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I am a computer scientist that studies biology and bioinformatics. In the last weeks, I have been trying to study new research directions, and I would like to deepen my knowledge on the role and behavior of genes and proteins in learning.
By learning, I mean the human process: the information I is absent at time T, and present at time T+1.
I would like to study more this problem, and I am wondering: how do proteins and genes behave during learning? I have read that proteins that participate in learning are called marker proteins. Is it true? Which role do they have?
Where could I find some resources to study this fascinating problem?
Thank you very much!
The storage of memories in cells is rarely thought of on the protein level of the cell. Cells are usually given a developmental state, but no memory. A cell may become a liver cell, cancerous, or diabetic, but this is not memory, but a physiological change in the cell which is usually not reversible to a previous state.
For example cancer treatments are entirely focused on identifying the cancerous cells and killing them. Internally the genomes of cancer cells often have deletions and duplications. They are cancerous, they have not learned to be cancerous. Though not as dramatic, it is now thought that cellular differentiation which creates different types of cells is heavily influenced by epigenetic modification of the genome; the DNA is marked by methyl groups which dictates the state of the cell by modifying the gene. This is mediated by proteins for sure, but is quite complex and not well understood at this time. Epigenetic markers can even change gene behavior between generations of offspring as well, though that is not usually called memory.
How is information stored in the brain? This is thought to be reflected in the organization of the neurons in the brain. There are many kinds of neurons. They can be distinguished by the sorts of axons and dendrites that emanate from the cell body. They can also be distinguished by the chemical variety of neurotransmitter they use (there are a score of different molecules). So to a great extent the type of cell and the specific proteins it chooses to use to mediate information is very important.
That being said, information is currently thought to highly related to the placement of the axons and dendrites connecting the neuron to sometimes scores of other cells, sometimes touching the cell body, other times other dendrites or neurons. As neural activity ensues, the cells will reconfigure their connections by physically moving them.
More recently, investigators have tried to understand the genes which internally modulate the neural signals within the cells. This nobel prize lecture discusses how the CREB/MAPK pathway can modulate Long Term Potentiation - the shape of the neuron response to a signal over time (days or hours).
Taken as a whole, you can see that memory is likely to be stored on several levels at once - the kinds of cells (dictated by differentiation) involved, structural arrangement of the neurons (axons and dendrites connecting to various cells and places on cells), as well as internal signaling circuitry that generates and modulate the electrical and chemical activity within the cell.
"Marker protein" only refers to a protein that you can follow to see some sort of activity in the cell. A typical example is Green Fluorescent Protein, which is colored, fused with a protein of interest. It has no specific meaning regarding learning I think.
If you're interested in understanding the maintenance of state, history, and information, I would look at hysteresis. The classic biophysics model for studying hysteresis has been the Lambda phage which has been extensively detailed in Mark Ptashne's A Genetic Switch
Proteins are the major ‘working molecules’ within every organism. Among their many jobs, proteins catalyse reactions, transport oxygen and defend organisms from infection . They’re also crucial building blocks of organisms. They are the major components of wool, cartilage and milk, they package up the DNA in chromosomes and they insulate the cells of the nervous system. In short, proteins are hugely important!
Proteins are made of large numbers of amino acids joined end to end. The chains fold up to form three-dimensional molecules with complex shapes – you could think of it as origami with a very long and thin piece of paper. The precise shape of each protein , along with the amino acids it contains, determines what it does.
Proteins: key examples on the Hub
Enzymes are proteins. Many enzymes have useful applications in medical or industrial biotechnology. Find out more in the video clip: Improving enzymes.
Insulin is a protein that regulates blood glucose . Type 1 diabetics do not produce insulin. Find out more in the video clip: Type 1 diabetes.
Mussels hold fast to rocks and piles using their strong byssal threads , which are made of protein. Find out more in the interactive: How mussels are farmed in New Zealand.
Antibodies are proteins, find out more in the article: The immune system.
Casein is the protein in milk that is used to make cheese. Find out more in the animated video: Cheese: a molecular view.
Transcription factors are specialised proteins that control the production of other proteins. Find out more in the video clip: What controls apple flesh colour?.
The macrofibrils within wool are made of protein. Find out more in the interactive: Wool fibre structures and properties.
