Tag: dna

Cancer

Personalized Cancer Treatment

The team solved the problem of delivery of siRNAs into cells by making a PTD fusion protein with a double-stranded RNA-binding domain, termed PTD-DRBD, which masks the siRNA’s negative charge. This allows the resultant fusion protein to enter the cell and deliver the siRNA into the cytoplasm where it specifically targets mRNAs from cancer-promoting genes and silences them.

2013-07-16: Cancer uses ancient genes

We envisage cancer as the execution of an ancient program pre-loaded into the genomes of all cells. It is rather like Windows defaulting to ‘safe mode’ after suffering an insult of some sort. The new theory predicts that as cancer progresses through more and more malignant stages, it will express genes that are more deeply conserved among multicellular organisms, and so are in some sense more ancient. Genes that are active in the embryo and normally dormant thereafter are found to be switched back on in cancer. These same genes are the ‘ancient’ ones, deep in the tree of multicellular life.

2014-05-17: Measles Virus as a Cancer Fighter. Remarkable: fighting one scourge with another.

2015-03-14: Cancer Cell Mutations

1 study of kidney cancers found that no 2 patients had exactly the same set of genetic mistakes; in fact, no 2 tumors within the same patient had the same mutations. Taking it one step further, 1 high-resolution DNA-sequencing study of breast cancer couldn’t find 2 cells within 1 tumor that were genetically identical

2015-08-26: Reprogramming cancer cells. Apply a large grain of salt to the claim, but the mechanism is still very interesting.

miRNAs orchestrate whole cellular programs by simultaneously regulating expression of a group of genes. The investigators found that when normal cells come in contact with each other, a specific subset of miRNAs suppresses genes that promote cell growth. However, when adhesion is disrupted in cancer cells, these miRNAs are misregulated and cells grow out of control. Restoring normal miRNA levels in cancer cells can reverse that aberrant cell growth.

2015-09-23: Dark matter cancer? This is pretty much speculation, but interesting speculation.

We can thus speculate that the mirror micrometeorite, when interacting with the DNA molecules, can lead to multiple simultaneous mutations and cause disease

2016-03-07: Winning the Cancer War

Unfortunately, we’re still stuck in dogma. We continue to live in a world where the standard of cancer care is built on the naïve, almost arrogant, assumption that simply understanding the gene is the only important thing. Or that understanding 50 genes or even 500 genes will give us all the information to unlock the secrets of cancer cell metastasis. But our research is beginning to show that this is no longer the case. The bottom-line is that the biology of cancer is extraordinarily complex. It’s so complex that the output of the gene—specifically, the downstream networks of proteins within our bodies—is even more important than the gene itself.

2016-11-18: CRISPR for lung cancer

Scientists at Sichuan University have injected a person with aggressive lung cancer with cells modified using the gene-splicing technology in a bid to make the patient’s immune system more effective at combating cancer cells.

2017-11-08: Cancer survival

cancer death rates continue to fall across most cancer types. From 2010 to 2014, overall death rates decreased by 1.8%. 5-year survival rates for most common types of cancer have increased quite significantly in the past 30-40 years.

2018-08-02: Cancer progress

Official statistics say we are winning the War on Cancer. Cancer incidence rates, mortality rates, and 5-year-survival rates have generally been moving in the right direction over the past few decades.

More skeptical people offer an alternate narrative. Cancer incidence and mortality rates are increasing for some cancers. They are decreasing for others, but the credit goes to social factors like smoking cessation and not to medical advances. Survival rates are increasing only because cancers are getting detected earlier. Suppose a certain cancer is untreatable and will kill you in 10 years. If it’s always discovered after 7 years, 5-year-survival-rate will be 0%. If it’s always discovered after 2 years, 5-year-survival-rate will be 100%. Better screening can shift the % of cases discovered after 7 years vs. 2 years, and so shift the 5-year-survival rate, but the same number of people will be dying of cancer as ever.

