Saturday, 9 January 2016
Some assembly required?
Can You Build WALL-E from Repeating Legos?
Evolution News & Views January 8, 2016 3:31 AM
"A central question in protein evolution is the extent to which naturally occurring proteins sample the space of folded structures accessible to the polypeptide chain." Thus begins a new paper on sequence space for proteins, a concept that has been key to work by leading ID theorists Douglas Axe, Stephen Meyer, and William Dembski. This is the question: Out of the vast space of possible amino acid sequences, how many can fold into functional proteins? ID argues that functional space is such a small subset of sequence space, the probability that a blind search will find any is vanishingly small.
Nine researchers led by some of our Seattle neighbors over at the University of Washington, publishing in Nature, decided to investigate how much of the sequence space nature has sampled. It's obviously far too big a space to search, so they limited it to just "repeat proteins" -- those that use certain structural motifs over and over.
To our knowledge, all designed repeat protein structures to date have been based on naturally occurring families. These families may cover all stable repeat protein structures that can be built from the 20 amino acids or, alternatively, natural evolution may only have sampled a subset of what is possible.
By applying experimental protein design, they show that you can get many more potential proteins by simply repeating certain "building blocks" over and over, something like assembling Lego pieces blindly. They manufactured some Lego-like protein kits by generating scads of "a simple helix-loop-helix-loop building block" and putting them together using an automated process. Out of 83 they built, 44 showed a stable fold. But is this experiment about evolution or intelligent design?
We have shown that a wide range of novel repeat proteins can be generated by tandem repeating a simple helix-loop-helix-loop building block. As illustrated by the comparison of 15 design models to the corresponding crystal structures (Fig. 4), our approach allows precise control over structural details throughout a broad range of geometries and curvatures. The design models and sequences are very different from each other and from naturally occurring repeat proteins, without any significant sequence or structural homology to known proteins (Extended Data Fig. 8). This work achieves key milestones in computational protein design: the design protocol is completely automatic, the folds are unlike those in nature, more than half of the experimentally tested designs have the correct overall structure as assessed by SAXS, and the crystal structures demonstrate precise control over backbone conformation for proteins over 200 amino acids. The observed level of control over the repeating helix-loop-helix-loop architecture shows that computational protein design has matured to the point of providing alternatives to naturally occurring scaffolds, including graded and tunable variation difficult to achieve starting from existing proteins. We anticipate that the 44 successful designs described in this work (Extended Data Fig. 9), and sets generated using similar protocols for other repeat units, will be widely useful starting points for the design of new protein functions and assemblies.
Note that word "function" at the end. A search of the paper shows nothing about whether any one of the design models actually does anything. Yet they seem to have one ear open to the possible whisper of Darwin speaking in the background:
Naturally occurring repeat protein families, such as ankyrins, leucine-rich repeats, TAL effectors and many others, have central roles in biological systems and in current molecular engineering efforts. Our results suggest that these families are only the tip of the iceberg of what is possible for polypeptide chains: there are clearly large regions of repeat protein space that are not sampled by currently known repeat protein structures. Repeat protein structures similar to our designs may not have been characterized yet, or perhaps may simply not exist in nature.
The authors only mention evolution twice. It's not really a focus in this paper. The word "design," however, appears a whopping 74 times, even before the Methods section. They did interesting and important work. But lest anyone think their conclusion weakens the arguments of Axe, Meyer, and Dembski by expanding the potential functional space accessible to random search within sequence space, let's apply a heavy dose of realism.
They sampled only part of the "repeat protein" portion of sequence space.
They began with "building block" motifs that already fold (helices and loops).
They used only left-handed (homochiral) amino acids.
They did not test to see if any of the stable structures perform a function.
They did not test to see if any of their structures could interact with other proteins or structures (for this problem, see this earlier article on this subject).
Their work was highly dependent on intelligent design (i.e., their own).
You could liken their results to a robot programmed to assemble Legos according to a rule: "fasten, twist, repeat." If the Lego pieces are already designed, the algorithm can say nothing about where the pieces came from. As all kids know, the holes in Lego pieces have to be spaced properly to fit together. Similarly, amino acids need to be properly sequenced to fold into a helix or loop. If that's a given, it's not surprising that you could generate quite a few unique structures by the algorithm "fasten, twist, repeat." Even WALL-E the robot could do that without thinking. Whether anything worthwhile would result is dubious.
