Bad Design in Biochemistry

"Given that biliverdin is water-soluble and readily excreted, why should mammals have evolved the energetically expensive, potentially toxic, and apparently unnecessary capacity to reduce biliverdin?" — David Baranano, Mahil Rao, Christopher Ferris and Solomon Snyder, PNAS, 2002¹

"Anyone with experience in manufacturing would agree that a production process with a 30 percent defect rate needs much improvement." — Fazale Rana, The Cell's Design, 2008²

Summary

The parent article, Arguments from Bad Design, sets the test: say exactly what is alleged, name the task and the cost, and compare a feasible alternative. This article runs that test on the cases below anatomy, where the charge is wasted energy, a toxic by-product, or a high error rate.

Who makes the charge. Edward Behrman, George Marzluf and Ronald Bentley argued in 2004 that some pathways contain "inefficiencies based on unnecessary steps" and favour "unfinished evolution rather than intelligent design."³ Only their abstract could be read. Fazale Rana, a biochemist at the old-earth ministry Reasons to Believe, states each charge himself before answering it in The Cell's Design.² His answer in each case is a second use.
The futile cycle. Two enzymes undo each other's work, which Berg's Biochemistry says "was regarded as an imperfection in metabolic control."⁴ Its main use, amplifying control signals, holds. Its heat use is weak even in bumblebees.⁵ Metabolic heat in general is not waste: about half of glucose's energy is caught as ATP, and the rest warms the body.
Bilirubin. Mammals spend energy turning a pigment that is easy to excrete into an insoluble, toxic one. Bilirubin is a strong antioxidant in the test tube and in cells.⁶ But the recycling loop Rana relies on was doubted by its own antioxidant camp,⁷ and the largest genetic test found no heart benefit.⁸ The use is real; that it pays for newborn jaundice is unproven.
Uric acid. Rana writes that "Except for primates, all mammals" break uric acid down further.² Many monkeys keep a working enzyme, while humans and apes carry the gene with stop codons in it.⁹ His answer, that high urate prevents cancer, came from a 1981 hypothesis.¹⁰ A review of 136 outcomes found a clear role for urate only in gout and kidney stones.¹¹ This is a broken gene, which a creation model can read as damage after the Fall.
Proteins discarded at birth. Rana's "Roughly 30 percent" of new proteins scrapped² was revised by its own lab to "closer to 25%," another lab found "at most, a few percent," and part of the discard is surplus parts, not defects.¹² The immune system uses the fragments, but yeast, with no such immune system, discards a similar fraction.¹² The use is real; it does not explain the rate.
RuBisCO. The carbon-fixing enzyme is slow and confuses oxygen with carbon dioxide. Rana's answer, from Tcherkez and colleagues, is that it sits near a chemical limit.¹³ A larger data set weakened their trade-off but confirmed the limit.¹⁴

Verdict: the answers hold for the futile cycle and RuBisCO, partly hold for bilirubin, overstate the purpose of discarded proteins, and fail for uric acid. Only uric acid shows a clear defect, and it is damage, which a creation model with a Fall predicts. None of the five, taken alone, decides between design and evolution.

Part 1: Who calls it bad design, and what Rana answers

The scholarly critic Rana names is a two-page letter. Its abstract reads: "We cite a number of examples from metabolic pathways that argue for unfinished evolution rather than intelligent design. In most cases these involve inefficiencies based on unnecessary steps. We also point out that molecular evolution directed by human intelligence is easy to achieve."³ The ERIC record adds that the cases are "a limited sample of inefficient situations in metabolism."³ The full letter is behind a paywall, so which pathways it names is unknown.

For uric acid, Rana cites only Stephen Jay Gould's essay on the panda's thumb, not a uric-acid source.² So for most cases the charge survives in Rana's own statement of it, and he states it fairly. On heme breakdown: "On the surface, heme degradation appears ill-conceived—something expected for a product of evolution, not for a God whose creation would stay within the well-defined lines of perfection."² On protein synthesis: "These problems challenge the notion that a Creator produced life's chemistry."²

Secular biochemists ask the same questions without any design argument in view. Baranano's question about biliverdin opens this article. Berg's textbook reports that the glycolysis cycle was once called futile.⁴ Jonathan Yewdell, who proposed the discarded-protein idea, asked of his own figure: "Are cells this wasteful?"¹⁵ Guillaume Tcherkez and colleagues called RuBisCO's performance "pitifully sluggish."¹³

Rana's reply sorts flaws three ways.² Some are real decay: "Over time, the accumulation of these damaging mutations can transform an optimally designed biochemical system into one with substandard performance."² Some are compromises: "if a system consists of finite resources and must accomplish numerous objectives, then the system must represent a compromise."² The rest are apparent flaws that dissolve with more knowledge.² He predicts that "new discoveries should yield insights that transform these biochemical aberrations into remarkable works of art."² That prediction can be scored case by case.

Part 2: The futile cycle and metabolic heat

What Rana actually defends

Glycolysis is sometimes listed as a case of wasted heat, but Rana's case is narrower. Phosphofructokinase adds a phosphate to a sugar, and fructose-1,6-bisphosphatase takes it off again, burning one ATP per turn for no net product. "The paired reactions catalyzed by phosphofructokinase and fructose 1,6-bisphosphatase are known as a futile cycle."²

He gives it two uses. The first is control. Berg's worked example runs the forward reaction at 100 and the back reaction at 90, for a net flow of 10. A 20% push each way gives 120 and 72, a net flow of 48, which is "a 380% increase in the net flux."⁴ A small signal makes a large change, which is why the textbook now calls such cycles "likely to be biologically important."⁴

The second is heat: "the cell's chemical energy is converted into heat, which helps provide organisms with necessary warmth."² The standard example is the bumblebee. In 1972 Eric Newsholme and colleagues proposed that the cycle warms a resting bee's flight muscles.¹⁶ In 2004 James Staples and colleagues measured the enzymes in North American bumblebees and concluded that the data "do not support a significant thermogenic role for the PFK/FbPase cycle."⁵ The heat use is weak. The control use carries the case, and it is enough.