The Cell's Secret Code
All the proteins in your body are made from protein building blocks called amino acids. There are twenty different amino acids used to make proteins, but there are only 4 different nucleotides in DNA and RNA. How can a 4-letter code specify 20 different amino acids?
Actually, the DNA code is designed to be read as triplets. Each "word" in the code, called a codon, is three letters long. There are also special "start" and "stop" codons that mark the beginning and end of a gene. As you can see, the code is redundant, that is, most of the amino acids have at least two different codons.
Just about every living thing uses this exact code to make proteins from DNA.
How are genes turned off and on?
Unless they schedule an appointment for highlights at the salon, many people who started out blond wave goodbye to their lighter-color hair as they grow up. Do the stresses of adulthood scare our childhood hair away? Or, let's take another example of a childhood trait lost to adulthood -- the ability to digest dairy. Thanks to an enzyme called lactase, most young children can digest milk. But as children grow older, it's common to lose that ability. What's happening here?
It all comes down to a process called gene regulation. This is how our genes are turned off and on, for minor things like hair color and vital functions like protection from cancer.
Within our bodies, we house trillions of cells, all busily going about doing their jobs while we enjoy our days. Each of those cells has a nucleus that contains our DNA -- genetic material passed on to us from our parents. DNA is composed of different sequences of our genes. These sequences hold directions for making the proteins that will carry out a cell's particular function. This is how one cell might end up being important to your kidneys, while another cell makes bone.
When a gene is turned off, it no longer provides the directions for making proteins. This means that the proteins needed to fulfill a particular job -- say, tolerate lactase -- aren't produced. Think about following driving directions on a GPS device in your car. What happens when you drive underground in a tunnel? The ground above you blocks the ability for your GPS to receive directions from its satellite. In other words, the directions are masked, and you might not know which way to go.
This metaphor is also a way of looking at gene regulation. However, when it comes to genes, it isn't a layer of dirt and metal obstructing the way. It could be one (or more) of a variety of factors: stages of your development, the environment, internal influences like hormones and genetic mutations. Keeping in mind this full range of factors also helps show that gene regulation isn't always a bad thing. Just as having to figure out our own directions every once in a while can be fulfilling to the explorer in all of us, turning certain genes off and on can be a completely natural process. Regulation can help our cells behave properly and aid us in adapting to our environment [source: National Center for Biotechnology Information].
Now that you have a brief overview on genetic regulation from afar, find out what's happening inside a cell to turn genes off and on.
Three Ways Your Genes Turn On and Off
Although gene regulation is complex and we still have a lot to learn, scientists do know of three ways in which our genes are turned off and on. We'll touch upon all three here.
The first way our genes get the big red or green light is through gene transcription. During transcription, the first step in reading the gene's directions and getting proteins made, the nucleus of the cell needs to figure out how to get its knowledge transferred. It does this by copying itself and sending the copy off to share the directions. This is like you copying out driving directions ahead of time and sharing them with everyone else.
Of course, if you can't get to those directions, you can't share them, either. That is how gene regulation works during transcription. A protein, called the transcription factor, can either cover up the gene directions or reveal them, thus determining whether the gene is on or off.
Recent discoveries have unveiled another means of gene regulation. This new area of science is called epigenetics, the study of how different environmental and lifestyle factors can alter how our genes behave, without actually changing our genetic makeup [source: Science].
So how can something like exposure to an environmental hazard boss our genes around without actually changing them? The answer is through DNA methylation. During methylation, methyl groups -- a gang of one carbon and three hydrogens -- move in and plop down on our genes. The methyl group tells that gene how to behave [source: Weinhold]. Some of these behavior changes appear to be linked with diseases, so researchers are trying to develop medications that can control them. Since these developments are in their infancy, though, researchers are faced with the challenges of inadvertently turning other behaviors on or off while trying to treat just one.
While we're on the topic of medications that drive methylation, let's talk further about how humans are taking genetics into our own hands. If our genes get turned off and on throughout our development or from external influences, can we become the traffic officers instead? It appears so.
Just as with the development of epigenetic medication, researchers are working on approaches to gene therapy. From a very basic level, in the new arena of gene therapy, healthy genes are added to areas where other genes have gone missing, have a mutation or are just "off." The hope is that the healthy genes will jump-start what the silent or missing genes are supposed to be doing.