Actually, you can assemble a WALL-E robot using Lego pieces now. The Lego company offers that and many other elaborate, complex kits that go well beyond the simple building-block sets from decades ago. A kid could put the WALL-E pieces together and show off his pride and joy in a matter of hours or maybe even minutes. But could nature pull that off by blind search? Think of the programming that would be required to get WALL-E to assemble his likeness out of Lego pieces! It's intelligent design all the way down.
Here's the take-home: Despite a hint of "protein evolution" in this paper, the experimental evidence has again vindicated ID. Without a mind directing assembly of amino acids according to a design goal, nothing interesting will happen by chance or repetition by an aimless process. Sequence space is too vast and functional space too vanishingly small to expect success by blind search.
Evolution News & Views January 8, 2016 3:31 AM
"A central question in protein evolution is the extent to which naturally occurring proteins sample the space of folded structures accessible to the polypeptide chain." Thus begins a new paper on sequence space for proteins, a concept that has been key to work by leading ID theorists Douglas Axe, Stephen Meyer, and William Dembski. This is the question: Out of the vast space of possible amino acid sequences, how many can fold into functional proteins? ID argues that functional space is such a small subset of sequence space, the probability that a blind search will find any is vanishingly small.
Nine researchers led by some of our Seattle neighbors over at the University of Washington, publishing in Nature, decided to investigate how much of the sequence space nature has sampled. It's obviously far too big a space to search, so they limited it to just "repeat proteins" -- those that use certain structural motifs over and over.
To our knowledge, all designed repeat protein structures to date have been based on naturally occurring families. These families may cover all stable repeat protein structures that can be built from the 20 amino acids or, alternatively, natural evolution may only have sampled a subset of what is possible.
By applying experimental protein design, they show that you can get many more potential proteins by simply repeating certain "building blocks" over and over, something like assembling Lego pieces blindly. They manufactured some Lego-like protein kits by generating scads of "a simple helix-loop-helix-loop building block" and putting them together using an automated process. Out of 83 they built, 44 showed a stable fold. But is this experiment about evolution or intelligent design?
We have shown that a wide range of novel repeat proteins can be generated by tandem repeating a simple helix-loop-helix-loop building block. As illustrated by the comparison of 15 design models to the corresponding crystal structures (Fig. 4), our approach allows precise control over structural details throughout a broad range of geometries and curvatures. The design models and sequences are very different from each other and from naturally occurring repeat proteins, without any significant sequence or structural homology to known proteins (Extended Data Fig. 8). This work achieves key milestones in computational protein design: the design protocol is completely automatic, the folds are unlike those in nature, more than half of the experimentally tested designs have the correct overall structure as assessed by SAXS, and the crystal structures demonstrate precise control over backbone conformation for proteins over 200 amino acids. The observed level of control over the repeating helix-loop-helix-loop architecture shows that computational protein design has matured to the point of providing alternatives to naturally occurring scaffolds, including graded and tunable variation difficult to achieve starting from existing proteins. We anticipate that the 44 successful designs described in this work (Extended Data Fig. 9), and sets generated using similar protocols for other repeat units, will be widely useful starting points for the design of new protein functions and assemblies.
Note that word "function" at the end. A search of the paper shows nothing about whether any one of the design models actually does anything. Yet they seem to have one ear open to the possible whisper of Darwin speaking in the background:
Naturally occurring repeat protein families, such as ankyrins, leucine-rich repeats, TAL effectors and many others, have central roles in biological systems and in current molecular engineering efforts. Our results suggest that these families are only the tip of the iceberg of what is possible for polypeptide chains: there are clearly large regions of repeat protein space that are not sampled by currently known repeat protein structures. Repeat protein structures similar to our designs may not have been characterized yet, or perhaps may simply not exist in nature.
The authors only mention evolution twice. It's not really a focus in this paper. The word "design," however, appears a whopping 74 times, even before the Methods section. They did interesting and important work. But lest anyone think their conclusion weakens the arguments of Axe, Meyer, and Dembski by expanding the potential functional space accessible to random search within sequence space, let's apply a heavy dose of realism.
They sampled only part of the "repeat protein" portion of sequence space.
They began with "building block" motifs that already fold (helices and loops).
They used only left-handed (homochiral) amino acids.
They did not test to see if any of the stable structures perform a function.
They did not test to see if any of their structures could interact with other proteins or structures (for this problem, see this earlier article on this subject).
Their work was highly dependent on intelligent design (i.e., their own).
You could liken their results to a robot programmed to assemble Legos according to a rule: "fasten, twist, repeat." If the Lego pieces are already designed, the algorithm can say nothing about where the pieces came from. As all kids know, the holes in Lego pieces have to be spaced properly to fit together. Similarly, amino acids need to be properly sequenced to fold into a helix or loop. If that's a given, it's not surprising that you could generate quite a few unique structures by the algorithm "fasten, twist, repeat." Even WALL-E the robot could do that without thinking. Whether anything worthwhile would result is dubious.