Is metabolic heat waste?

No critic was found who calls body heat itself bad design, but the charge is easy to make, so it is priced here. Burning a mole of glucose releases 2,870 kJ.¹⁷ The cell catches about 30 ATP from it, a figure that replaced the older 36.⁴ Measured maxima reach 33.45.¹⁸ At about 50 kJ per ATP under cell conditions,⁴ that is 52% to 58% of the energy captured.¹⁹ The rest is released as heat.

In a warm-blooded animal that heat is the body's furnace. David Rolfe and Guy Brown estimated that about 20% of mitochondrial oxygen use in resting mammals goes to a proton leak that makes heat and no ATP.²⁰ Martin Brand adds that brown fat uses a special protein "to uncouple oxidative phosphorylation, causing adaptive thermogenesis," and that the leak may also "attenuate mitochondrial radical production."²¹ A body that turns its efficiency down when it needs warmth is not showing a defect.

Verdict: the answer holds. The futile cycle is a control device, and the heat of metabolism is used.

Part 3: Bilirubin

The charge

When red cells die, heme is opened into green biliverdin. "For birds and reptiles, the process stops here," Rana writes; "Biliverdin is water-soluble and readily excreted."² Mammals spend more energy reducing it to yellow bilirubin, which will not dissolve in water, is carried by albumin to the liver, and must have sugars added before it can leave. Rana: "mammals employ several seemingly unnecessary energy-intensive steps to convert biliverdin (a compound easily eliminated) into bilirubin (a molecule that can't be secreted)."²

The cost is real. The American Academy of Pediatrics says "More than 80% of newborn infants will have some degree of jaundice," and defines kernicterus as "a permanent disabling neurologic condition."²² Vinod Bhutani and colleagues estimated that in 2010, 480,700 newborns worldwide had Rh disease or extreme jaundice, with 75,400 cases of kernicterus.²³ Of those 480,700, 373,300 were Rh disease, where the mother's antibodies destroy the baby's red cells. Most of that burden is Rh disease, an immune attack, not the pathway working as built.

The second use

Rana's answer is that "bilirubin is an effective antioxidant that reacts with oxygen and ROS."² That rests on good data. In 1987 Roland Stocker and colleagues, working with Bruce Ames, found that under 2% oxygen "bilirubin suppresses the oxidation more than alpha-tocopherol, which is regarded as the best antioxidant of lipid peroxidation."⁶ In 2002 Baranano and colleagues showed that "10 nM bilirubin IXα completely reverses cell death elicited by a 10,000-fold excess (100 μM) concentration of H2O2."¹ A 2002 commentary said bilirubin was "formerly dismissed as a waste product."²⁴

Three parts of Rana's account go further than the data.

The misreading. Rana writes, "Bilirubin eliminates ten thousand times its level of oxygen and ROS."² The experiment tested cell survival against hydrogen peroxide in a dish. It did not measure oxygen.
The loop. Baranano proposed that bilirubin, once oxidised, is turned back into bilirubin again and again, which would explain its power at tiny doses. Rana builds on this loop. In 2009 Stocker's own group tested it and found that making more of the enzyme "does not protect mammalian or yeast cells from hydrogen peroxide-mediated damage, thereby casting doubt on the importance of the putative BVR redox cycle."⁷ The antioxidant survives; the amplifier is in dispute.
The payoff in people. People with Gilbert syndrome carry mildly high bilirubin for life. Libor Vitek and colleagues found heart disease in 2% of 50 Gilbert subjects against 12.1% in the general population.²⁵ In the Framingham study, carriers of the high-bilirubin genotype had "approximately one third the risk" of heart disease.²⁶ But when Stefan Stender and colleagues pooled genetic studies of 14,711 cases and 60,324 controls, doubling bilirubin by genotype gave an odds ratio of 1.01, and they concluded bilirubin "is not causally associated with risk of IHD."⁸ A genetic test of this kind is harder to fool than a correlation, and it found nothing.

A second use Rana does not mention also exists. In pregnant guinea pigs, Antony McDonagh found that bilirubin crossed the placenta while biliverdin "did not appear to cross without prior reduction to bilirubin."²⁷ A fetus may need bilirubin to hand its waste to its mother. Baranano pointed out that the fetus uses a different form of the enzyme, so "the adult BVRA could not have evolved for fetal needs."¹ The placental use covers the fetus, not the adult.

Verdict: partly holds. The antioxidant is real, and a fetal use is likely. That the adult pathway's benefit outweighs its cost in newborns has not been shown. No critic has shown a mammal build that keeps both uses without the jaundice risk either.