If you take our GPS example, this is like getting your directions from the driver in the car next to you since your GPS doesn't work in the tunnel. However, keeping in mind all of the complexities of how genes are regulated and how we are learning more and more every day about what individual genes do and how they interact, the challenge here is developing therapy that is effective. After all, remember how many times you've received bad directions.
Animation 16: One gene makes one protein.
George Beadle and Edward Tatum present their experiments with Neurospora bread mold.
Hello, I'm George Beadle. In 1941, Edward Tatum and I did experiments using Neurospora crassa â€” red bread mold. Our experiments proved Archibald Garrod's 1902 theory that hereditary diseases are "inborn errors of metabolism" â€” missing or false steps in the body's chemical pathways. For most of its life cycle, Neurospora is a haploid organism. This means that there is only one copy of each gene, so we didn't have to worry about dominant and recessive alleles, as had Mendel. In the lab, Neurospora grows well on "minimal" agar that contains only a few simple sugars, inorganic salts, and the vitamin biotin. Neurospora must have enzymes that convert these simple substances into the amino acids and vitamins necessary for growth. We reasoned that if we mutate any one of the genes that makes an enzyme, for example gene A, we should get a Neurospora strain that cannot grow on minimal medium. The mutant would be able to grow if we add the enzyme product as a supplement. Edward Tatum and I set out to find these nutritional mutants. In 1927, Herman Muller showed that X-rays cause mutations in genes. So, we irradiated a Neurospora culture with X-rays. We expected to get some rare mutants that would not grow on minimal media. We grew the offspring of the irradiated Neurospora on "complete" media that contained all the vitamins and amino acids. Next, we tested the ability of each of these cultures to grow on minimal media. We grew the offspring of the irradiated Neurospora on "complete" media that contained all the vitamins and amino acids. Next, we tested the ability of each of these cultures to grow on minimal medium. Most of these cultures grew on minimal media, meaning they didn't have a genetic mutation of the kind we were looking for. However, the 299 the culture did not grow on minimal medium. We then tried growing Culture# 299 on minimal media supplemented with either amino acids or vitamins. We found that Culture# 299 did not grow on minimal medium with amino acid supplements, but did grow on minimal medium with vitamin supplements. Therefore, Culture# 299 must not be able to make one of the vitamins. We then had to figure which vitamin was missing in Culture# 299. We did this by testing Culture# 299's ability to grow on minimal medium supplemented with single vitamins. We found that Culture# 299 grew only if we provided the vitamin B6 . This was our first Neurospora mutant. It could not make vitamin B6 on its own because one of the enzymes in the B6 synthesis pathway must be affected. Thus, the gene making this enzyme must have been mutated by X-rays. By adding vitamin B6 as a supplement to the minimal medium, the mutation could be compensated for and Culture# 299 could grow. Using this method of selection and supplementation, we isolated many different types of Neurospora mutants. Genetic mutations affect metabolic pathways, and we confirmed the synthesis pathway for many vitamins and amino acids. For example, the amino acid arginine is synthesized in a step-wise process catalyzed by enzymes. A precursor molecule is converted into ornithine then citrulline and finally arginine. If one gene makes one enzyme, there should be a genetic mutation for each step of this synthesis pathway. Among the arginine mutants there should be strains that need either ornithine or citrulline or arginine as supplements. In 1944, our colleagues, Adrian Srb and Norman Horowitz, found these mutant strains. They started with Neurospora strains that needed arginine as a supplement. These strains had mutations in different genes. For example, Mutant# 1 couldn't make ornithine. So, the gene that makes the enzyme for ornithine synthesis must have been mutated. If ornithine is added to the media, citrulline and then arginine would be made and Mutant# 1 could grow. Similarly, a genetic mutation in Mutant# 2 affected the enzyme that makes the arginine precursor citrulline. Adding citrulline as a supplement complemented the mutation and drove arginine synthesis to completion. And a genetic mutation in #3 affected the final step of arginine synthesis â€” the conversion of citrulline to arginine. By adding arginine as a supplement, the mutation was complemented and Mutant# 3 could grow. With each mutated gene, only one step of the metabolic pathway is affected. Therefore, one gene is responsible for one enzyme or protein. We had biochemical proof of Sir Arthur Garrod's 1908 proposal of the"inborn errors of metabolism."
dominant and recessive alleles, archibald garrod, george beadle, bread mold, x rays, edward tatum
16359. Concept 16: One gene makes one protein.
Beadle and Tatum learn that mutations inactivate proteins.