Actually, you can assemble a WALL-E robot using Lego pieces now. The Lego company offers that and many other elaborate, complex kits that go well beyond the simple building-block sets from decades ago. A kid could put the WALL-E pieces together and show off his pride and joy in a matter of hours or maybe even minutes. But could nature pull that off by blind search? Think of the programming that would be required to get WALL-E to assemble his likeness out of Lego pieces! It's intelligent design all the way down.
Here's the take-home: Despite a hint of "protein evolution" in this paper, the experimental evidence has again vindicated ID. Without a mind directing assembly of amino acids according to a design goal, nothing interesting will happen by chance or repetition by an aimless process. Sequence space is too vast and functional space too vanishingly small to expect success by blind search.
Darwinism Vs. the real world XXIII
Defending the City: The Immune System's Irreducibly Complex System:
Howard Glicksman January 9, 2016 4:08 AM
Editor's note: Physicians have a special place among the thinkers who have elaborated the argument for intelligent design. Perhaps that's because, more than evolutionary biologists, they are familiar with the challenges of maintaining a functioning complex system, the human body. With that in mind, Evolution News & Views is delighted to present this series, "The Designed Body." For the complete series, see here. Dr. Glicksman practices palliative medicine for a hospice organization.
Let's review a few things that this series has shown are needed for human survival. The body is made up of trillions of cells, each of which must control its volume and chemical content while receiving what it needs from the blood to live, grow, and work properly. Since it is made up of matter, the body is subject to the laws of nature, which demand that it constantly take in oxygen to provide itself with the energy it needs to live. Unlike with glucose, the body can't store oxygen for future use.
These laws also demand that the body have the right amounts and distributions of water, sodium, and potassium for blood volume, and the proper resting membrane potential for adequate nerve, muscle, and heart function. Additionally, since blood has mass, it needs the heart to pump it through the circulatory system to the tissues with enough pressure against natural forces like inertia, vascular resistance, and gravity..
If the body doesn't have the right levels of oxygen, water, sodium, potassium, blood pressure, or blood flow, then cell death takes place. When the cells in the brainstem die -- the ones that tell the body to breathe in air, control its cardiovascular system, and make it conscious of its surroundings -- the body is considered dead. The most common pathway to death is by cardiopulmonary arrest. Without respiration, the body can't bring in new supplies of oxygen and get rid of toxic carbon dioxide. Without the heart pumping, there is no blood flow to the brain. So, together, cardiopulmonary arrest causes death very soon after.
Life does not exist in a vacuum or merely in the imagination of evolutionary biologists. As we saw in the most recent articles in this series, small blood vessels of the body constantly undergo injury from the everyday activities of life. For our earliest ancestors to survive long enough to reproduce, they needed a well-controlled clotting mechanism (hemostasis) in place that would turn on only when it was needed and turn off and stay off when it wasn't.
Bleeding disorders -- where the clotting mechanism won't turn on -- can cause a brain hemorrhage from even minimal trauma, or hypovolemic shock from spontaneous gastrointestinal bleeding. Hypercoagulable states -- where the clotting mechanism turns on at the wrong time -- can easily cause death from a heart attack, stroke, or pulmonary embolism. Either way, unless hemostasis is properly controlled, the body is as good as dead. But well-controlled hemostasis is dependent on having a finely tuned system of pro- and anti-clotting factors that must be produced in adequate quantities by the endothelium that lines the blood vessels and liver.
Hemostasis is a type of defense system the body uses to prevent itself from bleeding to death from injuries and accidents. But that's not the only one it has. The bones, muscles, and nerves work together to allow the body to detect danger and avoid or defend against it. However, survival also requires us to defend ourselves from enemies that we can't detect with the senses. We are perpetually exposed to germs: microorganisms that are too small to be seen with the naked eye. These consist mostly of bacteria, viruses, and fungi. If such microbes invade the body and become widespread, then serious disease, debility, and even death can result.
Against microbial attack, the body has a two-pronged defense strategy. The first line of defense is the epithelium.This tissue separates and protects the interior cells of the body from the effects of the outside world. The skin is an epithelial tissue consisting of many different types of cells that provides passive resistance to invasion by microbes. Skin also protects the body from mechanical and chemical injury, ultraviolet radiation, extreme heat and cold, excessive fluid loss, and helps to control body temperature. The respiratory, gastrointestinal, and genitourinary systems also have an epithelial lining that separates their underlying tissue from the effects of the environment. Microbes that are inhaled, or swallowed, or are able to enter the urinary tract, come up against these barriers.
