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It seems that the concern we always hear is that bacteria and viruses mutate to dodge our treatments either through random mutations or survival of the fittest. Do harmful living things ever mutate to become not harmful?
Mutations are random; the (pathogenic) bacteria (or any living being) will randomly acquire mutations that may be beneficial, deleterious or neutral to its fitness. Only beneficial and neutral mutations will survive the selection. Random mutations and survival of the fittest are not two independent mechanisms. The random mutations can alter the fitness as I mentioned and natural selection ensures the survival of the fittest.
Many pathogens have reduced genome (number of genes) compared to their free living relatives (Weinert and Welch, 2017). This is because they lack most of the genes required for synthesis of different metabolites required for survival. They rather obtain these metabolites from the host and hence they have the parasitic lifestyle. It is not possible for the pathogens to acquire that many genes to stop being pathogenic and become a free-living organism. It may be possible via lateral gene transfer wherein a bacteria may obtain an entire gene (or a set of genes) from another bacteria but the likelihood of that happening to convert a pathogenic bacteria to a non-pathogenic bacteria is negligible.
It is certainly possible that pathogens might lose the activity of some of the pathogenic genes (for example those required for toxin production) due to mutations. However, they may no longer be efficient pathogens and would be outgrown by the others who still retain those genes.
Harmful protein waste in the muscle
An international team of researchers led by the University of Bonn (Germany) has identified the cause of a rare, severe muscle disease. According to these findings, a single spontaneously occurring mutation results in the muscle cells no longer being able to correctly break down defective proteins. As a result, the cells perish. The condition causes severe heart failure in children, accompanied by skeletal and respiratory muscle damage. Those affected rarely live beyond the age of 20. The study also highlights experimental approaches for potential treatment. Whether this hope will be fulfilled, however, will only become clear in a few years. The results are published in the journal Nature Communications.
Anyone who has ever snapped a spoke on their bike or broken down with their car knows that mechanical stresses sooner or later result in damage that needs to be repaired. This also applies to the human musculature. "With each movement, structural proteins are damaged and have to be replaced," explains adjunct professor Dr. Michael Hesse from the Institute of Physiology at the University of Bonn, who led the study together with his colleague Prof. Dr. Bernd Fleischmann.
The defective molecules are normally broken down in the cell and their components are then recycled. An important role in this complex process is played by a protein called BAG3. The results of the new study show how important this is: The researchers were able to demonstrate that a single change in the genetic blueprint of BAG3 results in a fatal disease.
"The mutation causes BAG3 to form insoluble complexes with partner proteins that grow larger and larger," Hesse says. This brings the repair processes to a standstill -- the muscles become less and less efficient. Moreover, toxic levels of proteins accumulate over time, eventually resulting in the death of the muscle cell. "The consequences are usually first seen in the heart," Hesse says. "There, muscle is successively replaced by scar tissue. This causes the heart's elasticity to decrease until it can barely pump blood."
Affected individuals therefore usually require a heart transplant in childhood. Even this measure only provides temporary relief, as the disease also affects the skeletal and respiratory muscles. As a result, sufferers often die at a young age.
Very rare condition, therefore little research
The lethal mutation can arise spontaneously during embryo development. Fortunately, this is a very rare occurrence: There are probably only a few hundred affected children worldwide. However, due to its rarity, the disease has received little research attention to date. "Our study now takes us a great deal further," stresses Bernd Fleischmann.
This is because the researchers have succeeded for the first time in replicating the disease in mice and using the new animal model to identify its causes. This allows it to be researched better than before -- also with regard to possible therapies. Maybe the effect of the mutation can at least be reduced. Humans have two versions of each gene, one from the mother and the other from the father. This means that even if one version of BAG3 mutates during embryo development, there is still a second gene that is intact.
Unfortunately, however, the defective BAG3 also clumps with its intact siblings. The mutation in one of the genes is therefore sufficient to stop the breakdown of the defective muscle proteins. However, if the mutated version could be eliminated, the repair should work again. It would also prevent the massive accumulation of proteins in the cell that eventually results in its death.
There are indeed methods to specifically inhibit the activity of individual genes. "We used one of them to treat the sick mice," explains Kathrin Graf-Riesen of the Institute of Physiology, who was responsible for most of the experiments along with Dr. Kenichi Kimura and her colleague Dr. Astrid Ooms. The animals treated in this way then showed significantly fewer symptoms. Whether this approach can be transferred to humans, however, remains the subject of further research.
What is gene editing?
Just as gaining a better knowledge of world geography helped explorers centuries ago know which dangers were real and which were imagined, learning more about gene editing will help investors better understand the risks. Gene editing, which is also known as genome editing, involves the insertion, deletion, or replacement of DNA (deoxyribonucleic acid) in a gene.
DNA is where all genetic information is stored in the body. You've probably seen a picture or model of the DNA double helix, which looks similar to a ladder that has been twisted. The steps in this twisted ladder are DNA base pairs. Each base pair is made up of a combination of two chemical bases -- either adenine and thymine or cytosine and guanine. The sequences of these DNA base pairs provide instructions for how proteins are built, which in turn dictate how the body develops and functions.
In effect, gene editing is like using molecular scissors to cut specific sequences of DNA base pairs. But the actual process of gene editing is more complicated than just using scissors. In fact, there are several different methods that can be used to edit genes.