16316. Gallery 13: Sir Archibald Edward Garrod, ca 1910
Sir Archibald Edward Garrod, around 1910
16367. Gallery 16: Telegram sent to Edward Tatum telling him that he, George Beadle and Joshua Lederberg will share the 1958 Nobel Pri
Telegram sent to Edward Tatum telling him that he, George Beadle and Joshua Lederberg will share the 1958 Nobel Prize in Physiology or Medicine.
16317. Gallery 13: Colonel Archibald Edward Garrod
Colonel Archibald Edward Garrod in his World War I uniform.
16401. Gallery 18: 1958 Nobel Prize winners
1958 Nobel Prize winners: (L-R) George Beadle, Edward Tatum (Physiology or Medicine), I. Tamm (Physics), F. Sanger (Chemistry), P. Cherenkov (Physics), I. Frank (Physics), Joshua Lederberg (Physiology or Medicine).
16322. Biography 13: Sir Archibald Edward Garrod (1857-1936)
Archibald Garrod was the first to connect a human disorder with Mendel's laws of inheritance.
16372. Biography 16: Edward Lawrie Tatum (1909-1975)
Edward Tatum and George Beadle used Neurospora to prove that "one gene makes one protein." Tatum also had a role in starting bacterial genetics.
16371. Biography 16: George Wells Beadle (1903-1989)
George Beadle had successful research careers in corn and Drosophila genetics, before starting the field of Neurospora research.
16685. Biography 32: Barbara McClintock (1902 -1992)
Barbara McClintock did pioneer work in plant genetics. She received the Nobel Prize for Physiology or Medicine in 1983.
Correcting Popular Misrepresentations of Science
Until recently, the influences of genes were thought to be set, and the effects of children’s experiences and environments on brain architecture and long-term physical and mental health outcomes remained a mystery. That lack of understanding led to several misleading conclusions about the degree to which negative and positive environmental factors and experiences can affect the developing fetus and young child. The following misconceptions are particularly important to set straight.
- Contrary to popular belief, the genes inherited from one’s parents do not set a child’s future development in stone.
Variations in DNA sequences between individuals certainly influence the way in which genes are expressed and how the proteins encoded by those genes will function. But that is only part of the story—the environment in which one develops, before and soon after birth, provides powerful experiences that chemically modify certain genes which, in turn, define how much and when they are expressed. Thus, while genetic factors exert potent influences, environmental factors have the ability to alter the genes that were inherited.
- Although frequently misunderstood, adverse fetal and early childhood experiences can—and do—lead to physical and chemical changes in the brain that can last a lifetime.
Injurious experiences, such as malnutrition, exposure to chemical toxins or drugs, and toxic stress before birth or in early childhood are not “forgotten,” but rather are built into the architecture of the developing brain through the epigenome. The “biological memories” associated with these epigenetic changes can affect multiple organ systems and increase the risk not only for poor physical and mental health outcomes but also for impairments in future learning capacity and behavior.
- Despite some marketing claims to the contrary, the ability of so-called enrichment programs to enhance otherwise healthy brain development is not known.
While parents and policymakers might hope that playing Mozart recordings to newborns will produce epigenetic changes that enhance cognitive development, there is absolutely no scientific evidence that such exposure will shape the epigenome or enhance brain function. What research has shown is that specific epigenetic modifications do occur in brain cells as cognitive skills like learning and memory develop, and that repeated activation of brain circuits dedicated to learning and memory through interaction with the environment, such as reciprocal “serve and return” interaction with adults, facilitates these positive epigenetic modifications. We also know that sound maternal and fetal nutrition, combined with positive social-emotional support of children through their family and community environments, will reduce the likelihood of negative epigenetic modifications that increase the risk of later physical and mental health impairments.
The epigenome can be affected by positive experiences, such as supportive relationships and opportunities for learning, or negative influences, such as environmental toxins or stressful life circumstances, which leave a unique epigenetic “signature” on the genes. These signatures can be temporary or permanent and both types affect how easily the genes are switched on or off. Recent research demonstrates that there may be ways to reverse certain negative changes and restore healthy functioning, but that takes a lot more effort, may not be successful at changing all aspects of the signatures, and is costly. Thus, the very best strategy is to support responsive relationships and reduce stress to build strong brains from the beginning, helping children grow up to be healthy, productive members of society.