Part 4: Uric acid

Rana's case and its first error

Humans end the breakdown of DNA and RNA building blocks at uric acid, which dissolves poorly and can form crystals in joints and kidneys. About 3.9% of US adults have gout.²⁸ Rana states the charge: "For evolutionists, the elimination of adenine and guanine in the form of uric acid is the type of evidence that makes a potent case for evolution, because it appears to be a poor design."²

His framing starts with an error. "Except for primates, all mammals further metabolize uric acid to a more soluble derivative. Evolutionary biologists think the enzymes responsible for this transformation were lost in the evolutionary process that led to primates."² Monkeys are primates, and many keep the enzyme. Masako Oda and colleagues report that "prosimians and Old World monkeys exhibit a moderate level of the enzymatic activity," while "hominoids and some New World monkeys do not show any detectable level of the activity."⁹ The baboon gene encodes a full-length enzyme.²⁹

The gene is present and broken

The human gene, urate oxidase, is still there, with stop signals in it. Xiangwei Wu and colleagues found "Two nonsense mutations at codon positions 33 and 187 and an aberrant splice site" in the human gene, and the same three in the chimpanzee.³⁰ Oda's group sequenced the gene across the apes. The stop at codon 33 "is shared by the human and the great apes," and gibbons lost the gene by a different mutation.⁹ They also found that the gene's switch was weakened before the stops appeared, "a two-step deterioration process, first in the promoter and second in the coding region."⁹

James Kratzer and colleagues rebuilt inferred ancestral forms of the enzyme in 2014. Activity falls stepwise toward the apes, and "uricase function was nearly enzymatically abolished before the pseudogenization events."³¹ Their ancestral forms and their date of about 17 million years come from a common-descent tree, which a young-earth reader will not grant. The measurement that matters here does not depend on that tree: the working enzyme exists in monkeys, and the human copy is a damaged version of it.

Rana did not say the enzyme was never there; he wrote what "Evolutionary biologists think" about its loss and moved on to defend the high urate that results.² In 2013 he gave a different answer to genes of this kind, calling shared broken genes like the vitamin C gene "common design features in the genomes of humans and the great apes."³² That page does not discuss urate oxidase, and no function for the broken human copy turned up in the sources read.

Does high urate pay for itself?

Rana's use for the high urate matches a hypothesis Bruce Ames proposed in 1981. "This compound is a potent antioxidant," he writes, and the high level will "help prevent cancer and may contribute to long human life spans," which makes gout and stones "a small price to pay."²² Ames and colleagues titled their paper "A hypothesis." In the test tube, "Urate is about as effective an antioxidant as ascorbate."¹⁰

The hypothesis has since been tested.

Xue Li and colleagues reviewed hundreds of meta-analyses and Mendelian randomisation studies covering 136 outcomes in 2017: "convincing evidence of a clear role of SUA level only exists for gout and nephrolithiasis." Nephrolithiasis means kidney stones. For cancer, people in the highest urate group had a relative risk of 1.04, with a 95% range of 0.99 to 1.08, across 456,053 people in five cohorts.¹¹¹¹ People with the highest urate had no less cancer.
The SURE-PD3 trial raised urate on purpose in 298 early Parkinson patients for up to two years, on the antioxidant rationale. Progression did not differ, and the treated group had "more kidney stones (7.0 vs 1.4 stones per 100 patient-years)."³³

Kratzer's paper notes that urate's role in oxidative stress "has been disputed,"³¹ and its favoured evolutionary story is now fat storage from fruit sugar, not antioxidant defence.³¹ Wu in 1992 had already argued that two separate losses meant "the loss of urate oxidase may have evolutionary advantages."³⁰ Whether or not the loss helped some ancestor, it is still a loss.

What the broken gene means for a creation model

A young-earth model does not need uric acid to be design. Jerry Bergman, answering Nathan Lents on the broken vitamin C gene, writes that it "is not a result of poor design, but due to one or more mutations," and "this would be expected from the Fall."³⁴ Urate oxidase fits the same reading: a working enzyme, damaged.

That reading has a cost the model must pay. Every living human carries the broken gene. So the damage must have happened early and then reached every human line. A small founding population, such as the eight people of the Flood, makes that easier, but no young-earth author was found who has worked it through for this gene. The same codon-33 stop also sits in every great ape, and the codon-187 stop and splice error are shared with the chimpanzee.³⁰ Separate creation of humans and apes needs those lesions either to arise more than once or to have been made that way, which is Rana's 2013 answer for genes of this kind. Oda found that the same kind of codon, CGA, turned into a stop again and again across the apes, and that one stop "requires multiple origins."⁹ That helps the repeat-mutation reading, but three matching lesions in one gene is a harder case than one. The Shared Genetic Errors article weighs that pattern.

Verdict: Rana's answer fails. The broken-gene reading holds, and it is a damage case, not a design case.

Part 5: Proteins discarded at birth

Where the thirty percent came from

In 1996 Yewdell and colleagues proposed that the immune system samples "defective ribosomal products (DRiPs)," and said they "are produced entropically, due to the inevitable imperfections inherent to protein synthesis or folding."³⁵ In their view the errors come first and the immune use follows. In 2000 Ulrich Schubert and colleagues reported "that DRiPs constitute upwards of 30% of newly synthesized proteins."³⁶ The wording is "upwards of," not "up to."

Rana took the figure as settled: "Roughly 30 percent of all proteins synthesized must be degraded by the cell because they are improperly made."² His answer is the immune use: "The high level of defective proteins produced by the cell allows for an efficient immune response to viral infection—the perfect plan of a Master who colors inside the lines."² Cells cut proteins into fragments and display them on class I MHC molecules, and fragments of newly made viral proteins let a killer T cell spot an infected cell early.

What the number became

The figure did not hold still.

The originating lab "revised the fraction of RDPs to closer to 25%."¹² RDPs are rapidly degraded polypeptides, the measured quantity.
Vabulas and Hartl, using a different method, "concluded that RDPs represented, at most, a few percent of total synthesis."¹²
Among human myeloma cell lines the fraction "varied between 1% and 30%."¹²
Yewdell's own summary in 2011: "The bottom line is that the RDP fraction is uncertain."¹⁵

Nor is it all defects. Yewdell's group split the rapidly degraded proteins into DRiPs and "SLiPs," and wrote that "SLiPs include excess subunits of multiprotein complexes that failing to assemble and hence, achieve a stable conformation, are treated as defective proteins."¹² McShane and colleagues found that many proteins degraded young are subunits "produced in super-stoichiometric amounts."³⁷ Making a few extra parts and scrapping the leftovers is ordinary assembly-line practice. Rana's "improperly made" is wrong for that share.