Zinc finger nuclease (ZFN) technology has been used longer than any other gene-editing method. First developed in the 1990s, this approach involves the binding of a pair of ZFNs to a DNA target. ZFNs are engineered proteins that are made up of two parts: (1) a chain of zinc modules that look like fingers and seek out specific DNA sequences, and (2) an enzyme known as a nuclease that can split DNA. You can think of ZFNs like two bookends that search for certain books on a library shelf and then knock the books off the shelf. The DNA sequence between two ZFNs is cut, which causes the cell to begin to repair the break. The ZFN approach can either insert a new DNA sequence into the space where DNA has been cut out, or totally remove the original DNA sequence.
In 2009, a different but similar gene-editing method called transcription activator-like effector nuclease (TALEN) was developed. TALENs are produced by a common type of plant bacteria. Like ZFNs, TALENs bind to and cut targeted DNA sequences. A key advantage the TALEN gene-editing method holds over ZFN is that engineering TALENs is simpler than using ZFNs.
Probably the biggest development in gene editing was the discovery of clustered regularly interspaced short palindromic repeats (CRISPRs). While research on CRISPRs began as early as 1993, the first scientific paper detailing the use of CRISPR to edit genes was published in early 2013. The CRISPR method uses bacterial enzymes to target and cut specific sections of DNA. CRISPR is simpler and cheaper than earlier gene-editing methods.
Even a Silver Lining Has a Potential Cloud
While having two copies of the CCR5-∆32 gene variant is beneficial for those who have an HIV infection, or have been exposed to HIV, it appears to be deleterious for everyone else. It leads to an earlier death rate and an increased chance of infection (and mortality) to other infectious diseases. As Nielson and Wei both pointed out, gene-editing babies, even with a desire to protect against disease, can have unintended consequences. It also appears that this desire to manipulate the CCR5 gene to protect against HIV infection is not going to be a single occurrence, despite the public outcry. A new article in Nature mentions that Russian scientist, Denis Rebrikov, is planning on gene-editing the CCR5 gene in HIV-positive Russian women volunteers.7
Evolution's Deadly Tradeoffs? Diseases That Can Kill Us May Also Save Lives And Increase IQ
Is it possible that some of the maladies that plague us have helped humans survive and even thrive through evolutionary history?
Could it be that mutant genes may actually make endogamous populations 'smarter'?
Consider sickle cell anemia, a genetic disease common to many American blacks and persons of West and Central African ancestry. It is characterized by severe anemia with symptoms of pallor, muscle cramps, weakness, and susceptibility to fatigue. Additional symptoms include heart enlargement, brain cell atrophy, and severe pain in the abdomen, back, head, and extremities (see diagram below). Many victims of sickle-cell anemia die before the age of twenty, though some survive past fifty. It's an ugly list of maladies. Usually genetic disorders with such horrific consequences lead to the extinction of the 'bad' mutation-it ends up literally killing off all its carriers, so the faulty gene is not passed on to future generations.
So why is sickle cell still with us? Because like the mutations that cause a range of other disorders such as inflammatory bowel disease, psoriasis, Tay-Sachs disease and certain breast cancers, there are beneficial dimensions to these mutations. In the case of sickle cell, the gene has a beneficial aspect: it provides protection against malaria.
Evolution can be weird that way. The genes for some afflictions may actually have been preserved through Darwinian selection. The reason has to do with the specifics of each disease, but often is easily figured out, based on associations between various genes, the disease, and factors affecting aspects of biology not directly connected with the disease.
Immune system can be helpful or harmful
Autoimmune diseases represent a large category of conditions resulting from the immune system wrongfully identifying a person's own tissue as foreign. Depending on which type of tissue, and where in the body this happens, the disease can autoimmune disease can manifest in very different ways. Psoriasis, for instance, results from an autoimmune attack in skin. Often, it occurs together with rheumatoid arthritis, which also is an autoimmune conditions, but in connective tissue of the joints. Inflammatory bowel disease (IBD), Crohn disease for example, also develops through an autoimmune mechanism, and many of these diseases feature autoimmune attacks in multiple systems.
According to research by Omer Gokcumen and colleagues at the University at Buffalo, such autoimmune diseases were present in certain prehistoric humans, such as Neanderthals and Denisovans, who are thought to have mixed with our ancestors. Additionally, the presence of such diseases was probably protective, even protective enough to offset the disadvantages of carrying the disease. In fact, in the environment in which the ancient humans live, the disease effects may not have been as bad as they are in modern humans. Gokcumen:
Our findings suggest that there may be some unknown factor -now or in the past- that counteracts the danger when you carry genetic features that may increase susceptibility for [Crohn disease and psoriasis]. One can imagine that in a pathogen-rich environment, a highly active immune system may actually be a good thing, even if it increases the chances of an auto-immune response.
Sickle cell anemia, also called sickle cell disease, is one the best known examples of a recessive genetic disease caused by a gene that seems to help the population. In sickle cell disease, the problem involves hemoglobin, the protein that carries oxygen in red blood cells. Sickle cell carriers (people with one gene for sickle cell hemoglobin and one normal hemoglobin gene) are not sick under normal circumstances.
Those who are carriers are said to have the sickle cell trait, however, because their red blood cells do produce some defective hemoglobin. Under extreme stress (high altitude and extreme physical activity), people with sickle cell trait, actually can develop what's called a sickle cell crisis (the same thing that happens to people with sickle cell disease under normal conditions), because some of their red blood cells are affected by the small amounts of defective hemoglobin.
