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Josh: This isn’t a field I’m that familiar with, but is it known how the baby’s immune system uses the antibodies provided by the mother’s milk? How does it stimulate the baby’s cells to produce the same anti-bodies? The mention of the clathrin coat not being completely shed is particularly interesting. Either their observations were flawed, other researchers never noticed that the coat was not completely shed, or this is a special case where the coat is just not completely shed.
The transportation of antibodies from a mother to her newborn child is vital for the development of that child’s nascent immune system. Those antibodies, donated by transfer across the placenta before birth or via breast milk after birth, help shape a baby’s response to foreign pathogens and may influence the later occurrence of autoimmune diseases. Images from biologists at the California Institute of Technology (Caltech) have revealed for the first time the complicated process by which these antibodies are shuttled from mother’s milk, through her baby’s gut, and into the bloodstream, and offer new insight into the mammalian immune system.
Newborns pick up the antibodies with the aid of a protein called the neonatal Fc receptor (FcRn), located in the plasma membrane of intestinal cells. FcRn snatches a maternal antibody molecule as it passes through a newborn’s gut; the receptor and antibody are enclosed within a sac, called a vesicle, which pinches off from the membrane. The vesicle is then transported to the other side of the cell, and its contents–the helpful antibody–are deposited into the baby’s bloodstream.
Pamela Bjorkman, Max Delbrück Professor of Biology at Caltech and an investigator with the Howard Hughes Medical Institute, and her colleagues were able to watch this process in action using gold-labeled antibodies (which made FcRn visible when it picked up an antibody) and a technique called electron tomography. Electron tomography is an offshoot of electron microscopy, a now-common laboratory technique in which a beam of electrons is used to create images of microscopic objects. In electron tomography, multiple images are snapped while a sample is tilted at various angles relative to the electron beam. Those images can then be combined to produce a three-dimensional picture, just as cross-sectional X-ray images are collated in a computerized tomography (CT) scan.
“You can get an idea of movement in a series of static images by taking them at different time points,” says Bjorkman, whose laboratory studies how the immune system recognizes its targets, work that is offering insight into the processes by which viruses like HIV and human cytomegalovirus invade cells and cause disease.
The electron tomography images revealed that the FcRn/antibody complexes were collected within cells inside large vesicles, called “multivesicular bodies,” that contain other small vesicles. The vesicles previously were believed to be responsible only for the disposal of cellular refuse and were not thought to be involved in the transport of vital proteins.
The images offered more surprises. Many vesicles, including multivesicular bodies and other more tubular vesicles, looped around each other into an unexpected “tangled mess,” often forming long tubes that then broke off into the small vesicles that carry antibodies through the cell. When those vesicles arrived at the blood-vessel side of the cell, they fused with the cell membrane and delivered the antibody cargo. The vesicles also appeared to include a coat made from a molecule called clathrin, which helps form the outer shell of the vesicles. Researchers previously believed that a vesicle’s clathrin cage was completely shed before the vesicle fused with the cell membrane. The new results suggest that only a small section of that coating is sloughed off, which may allow the vesicle to more quickly drop its load and move on for another.
“We are now studying the same receptor in different types of cells in order to see if our findings can be generalized, and are complementing these studies with fluorescent imaging in live cells,” Bjorkman says. “The process of receptor-mediated transport is fundamental to many biological processes, including detection of developmental decisions made in response to the binding of hormones and other proteins, uptake of drugs, signaling in the immune and nervous systems, and more. So understanding how molecules are taken up by and transported within cells is critical for many areas of basic and applied biomedical research,” she adds.
Josh: I wrote about this same enzyme earlier in the year, but this is a new paper on it. The earlier study reported the NMR structure of the enzyme, but this study focused on the X-ray crystal structure. The authors note “In the X-ray structure, these APOBEC3G active-site loops [that are directly involved in substrate binding] form a continuous ‘substrate groove’ around the active centre. The orientation of this putative substrate groove differs markedly (by 90 degrees) from the groove predicted by the NMR structure”.
Humans have a built-in weapon against HIV, but until recently no one knew how to unlock its potential.
A study published online by the journal Nature reveals the atomic structure of this weapon – an enzyme known as APOBEC-3G – and suggests new directions for drug development.
APOBEC-3G is present in every human cell. It is capable of stopping HIV at the first step of replication, when the retrovirus transcribes its RNA into viral DNA.
