fiber yield were identical to those of the conventional method. Yield and quality were both lower with no fertilizer than when the conventional method or early application was used.

“The study included a calculation of fertilizer use efficiency,” Echer told Agência FAPESP. “We found that early application enabled the forage grass used as a cover crop to recover nutrients from the soil, in addition to the function of protecting it. This plant has a deep rhizosphere and its roots are able to find soil nutrients lost via leaching from previous crops, recycling them, and pushing them back to the surface. When the plant dries out, it releases potassium in the first rain to the crops that come next.”

The main advantage of early application, however, is that it increases the commercial value of the cotton produced. The analysis of fiber quality and cotton value found that fertilizing the cover crop with potassium led to a smaller proportion of short fibers, which depreciate the finished product, and also enhanced fiber fineness (micronaire), maturity and strength. “These characteristics are important. They represent higher commercial value for the production of finer cotton fabric, which is better quality and fetches a higher price on the market,” Echer said.

The improvement in quality relates to the availability of potassium in the soil and plant water status. “Cotton fiber is a cell, and like all cells it needs water to expand. By conserving more water in the soil and in the plant, we can also improve fiber size,” he explained.

Potassium plays a key role in the control of plant water loss. It regulates stomata functioning, carbon dioxide fixation, enzyme activation, and nutrient transport, as well as aiding stress tolerance. Soil potassium reaches plant roots mainly by diffusion, which accounts for 72%-96% of each plant’s requirement.

“Extreme weather events, high temperatures, and droughts have become more frequent because of global warming, and conservationist soil management techniques such as those suggested by the study can mitigate the adverse effects of all this on production,” Echer said. “Inconsistent rainfall may limit crop viability, and because only about 8% of Brazil’s cotton plantations are irrigated, the use of a cover crop is especially important. Straw mulch helps reduce soil temperature, which in turn helps conserve water.”

In western São Paulo, where the experimental farm used in the study is located, the temperature can reach 70°C on cotton plantations without a cover crop (and hence with exposed soil). The use of a cover crop keeps the soil at about 28°C-30°C, conserving soil moisture.

Early application of potassium is widely used in plantations with clayey soil, Echer added, but the technique had not yet been tested on sandy soil with little organic matter, making nutrient retention harder. “Farmers were reluctant to apply fertilizer early in the case of crops planted in sandy soil,” he said. “The study proves that applying potassium to the cover crop maintains yield and improves fiber quality even in sandy soil, which is more fragile, stores less water and makes potassium more susceptible to leaching.”

According to the researchers, the method analyzed in western São Paulo can be replicated in cotton plantations with sandy soil in Mato Grosso (the leading cotton producer in Brazil) and Bahia, as well as in other countries. “The cover crop can be different from the one we used in this study, because the climate may be different, but a precedent has been set for testing new cover species in other parts of the world,” Echer said.

The article “Potassium application to the cover crop prior to cotton planting as a fertilization strategy in sandy soils” (doi: 10.1038/s41598-020-77354-x) by Fábio Rafael Echer, Vinicius José Souza Peres and Ciro Antonio Rosolem can be read at: www.nature.com/articles/s41598-020-77354-x.

Featured image: In an article published in Scientific Reports, Brazilian researchers show that besides simplifying operational logistics and improving production, fertilization of the grass used as a cover crop can reduce fertilizer use in the long run (photo: Vinícius Peres)


Provided by FAPESP

Can We Able To Escape Big Rip? PART 2: Berkenstein Bound (Quantum / Astronomy / Cosmology)

Previously on “Can We Able to escape big rip? PART 1: Achronal Cosmic Future”, We saw that In 2004, Pedro F. González Diaz obtained that the accretion of dark energy leads to a gradual increase of the wormhole throat radius which eventually overtakes the superaccelerated expansion of the Universe and becomes infinite at a time in the future before the occurrence of the big rip singularity.

After that time, as it continues accreting dark energy, the wormhole becomes an Einstein-Rosen bridge which can, in principle, be used by the future advanced civilizations in their efforts to escape from the big rip. However, in this activity the future civilizations will have to face but another problem: an “extremely stringent information’s bound”.