How Genes Can Cause Disease – Understanding Transcription and Translation
To begin this analysis and discussion activity, students learn about hemophilia. They learn that different versions of a gene give the instructions to make different versions of a protein, which result in hemophilia or normal health.
Then, students learn how genes provide the instructions for making a protein via the processes of transcription and translation. They develop an understanding of the roles of RNA polymerase, the base-pairing rules, mRNA, tRNA and ribosomes.
Then, students use their understanding of transcription and translation to explain how a change in a single nucleotide in the hemoglobin gene can result in sickle cell anemia.
Finally, students use their understanding of translation to develop a partial explanation of how the coronavirus replicates inside our cells.
Throughout, students use the information in brief explanations, videos and figures to answer analysis and discussion questions.
This activity can be used to introduce students to transcription and translation or to reinforce and enhance student understanding.
More Information on Epigenetics
Infographic: What is Epigenetics? And How Does it Relate to Child Development?
This infographic shows how a child’s environment can change the chemistry of their genes&mdashboth negatively and positively.
Adverse Early Experiences Can Have Lifelong Consequences
Epigenetic “markers” control where and how much protein is made by a gene, effectively turning the gene “on” or “off.” Such epigenetic modification typically occurs in cells that comprise organ systems, thereby influencing how these structures develop and function. Therefore, experiences that change the epigenome early in life, when the specialized cells of organs such as the brain, heart, or kidneys are first developing, can have a powerful impact on physical and mental health for a lifetime.
The fact that genes are vulnerable to modification in response to toxic stress, nutritional problems, and other negative influences underscores the importance of providing supportive and nurturing experiences for young children in the earliest years, when brain development is most rapid. From a policy perspective, it is in society’s interest to strengthen the foundations of healthy brain architecture in all young children to maximize the return on future investments in education, health, and workforce development.
Learn about Genetic Engineering through a Few Questions and Answers
Biotechnology is the application of biological knowledge to obtain new techniques, materials and compounds for pharmaceutical, medical, agricultural, industrial and scientific use, that is, for practical use.
The first fields of biotechnology were agriculture and the food industry. Nowadays, many other practical fields use its techniques.
Genetic Engineering Definition
More Bite-Sized Q&As Below
2. What is genetic engineering?
Genetic engineering is the use of genetic knowledge to artificially manipulate genes. It is one of the fields of biotechnology.
3. At the present level of advancement of biotechnology, what are the main techniques of genetic engineering?
The main genetic engineering techniques used today are: recombinant DNA technology (also called genetic engineering), in which pieces of genes from an organism are inserted into the genetic material of another organism to produce recombinant organisms nucleus transplantation technology, popularly known as “cloning”, in which the nucleus of a cell is grafted into an enucleated egg cell of the same species to create a genetic copy of the donor (of the nucleus) individual and DNA amplification technology, or PCR (polymerase chain reaction), which allows to produce millions of replications of the chosen fragments of a DNA molecule.
Recombinant DNA technology is used to create transgenic organisms, such as mutant insulin-producing bacteria. Nucleus transplantation technology is in its initial development but is the basis, for example, of the creation of “Dolly” the sheep. PCR has numerous practical uses, such as in medical tests to detect microorganisms present in blood and tissues, DNA fingerprinting and the obtainment of DNA samples for research.
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Restriction Enzymes and RecombinantNA Technology
4. What are restriction enzymes? How do these enzymes participate in recombinant DNA technology?
Restriction enzymes, or restriction endonucleases, are enzymes specialized in the cutting of DNA fragments, which each have an effect on specific sites of the DNA molecule. Restriction enzymes are used in recombinant DNA technology to obtain with pieces of DNA molecules with precision, which will later be inserted into other DNA molecules cut by the same enzymes.
5. What are DNA ligases? How do these enzymes participate in recombinant DNA technology?
DNA ligases are enzymes specialized in tying the complementary DNA chains that form the DNA double helix. These enzymes are used in recombinant DNA technology to insert pieces of DNA cut by restriction enzymes into other DNA molecules undergoing the effect of the same endonucleases.
6. What are plasmids?
Plasmids are circular DNA molecules present in the genetic material of some bacteria. They may contain the genes responsible for bacterial resistance to some antibiotics as well as the genes for producing proteins that cause virulence (pathogenic hostility).