Specifically, the affected red blood cells take on a crescent or sickle shape, which actually keeps out the parasites that cause malaria. For this reason, in malaria infested regions, individuals with the sickle cell trait -one gene for sickle cell anemia- actually are better off than people with two normal hemoglobin genes. Thus, survival of the the sickle cell gene is promoted by environments in which malaria parasites thrive, just as survival of Tay-Sachs genes may have been promoted in areas where tuberculosis was common.
"Jewish diseases" and high IQ?
In the cases of recessive genetic conditions-diseases that manifest usually only if an individual receives a defective gene for some important enzyme from both parents-evolutionary biology suggests protective benefits are conferred on some carriers (people with one defective (disease-causing) gene who don't have the condition itself). For instance, while Tay-Sachs disease is deadly, usually within three years of birth, It's thought that having one Tay-Sachs gene (being a Tay-Sachs carrier) might have been protective against tuberculosis, particularly among ancestors of Ashkenazi Jews, who carry a couple of the most well-known and notorious Tay-Sachs gene mutations.
It's also theorized that a host of diseases that afflict Ashkenazim may persist because they provide some evolutionary benefits. Henry Harpending, an evolutionary anthropologist at the University of Utah, and Gregory Cochran, a physicist turned genetic theorist, have riveted the attention of the chattering classes by addressing the scientific mystery of why an odd cluster of brain, nervous system, and DNA "repair" disorders, including Tay Sachs and breast cancer, stubbornly persist among Jews of European descent.
Why weren't these deadly disease genes filtered out of the gene pool, eradicated by natural selection, as regularly happens in evolution? Cochran and Harpending--along with numerous other scientists--postulated that centuries of endogamy within the Ashkenazi Jewish community preserved Jewish culture but at a cost. It turns out that people who suffer from these genetically related diseases share another similarity besides their Ashkenazi ancestry--they are often of unusually high intelligence as measured by standardized IQ tests.
This subgroup of world Jewry may have inherited extra brain power, but the same genetic factors that helped increase IQ may have led to nervous system and brain disorders linked to the very same mutations. In other words, these genetic mistakes may offer real but costly survivor benefits.
How could this be? Harmful mutations usually disappear because people who carry mutant genes often die at an early age or have difficulty in finding mates. But there are exceptions to the grinding work of nature: when a mutation offers some survival benefit. As I outlined in my book Abraham's Children: Race, Identity and the DNA of The Chosen People, Cochran, who developed the theory, theorized that these DNA disorders are genetically linked to dendrite development. Those who have these mutations have more neural connections--but also more opportunities for 'breakdowns' in the neural pathways. He dubbed it "overclocking"--computerspeak for eking out extra performance.
The problem with overclocking, Cochran has said, is that "Sometimes you get away with it, sometimes you don't"-some geeks run their hard drives faster than they were designed to, which can cause crashes or breakdowns. Could the mutations work the same way? Perhaps two copies can leave the brain wasted one copy and you're smart?
Because Ashkenazi Jews maintained and followed restrictions on intermarriage, certain gene frequencies, including a proclivity to these diseases, have remained common among sub-populations of Jews that did not marry outside their group--they were not "bred out." And because of cultural factors honed over many centuries, Jews may have historically chosen mates with higher intelligence, risking the possibility of having children with debilitating diseases. By some mysterious, evolution-driven psychic calibration, some Jews may have historically valued brains over health-and that proclivity became embedded in their genes.
(Note: Genetic studies suggest that Sephardic Jews--descendants of Jews whose ancestry traces to North Africa and Spain--did not have children as exclusively 'within the tribe,' and hence the Sephardic gene pool is not as insular. IQ tests of Sephardic Jews suggest that on average, their scores are not markedly different than the global average of 100).
Gaucher: Debating the theory of 'beneficial' genes
The Cochran-Harpening theory--genes that stimulate the extra growth and branching that connect nerve cells together might promote intelligence--has not been definitively embraced. But it has not been dismissed, and there is at least some studies that lend credence to it. Consider a 1995 study on rats afflicted with Gaucher. If there were two copies of the gene-recessive mutations donated by the mother and father-a chemical in the brain built up and the branching of the neurons grew wildly, leading to a debilitating brain disease. However, if there was only a single copy of these "IQ genes" the chemical build-up led to more intense but relatively controlled growth in the brain. That's what appeared to happen to the rats with a single copy of the Gaucher mutation. Is it working that way in humans?
Gaucher is the most common disease found disproportionately in Jews, with the mutation showing up in 6 percent of Ashkenazim. There is at least circumstantial evidence linking Gaucher to high IQ. At Cochran's request, the Gaucher Clinic at Jerusalem's Shaare Zedek Medical Centre furnished him with a list of occupations of more than 250 adult patients, essentially all the adult Gaucher sufferers in the country. "Many of my patients are well known intellectuals," said Ari Zimran, director of the clinic. Fifteen percent of the patients were engineers or scientists versus an estimated 2.25 percent of the Israeli Ashkenazi working age population and there were 20 times as many physicists as might otherwise be expected. That's not slam dunk science, but it's intriguing.
It's a controversial and speculative theory but not without precedent. In 1994, UCLA scientist Jared Diamond promoted a similar but more simplistic version of this theory, writing that the operant mutations might have been positively selected "in Jews for the intelligence putatively required to survive recurrent persecution, and also to make a living by commerce, because Jews were barred from the agricultural jobs available to the non-Jewish people."