This post tries to figure out which narrative is more accurate.

and another perspective:

Death rates from the disease in the US dropped in the 2016-2017 period by their largest recorded %. This is unequivocally good news, and is attributed to advances in treatment – specifically, the advent of immunotherapies and of various targeted agents for lung and skin cancer. It may come as a surprise to some, but these death rates have actually been falling since the early 1990s at ~1.5% a year, a good part of which can be attributed to the decline in smoking. But the 2016-2017 decline bumped up to 2.2%, which has never been seen before

2019-08-20: Cancer Speciation

Aggressive cancers can spread so fiercely that they seem less like tissues gone wrong and more like invasive parasites looking to consume and then break free of their host. If a wild theory recently floated in Biology Direct is correct, something like that might indeed happen on rare occasions: Cancers that learn how to roam between hosts may gradually evolve into their own multicellular species. Researchers are now scrutinizing a peculiar group of marine parasites called myxosporeans to see whether they might be the first known example.

2021-05-22: Starving Cancer

Scientists are unraveling the molecular pathways by which slashing calories or removing a dietary component can bolster the effects of drugs. In mice with cancer, the effects are oftentimes on the same order of magnitude as those from the drugs that we give patients. If those trials show the ketogenic diet helps curb tumor growth for 2 years longer than the PI3K inhibitor otherwise would, the diet could become the standard of care. “That will be what physicians will tell patients to do.”


2022-08-14: Tumors recruit the nervous system to help them spread.

“The nervous system controls everything in normal tissues—growth or atrophy, or anything else”. So there’s a reason to believe that the same is happening with malignancies. “Cancer tissue grows fast so it needs the support of the nervous system”. Moreover, scientists know that certain cancers have a particular predilection for nerves. “For example, breast and prostate tumors have a propensity to look for nerves and kind of invade and travel through those nerves. That suggests that there is synergy there.”

The observational knowledge suggests that a greater amount of nerves bunching up around a tumor signals grimmer prognosis. For example, when pathologists assess the severity of prostate cancer, the number of nerves that surround these tissues factors in. “The pathologist will score that, and if there’s a lot of nerves in the area, it usually means a worse, or a more urgent situation. To us, that seems like a blind spot or a missing link.”

2022-11-23: Cancer vaccines?

After several decades, therapeutic cancer vaccines now show signs of efficacy and potential to help patients resistant to other standard-of-care immunotherapies, but they have yet to realize their full potential and expand the oncologic armamentarium. Here, we classify cancer vaccines by what is known of the included antigens, which tumors express those antigens and where the antigens colocalize with antigen-presenting cells, thus delineating predefined vaccines (shared or personalized) and anonymous vaccines (ex vivo or in situ). To expedite clinical development, we highlight the need for accurate immune monitoring of early trials to acknowledge failures and advance the most promising vaccines.

Consanguinity

Royal inbreeding

From 1516 to 1700, it has been estimated that over 80% of marriages within the Spanish branch of the Habsburg dynasty were consanguineous.

2013-04-26: Cousin Marriage and Democracy. I had no idea this was so common in some parts of the world.

Approximately 0.2% of all marriages are consanguineous in the United States but in India 26.6% marriages are consanguineous, in Saudi Arabia the figure is 38.4% and in Niger, Pakistan and Sudan a majority of marriages are consanguineous. A recent paper finds that consanguinity is strongly negatively correlated with democracy.

2016-03-07: Middle east Cousin marriage. This explains a lot of problems.

Once common practice in Western societies, estimates suggest the Middle East, along with Africa, continue to have the highest levels in the world. In Egypt, around 40% of the population marry a cousin; the last survey in Jordan, admittedly way back in 1992, found that 32% were married to a first cousin; a further 17.3% were married to more distant relatives. Rates are thought to be even higher in tribal countries such as Iraq and the Gulf states of Saudi Arabia, Yemen and Kuwait.

2018-03-03: US Cousin Marriage

Taken together, the data show a 50-year lag between the advent of increased familial dispersion and the decline of genetic relatedness between couples. During this time, individuals continued to marry relatives despite the increased distance. From these results, we hypothesize that changes in 19th-century transportation were not the primary cause for decreased consanguinity. Rather, our results suggest that shifting cultural factors played a more important role in the recent reduction of genetic relatedness of couples in Western societies.

