Uncertainty

Back in the 1960s when I worked on Apollo and wrote my first book, one thing we knew, was that the world was filled with uncertainty. Send a rocket to the moon, and no matter what you do, the uncertainties of the measurements must be continually accounted for. Burn the retro rockets at the wrong moment and one has problems.

One can estimate and project but one must include the uncertainty of one's model as well as ones measurements. The estimate is what we think now. So then try and project forward and the uncertainty starts to get larger.

So where am I going with this? Climate change. We have uncertainty in old measurements, uncertainty in models but as I try to scan the literature no one has ever included these in the results or projections. The line going forward is faultless, no error bands. Why?

Good question. Any engineer would or must include them. Scientists it seems almost deny their existence.

Merry Christmas

1.              factum est autem in diebus illis exiit edictum a Caesare Augusto ut describeretur universus orbis

2.              haec descriptio prima facta est praeside Syriae Cyrino

3.              et ibant omnes ut profiterentur singuli in suam civitatem

4.              ascendit autem et Ioseph a Galilaea de civitate Nazareth in Iudaeam civitatem David quae vocatur Bethleem eo quod esset de domo et familia David

5.              ut profiteretur cum Maria desponsata sibi uxore praegnate

6.              factum est autem cum essent ibi impleti sunt dies ut pareret

7.              et peperit filium suum primogenitum et pannis eum involvit et reclinavit eum in praesepio quia non erat eis locus in diversorio

8.              et pastores erant in regione eadem vigilantes et custodientes vigilias noctis supra gregem suum

9.              et ecce angelus Domini stetit iuxta illos et claritas Dei circumfulsit illos et timuerunt timore magno

10.          et dixit illis angelus nolite timere ecce enim evangelizo vobis gaudium magnum quod erit omni populo

11.          quia natus est vobis hodie salvator qui est Christus Dominus in civitate David

12.          et hoc vobis signum invenietis infantem pannis involutum et positum in praesepio

13.          et subito facta est cum angelo multitudo militiae caelestis laudantium Deum et dicentium

14.          gloria in altissimis Deo et in terra pax in hominibus bonae voluntatis

15.          et factum est ut discesserunt ab eis angeli in caelum pastores loquebantur ad invicem transeamus usque Bethleem et videamus hoc verbum quod factum est quod fecit Dominus et ostendit nobis

16.          et venerunt festinantes et invenerunt Mariam et Ioseph et infantem positum in praesepio

17.          videntes autem cognoverunt de verbo quod dictum erat illis de puero hoc

18.          et omnes qui audierunt mirati sunt et de his quae dicta erant a pastoribus ad ipsos

19.          Maria autem conservabat omnia verba haec conferens in corde suo

20.          et reversi sunt pastores glorificantes et laudantes Deum in omnibus quae audierant et viderant sicut dictum est ad illos

1 And it came to pass in those days that a decree went out from Caesar Augustus that all the world should be registered.

2 This census first took place while Quirinius was governing Syria.

3 So all went to be registered, everyone to his own city.

4 Joseph also went up from Galilee, out of the city of Nazareth, into Judea, to the city of David, which is called Bethlehem, because he was of the house and lineage of David,

5 to be registered with Mary, his betrothed wife, who was with child.

6 So it was, that while they were there, the days were completed for her to be delivered.

7 And she brought forth her firstborn Son, and wrapped Him in swaddling cloths, and laid Him in a manger, because there was no room for them in the inn.

8 Now there were in the same country shepherds living out in the fields, keeping watch over their flock by night.

9 And behold, an angel of the Lord stood before them, and the glory of the Lord shone around them, and they were greatly afraid.

10 Then the angel said to them, “Do not be afraid, for behold, I bring you good tidings of great joy which will be to all people.

11 For there is born to you this day in the city of David a Savior, who is Christ the Lord.

12 And this will be the sign to you: You will find a Babe wrapped in swaddling cloths, lying in a manger.”

13 And suddenly there was with the angel a multitude of the heavenly host praising God and saying:

14 “ Glory to God in the highest, And on earth peace, goodwill toward men!

15 So it was, when the angels had gone away from them into heaven, that the shepherds said to one another, “Let us now go to Bethlehem and see this thing that has come to pass, which the Lord has made known to us.”

16 And they came with haste and found Mary and Joseph, and the Babe lying in a manger.

17 Now when they had seen Him, they made widely^[d] known the saying which was told them concerning this Child.

18 And all those who heard it marveled at those things which were told them by the shepherds.

19 But Mary kept all these things and pondered them in her heart.

20 Then the shepherds returned, glorifying and praising God for all the things that they had heard and seen, as it was told them.