In private conversations with dozens of geneticists, almost no one was willing to categorically rule out the theory that Ashkenazi Jews may have received a genetic gift of intelligence as recompense for the extraordinary number of brain diseases. "Yes, selection for intelligence is credible," Hebrew University's Joel Zlotogora, one of the few scientists willing to be quoted, told me. "For me everything is credible. I think the founder effect is true for only some disorders, but not for all of them, and there must be something else. There could very well be positive selection."
At least for now most scientists are reluctant to embrace positive selection as an explanation of Jewish intelligence, although it remains a respected theory. David Goldstein, a geneticist at Duke University and author of the book Jacob's Legacy: A Genetic View of Jewish History, called the theory "tantalizing, circumstantial, politically incorrect in the extreme. [but] cannot be ruled out."
Jon Entine, executive director of the Genetic Literacy Project, is a Senior Fellow at the World Food Center Institute for Food and Agricultural Literacy, University of California-Davis. Follow @JonEntine on Twitter
COVID-19 vaccines don’t hamper the function of the immune system and are likely to limit the generation of variants no evidence that they produce more lethal variants
In the video, Coleman alleged that the COVID-19 vaccines could lead to the death of thousands of people in the future, should be considered “weapons of mass destruction”, and could even “wipe out the human race”. However, Coleman’s conclusions are based on unsupported assertions and ambiguous reasoning, as we explain below.
Claim 1 (Inaccurate): “COVID-19 vaccines are dangerous, having killed many people and causing serious adverse effects on many more”
COVID-19 vaccines are safe, as demonstrated in clinical trials and the COVID-19 vaccination campaign, in which millions of doses have already been administered.
Common side effects caused by COVID-19 vaccines are short-lived and minor, including fever, headache, fatigue or pain at the injection site. These side effects tend to disappear within a few days after people receive the vaccines and are a sign that their immune systems are responding to the vaccine as expected. The most serious side effect caused by COVID-19 RNA vaccines is anaphylaxis, which is a severe allergic reaction that can be life-threatening. However, anaphylaxis is easily treated and isn’t fatal if the correct medical treatment is provided in time.
About 10 million doses of the Pfizer-BioNTech COVID-19 vaccine and about 7.5 million doses of the Moderna COVID-19 vaccine were administered in the U.S. between December 2020 and January 2021  . The incidence of anaphylaxis in vaccinated people was 4.7 cases per million vaccinated people for the Pfizer-BioNTech vaccine, and 2.5 cases per million for the Moderna vaccine. The U.S. Centers for Disease Control and Prevention (CDC) discourages people who had severe allergic reactions to the first dose of these vaccines from receiving the second dose.
None of the evidence so far supports Coleman’s claim that the COVID-19 vaccines may cause strokes, neurological problems, blindness or paralysis.
Claim 2 (Unsupported): “People who got the COVID-19 vaccine have been pathogenic primed, their immune system is going to overreact when in contact with the virus, causing lots of deaths”
First, Coleman’s claim is inaccurate, as the COVID-19 vaccines authorized for use by the U.S. Food and Drug Administration (FDA) don’t contain the virus that causes COVID-19, SARS-CoV-2. Instead, they contain a viral vector that triggers the production of a viral spike protein specific to SARS-CoV-2 or the RNA sequence encoding that protein. When individuals receive the COVID-19 vaccine, they produce immune responses to these proteins, protecting them from future encounters with the virus.
Coleman’s claim is based on a phenomenon called antibody-dependent enhancement (ADE). ADE occurs when antibodies bind to a virus in a manner that fails to neutralize it, but instead makes the viral infection more severe  . In some respiratory diseases like MERS and SARS, ADE occurs when antibody–antigen immune complexes are formed, leading to an excessive response of the immune system in lung tissue  .
As these articles from PNAS and Nature showed, vaccine researchers are aware of the potential risk of ADE from COVID-19 vaccination and have called for close monitoring of vaccinated people, in the event that a vaccine candidate has to be discarded if this effect happens  . Notably, researchers haven’t detected any cases of ADE in relation to COVID-19 to date, either in people who were reinfected with the virus or in people vaccinated against the disease. As this Health Feedback review showed, no cases of ADE were detected in clinical trials of the COVID-19 vaccines authorized by the FDA for emergency use.
ADE was observed in the infectious disease dengue fever, a mosquito-borne viral infection. Dengue fever is caused by the dengue virus, which exists in four subtypes, which scientists call “serotypes”. Antibodies against one serotype can lead to more severe disease caused by another serotype due to ADE  . The first dengue vaccines developed effectively protected individuals against one serotype of the virus, but only partially against the other serotypes. If vaccinated individuals were infected with a serotype other than the one they were fully protected against, ADE may occur and the resulting infection may be more virulent.
Overall, the available evidence indicates that the COVID-19 vaccines don’t cause ADE. As this article by Yale Medicine reports, the vaccines protect against severe illness, contradicting Coleman’s claim.
Claim 3 (Unsupported): “Vaccines suppress the NK cells, destroying the immune system of tens or hundreds of millions who are receiving the vaccines”
Later in the video, Coleman referred to claims made by Geert Vanden Bossche, an independent consultant who previously worked in vaccine development. Vanden Bossche claimed in an open letter on Twitter, addressed to the World Health Organization, that mass vaccination against COVID-19 would lead to more severe disease. This Health Feedback review demonstrated why Vanden Bossche’s claim is misleading and unsupported by scientific evidence.