The study’s authors, led by Xiaojiang Chen of the University of Southern California, were able to show the atomic structure of the active portion of APOBEC-3G.
The discovery suggests how and where the enzyme binds to the viral DNA, mutating and destroying it.
“We understand how this enzyme can interact with DNA,” said Chen, a professor of molecular and computational biology at USC. “This understanding provides a platform for designing anti-HIV drugs.”
If APOBEC-3G works so well, why do people get AIDS? Because the HIV virus has evolved to encode the protein Vif, known as a “virulence factor,” that blocks APOBEC-3G.
With APOBEC-3G out of the way, the RNA of the HIV virus can be successfully transcribed to viral DNA, an essential step for infection and for producing many more HIV viruses.
Chen said his group’s research offers important clues on where Vif binds to APOBEC-3G. The knowledge could be used to design drugs that would prevent Vif from binding and allow APOBEC-3G to do its job, Chen said.
That would unlock humans’ innate ability to fight HIV.
“We were born with it, and it’s there waiting,” Chen said.
In addition to fighting HIV, APOBEC-3G can inhibit the Hepatitis B virus. Other members of the APOBEC family serve important roles in antibody maturation, fat metabolism and heart development.
Mapping the structure of APOBEC-3G at the atomic level is a goal that “has been sought after worldwide because of its significance,” Chen said.
Statistics and disease risks are invented for this exercise!
1% of people will have Hubbub Disease by age 70. Up to 80% of people with Disease will get positive HEBOT mutation tests. 9.6% of people without Hubbub Disease will also get positive HEBOT mutation tests. A patient had a positive HEBOT mutation test in genomic screening. What is the probability that patient will have Hubbub Disease by age 70?
The correct answer is about 68.1%. If you got this, good job, you’re qualified, click here.
If you got a different answer or need an explanation, click here.
note: updated to be even more nonsensical to avoid confusion. Thanks, neandrothal.
Josh: For those interested, I wrote a paper for a class 2 years ago applying Bayes Theorum to medicine. It’s moderately related to the post.
I feel rationally obligated to distrust anything self-promoted as “Web 2.0″ in the same way I distrust statistics tacked with some vague quality like “40% more kick!” It’s as if those tacks are nailed right in to the body of Science itself, and I feel its pain. I feel it. Nonetheless, as I can be trusted to regularly grease the world economy $3.29 USD every late night caffeine sortie at the 7/11 across the street, there’s nothing physically impairing me from both believing that savant-like super powers wrought at the heights of all human achievement will give me more energy and help my money work for me while simultaneously loathing the idiocy that same electric blue sans-serif salespitch will sap my attention and wallet if only they could brand their goods with some impressive looking number. You know, like science and stuff. It’s as if behind the decimal point lies a secret realm where mere digits morph into runes of ancient magic, drawing the true, terrible power of tenth decimal place into a furious ball of psychogenic witchcraft burned by marketers into every web service and sugary softdrink for their duplicitous intent of short-circuiting my brain —not impairing rational thought itself, merely its ability to keep my money in my pocket and my faith to myself. It’s a near optimal function to illicit self-disgust.
Hey, I have an idea for a radical new financial instrument, it’s called: the hundredth decimal place. With marketing that tight, I may as well be selling soma to cashiers, right? It’s a brave new world out here on the interwebs, and I’ve got the confidence interval for you right anterior to my magic symbol “%.”
What was I talking about? Oh right.
Bertalan Meskó of Science Roll has officially launched Webicina, a service that sells education material and consulting to doctors about using the Internet and helps them launch a website. Regarding doctor blogs: Dr. Steven Murphy said today about his doctor blog, Gene Sherpas: “all they good things that happened to me this year have come from my blog.” Webicina is a valuable service that I endorse that will help your professional career as a medical professional —and it’s fun, too.
Here’s a funny picture of a dancing little boy wearing decimal point on his shirt. I want you think of it every time somebody uses a decimal point or any other statistic without justifying their significant digits or measurement confidence.
PS: I never want to see the expression “Web 2.0″ ever again, and God help you if I see anybody try to peddle *shutter* “Web 3.0.” To a lesser extent, that goes for that “59.5%” penetrance estimate for g2019s LRRK2 report at 23andMe, too.