Eleven Years Old

We have been at this for eleven years. Back in 2008 the driver was initially the economy. Not so much now. Then it became healthcare, still is to some degree.

Over the years we have commented on things as diverse as cancer and bees, squirrels and yield curves. Overall some observations are worthy or note.

Politics is Off Limits: Politics as a topic is a swamp, not just the people. No matter what one says it tends to get other aggravated.

Religion is an Open Topic: I never would comment on John Paul II nor Benedict. The current fellow however seems to evoke continued commentary. Why? I suspect he is a closet Marxist but that is the opinion of an American.

Economics: The more I study it and its application the more I am convinced that it is a useless area of endeavor. Civil Engineers build bridges, Economists tell stories.

Cancer: In the past eleven years we have seen monumental advancements in treatment. However what has become clear is that each step forward tends to open doors or more questions and new insights. It appears as if it were and endless process. Yet if one wants to have great challenges with fantastic payoffs, try this area, the world really does not need another App!

Telecommunications: Despite the hype, the industry has consolidated into a duopoly. Technology in terms of 5G really is a natural progression of what I had projected some thirty years ago. It still has a way to go but it is getting there. Wireless will dominate because getting fiber to homes, despite what many of the unknowing attorneys state is very hard, politically.

Health Care: I spent much time examining health care.  Nothing has changed and Obamacare just kind of flopped. Universal health care is essential but it should be akin to auto insurance. However there are so many entrenched players that anything will take forever.

Obesity: This will be the most costly element in our society. Admittedly some 1-5% is genetic but given the explosion of self induced obesity that percent will drop.

You Can't Make This Up!

Back in the mid 60s I worked at the Instrumentation Lab at MIT on Apollo and other programs. I was responsible for elements of the Navigation system, getting things in the right place. Our on board computer had a 64K memory, yep 64K.

Now Boeing seems in my opinion to have been filled with incompetents. The most recent is sending a launch into the wrong orbit. As the NY Times notes:

The Starliner test flight, which was intended to test the automated systems and did not carry any astronauts, ended up in the wrong orbit. The mission will now be cut short, without docking at the International Space Station and likely delaying plans that are already a couple of years behind schedule....The first test of Starliner, built by Boeing’s space and defense division, was postponed multiple times this year. The Atlas 5 performed as designed, placing the capsule on an elliptical trajectory. The capsule itself was to make a final maneuver that would shift the orbit from elliptical to circular and allow it to meet up with the International Space Station on Saturday. But somehow, the spacecraft’s clock was set to the wrong time, and a flawed thruster burn pushed the capsule into the wrong orbit.

Yep, indeed, they set the clock wrong! Can't blame the Chinese for this one, nor the Russians, nor the Ukrainians.

First, in my opinion you must rid the company of its current management, hire competent people, and then manage the program. We did that more than half a century ago. Why not now!

Unintended Consequences

With the many new cancer therapeutics coming almost daily it is being discovered that some of these check certain deficiencies and evoke others. In a recent Science piece the authors note:

Russo et al. found that human CRC cell lines that were treated with EGFR or BRAF inhibitors down-regulated the expression of high-fidelity DNA repair proteins and increased that of error-prone DNA repair proteins, which may both increase mutation rates. Using reporter assays, they further showed that the fidelity of DNA mismatch repair (MMR) and homologous recombination (HR) repair systems were impaired and that DNA damage increased during drug treatment. Genetic analysis of cell lines that had been exposed to these inhibitors revealed subclonal mutations in dinucleotide repeats, which are characteristic of defective MMR. In contrast to other cancer mutational processes—such as genetically encoded HR or MMR defects that lead to persistent mutation acquisition or overexpression of the APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) DNA cytidine deaminases, which generates mutational bursts—the mutagenesis program identified by Russo et al. was tightly coupled to drug exposure and ceased after drug removal. This study demonstrates that nongenotoxic targeted oncogene pathway inhibitors can promote a temporally restricted increase in mutability by switching from high-fidelity to error-prone DNA repair. Adaptive mutagenesis is a mechanism described in bacteria that increases the mutation rate in response to cell stress. This is triggered by a cell-stress signaling pathway that activates error-prone DNA double-strand break repair and it is accompanied by suppression of MMR. Adaptive mutagenesis increases the probability of generating mutations that enable evolutionary adaptation of unicellular organisms to new environments. On the basis of the pronounced similarities of drug-induced mutagenesis in CRC and adaptive mutagenesis in bacteria, Russo et al. explored whether the mammalian target of rapamycin (mTOR) pathway, a major stress signaling pathway in humans, controls drug-induced mutagenesis in cancer cells. mTOR signaling was indeed inactivated by drug treatment, but inhibiting the mTOR pathway alone did not phenocopy the changes in DNA repair protein expression. The trigger of drug-induced mutagenesis in CRC cells is therefore either more complex or different from that in bacteria.