Coleman claimed that vaccines promote the generation of specific antibodies that compete with NK cells, which he called “the body’s natural defenses”. He asserted that this would render NK cells ineffective.
But Coleman’s claim isn’t consistent with what we know of NK cells. NK cells, or natural killer cells, are a type of white blood cell that recognize virus-infected cells without relying on antibodies, and thus can respond to a viral infection faster than other types of immune cells, since the body can take days to weeks to produce antibodies.
However, even though NK cells can generate an immune response in the absence of antibodies, there are also mechanisms by which antibodies promote NK cell action, known as antibody-dependent cellular cytotoxicity  . This antibody-mediated activation causes NK cells to eliminate cells that have been infected by a pathogen. This demonstrates that antibodies don’t render NK cells ineffective, as Coleman claimed. Rather, they assist NK cells in fighting infection. Coleman offered no evidence showing otherwise.
The role of NK cells in fighting COVID-19 is unclear at the moment, although researchers detected elevated levels of activated NK cells in patients with severe COVID-19  . Overall, Coleman’s claim that antibodies induced by vaccination interfere with NK cell function is unsupported by scientific evidence, since this effect has not been detected in vaccinated persons.
Claim 4 (Unsupported): “Vaccines promote virus lethality” “new virus variations are appearing in areas where the vaccine has been given to lots of people” ”giving the vaccines will give the virus an opportunity to become infinitely more dangerous” “bodies of vaccinated people are laboratories making lethal viruses”
Finally, Coleman asserted that vaccines enhance the lethality of COVID-19 by selecting and promoting the emergence of newer and more deadly variants of the virus, citing Vanden Bossche as a basis for this claim.
Virus mutations occur periodically and result from errors in the replication process, when a virus copies its genetic material during an infection. Mutations are more likely to occur during longer infections and when more people are infected  . As virus mutations accumulate, variants may appear. In most cases, mutations either don’t affect the virus or result in a weakened virus  . Therefore, virus variants aren’t necessarily more deadly or contagious.
Coleman offered no evidence to support the claim that vaccines promote the emergence of more deadly virus variants. In fact, the evidence points to the opposite trend. Some COVID-19 vaccines reduce the likelihood of infection, as well as the risk of severe disease in vaccinated individuals. There is also some evidence that certain COVID-19 vaccines reduce the risk of transmission  . All three observations suggest that COVID-19 vaccines will reduce virus replication, thereby limiting the opportunity for new variants to emerge. Notably, the three SARS-CoV-2 variants of concern that were detected in the U.K., South Africa, and Brazil evolved naturally in unvaccinated populations.
In conclusion, Coleman’s claims about the side effects of COVID-19 vaccines don’t correspond to the effects observed during clinical trials and in the real-work vaccination campaigns. In addition, claims that COVID-19 vaccines predispose people to more virulent infections or interfere with immune system functions are inconsistent with the existing evidence on how these vaccines work. Finally, the COVID-19 vaccines don’t promote the emergence of new, more lethal variants of existing viruses, but instead reduce virus transmission and thus the emergence of new variants.
- 1- Shimabukuro et al. (2021) Reports of Anaphylaxis After Receipt of mRNA COVID-19 Vaccines in the US—December 14, 2020-January 18, 2021. Journal of the American Medical Association.
- 2- Arvin et al. (2020). A perspective on potential antibody-dependent enhancement of SARS-CoV-2. Nature.
- 3- Lee et al. (2020). Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies. Nature Microbiology.
- 4- Iwasaki and Yang (2020). The potential danger of suboptimal antibody responses in COVID-19. Nature Reviews Immunology.
- 5- Guzman and Vazquez (2020). The complexity of antibody-dependent enhancement of dengue virus infection. Viruses.
- 6- Gómez-Román et al. (2014). Chapter 1 – Antibody-Dependent Cellular Cytotoxicity (ADCC). Antibody Fc: Linking Adaptive and Innate Immunity.
- 7- Maucourant et al. (2020). Natural killer cell immunotypes related to COVID-19 disease severity. Science Immunology.
- 8- Stern and Andino (2016), Chapter 17 – Viral Evolution: It Is All About Mutations. Viral Pathogenesis (Third Edition).
- 9- Grubaugh et al. (2020). We shouldn’t worry when a virus mutates during disease outbreaks. Nature Microbiology.
- 10- Levine-Tiefenbrun et al. (2021). Decreased SARS-CoV-2 viral load following vaccination. medRxiv. [Note: This is a pre-print that has not yet been peer-reviewed.]
Published on: 01 Apr 2021 | Editor: Rubén Portela Carballeira
Health Feedback is a non-partisan, non-profit organization dedicated to science education. Our reviews are crowdsourced directly from a community of scientists with relevant expertise. We strive to explain whether and why information is or is not consistent with the science and to help readers know which news to trust.
Please get in touch if you have any comment or think there is an important claim or article that would need to be reviewed.
Looking Closer: Recombinant DNA Technology
More than 3,000 human diseases have been shown to have a genetic component, caused or in some way modulated by the person&rsquos genetic composition. Moreover, in the last decade or so, researchers have succeeded in identifying many of the genes and even mutations that are responsible for specific genetic diseases. Now scientists have found ways of identifying and isolating genes that have specific biological functions and placing those genes in another organism, such as a bacterium, which can be easily grown in culture. With these techniques, known as recombinant DNA technology, the ability to cure many serious genetic diseases appears to be within our grasp.