Does the immune use explain the rate?

No. Yewdell writes that the fraction of immunologically useful DRiPs "can be minute (1% of translation or less)."¹⁵ If 1% would do, the immune use cannot justify 25%. And a similarly high fraction turns up "in yeast, extending the phenomenon to a unicellular organism with no need to generate antigenic peptides."¹² Whatever sets the discard rate, it is not the immune system. The use rides on top of it. Rana's own source said as much in its title, which he cites: Schild and Rammensee's "Perfect Use of Imperfection."²

Verdict: the immune use is real and clever, and it answers "this waste is useless." It does not answer "this waste is too high," because the rate is uncertain, partly not waste, and present in cells with no immune system.

Part 6: RuBisCO

RuBisCO fixes nearly all the carbon in the living world. Tcherkez, Graham Farquhar and T. John Andrews wrote in 2006 that plants invest heavily in the enzyme "to counter the enzyme's pitifully sluggish catalytic performance," and that its "tendency to confuse the substrate of photosynthesis, CO2, with the product, O2, saddles all aerobic photosynthetic organisms with energy-wasting photorespiration."¹³ Rana notes that the enzyme "has acquired the reputation among biochemists as a wasteful enzyme."²

Rana's answer is their conclusion: "most Rubiscos may be near-optimally adapted to their different gaseous and thermal environments."¹³ That view rested on about 20 organisms. In 2019 Avi Flamholz and colleagues re-examined about 300. The trade-off between speed and choosiness was "substantially attenuated," yet the measured values "display extremely limited variation, consistent with a view of Rubisco as a highly constrained enzyme." More than 95% of turnover rates fall between 1 and 10 per second, and none exceeds 15.¹⁴ The exact trade-off Rana relied on weakened, while the hard limit he pointed to held.

The cost downstream can be beaten. Paul South and colleagues note that photorespiration "can reduce yields by 20 to 50% in C3 crops," and their engineered bypass raised field biomass "by >40%."³⁸ That improves the salvage pathway, not the enzyme, in a fertilised crop field rather than a wild plant's habitat.

Verdict: holds for the enzyme. The salvage pathway can be improved in crops, which Rana does not address.

Objections and responses

"A second use does not answer the charge. A designer could get the antioxidant without the jaundice." That is fair, and it is the parent article's test. The critic has to show a feasible build that keeps the uses. For bilirubin no such build has been shown, but the design side has not shown the benefit is large either. The case stays open, and this article scores it as a partial answer.
"Uric acid is one of the main antioxidants in human plasma, so the hypothesis is alive." Ames showed that it is one of "the major antioxidants in humans."¹⁰ Being present as an antioxidant and preventing disease are different claims. The tests of the second, from genetics and from a randomised trial, found gout, stones and no cancer benefit.
"Calling uric acid a broken gene concedes evolution." It concedes that this case is not design. Loss of function after the Fall is part of the young-earth model, as Bergman says. Whether the shared lesions with apes favour common descent is a separate argument, handled in Shared Genetic Errors.
"The 30% figure is dead, so the case is moot." The originating lab put the pulse-chase figure near 25% in 2014, and the best current statement is "uncertain." Neither side should build on 30%, and neither should build on zero.
"Evolution predicts kludges, so every inefficiency counts for evolution." The parent article's Part 4 shows that evolution does not predict universal bad engineering either. A tuned control loop and a near-limit enzyme fit selection as well as design. These cases score the design side's specific answers. They do not by themselves score either origin.
"Rana is an old-earth creationist. Why build on him?" His chapter is the only design-side treatment of these cases that was found, and two searches of young-earth sites found none of the uric-acid gene. His biochemistry is judged on its sources.

Issues and unanswered questions

The critics' own words. The Behrman letter was read only as an abstract. Which pathways it names, and whether it names bilirubin or uric acid, is unknown. Rana's notes 17 and 20, his uric-acid sources, could not be recovered from the unborrowable archive.org copy.
Primary papers not read in full. Schubert 2000 and Vabulas and Hartl 2005 are behind paywalls. Their figures come from their abstracts and from Yewdell's accounts, and Yewdell is a party to the dispute.
Bilirubin's balance sheet. Nobody has weighed the adult antioxidant benefit against newborn jaundice with numbers. The genetic evidence against a heart benefit is strong; benefits for other outcomes were not searched.
The urate oxidase gene and the young-earth model. No young-earth treatment of this gene was found. A model that reads it as post-Fall damage has to explain how the loss reached every human, and why three matching lesions sit in the chimpanzee.
Why cells discard what they do. Neither side has measured a speed-against-accuracy cost for protein synthesis. If faster, sloppier synthesis plus cleanup beats slower, cleaner synthesis, the discard is a trade-off. That has not been shown.
The heat arithmetic is rough. The 52% to 58% capture figure mixes a standard free energy for glucose with a cellular one for ATP.¹⁹

Verdict

Case	The charge	Rana's answer	What the evidence shows	Verdict
Futile cycle	Burns ATP for nothing	Signal control and heat	Control gain holds; heat use weak	Holds
Metabolic heat	Half of glucose energy lost	Not argued	Heat is used; brown fat makes it on purpose	Not a defect
Bilirubin	Extra steps make a toxin	Antioxidant	Real in cells; loop disputed; no causal heart benefit	Partly holds
Uric acid	Enzyme missing, gout	Antioxidant, longer life	Gene broken; monkeys keep it; no health benefit found	Fails; damage
New proteins	About 30% scrapped	Immune warning	Rate uncertain, partly surplus, same in yeast	Use real, rate unexplained
RuBisCO	Slow, confuses gases	Near-optimal compromise	Hard limit confirmed; salvage pathway improvable	Holds for the enzyme

Rana predicted that further study would turn apparent flaws into "remarkable works of art."² For the futile cycle and RuBisCO it did. For bilirubin it half did. For discarded proteins it found a use but not a reason for the rate. For uric acid it went the other way: the flaw is real, and it is damage to a working gene. A creation model with a Fall expects some cases like that, so the result is not a loss for creation. It is a reason to stop using uric acid as an example of design.