 This is not at all unexpected. Indeed this is a clear suggestion that any single genetic control can and is adaptively bypassed. Initial control may be effected but it will be essential to treat many cancers as chronic diseases as they move from genetic change to genetic change. 

The challenge going forward will be to detect and address these changes in some dynamic basis. One suspects that non-invasive liquid biopsies may be effective.

From the Past

Congress has from time to time, and unfortunately too frequently, attacked individuals based upon their gross misunderstandings. I recall the most famous case from The Scientist:

The Dingell subcommittee has focused specifically on a disputed 1986 paper published in Cell (vol. 45, pages 247-259) and coauthored by David Baltimore, a Nobel laureate. Two university reviews and an official NIH investigation of the paper agree that certain data were misinterpreted but not intentionally misrepresented. All agree that the paper is an example of scientific error, not fraud.
This important distinction is lost on Dingell. At the May hearings, Dingell stressed his interest in preventing the waste of taxpayers' money on "faked" research. He has implied that a composite autoradiograph in the paper was a "fabrication," despite the authors' explanation that composites are commonly used. Dingell's obvious bias has alarmed scientists and his own colleagues. Reps. Norman Lent (R-N.Y.) and Alex McMillan (R-N.C.) felt compelled to set the record straight. They stressed the NIH panel's conclusion that no evidence of fraud or misconduct was found. Lent also expressed misgivings about Dingell's aggressive prosecutorial style and the growing impression that Baltimore was being singled out for harassment. He cautioned against "misguided attacks and public efforts to discredit our best and brightest." But this caution fell on deaf ears. Dingell bluntly greeted Baltimore and his colleagues by saying he had concerns about their integrity. After hearing their testimony, Dingell accused the authors of not being forthright.

Prof Baltimore, a Nobel Prize winner, was in the midst of solving the issue related to stemming the AIDS epidemic. Everything came to a halt as people had to genuflect to the Congressperson. The question may be asked: How many perished due to this unfounded delay?  How many lives were scrambled as a result. Some of us remember quite well. "Have you no shame?"

From Encyclopedia.com we have the following:

After David Baltimore, Nobel laureate and coauthor of the infamous Cell paper, locked horns with Congressman Dingell while defending Imanishi-Kari, Dingell vowed, "I'm going to get that son of a bitch. I'm going to get him and string him up high." From this scientific vantage point, Dingell embarked on a witch-hunt that many later compared to the workings of McCarthy in his time. Like McCarthy, he had the power of the government at his side, and immunity as a member of Congress. This meant that Dingell could circumvent the law and access information that was personal and confidential, and completely irrelevant to the case he was "investigating." In one instance, according to Dr. Bernadine Healy, director of NIH between 1991 and 1993, Dingell's committee accessed medical information in the personnel records of an accused scientist.

This says enough.

Mucus: The Good, the Bad and the Ugly

Mucus has generally been thought of as a nasty thing. Dripping noses, slimy substance etc. However, in a recent NIH piece there is a significant discussion of its complex and efficacious work[1]. As Dr. Collins notes:

Mucus covers the moist surfaces of the human body, including the eyes, nostrils, lungs, and gastrointestinal tract. In fact, the average person makes more than a liter of mucus each day! It houses trillions of microbes and serves as a first line of defense against the subset of those microorganisms that cause infections. For these reasons, NIH-funded researchers, led by Katharina Ribbeck, Massachusetts Institute of Technology, Cambridge, are out to gain a greater understanding of the biology of healthy mucus—and then possibly use that knowledge to develop new therapeutics.

The author concluded:

The researchers found that in the presence of glycans, P. aeruginosa was rendered less harmful and infectious. The bacteria also produced fewer toxins. The findings show that it isn’t just that microbes get trapped in a tangled web within mucus, but rather that glycans have a special ability to moderate the bugs’ behavior. The researchers also have evidence of similar interactions between mucus and other microorganisms, such as those responsible for yeast infections. The new study highlights an intriguing strategy to tame, rather than kill, bacteria to manage infections. In fact, Ribbeck views mucus and its glycans as a therapeutic gold mine. She hopes to apply what she’s learned to develop artificial mucus as an anti-microbial therapeutic for use inside and outside the body. Not bad for a substance that you might have thought was nothing more than slimy stuff.