Isolating the specific gene or genes that cause a particular genetic disease is a monumental task. One reason for the difficulty is the enormous amount of a cell&rsquos DNA, only a minute portion of which contains the gene sequence. Thus, the first task is to obtain smaller pieces of DNA that can be more easily handled. Fortunately, researchers are able to use restriction enzymes (also known as restriction endonucleases), discovered in 1970, which are enzymes that cut DNA at specific, known nucleotide sequences, yielding DNA fragments of shorter length. For example, the restriction enzyme EcoRI recognizes the nucleotide sequence shown here and cuts both DNA strands as indicated:
Once a DNA strand has been fragmented, it must be cloned that is, multiple identical copies of each DNA fragment are produced to make sure there are sufficient amounts of each to detect and manipulate in the laboratory. Cloning is accomplished by inserting the individual DNA fragments into phages (bacterial viruses) that can enter bacterial cells and be replicated. When a bacterial cell infected by the modified phage is placed in an appropriate culture medium, it forms a colony of cells, all containing copies of the original DNA fragment. This technique is used to produce many bacterial colonies, each containing a different DNA fragment. The result is a DNA library, a collection of bacterial colonies that together contain the entire genome of a particular organism.
The next task is to screen the DNA library to determine which bacterial colony (or colonies) has incorporated the DNA fragment containing the desired gene. A short piece of DNA, known as a hybridization probe, which has a nucleotide sequence complementary to a known sequence in the gene, is synthesized, and a radioactive phosphate group is added to it as a &ldquotag.&rdquo You might be wondering how researchers are able to prepare such a probe if the gene has not yet been isolated. One way is to use a segment of the desired gene isolated from another organism. An alternative method depends on knowing all or part of the amino acid sequence of the protein produced by the gene of interest: the amino acid sequence is used to produce an approximate genetic code for the gene, and this nucleotide sequence is then produced synthetically. (The amino acid sequence used is carefully chosen to include, if possible, many amino acids such as methionine and tryptophan, which have only a single codon each.)
After a probe identifies a colony containing the desired gene, the DNA fragment is clipped out, again using restriction enzymes, and spliced into another replicating entity, usually a plasmid. Plasmids are tiny mini-chromosomes found in many bacteria, such as Escherichia coli (E. coli). A recombined plasmid would then be inserted into the host organism (usually the bacterium E. coli), where it would go to work to produce the desired protein.
Proponents of recombinant DNA research are excited about its great potential benefits. An example is the production of human growth hormone, which is used to treat children who fail to grow properly. Formerly, human growth hormone was available only in tiny amounts obtained from cadavers. Now it is readily available through recombinant DNA technology. Another gene that has been cloned is the gene for epidermal growth factor, which stimulates the growth of skin cells and can be used to speed the healing of burns and other skin wounds. Recombinant techniques are also a powerful research tool, providing enormous aid to scientists as they map and sequence genes and determine the functions of different segments of an organism&rsquos DNA.
In addition to advancements in the ongoing treatment of genetic diseases, recombinant DNA technology may actually lead to cures. When appropriate genes are successfully inserted into E. coli, the bacteria can become miniature pharmaceutical factories, producing great quantities of insulin for people with diabetes, clotting factor for people with hemophilia, missing enzymes, hormones, vitamins, antibodies, vaccines, and so on. Recent accomplishments include the production in E. coli of recombinant DNA molecules containing synthetic genes for tissue plasminogen activator, a clot-dissolving enzyme that can rescue heart attack victims, as well as the production of vaccines against hepatitis B (humans) and hoof-and-mouth disease (cattle).
Scientists have used other bacteria besides E. coli in gene-splicing experiments and also yeast and fungi. Plant molecular biologists use a bacterial plasmid to introduce genes for several foreign proteins (including animal proteins) into plants. The bacterium is Agrobacterium tumefaciens, which can cause tumors in many plants, but which can be treated so that its tumor-causing ability is eliminated. One practical application of its plasmids would be to enhance a plant&rsquos nutritional value by transferring into it the gene necessary for the synthesis of an amino acid in which the plant is normally deficient (for example, transferring the gene for methionine synthesis into pinto beans, which normally do not synthesize high levels of methionine).
Restriction enzymes have been isolated from a number of bacteria and are named after the bacterium of origin. EcoRI is a restriction enzyme obtained from the R strain of E. coli. The roman numeral I indicates that it was the first restriction enzyme obtained from this strain of bacteria.
Scientific journal article for further reading
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5. PMID: 25741868 PMCID: PMC4544753.
DNA Repair Mechanisms
Cells have extensive repair mechanisms that can effectively repair any mutation in the genes. The harmful effects of mutations are only seen when the DNA repair mechanisms fail to correct these mutations.
The following mechanisms are employed by the cells to tackle with the mutations.
The mutations in which bases are mismatched in the DNA strand are corrected via this mechanism. It involves the use of special proteins called Mut proteins.
When the mismatch occurs in a daughter DNA strand, the mismatch is recognized by the Mut proteins. They release a segment of daughter DNA containing the mismatch portion. The gap in the strand is then filled by DNA polymerase with the correct base. The ligase enzyme is then used to join the newly synthesized piece of DNA.
Nucleotide Excision Repair
This mechanism is used to repair the dimers formed by UV rays. The dimers are recognized by a UV specific endonuclease and exonuclease (a single enzyme with two activities). This enzyme creates a kink on both sides of a small segment containing dimer. This segment is then removed from the strand. the gap thus created is filled by the DNA polymerase while DNA ligase is used to join the segments.