Sources

1.
Baranano, David E. et al. “Biliverdin reductase: A major physiologic cytoprotectant.” Proceedings of the National Academy of Sciences USA 99(25):16093–16098. 2002. Read from the PMC PDF. The Johns Hopkins work Rana cites. Mirror: PMC
1. 1a.
  Page 16093, introduction, left column: “Given that biliverdin is water-soluble and readily excreted, why should mammals have evolved the energetically expensive, potentially toxic, and apparently unnecessary capacity to reduce biliverdin?” ↩
2. 1b.
  Page 16093, introduction, left column: “However, the fetus expresses a distinct biliverdin reductase, BVRB, with different isomer specificity.” “Accordingly, the adult BVRA could not have evolved for fetal needs.” ↩
3. 1c.
  Page 16094: “In HeLa cells, 10 nM bilirubin IXα completely reverses cell death elicited by a 10,000-fold excess (100 μM) concentration of H2O2”. ↩
2.
Rana, Fazale. The Cell's Design: How Chemistry Reveals the Creator's Artistry. Baker Books. 2008. Rana is a biochemist at Reasons to Believe, an old-earth creationist ministry. Chapter 13, Coloring Outside the Lines, pages 245–268; notes on pages 309–312. The archive.org copy is in the printdisabled collection and cannot be borrowed; it was read paragraph by paragraph through archive.org search-inside and not stored. Printed page is leaf minus 2 throughout, from the BookReaderJSIA page map, anchored on the running heads 246 The Cell's Design on leaf 248 and 264 The Cell's Design on leaf 266, and on the index entry bilirubin, 253-54. Quotations corrected only for OCR line-break hyphens.
1. 2a.
  Page 245: “Still, most evolutionary biologists reject the notion of intelligent design, partly because of the apparent defects and faulty designs of some biochemical systems.” Page 309: Note 1 to that sentence opens See, for example, and cites Behrman, Marzluf and Bentley, Evidence from Biochemical Pathways in Favor of Unfinished Evolution Rather than Intelligent Design, Journal of Chemical Education 81 (July 2004), 1051–52. Read on leaf 311. ↩
2. 2b.
  Pages 247–266: Real decay is treated on page 247, apparent flaws on pages 249–261, and deliberate suboptimization on pages 261–266, which open: Page 261: “In some instances biochemical systems appear to be purposely suboptimized to balance trade-offs.” ↩
3. 2c.
  Page 247: “Over time, the accumulation of these damaging mutations can transform an optimally designed biochemical system into one with substandard performance.” ↩
4. 2d.
  Page 248: “Engineers who invent complex systems often face trade-offs and must purposely design some components to be suboptimal in order to achieve the maximum overall performance. In fact, if a system consists of finite resources and must accomplish numerous objectives, then the system must represent a compromise.” ↩
5. 2e.
  Page 249: “When evolutionary biologists label a biochemical system 'imperfect,' they do so largely from ignorance.” The OCR drops the closing quotation mark after imperfect. ↩
6. 2f.
  Page 249: “If life is indeed the product of a Creator, then new discoveries should yield insights that transform these biochemical aberrations into remarkable works of art.” ↩ ↩
7. 2g.
  Page 250: “The paired reactions catalyzed by phosphofructokinase and fructose 1,6-bisphosphatase are known as a futile cycle.” ↩
8. 2h.
  Page 251: “Another function for futile cycles is heat production. By cycling back and forth between fructose-6-phosphate and fructose-1,6-bisphosphate, the cell's chemical energy is converted into heat, which helps provide organisms with necessary warmth.” ↩
9. 2i.
  Page 253: “Prior to elimination, an enzyme (heme oxygenase) converts the heme ring into a linear molecule, biliverdin, in an energy-intensive process. For birds and reptiles, the process stops here. Biliverdin is water-soluble and readily excreted from the body of these animals.” ↩
10. 2j.
  Page 253: “In other words, mammals employ several seemingly unnecessary energy-intensive steps to convert biliverdin (a compound easily eliminated) into bilirubin (a molecule that can't be secreted).” ↩
11. 2k.
  Page 253: “Lastly, bilirubin is toxic. This compound causes jaundice, brain damage, and other disorders. On the surface, heme degradation appears ill-conceived—something expected for a product of evolution, not for a God whose creation would stay within the well-defined lines of perfection.” ↩
12. 2l.
  Page 253: “It turns out bilirubin is an effective antioxidant that reacts with oxygen and ROS.” ↩
13. 2m.
  Page 254: “This cycle amplifies bilirubin's antioxidative potential. Bilirubin eliminates ten thousand times its level of oxygen and ROS.” ↩
14. 2n.
  Page 254: “A flawed process. Except for primates, all mammals further metabolize uric acid to a more soluble derivative. Evolutionary biologists think the enzymes responsible for this transformation were lost in the evolutionary process that led to primates.” ↩ ↩ ↩
15. 2o.
  Pages 254–255: “For evolutionists, the elimination of adenine and guanine in the form of uric acid is the type of evidence that makes a potent case for evolution, because it appears to be a poor design.” The page break falls after adenine. ↩
16. 2p.
  Page 309: The potent-case sentence carries note 19, which reads: “Gould, The Panda’s Thumb, 19-26.” Pages 19–26 of Gould's 1980 book are the essay on the panda's thumb itself. ↩
17. 2q.
  Page 255: “This compound is a potent antioxidant that scavenges the chemically corrosive hydroxyl free radical, singlet oxygen, and superoxide anion, all produced by the metabolic pathways the cell uses to harvest chemical energy.” ↩