Guys during 1980’s, Bekenstein proposed a information bound, which is also called as “Berkenstein Bound”, which shows that the total amount of information, which can be stored in region of radius R is I < Im = 2πRE/(hc log 2). Thus,

So, in his paper, he calculated the horizon radius and found that its in the order of Planck scale. Thus, he found the Berkenstein Bound results in,

What it actually mean? Well, it means that, the largest amount of information to be processed and therefore – sent through the Einstein-Rosen bridge is no way greater then 69 bits. Yeah, just 69 bits. As a comparison, the superior limit of amount of information encoded in a human being is about 1045 bits. This value is surely an excess, for any object existing in current universe is encoded far less than any quantum field theory’s constraints, but in any case the amount of 69 bits seems terribly small. For example, the amount of information in a typical book is I ∼ 107 bits, and 1015 bits stands for all books in the Library of Congress. 69 bits is, in fact, slightly higher then the total amount of information that can be coded in the proton, viz. 44 bits!

So, it means you wont be able to leave this universe. The only way to save yourself, is to prevent big rip. And for that, you will need quantum effects.

To be continued in next part..


Reference: Jacob D. Bekenstein, “Energy Cost of Information Transfer”, Phys. Rev. Lett. 46, 623 – Published 9 March 1981. https://journals.aps.org/prl/abstract/10.1103/PhysRevLett.46.623 (2) Schiffer M, Bekenstein JD. Proof of the quantum bound on specific entropy for free fields. Phys Rev D Part Fields. 1989 Feb 15;39(4):1109-1115. doi: 10.1103/physrevd.39.1109. PMID: 9959747. (3) Marcelo Schiffer and Jacob D. Bekenstein, “Do zero-frequency modes contribute to the entropy?”, Phys. Rev. D 42, 3598 – Published 15 November 1990. https://journals.aps.org/prd/abstract/10.1103/PhysRevD.42.3598


Copyright of this article totally belongs to our author S. Aman. One is allowed to reuse it only by giving proper credit either to him or to us

Can We Able To Escape Big Rip?: PART 1: Achronal Cosmic Future (Quantum / Cosmology / Astronomy)

Summary:

In 2004, Pedro F. Gonzalez-Diaz obtained that the accretion of phantom energy leads to a gradual increase of the wormhole throat radius which eventually overtakes the superaccelerated expansion of the Universe and becomes infinite at a time in the future before the occurrence of the big rip singularity. After that time, as it continues accreting phantom energy, the wormhole becomes an Einstein-Rosen bridge whose corresponding mass decreases rapidly and vanishes at the big rip.


In 2004, Pedro F. Gonzalez-Diaz had shown that phantom/ dark energy can results in achronal cosmic future where the wormholes become infinite before the occurence of the big rip singularity. To show this he considered the wormhole with the throat radius of, b0 = 10¯33 cm (Planck scale). It was shown by him that if p = – (1+ ϵ) c²ρ is a fluid’s equation of state, then

Equation 1

where, b(t) is the throat radius of a Morris-Thorne wormhole and D is dimensionless quantity. According to Pedro, we can choose D ∼ 4. The above equation describes the changing of the b(t) with regard to the phantom energy’s accretion. Integration of this equation gets us

Equation 2

Therefore at

Equation 3

we get, b(t˜) = ∞. As we can see t < t˜∗, and therefore this universe indeed will be achronal before the occurance of the big rip. In accord to Pedro F. Gonzalez-Diaz, at t >t˜, while in process of the phantom energy’s accretion, the wormhole becomes an Einstein-Rosen bridge which can, in principle, be used by the future advanced civilizations in their efforts to escape from the big rip. However, in this activity the future civilizations will have to face but another problem: an “extremely stringent information’s bound”. What is it actually?

Well, don’t worry i will explain it in the next part of this article..


Reference: Pedro F. González-Día, “Achronal Cosmic Future”, Phys. Rev. Lett. 93, 071301 – Published 13 August 2004. https://journals.aps.org/prl/abstract/10.1103/PhysRevLett.93.071301


Copyright of this article totally belongs to our author S. Aman. One is allowed to reuse it only by giving proper credit either to him or to us