7. How is genetic engineering used to create bacteria capable of producing human insulin?
In the production of human insulin by bacteria, the human insulin gene is incorporated into the genetic material of these microorganisms. The mutant bacteria multiply, forming lineages of insulin-producing bacteria.
Bacteria contain circular strands of DNA called plasmids, which are mini-chromosomes that act as an accessory to the primary DNA. To create mutant bacteria capable of producing insulin, a plasmid is submitted to the effect of restriction enzymes (restriction endonucleases) specialized in cutting DNA fragments. The once circular plasmid is opened by the restriction enzyme. The same enzyme is used to cut a human DNA molecule containing the insulin gene. The piece of human DNA containing the insulin gene is then bound to the plasmid at its ends through the help of DNA ligases. The recombinant plasmid containing the human insulin gene is then inserted into the bacteria.
Another human hormone already produced by recombinant bacteria is GH (somatotropin, or growth hormone).
The insertion of DNA molecules into the cells of an individual is also used in gene therapy, a promising treatment for genetic diseases. In gene therapy, cells from an organism deficient in the production of a given protein receive (by means of vectors, such as virus) pieces of DNA containing the protein gene and then begin to synthesize the protein.
8. What is cloning?
Cloning is the production of an organism genetically identical to another by means of genetic engineering.
The basis of cloning is nucleus transplantation technology. A nucleus from a cell is extracted, generally from an embryonic (undifferentiated) cell and this nucleus is inserted into a previously enucleated reproductive cell (in general an egg cell) the egg is then implanted in the organ where the embryonic development will take place. If embryonic development occurs, the new organism will have an identical genetic content to the organism organism whose cell nucleus was used in the transplantation.
Polymerase Chain Reaction
9. What is PCR? How does PCR works?
PCR, polymerase chain reaction, is a method to synthesize many copies of specific regions of a DNA molecule known as target-regions. Its inventor, Kary Mullis, won the Nobel Prize for Chemistry in 1993.
First, the DNA to be tested is heated to cause the double helix to rupture and the polynucleotide chains to be exposed. Then, small synthetic sequences of DNA known as primers and containing nucleotide sequences similar to the sequences of the extremities of the region to be studied (for example, a region containing a known gene exclusive to a given organism) are added. The primers are paired with the original DNA at the ends of the gene to be amplified. Enzymes known as polymerases, which catalyze DNA replication, and nucleotide supply are added. The primers are then completed and the chosen region is replicated. In the presence of more primers and more nucleotides, millions of copies of that specific region are generated. (PCR is very sensitive, even when using a minimal amount of DNA).
10. What molecular biology principle is the basis for DNA fingerprinting?
DNA fingerprinting, the method of the identification of individuals using DNA, is based on the fact that the DNA of every individual (except for identical twins and individual clones) contains nucleotide sequences exclusive to each individual.
Although normal individuals of the same species have the same genes in their chromosomes, each individual has different alleles and even in the inactive portions of the chromosomes (heterochromatin), there are differences in nucleotide sequences among individuals.
Genetic Engineering Dangers and Ethics
11. Why are recombinant DNA technology and nucleus transplantation technology still dangerous?
Recombinant DNA technology and nucleus transplantation technology (cloning) are extremely dangerous since they are able to modify, in a very short time, the ecological balance that evolution has taken millions of years to create on the planet. During the evolutionary process, under the slow and gradual effect of mutations, genetic recombinations and natural selection, species emerged, were modified, and genetic heritages were formed. With genetic engineering, however, humans can mix and modify genes, making changes with unpredictable long-term consequences, risking the creation of new plant or animal diseases, new types of cancers and new disease outbreaks. It is a field as potentially dangerous as the manipulation of nuclear energy.
12. What is the main moral problem regarding the cloning of human individuals?
In addition to the biological perils, a very serious moral problem involves nucleus transplantation technology concerning humans: the individual rights of a human being are violated when a man or woman is made as a copy of another.
Since it is impossible to first ask if the person to be cloned wants to be a genetic copy of another person or not, it is clear that the most important human right is being violated when making one human as a copy of another: the right to individual freedom. This is a danger to democracy, whose most basic principle is the respect of individual freedom.