18. 2r.
  Page 255: “The maximal levels of uric acid in the blood serum, though precariously poised to precipitate as stones in the urinary tract, help prevent cancer and may contribute to long human life spans.” “If an inborn metabolic error occurs in the salvage pathway enzymes or if one eats an unbalanced diet, then kidney stones (and gout) can result—a small price to pay for cancer prevention and longer life expectancies.” ↩
19. 2s.
  Page 261: “These problems challenge the notion that a Creator produced life's chemistry.” ↩
20. 2t.
  Page 261: “Roughly 30 percent of all proteins synthesized must be degraded by the cell because they are improperly made.” ↩ ↩
21. 2u.
  Page 261: “Anyone with experience in manufacturing would agree that a production process with a 30 percent defect rate needs much improvement.” ↩
22. 2v.
  Page 262: “This cutting-edge discovery reveals elegant design in the inefficiency of protein synthesis. The high level of defective proteins produced by the cell allows for an efficient immune response to viral infection—the perfect plan of a Master who colors inside the lines.” The running head on this leaf OCRs as 162; the page map and its neighbours make it 262. ↩
23. 2w.
  Page 312: Note 50 cites Hansjörg Schild and Hans-Georg Rammensee, Perfect Use of Imperfection, Nature 404 (2000): 709-10, with Reits et al. 2000. ↩
24. 2x.
  Page 264: “In spite of its significance, rubisco has acquired the reputation among biochemists as a wasteful enzyme.” ↩
3.
Behrman, Edward J. et al. “Evidence from Biochemical Pathways in Favor of Unfinished Evolution rather than Intelligent Design.” Journal of Chemical Education 81(7):1051. Jul 2004. Abstract only. The letter is paywalled at the American Chemical Society, and OpenAlex lists no open copy. The ERIC record lists only Behrman and Marzluf and gives two pages. Mirror: Eric.ed.gov
1. 3a.
  Page 1051, abstract: “We cite a number of examples from metabolic pathways that argue for unfinished evolution rather than intelligent design. In most cases these involve inefficiencies based on unnecessary steps. We also point out that molecular evolution directed by human intelligence is easy to achieve.” ↩ ↩
2. 3b.
  The abstract in the ERIC record, supplied by the author: “An argument is made in favor of imperfect or unfinished evolution based on some metabolic pathways in which it seems that intelligent design would have done better. The case studies noted indicate the absence of highly intelligent design and are not intended as comprehensive collection but as a limited sample of inefficient situations in metabolism.” ↩
4.
Berg, Jeremy M. et al. Biochemistry. W. H. Freeman. 6th edition. 2007. The archive.org copy is in the printdisabled collection; read through archive.org search-inside and not stored. Printed page is leaf minus 40, from the BookReaderJSIA page map, confirmed by the index entries substrate cycles in, 467-468 and in substrate cycles, 467-469.
1. 4a.
  Page 413: “Under typical cellular concentrations, the actual ΔG for these hydrolyses is approximately −50 kJ mol−1 (−12 kcal mol−1).” ↩ ↩
2. 4b.
  Page 467: “This cycling was regarded as an imperfection in metabolic control, and so substrate cycles have sometimes been called futile cycles.” The OCR reads Phis for This. ↩ ↩
3. 4c.
  Page 468: “Despite such extraordinary circumstances, substrate cycles now seem likely to be biologically important. One possibility is that substrate cycles amplify metabolic signals.” The worked example on the same page takes 100 forward and 90 back to 120 and 72, a change in net flow from 10 to 48, and calls it. “a 380% increase in the net flux”. ↩ ↩
4. 4d.
  Page 531: “The current value of 30 molecules of ATP per molecule of glucose supersedes the earlier one of 36 molecules of ATP.” ↩ ↩
5.
Staples, J. F. et al. “Futile cycle enzymes in the flight muscles of North American bumblebees.” Journal of Experimental Biology 207(5):749–754. 2004. Abstract only, read through the Europe PMC API.
1. 5a.
  Page 749, abstract: “These data, taken with estimates of maximal rates of heat production by cycling, do not support a significant thermogenic role for the PFK/FbPase cycle.” ↩ ↩
6.
Stocker, Roland et al. “Bilirubin is an antioxidant of possible physiological importance.” Science 235(4792):1043–1046. 1987. Abstract only, read through the Europe PMC API.
1. 6a.
  Page 1043, abstract: “Furthermore, under 2% oxygen, in liposomes, bilirubin suppresses the oxidation more than alpha-tocopherol, which is regarded as the best antioxidant of lipid peroxidation.” ↩ ↩
7.
Maghzal, Ghassan J. et al. “Limited role for the bilirubin-biliverdin redox amplification cycle in the cellular antioxidant protection by biliverdin reductase.” Journal of Biological Chemistry 284(43):29251–29259. 2009. Stocker is the lead author of the 1987 bilirubin-antioxidant paper. Mirror: PMC
1. 7a.
  Page 29251, abstract: “Furthermore, overexpression of BVR does not protect mammalian or yeast cells from hydrogen peroxide-mediated damage, thereby casting doubt on the importance of the putative BVR redox cycle for cellular antioxidant protection.” ↩ ↩
8.
Stender, Stefan et al. “Genetically elevated bilirubin and risk of ischaemic heart disease: three Mendelian randomization studies and a meta-analysis.” Journal of Internal Medicine 273(1):59–68. 2013. Abstract only, read through the Europe PMC API.
1. 8a.