If the invading microorganisms breach the first line and enter into the tissues, then the second line of defense, the immune system, swings into action. The immune system consists of many different cells and proteins. In ancient times, when invaders breached the walls of a town, they usually met armed resistance. By using their weapons and shields for protection, the intruders would kill and loot their way through the town, thus conquering it. Similarly, after breaching a passive barrier like the skin, usually through a cut or scrape, invading microbes attempt to loot the body by using the nutrients in its fluids to live, grow, and multiply.
As with a town stormed by a finite number of attackers, a microbial infection usually involves a relatively small invading force. But once inside the body, the infection is able to multiply rapidly by using the resources of its host. It's the job of the immune system to limit this activity as much as possible to preserve organ function.
Although there are many different types of bacteria, viruses, and fungi, the few that have developed the ability to breach the first line of defense and do battle with the immune system are called pathogens (Gk. pathos = disease + gennan = to produce). Some of these pathogenic organisms enter the cells, take over their metabolism, rapidly reproduce and then send out the next generation of microbes into the body after the cell dies. Many others can live within the tissue fluid between the cells and multiply and spread locally.
Infections are possible in almost every organ of the body. Progression of infection within a given organ system can lead to severe body malfunction. If the lungs develop pneumonia, this can significantly diminish their ability to bring in oxygen and release carbon dioxide and, particularly in people with emphysema, can lead to respiratory failure and cardiopulmonary arrest. If the gastrointestinal tract develops gastroenteritis, the associated vomiting and diarrhea, particularly in the very young and old, can lead to dehydration, chemical imbalance, hypovolemic shock, and cardiopulmonary arrest. If the brain develops encephalitis or meningitis, the nerve malfunction aggravated by the increased pressure can lead to brain death.
If the pathogens are not stopped within the tissues they initially infect, they can migrate into the lymphatics. The lymphatic system consists of very thin walled tiny channels that carry lymph (L. lympha = water), a liquid that comes from the fluid not reabsorbed at the venous end of the capillary. Every tissue and organ in the body is drained by lymphatic vessels, which eventually come together to drain into the venous system.
It is through the lymphatic system that microbes gain access to the bloodstream and all of the tissues and organs of the body. By working their way through the lymphatics and into the bloodstream, these organisms can cause septicemia and irreversible shock, resulting in death for about 250,000 people in this country every year.
Without the epithelial tissue of the body protecting it from microbial invasion, life would have been impossible for our earliest ancestors. But the experience of death-dealing infections throughout the world also tells us that without a properly working immune system, the same applies. How the immune system works and what it takes to control it so we can live within the world of microbes will be the subject of my next few articles.
Howard Glicksman January 9, 2016 4:08 AM
Editor's note: Physicians have a special place among the thinkers who have elaborated the argument for intelligent design. Perhaps that's because, more than evolutionary biologists, they are familiar with the challenges of maintaining a functioning complex system, the human body. With that in mind, Evolution News & Views is delighted to present this series, "The Designed Body." For the complete series, see here. Dr. Glicksman practices palliative medicine for a hospice organization.
Let's review a few things that this series has shown are needed for human survival. The body is made up of trillions of cells, each of which must control its volume and chemical content while receiving what it needs from the blood to live, grow, and work properly. Since it is made up of matter, the body is subject to the laws of nature, which demand that it constantly take in oxygen to provide itself with the energy it needs to live. Unlike with glucose, the body can't store oxygen for future use.
These laws also demand that the body have the right amounts and distributions of water, sodium, and potassium for blood volume, and the proper resting membrane potential for adequate nerve, muscle, and heart function. Additionally, since blood has mass, it needs the heart to pump it through the circulatory system to the tissues with enough pressure against natural forces like inertia, vascular resistance, and gravity..
If the body doesn't have the right levels of oxygen, water, sodium, potassium, blood pressure, or blood flow, then cell death takes place. When the cells in the brainstem die -- the ones that tell the body to breathe in air, control its cardiovascular system, and make it conscious of its surroundings -- the body is considered dead. The most common pathway to death is by cardiopulmonary arrest. Without respiration, the body can't bring in new supplies of oxygen and get rid of toxic carbon dioxide. Without the heart pumping, there is no blood flow to the brain. So, together, cardiopulmonary arrest causes death very soon after.