Base Excision Repair
This process removes the abnormal bases present in the gene. The abnormal base is recognized by a specific glycosylase enzyme that hydrolytically cleaves the base from the strand, leaving behind an empty site.
The empty site is then filled by the action of DNA polymerase and DNA ligase.
This mechanism is used to remove the strand breaks in DNA. This repair can be carried out in two ways
- Non-homologous end-joining the non-homologous DNA strands are joined. processed and ligated
- Homologous end-joining involves the joining of homologous DNA strands
Of Hyperaging and Methuselah Genes
Three-year-old Sam likes to feel starfish in his hands, and you can just forget about changing the subject when he&rsquos discussing planets. But Sam is not quite your average toddler. He&rsquos almost bald, his seven teeth don&rsquot align properly, and he is smaller than his peers. So far these are the only clues that he has Hutchinson-Gilford syndrome, a rare genetic disorder that mimics some aspects of aging.
No one can predict what course Sam&rsquos disease will take, but children with Hutchinson-Gilford syndrome typically develop arthritis and grow slowly. Their skin becomes thin, and age spots and prominent veins emerge. Most acquire severe atherosclerosis that can thwart blood flow to the brain and other organs. About 50 percent of afflicted children die of heart disease or stroke by their early teens.
When Sam&rsquos mother isn&rsquot talking to him about Neil Armstrong and Buzz Aldrin, she&rsquos in the laboratory, looking for the biochemical basis of her son&rsquos disease. Leslie B. Gordon&rsquos work on Hutchinson-Gilford syndrome&mdashand research on other related disorders&mdashmay have implications far beyond finding a cure for a rare disease. It might also provide clues about the normal human aging process and yield insight into diseases common to old age, such as atherosclerosis, which could lead to new avenues of research for treatments that prolong life.
Hutchinson-Gilford syndrome is one of several human progerias &ldquoprogeria&rdquo means premature aging. Very little is known about the disease, and the condition is extremely rare&mdashonly about 100 cases have been documented since it was first described in 1886. Although the disease appears to be caused by a genetic defect, it doesn&rsquot run in families, suggesting that the mutation occurs randomly in egg or sperm cells or at some point after fertilization. Because researchers can&rsquot track the gene through relatives, this disorder doesn&rsquot lend itself to traditional gene-hunting approaches.
So Gordon, a research associate in the department of anatomy and cell biology at Tufts University School of Medicine, is taking a different tack. She&rsquos focusing on the one consistent difference between Hutchinson-Gilford patients and healthy children: sick kids have much higher levels of a particular compound&mdashhyaluronic acid (HA)&mdashin their urine. HA is necessary for life because it helps hold tissue together, but too much of it might be a bad thing, Gordon says. People with another form of progeria, called Werner syndrome, also have high levels of HA, and its concentrations creep up in elderly people, too.
A Trickle of Evidence
Plaques that build up in the blood vessels of people who die of heart disease are steeped in HA. &ldquoWhether it&rsquos cause or effect, no one really knows,&rdquo Gordon says. &ldquoThese kids have these same plaques throughout their bodies, and that&rsquos what plays a major role in causing heart attacks and strokes.&rdquo
The idea that HA contributes to heart disease is not new, but work in this area has been fostered recently by new analytical tools. In this relatively unexplored area of research, Gordon is trying to follow the trickle of evidence to its source. She wants to find out whether the disease grows more severe as HA levels rise and to establish whether the chemical does indeed promote plaque formation. If such a connection were confirmed, it could lead to therapies that fight both Hutchinson- Gilford syndrome and cardiovascular disease by lowering HA levels. &ldquoAny treatments that help these children will methuselah of hyperaging and genes very likely help millions of people with cardiovascular disease and potentially other problems associated with aging,&rdquo she says.
In another classical premature aging disease, Werner syndrome (WS), symptoms don&rsquot begin until adolescence or early adulthood. In this syndrome, hair thins and goes gray, skin wrinkles, and muscles atrophy. Individuals with this condition suffer from cataracts, diabetes, heart disease and other afflictions that don&rsquot typically strike until old age.
Although people with Hutchinson- Gilford and WS look old and share many ailments with geriatric patients, the physiological changes overlap only partially with how people usually age. WS sufferers experience a high incidence of cancer, for example, but &ldquothey include rare, weird cancers that you don&rsquot see too often,&rdquo says George M. Martin of the University of Washington.
Still, these disorders can provide some intriguing insights, says W. Ted Brown of the Institute for Basic Research in Developmental Disabilities in Staten Island, N.Y. &ldquoMutations in one gene can produce a set of effects that dramatically resemble aging. That implies that relatively few genes could be controlling aging.&rdquo
Several years ago scientists tracked down the gene responsible for WS. In its healthy form the gene encodes a protein that unwinds DNA, presumably so other proteins that manipulate DNA can wriggle between the strands to do their work. No one yet knows exactly how a defective version of this gene, which would give rise to a faulty protein, could lead to WS. But many ideas are floating around. In test-tube experiments, WS cells are much more susceptible than normal to harm from a compound that is toxic to DNA. These results suggest that the abnormal WS protein might fail to repair damaged DNA.