  Page 59, abstract: “Finally, in a meta-analysis of the present three studies and eight previous studies including a total of 14 711 cases and 60 324 controls, the random effects OR for ischaemic cardiovascular disease for genotypes with approximately 100% increased bilirubin levels versus reference genotypes was 1.01 (95% CI, 0.88-1.16).” “These data suggest that plasma bilirubin is not causally associated with risk of IHD.” ↩ ↩
9.
Oda, Masako et al. “Loss of Urate Oxidase Activity in Hominoids and its Evolutionary Implications.” Molecular Biology and Evolution 19(5):640–653. 2002. Read from the publisher PDF. Pages anchored on the running heads 642 Oda et al. and Primate Urate Oxidase 643.
1. 9a.
  Page 640, abstract: “Although we confirm the previous observation that the inactivation of the gene in the clade of the human and the great apes results from a single CGA to TGA nonsense mutation in exon 2, we find that the inactivation in the gibbon lineage results from an independent nonsense mutation at a different CGA codon in exon 2 or from either one-base deletion in exon 3 or one-base insertion in exon 5”. ↩
2. 9b.
  Page 640, introduction: “prosimians and Old World monkeys exhibit a moderate level of the enzymatic activity relative to mice and rabbits”. “In contrast, hominoids and some New World monkeys do not show any detectable level of the activity”. ↩
3. 9c.
  Page 640, abstract: “We suggest that although the inactivation of the hominoid Uox gene was caused by independent nonsense or frameshift mutations, the gene has taken a two-step deterioration process, first in the promoter and second in the coding region during primate evolution.” ↩
4. 9d.
  Page 643: “Of these nonsense mutations, three occur in species-specific manners, and only one at codon 33 in exon 2 is shared by the human and the great apes.” ↩
5. 9e.
  Page 643: “The nonsense mutation (TGA) at codon 107 is, however, more complicated than others. It occurs in the gorilla, the orangutan, and the gibbon, and therefore requires multiple origins of this nonsense mutation. Overall, it is remarkable that, except one CGA codon in exon 6, all the other four CGA codons are converted to the TGA termination codon in all or some of the hominoids.” ↩
10.
Ames, Bruce N. et al. “Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: A hypothesis.” Proceedings of the National Academy of Sciences USA 78(11):6858–6862. 1981. Read from the PMC scan. Mirror: PMC
1. 10a.
  Page 6858, abstract: “We propose that one of these protective systems is plasma uric acid, the level of which increased markedly during primate evolution as a consequence of a series of mutations.” ↩
2. 10b.
  Page 6858, abstract: “The plasma urate level in humans (about 300 µM) is considerably higher than the ascorbate level, making it one of the major antioxidants in humans.” ↩
3. 10c.
  Page 6858, abstract: “Urate is about as effective an antioxidant as ascorbate in these experiments.” ↩
11.
Li, Xue et al. “Serum uric acid levels and multiple health outcomes: umbrella review of evidence from observational studies, randomised controlled trials, and Mendelian randomisation studies.” BMJ 357:j2376. 2017. CC BY-NC 4.0. Read from the PMC HTML. Mirror: PMC
1. 11a.
  Section Abstract, Conclusion: “Despite a few hundred systematic reviews, meta-analyses, and Mendelian randomisation studies exploring 136 unique health outcomes, convincing evidence of a clear role of SUA level only exists for gout and nephrolithiasis.” ↩ ↩
2. 11b.
  Table 1: Cancer outcomes, cancer incidence, general population, prospective cohorts, highest against lowest urate category: 5 studies, 456,053 participants, 14,355 cases, relative risk 1.04 (0.99 to 1.08), not significant. ↩
12.
Antón, Luis C., and Jonathan W. Yewdell. “Translating DRiPs: MHC class I immunosurveillance of pathogens and tumors.” Journal of Leukocyte Biology 95(4):551–562. 2014. Read from the PMC copy, which has no journal page numbers; located by section. Mirror: PMC
1. 12a.
  Section DRiPs, SLiPs: all in the RDP family: “This only came after [45, 46] we discovered that upward of 30% of proteins in pulse-chase labeling experiments are degraded within minutes of their synthesis [47]. With improved methodology, we revised the fraction of RDPs to closer to 25%”. ↩ ↩
2. 12b.
  Section DRiPs, SLiPs: all in the RDP family: “SLiPs include excess subunits of multiprotein complexes that failing to assemble and hence, achieve a stable conformation, are treated as defective proteins.” ↩
3. 12c.
  Section DRiPs, SLiPs: all in the RDP family: “The high RDP fraction in cultured cells was challenged by Vabulas and Hartl [53], who using a different strategy (measuring the amount of protein synthesized over short times in the presence and absence of proteasome inhibitors), concluded that RDPs represented, at most, a few percent of total synthesis.” Reference 53 is Vabulas and Hartl, Science 2005, which was not obtained. ↩
4. 12d.
  Section DRiPs, SLiPs: all in the RDP family: “More recently, Cenci et al. [55] found in traditional pulse-chase experiments that the RDP fraction varied between 1% and 30% among human myeloma cell lines and was altered by cellular activation.” ↩
5. 12e.
  Section DRiPs, SLiPs: all in the RDP family: “Consistent with this idea, Ha et al. [58] report a similarly high RDP fraction in yeast, extending the phenomenon to a unicellular organism with no need to generate antigenic peptides.” ↩ ↩
13.
Tcherkez, Guillaume G. B. et al. “Despite slow catalysis and confused substrate specificity, all ribulose bisphosphate carboxylases may be nearly perfectly optimized.” Proceedings of the National Academy of Sciences USA 103(19):7246–7251. 2006. Read from the PMC PDF. Rana's note 53. Mirror: PMC