Life does not exist in a vacuum or merely in the imagination of evolutionary biologists. As we saw in the most recent articles in this series, small blood vessels of the body constantly undergo injury from the everyday activities of life. For our earliest ancestors to survive long enough to reproduce, they needed a well-controlled clotting mechanism (hemostasis) in place that would turn on only when it was needed and turn off and stay off when it wasn't.
Bleeding disorders -- where the clotting mechanism won't turn on -- can cause a brain hemorrhage from even minimal trauma, or hypovolemic shock from spontaneous gastrointestinal bleeding. Hypercoagulable states -- where the clotting mechanism turns on at the wrong time -- can easily cause death from a heart attack, stroke, or pulmonary embolism. Either way, unless hemostasis is properly controlled, the body is as good as dead. But well-controlled hemostasis is dependent on having a finely tuned system of pro- and anti-clotting factors that must be produced in adequate quantities by the endothelium that lines the blood vessels and liver.
Hemostasis is a type of defense system the body uses to prevent itself from bleeding to death from injuries and accidents. But that's not the only one it has. The bones, muscles, and nerves work together to allow the body to detect danger and avoid or defend against it. However, survival also requires us to defend ourselves from enemies that we can't detect with the senses. We are perpetually exposed to germs: microorganisms that are too small to be seen with the naked eye. These consist mostly of bacteria, viruses, and fungi. If such microbes invade the body and become widespread, then serious disease, debility, and even death can result.
Against microbial attack, the body has a two-pronged defense strategy. The first line of defense is the epithelium.This tissue separates and protects the interior cells of the body from the effects of the outside world. The skin is an epithelial tissue consisting of many different types of cells that provides passive resistance to invasion by microbes. Skin also protects the body from mechanical and chemical injury, ultraviolet radiation, extreme heat and cold, excessive fluid loss, and helps to control body temperature. The respiratory, gastrointestinal, and genitourinary systems also have an epithelial lining that separates their underlying tissue from the effects of the environment. Microbes that are inhaled, or swallowed, or are able to enter the urinary tract, come up against these barriers.
If the invading microorganisms breach the first line and enter into the tissues, then the second line of defense, the immune system, swings into action. The immune system consists of many different cells and proteins. In ancient times, when invaders breached the walls of a town, they usually met armed resistance. By using their weapons and shields for protection, the intruders would kill and loot their way through the town, thus conquering it. Similarly, after breaching a passive barrier like the skin, usually through a cut or scrape, invading microbes attempt to loot the body by using the nutrients in its fluids to live, grow, and multiply.
As with a town stormed by a finite number of attackers, a microbial infection usually involves a relatively small invading force. But once inside the body, the infection is able to multiply rapidly by using the resources of its host. It's the job of the immune system to limit this activity as much as possible to preserve organ function.
Although there are many different types of bacteria, viruses, and fungi, the few that have developed the ability to breach the first line of defense and do battle with the immune system are called pathogens (Gk. pathos = disease + gennan = to produce). Some of these pathogenic organisms enter the cells, take over their metabolism, rapidly reproduce and then send out the next generation of microbes into the body after the cell dies. Many others can live within the tissue fluid between the cells and multiply and spread locally.
Infections are possible in almost every organ of the body. Progression of infection within a given organ system can lead to severe body malfunction. If the lungs develop pneumonia, this can significantly diminish their ability to bring in oxygen and release carbon dioxide and, particularly in people with emphysema, can lead to respiratory failure and cardiopulmonary arrest. If the gastrointestinal tract develops gastroenteritis, the associated vomiting and diarrhea, particularly in the very young and old, can lead to dehydration, chemical imbalance, hypovolemic shock, and cardiopulmonary arrest. If the brain develops encephalitis or meningitis, the nerve malfunction aggravated by the increased pressure can lead to brain death.
If the pathogens are not stopped within the tissues they initially infect, they can migrate into the lymphatics. The lymphatic system consists of very thin walled tiny channels that carry lymph (L. lympha = water), a liquid that comes from the fluid not reabsorbed at the venous end of the capillary. Every tissue and organ in the body is drained by lymphatic vessels, which eventually come together to drain into the venous system.
It is through the lymphatic system that microbes gain access to the bloodstream and all of the tissues and organs of the body. By working their way through the lymphatics and into the bloodstream, these organisms can cause septicemia and irreversible shock, resulting in death for about 250,000 people in this country every year.
Without the epithelial tissue of the body protecting it from microbial invasion, life would have been impossible for our earliest ancestors. But the experience of death-dealing infections throughout the world also tells us that without a properly working immune system, the same applies. How the immune system works and what it takes to control it so we can live within the world of microbes will be the subject of my next few articles.
Subscribe to:
Posts (Atom)