2022-12-06: The MFP may have been a big part of why Europe developed differently

the Church’s “Marriage and Family Plan” (MFP), which included features like monogamy in addition to an obsession with preventing broadly-defined incest, had important downstream consequences in practically every aspect of life. Young men would be more likely to find marriage partners since a few high-status leaders could not claim a disproportionate share of women, creating incentives for individuals to be more hard-working and less violent. The power of elders was further reduced by an inability to arrange marriages in ways that would keep wealth and resources within the same family, unlike in Muslim societies where the son of one brother would often be wedded to the daughter of another. When incest taboos extended to 6th cousins, an individual may have had 10k relatives that were off limits in the marriage market. This wouldn’t be a big deal in a modern city, but when most people lived in small villages it would have created major difficulties for anyone trying to find a spouse. This led to a population that was more mobile, less embedded in kinship networks, and ultimately more individualistic.

What is sure to be one of the most surprising findings discussed in the book relates to how rare the individual components of the MFP have been throughout history. According to one database looking at 1200 societies before industrialization, only 5% had newlywed couples start their own households, 8% organized domestic life around nuclear families, 15% had only monogamous marriages, 25% had little or no cousin marriage, and 28% had bilateral descent, meaning that lineages are traced through both the mother and father. Christian Europe under the MFP had all five, which wasn’t true for over 99% of other societies. Today, after the rest of the world has been heavily influenced by Western culture, given its success, it’s easy to lose sight of how unique its mating and familial practices have been in the larger historical context.

People prone to individualism would go on to achieve high rates of urbanization and form guilds, universities, marketplaces, and other voluntary institutions that were based on principles of mutual self-interest and competed with one another. Ultimately, Western Europe would conquer the world on the back of the strengths of these institutions, with democracy and capitalism being arguably the most important among them.

Paleogenetics

We recently put together a DNA sequence for the earliest mammal genome, 75 ma old. The cool thing is that you can get a lot of information about ancestral genomes just by crunching probabilities — even if you don’t have any fossils, or mosquitos-trapped-in-amber, or time machines, or whatever.

2008-11-20: Scientists are also reactivating a disabled virus in human DNA after millions of years. Welcome to Paleovirology. And crappy michael crichton novels, probably. And you can take it further to Paleo‐metagenomics:

Surviving fragments of genetic material preserved in sediments allow metagenomics researchers to see the full diversity of past life — even microbes.

2014-02-14: The largest unwritten story is ~200 ka of prehistory. We’ll write the major outlines of it in the next 100 years.

Genetic data identified over 100 events occurring over the past 4 ka: the Mongol empire, Arab slave trade, Bantu expansion, European colonialism, as well as unrecorded events, revealing admixture to be an almost universal force shaping human populations

2014-03-27: Amazing overview from the guy who sequenced neanderthals and denovisans, including recent research into FOXP2, the language gene.

2015-06-16: (long) overview of the state of genetics in prehistory

By the middle years of the 2000s researchers had gone back to a focus on recombining autosomal markers. But now they had a whole human genome to compare it to, as well as SNP-chips which quickly yielded large troves of data with little effort. In 2008 a paper was published which took the origin HGDP data set collected by Cavalli-Sforza and his colleagues, and utilized the new technologies to make deeper inferences. First, instead of 100s of markers you had 650k SNPs. Second, the emergence of powerful new analytic and computational resources allowed for the complemention of tree-based and PCA visualizations of genetic relationship with model-based understandings of genetic variation and population structure. By “model-based,” I mean that the algorithm posits particular parameters (e.g., “3 ancestral populations”) and operates upon the data (e.g., “650k SNPs in 1000 individuals”) , to generate results which are the best representation of the fit of the data to the model. This different from PCA, which has fewer assumptions, and represents genetic variation geometrically (each axis represents an independent dimension of variation within the data). Model-based clustering is very clear and aesthetically appealing. It gives precise results. But, the model itself is not necessarily right.