One of the referred authors has noted:

A slimy, hydrated mucus gel lines all wet epithelia in the human body, including the eyes, lungs, and gastrointestinal and urogenital tracts. Mucus forms the first line of defence while housing trillions of microorganisms that constitute the microbiota1. Rarely do these microorganisms cause infections in healthy mucus1, suggesting that mechanisms exist in the mucus layer that regulate virulence. Using the bacterium Pseudomonas aeruginosa and a three-dimensional (3D) laboratory model of native mucus, we determined that exposure to mucus triggers downregulation of virulence genes that are involved in quorum sensing, siderophore biosynthesis and toxin secretion, and rapidly disintegrates biofilms—a hallmark of mucosal infections. This phenotypic switch is triggered by mucins, which are polymers that are densely grafted with O-linked glycans that form the 3D scaffold inside mucus. Here, we show that isolated mucins act at various scales, suppressing distinct virulence pathways, promoting a planktonic lifestyle, reducing cytotoxicity to human epithelia in vitro and attenuating infection in a porcine burn model. Other viscous polymer solutions lack the same effect, indicating that the regulatory function of mucin does not result from its polymeric structure alone. We identify that interactions with P. aeruginosa are mediated by mucin-associated glycans (mucin glycans). By isolating glycans from the mucin backbone, we assessed the collective activity of hundreds of complex structures in solution. Similar to their grafted counterparts, free mucin glycans potently regulate bacterial phenotypes even at relatively low concentrations. This regulatory function is likely dependent on glycan complexity, as monosaccharides do not attenuate virulence. Thus, mucin glycans are potent host signals that ‘tame’ microorganisms, rendering them less harmful to the host.

This has been generally thought to be the case but this closer examination opens doors to understanding perhaps how to use mucus as a therapeutic and/or preventive agent.

A second referred to article by Co et al notes:

Mucus is a biological gel that lines all wet epithelia in the body, including the mouth, lungs, and digestive tract, and has evolved to protect the body from pathogenic infection. However, microbial pathogenesis is often studied in mucus-free environments that lack the geometric constraints and microbial interactions in physiological three-dimensional mucus gels. We developed fluid-flow and static test systems based on purified mucin polymers, the major gel-forming constituents of the mucus barrier, to understand how the mucus barrier influences bacterial virulence, particularly the integrity of Pseudomonas aeruginosa biofilms, which can become resistant to immune clearance and antimicrobial agents. We found that mucins separate the cells in P. aeruginosa biofilms and disperse them into suspension. Other viscous polymer solutions did not match the biofilm disruption caused by mucins, suggesting that mucin-specific properties mediate the phenomenon. Cellular dispersion depended on functional flagella, indicating a role for swimming motility. Taken together, our observations support a model in which host mucins are key players in the regulation of microbial virulence. These mucins should be considered in studies of mucosal pathogenesis and during the development of novel strategies to treat biofilms.

This appears to have been a further proof of the observations.

Biofilms often can get established on various bodily surfaces. As noted in McGarty (2016):

Biofilms present a challenge to any system which processes and distributes fluids across uncontrolled environments. This is particularly the case in the deployment and operations of public drinking water systems. The biofilm is the result of the colonization and extension of micro-organisms which adhere to the surfaces and in turn create a colony of more micro-organisms and the agglomeration of microbiological products in an extracellular matrix producing and ever increasing colony of microorganisms which result in impairments to the flow of the water and putatively could result in significant contamination of the water as well. In this paper we examine the issue of the creation and sustaining of biofilms as a function of surface roughness. It has been demonstrated that the application of nano Se or the application of lipase to create and equivalent nano roughness can act as a bacteriostatic environment and deter the growth of bacteria. The explanation of this phenomena has been presented in a multiplicity of ways all having substantial difficulties. At one extreme one uses the concept of surface energy in terms of Gibbs free energy. This assume a large scale phenomenon and fails to adequately account for the detailed physics of adhesion. At the other extreme we have the DLVO model which includes a combination of van der Waals forces along with dual barrier forces creating double energy catching levels, one for reversible and one irreversible. However, it appears that all such models are deficient. We examine these models, and make some observations that may assist in a process leading to some clarity. We also present this in the context of biofilm control for potable water systems, a significant problem.