And that&rsquos just one thought. Studies on a yeast protein that resembles the WS protein have suggested that it undermines DNA integrity in other ways. A mutation in a yeast gene that encodes this protein shortens life span. In cells carrying the altered gene, DNA is cut after it loops into circles, and the ends stick together. The resulting DNA circles contribute to the cell&rsquos eventual demise. No one has detected similar DNA rings in cells of people with WS or from old individuals. Some researchers have conjectured, however, that the normal WS protein quashes formation of aberrant DNA structures in humans, a process that might go awry when the gene suffers a mutation.
Already studies on WS have spurred investigators to think about new ways of looking at common disorders of human aging. Perhaps DNA damage from subtle but common variations in the WS gene may predispose people to vascular disease, cataracts and diabetes, even if they don&rsquot suffer from a full-blown form of the disease.
The big limitation of studying humans, of course, is that you can&rsquot manipulate people as you can laboratory animals. Enter a mutant mouse strain that is afflicted at a young age with many of the diseases common to older humans. The defect in the responsible mouse gene&mdashcalled klotho, after the goddess in Greek mythology who spins the thread of life&mdashaccelerates the onset of disorders such as atherosclerosis and osteoporosis.
Researchers have isolated the klotho gene from both mice and humans. The human klotho lies in a region of the chromosome with no known genetic disorders. Because mice with defective klotho exhibit some aspects of premature aging, the gene may be analogous to progeria genes, such as those responsible for Hutchinson-Gilford and Werner syndromes. It&rsquos even possible that klotho is the yet to be revealed gene that underlies Hutchinson-Gilford. &ldquoIt would be interesting to see if Hutchinson- Gilford patients have a mutation in the klotho gene,&rdquo says Makoto Kuro-o of the University of Texas Southwestern Medical Center at Dallas.
Based on an analysis of klotho&rsquos DNA and the symptoms exhibited by the mice, Kuro-o hypothesizes that the mutated gene encodes an aberrant protein that circulates in the blood and triggers age-related processes in different tissues&mdashperhaps a buildup of plaque in blood vessels. If so, the normal version of the protein might do the opposite&mdashserving as what Kuro-o calls an &ldquoantiaging hormone.&rdquo The idea of such a blood-borne factor that might keep at least some tissues healthy is a new concept for mammalian aging, Kuro-o says. He is trying to identify the molecules with which the klotho protein interacts in tissues and to figure out how cells with defective klotho behave differently from normal cells.
When healthy versions of genes such as klotho or the one underlying WS go haywire, they expedite an organism&rsquos demise. Studying these mutations and disorders may well yield insight into particular illnesses and conditions of old age. But they will probably not shed much light on one of the most important questions surrounding aging research&mdashthat is, how scientists might move beyond simply fighting diseases of old age to finding ways of extending life span beyond the current maximum limit of about 120 years.
To go further, investigators have begun to examine how overproducing some proteins prolongs the lives of microbes, flies and mammals. In yeast, extra servings of a protein called Sir2 lengthen lifetime, increasing the number of times the organism can duplicate. In contrast, yeast harboring a defect in Sir2 has a curtailed life span.
Yeast Sir2 keeps large stretches of genes turned off. Perhaps, as organisms age, they lose their ability to silence genes effectively, suggests Leonard P. Guarente of the Massachusetts Institute of Technology. In this scenario, activation of particular genes would spur changes in physiology that lead to aging. Mammals, too, carry a Sir2-like protein, and it may function in a manner similar to that of the one in yeast. Adding to the evidence, results in mice suggest that loss of silencing may promote mouse aging, says Bruce M. Howard of the National Institutes of Health. Other genes increase life span when overproduced as well. In flies, extra copies of enzymes that neutralize oxidants, harmful oxygen-containing molecules, extend the insects&rsquo lifetimes.
If natural aging results from general deterioration of various bodily functions, it might seem surprising that single mutations could dramatically lengthen life. Last year, though, researchers reported a strain of mouse that can live almost a third longer than normal because of a mutation in one gene.
It&rsquos now known that single gene mutations in other organisms can lengthen life span. Several long-lived worms carry mutations in a gene involved in a process that appears to use chemical signals to trigger activities inside cells. The gene resembles one in humans that encodes a protein that receives messages from hormones such as insulin and growth factors. Researchers believe genetic alterations in the worms that render this protein insensitive to such hormones increase their life span. No one knows exactly how this works, but the mutant worms&mdashknown as daf-2 mutants&mdash increase production of enzymes that protect cells from oxidants.
Studying worms suggests a general strategy for antiaging therapies. &ldquoIf aging is regulated by a hormone, it can probably be slowed by a hormone,&rdquo says Gary B. Ruvkun of Harvard Medical School. A drug that regulates such a hormone, however, may be a mixed blessing. Some but not all mutations predicted to decrease hormone signaling in worms also slow metabolism. As for possible antiaging treatments, what&rsquos the point of being alive if your metabolism is so slow that you&rsquore essentially asleep? Still, it&rsquos possible that scientists could find a hormone that affects longevity but not metabolism. Drugs that target such a hormone might prolong life without making people sluggish. Furthermore, many daf-2 mutants remain healthy and vigorous for much longer than their normal counterparts do, suggesting that extending life without slowing anyone down might be relatively easy, says Cynthia J. Kenyon of the University of California at San Francisco.
Every organism has its idiosyncrasies, but many basic truths of nature apply across the boundaries of species. The discovery of hormones that apparently control life span, or some aspect of agerelated diseases in worms and mice, hints at a general biological mechanism for health and longevity that extends beyond any single organism. In the future, we may be able to apply lessons learned from our simpler cohabitants to stay younger and healthier ourselves.