2015-09-15: A perspective

Ancient genomics is a powerful tool for the study of prehistory, but it is still in its infancy. The first true population studies using ancient nuclear DNA – with samples numbering in the 10s instead of single digits – are only 1 month old. For the moment, we have just 2 ancient genomes from the Americas. For other parts of the world, such as Africa, South and East Asia, we have 1 or 0. With so few data points available, the world of prehistory seen through the lens of ancient DNA is like a landscape sporadically illuminated by lighting. Plenty of surprises are left in store. The situation right now is a bit like that of archaeology just after the invention of Carbon-14 dating. A revolution is on its way, but we don’t yet know what it will bring.

2016-05-10: There have been multiple population replacements in Europe

~50 ka ago humans leave Africa, and mix with a number of Neanderthals. ~40 ka ago, they arrive in Europe. ~35-40 ka ago the first modern Europeans are replaced by another population. This second population is culturally similar to the first, and contributes some (though small proportionally) ancestry to modern Europeans. It is replaced by another population, which does not contribute much to modern Europeans (Gravettians), though populations related to it do. It is replaced by a population related to the first Europeans with descendants (Magdalenians, who are descended in part from Aurignacians, and do not share much drift with Gravettians). Then, the Magdalenians are replaced by Villabruna populations, the very late Paleolithic populations at the tail end of the Ice Age. The Villabruna have mixture from both the Near East, and to a lesser extent East Asia. Or, Villabruna populations were intrusive to the Near East, and possibly East Asia, or there were mediating populations between. It is all somewhat unclear. Then the Villabruna populations, which become Mesolithic hunter-gatherers, are overwhelmed by Near Eastern groups, which have very exotic ancestry unrelated to all other non-Africans (Basal Eurasian). Finally, the Neolithic groups are overwhelmed by populations from the steppe, who are themselves compounds of very distinct elements.

2019-09-30: We can also detect missing species, or genetic ghosts if you will

Genes from an extinct “ghost ape” live on in modern bonobos. Because apes have their natural habitat in the trees of the rainy tropical forest, with an acidic soil where the organic matter decomposes very quickly, the fossil record for our closest relatives is poor, but genetic data in living bonobos could help fill in gaps. Similar, but different: David Gokhman summoned a ghost, using information for 32 skeletal features encoded in DNA that was extracted from a pinky bone. DNA reveals first look at enigmatic human relative, providing more details of the physical structure of Denisovans.

2023-01-17: Using DNA to study parental age differences. Amazing.

The research used genetic mutations in modern human DNA to create a timeline of when people have tended to conceive children over the past 250 ka, since our species first emerged. 26.9 years was the overall average age of conception during the past 250 ka. But breaking this down by sex showed that men averaged 30.7 years when they conceived a child, compared with 23.2 years for women. The numbers fluctuated over time, but the model suggested that men consistently had children later in life than women.

Henrietta Lacks

Every single one of the cell lines Gartler was investigating, and countless others being used around the world, had been contaminated by HeLa cells. They had taken over every Petri dish of cells they had come near.

2014-06-10: A bit more on HeLa contamination

As we have more cell lines to work with and as we’re able to learn more about the molecular specifics that identify those cell lines, people are starting to go back and re-evaluate old research.

Not only is it becoming clear that results have been skewed by the use of less-than-ideal cell lines, in many cases, the scientists weren’t even using the cell lines they thought they were using. Instead, mistakes in the laboratory meant that cell lines got mixed up with one another. A common problem: Tough, fast-growing cells finding their way into a dish of weaker-growing cells, where they quickly take over. The dish is labeled as being one thing, but the cells now growing there are totally different. HeLa, the line of cells derived from the cervical cancer tumor of an African American woman named Henrietta Lacks, are infamous for invading test tubes all over the world. “You don’t even need sloppy lab technique. All it takes is for a droplet of HeLa to fall into another culture. Then it’s survival of the fittest and HeLa is very fit.”