Thus, biofilms seem to be inhibited by mucins, and the benefit may be extensive. The next issue is what initiates mucus? As Hopkins has noted:

Chronic rhinosinusitis includes a heterogeneous group of conditions with differing pathophysiologies. Two main subgroups are described: with and without nasal polyps. Chronic rhinosinusitis without nasal polyps may be idiopathic or odontogenic or may be caused by immunodeficiency, vasculitis, or other autoimmune conditions. The majority of cases of chronic rhinosinusitis with nasal polyps are idiopathic but may also occur as part of genetic, metabolic, or immunologic diseases. The majority of white patients with chronic rhinosinusitis with nasal polyps have a type 2 pattern of inflammation, characterized by eosinophilia and elevated levels of interleukin-4, interleukin-5, and interleukin-13 cytokines. This finding may not apply to other racial groups, but further study is required.  

Thus mucus in the nasal sinuses, a major site of such, protective of many infections, may be over-activated by polyps, which in a sense are neoplasia in the cavity, as well as by other irritations such as dental changes irritating the basal cilia of the sinus, a mechanical or even thermal irritant and the response thereto.

It is interesting to examine this common phenomenon as a disease inhibitor and preventive.

References

1.     Co et al, Mucins trigger dispersal of Pseudomonas aeruginosa biofilms, npj Biofilms Microbiomes 4, 23 (2018)

2.     Hopkins, Chronic Rhinosinusitis with Nasal Polyps, NEJM, V 381, July 4, 2019

3.     Lai et al, Micro- and macrorheology of mucus, Adv Drug Deliv Rev. 2009 February 27; 61(2): 86–100

4.     McGarty, Biofilm Growth and Infiltration, https://www.researchgate.net/publication/301803414_Biofilm_Growth_and_Infiltration

5.     Shale and Ionescu, Mucus hypersecretion: a common symptom, a common mechanism?, Eur Respir J 2004, 23, 797-798

6.     Wheeler et al, Mucin glycans attenuate the virulence of Pseudomonas aeruginosa in infection, Nature Microbiology volume 4, pages2146–2154, 2019

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[1] https://directorsblog.nih.gov/2019/12/19/how-mucus-tames-microbes/

Shocking but Expected

Since we wrote the tie in between Obesity Type 2 Diabetes and Cancer some ten years ago there has been a continuing drum beat that it is solely genetic and a disease not a controllable human state. Now NEJM notes:

The findings from our approach suggest with high predictive accuracy that by 2030 nearly 1 in 2 adults will have obesity (48.9%; 95% confidence interval [CI], 47.7 to 50.1), and the prevalence will be higher than 50% in 29 states and not below 35% in any state. Nearly 1 in 4 adults is projected to have severe obesity by 2030 (24.2%; 95% CI, 22.9 to 25.5), and the prevalence will be higher than 25% in 25 states. We predict that, nationally, severe obesity is likely to become the most common BMI category among women (27.6%; 95% CI, 26.1 to 29.2), non-Hispanic black adults (31.7%; 95% CI, 29.9 to 33.4), and low-income adults (31.7%; 95% CI, 30.2 to 33.2).

 They conclude:

We project that given current trends, nearly 1 in 2 U.S. adults will have obesity by 2030, and the prevalence will be higher than 50% in 29 states and not below 35% in any state — a level currently considered high. Furthermore, our projections show that severe obesity will affect nearly 1 in 4 adults by 2030 and become the most common BMI category among women, black non-Hispanic adults, and low-income adults.

We would project that the cost of the obesity epidemic will result in a collapse of our health care system. Diseases from kidney failure and cancer, cardiac diseases, oracular diseases, and various other chronic and acute disorders resulting from this will create an explosive pandemic. The cause is simple, overeating. Recent work by Roden and Schulman noted the details of T2 diabetes and obesity.

The solution must be an attempt to put a price on obesity. In a sense obesity is more of a threat to humanity than global warming, at least in the short term. It is possible that the sequellae from obesity can cause a major economic and social collapse.

Roden and Shulman, The Intehrative Biology of Type 2 Diabetes, Nature, Vol 576, 5 Dec 2019.

Meeting of the Witches

First Witch

When shall we three meet again?

In thunder, lightning, or in rain?

Second Witch

When the hurly-burly’s done,

When the battle’s lost and won.

Third Witch

That will be ere the set of sun.

First Witch

Where the place?

Second Witch

Upon the heath.

Third Witch

There to meet with ........