Story: genetic councilors are people you pay to console you about the results of a genetic test report to make you feel better and help you make rational decisions about your health when your reasoning may be distorted by emotional distress. If that’s a service you want, buy a couple hours from a genetic councilor.
Computers can never provide human consolation, no matter how excellent and rational their reports. Doctors and scientists feel that councilor work is beneath them, nor are they typically any good at it, nor do they realistically have the capacity to do it. However, scientists tend to be much better at analyzing complex information, and medical doctors can use reports to better synthesize a general understanding of your health to recommend medical action not already prescribed by obvious standard practice.
For example, I would probably make an excellent systems biologist, but the world’s worst genetic councilor. “Beep-bop-boop, you have Huntington’s. Don’t have children.” See? A that’s perfectly rational statement, but it’s illustrative why genetic councilors are important.
But how many people in health care today can read the following expression? Or write it? Or tell me what it means not just clinically, but biologically?
Steve at Gene Sherpas reports systemic medical insurance fraud in many top institutions providing genetic health care. Clinics are billing as if doctors are seeing patients, but only genetic councilors ever see the patient. “But I have a solution,” Steve exclaims. “The answer: Nurse Geneticists.” He continues, “Call your insurer. Demand to be seen by a physician or physician extender… Why should you demand this service? It will put stress on the broken system. To repair that system, we must first rebuild the foundation.”
Be careful what you wish for, Steve. Systemic abuses like this that risk high liability for meager reimbursements suggest a deeper problem than petty greed. Either the system has collectively concluded that genetic councilors are sufficient to perform the service and that they are following procedure “in spirit,” or they are desperate to keep unsustainably high margins and must resort to abuse to protect them. I suspect some of both.
The problem genetic councilors is political. Genetics used to be called “eugenics,” literally, “the science of the well born.” After World War 2 and the civil rights movement, it became taboo to socially direct population growth and the practice of human genetics was legally and institutionally castrated. Today’s “non-directive” genetic councilors are the progeny of this purposefully impotent profession.
However, scientific progressed. We discovered DNA. We learned molecular biology. We sequenced the human genome. Suddenly, the members of this small, marginalized profession were both keepers of the hereditary taboo and keepers of the code of life.
So, that’s what genetic councilors are: specialized nurses who aren’t supposed to touch you or tell you to do anything, but who have become the hands, eyes, voices, and smiles of this newest, most vital paradigm of medicine. So long as people need a warm consult and an authoritative opinion, there will be a place for you.
That’s probably the nicest thing I’ve ever said on this website.
Old medicine was dead the day you adopted “evidence-based medicine.”
There, I feel better.
What medicine? Scientific medicine. Mathematical medicine. Mechanized medicine. Terabytes of cited hyper-linked studies compiled into statistically weighted results medicine. Input symptoms and test results, output diagnosis and CPT medical billing code medicine.
Beep-bop-boop you’re dead, have a nice day. (the industry, the not patient, who of this ethnicity and phenotypic profile can expect 55.2% efficacy and 82.1% efficiency over control who received traditional care)
And no other medicinal discipline is as scientific mechanical as genetics. How mechanized? Watch, I’ll make a free clinical diagnosis machine prototype right here on my blog. Yes, not a risk report, a real diagnosis. Just input your genome sequence service account login, and my machine download your genome securely from your sequence service and practice medicine.
Would you like to subscribe to our genetic counseling service? Now, only $89.95 a month!
Don’t have a sequence? Sequence with us! Now only $999.
Enter your credit card and you gmail account and password below.
The real question is: are you dead like “mama bell” AT&T, the century-old institution that suddenly crumbled and consolidated. Or, are you dead like the newspaper, a slow and humiliating decline of consolation and standards of with only a few prestigious survivors?
So, OK, some genetic councilors will go back to school for additional nursing or physician assistant credentials, and some genetic centers may begin staffing appropriately if they can afford to despite the gross waste in health care already. But realistically, I’m supposed to believe that genetically-trained nurses are the solution? A new, more expensive kind of medical profession for which academic and institutional support will take decades to mature? When America is straining under grossly inflated health care costs during an economic depression? Meanwhile, I can hypothetically write a Python script to practice medicine and hire a perky and well-educated Indian genetic councilor to answer phones now for cheap?
Have fun breaking the system, Dr. Murphy. It needs to be broken, sure, but I’ll meet you down here at the bottom.
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