Now that you have finished studying Genetic Engineering, these are your options:
Viruses are one of the most dangerous enemies to our health, attacking cells and causing deadly diseases like AIDS and influenza. However, scientists are currently discovering ways to trick viruses into improving our health instead of causing disease. Adenovirus is one of the viruses being used in this work. It is found around the world, but it usually causes only mild disease when it infects cells. It can be life-threatening, however, in infants or people with weakened immune systems. Modified forms of the virus are being developed to cure genetic diseases, to fight cancer, and to deliver vaccines.
The Adenovirus Capsid
Adenovirus is a large virus, composed of a complex protein capsid surrounding its DNA genome and core proteins. The structure of the capsid has recently been solved by cryo-electron microscopy (PDB entry 3iyn ) and x-ray crystallography (PDB entry 1vsz ). The capsid is icosahedral: the faces are composed of 240 hexons, each composed of three identical proteins, and 12 pentons sit on the vertices, each composed of five protein chains. A long fiber extends from each vertex, composed of three identical chains that form a knob at the end (PDB entry 1qiu ). In addition, several types of "minor" proteins bind in the grooves between the hexons and pentons, guiding the assembly of the capsid and gluing the entire structure together.
The adenovirus capsid has the job of finding a cell and delivering the viral genome inside. Most of the action occurs at the vertices. The long fibers bind selectively to receptors on the surface of the cell. The most common receptor is CAR, a protein of unknown function that is found on most types of cells. Other strains of adenovirus use CD46, a regulatory protein in the complement system. Once the virus attaches to the cell surface, it is drawn into vesicles by the normal process of endocytosis. Then, the penton attaches to integrins, ultimately breaking through the vesicle membrane and releasing the viral DNA. It then enters the nucleus and builds thousands of new viruses.
Engineered adenovirus is being developed to deliver genes to cells. The idea has great promise: for instance, a functional CFTR gene could be delivered to cells in people with cystic fibrosis, replacing the defective gene and restoring the function. However, things always get complicated when biology is involved, and scientists have faced many challenges with this work. The early studies replaced one viral gene with the therapeutic gene. These engineered viruses infect cells, deliver the gene, but are unable to replicate, so the infection can be controlled. However, the immune system rapidly discovers these cells, since they contain viruses, and destroys them in a matter of hours. This is okay if you're using the engineered virus to treat cancer or deliver a vaccine--the virus can go in, do its job, and then be cleared away. For long-lasting gene therapy, however, a more permanent approach is necessary, and many new ideas are currently being explored.
Exploring the Structure
The end of each adenovirus fiber forms a knob that binds to the cellular receptor. Several structures of adenovirus and its cellular receptors have been solved, including the complex of the fiber knob with CAR (PDB entry 1kac ) and the complex with CD46 (PDB entry 2o39 ). In both cases, three copies of the receptor protein bind in the grooves between subunits in the fiber knob. To take a closer look at this interaction, click on the images here for an interactive jmol.
Topics for Further Discussion
- Several other adenovirus proteins are available in the PDB: what are their functions in the viral lifecycle?
- Crystal structures for the purified hexons and pentons were solved before the structure of the entire capsid was available. Can you find them in the PDB? Notice that the purified pentons form an unusual mini-capsid.
Related PDB-101 Resources
- J. J. Rux and R. M. Burnett (2004) Adenovirus structure. Human Gene Therapy 15, 1167-1176.
- W. Wu and G. R. Nemerow (2004) Virus yoga: the role of flexibility in virus host cell recognition. Trends in Microbiology 12, 162-169.
- M. A. F. V. Goncalves and A. A. F. deVries (2006) Adenovirus: from foe to friend. Review of Medical Virology 16, 167-186.
- L. S. Young, P. F. Searle, D. Onion and V. Mautner (2006) Viral gene therapy strageies: from basic science to clinical application. Journal of Pathology 208, 299-318.
December 2010, David Goodsell
PDB-101 helps teachers, students, and the general public explore the 3D world of proteins and nucleic acids. Learning about their diverse shapes and functions helps to understand all aspects of biomedicine and agriculture, from protein synthesis to health and disease to biological energy.
Why PDB-101? Researchers around the globe make these 3D structures freely available at the Protein Data Bank (PDB) archive. PDB-101 builds introductory materials to help beginners get started in the subject ("101", as in an entry level course) as well as resources for extended learning.