1. 13a.
  Page 7246: “This immense N investment is required to counter the enzyme's pitifully sluggish catalytic performance. Furthermore, Rubisco's tendency to confuse the substrate of photosynthesis, CO2, with the product, O2, saddles all aerobic photosynthetic organisms with energy-wasting photorespiration”. ↩ ↩
2. 13b.
  Page 7250: “Further, it raises the possibility that, despite appearing sluggish and confused, most Rubiscos may be near-optimally adapted to their different gaseous and thermal environments.” ↩ ↩
14.
Flamholz, Avi I. et al. “Revisiting Trade-offs between Rubisco Kinetic Parameters.” Biochemistry 58(31):3365–3376. 2019. Abstract read through the Europe PMC API. Mirror: PMC
1. 14a.
  Page 3365, abstract: “However, the reasoning that established this view was based on data from ≈20 organisms. Here, we re-examine models of trade-offs in Rubisco catalysis using a data set from ≈300 organisms. Correlations between kinetic parameters are substantially attenuated in this larger data set, with the inverse relationship between kcat,C and SC/O being a key example. Nonetheless, measured kinetic parameters display extremely limited variation, consistent with a view of Rubisco as a highly constrained enzyme.” “More than 95% of kcat,C values are between 1 and 10 s-1, and no measured kcat,C exceeds 15 s-1.” ↩ ↩
15.
Yewdell, Jonathan W. “DRiPs solidify: progress in understanding endogenous MHC class I antigen processing.” Trends in Immunology 32(11):548–558. 2011. Read from the PMC author manuscript, which has no journal page numbers; located by section. Mirror: PMC
1. 15a.
  Section DRiPonomics Revisited: “One of the troubling issues raised by a 30% RDP fraction is that since protein synthesis is so energy intensive, 10% of cellular energy would be consumed synthesizing defective or unneeded proteins [19]. Are cells this wasteful?” ↩
2. 15b.
  Section DRiPonomics Revisited: “The bottom line is that the RDP fraction is uncertain.” ↩
3. 15c.
  Section DRiPonomics Revisited: “At the same time, it is important to recognize that the fraction of proteins that represent immunologically relevant DRiPs can be minute (1% of translation or less) if the efficiency of generating pMHC I complexes from degraded substrates is high.” ↩
16.
Newsholme, Eric A. et al. “The activities of fructose diphosphatase in flight muscles from the bumble-bee and the role of this enzyme in heat generation.” Biochemical Journal 128(1):89–97. 1972. Abstract read through the Europe PMC API. Mirror: PMC
1. 16a.
  Page 89, abstract: “Such a cycle would produce continuous hydrolysis of ATP, with the release of energy as heat, which would help to maintain the thoracic temperature during rest periods at a level adequate for flight.” ↩
17.
Bettendorff, Lucien, and Pierre Wins. “Energy-Rich Molecules and Group Transfer Potentials in Energetic Coupling Reactions.” Molecules 31(2):242. 2026. CC BY. Mirror: PMC
1. 17a.
  Section 2.2: “C6H12O6 + 6 O2 → 6 CO2 + 6 H2O ΔG′° = −2870 kJ mol−1”. ↩ ↩
18.
Mookerjee, Shona A. et al. “Quantifying intracellular rates of glycolytic and oxidative ATP production and consumption using extracellular flux measurements.” Journal of Biological Chemistry 292(17):7189–7207. 2017. Mirror: PMC
1. 18a.
  Section Results, ATP yields from glucose: “the maximum total yield is 33.45 ATP/glucose and the maximum overall P/O ratio is 2.78.” ↩ ↩
19.
Complete oxidation of a mole of glucose releases 2,870 kJ under standard conditions.¹⁷ At about 30 ATP per glucose and about 50 kJ per mole of ATP under cellular conditions,⁴⁴ the ATP holds 30 × 50 = 1,500 kJ, or 52% of 2,870. At the measured maximum of 33.45 ATP,¹⁸ it holds 1,672 kJ, or 58%. The comparison sets a standard free energy for glucose against a cellular one for ATP, so the figure is rough. ↩ ↩
20.
Rolfe, D. F., and Guy C. Brown. “Cellular energy utilization and molecular origin of standard metabolic rate in mammals.” Physiological Reviews 77(3):731–758. 1997. Abstract only.
1. 20a.
  Page 731, abstract: “We estimate that approximately 90% of mammalian oxygen consumption in the standard state is mitochondrial, of which approximately 20% is uncoupled by the mitochondrial proton leak and 80% is coupled to ATP synthesis.” ↩
21.
Brand, Martin D. “The efficiency and plasticity of mitochondrial energy transduction.” Biochemical Society Transactions 33(5):897–904. 2005. Abstract only.
1. 21a.
  Page 897, abstract: “Up to 20% of the basal metabolic rate may be used to drive this basal leak. In addition, UCP1 (uncoupling protein 1) is used in specialized tissues to uncouple oxidative phosphorylation, causing adaptive thermogenesis.” “they may function to decrease coupling efficiency and so attenuate mitochondrial radical production.” ↩
22.
Kemper, Alex R. et al. “Clinical Practice Guideline Revision: Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation.” Pediatrics 150(3):e2022058859. 2022. American Academy of Pediatrics guideline. No page numbers; located by section.
1. 22a.
  Section Introduction: “More than 80% of newborn infants will have some degree of jaundice.” “Kernicterus is a permanent disabling neurologic condition”. ↩
23.
Bhutani, Vinod K. et al. “Neonatal hyperbilirubinemia and Rhesus disease of the newborn: incidence and impairment estimates for 2010 at regional and global levels.” Pediatric Research 74(Suppl 1):86–100. 2013. Abstract read through the Europe PMC API. Mirror: PMC
1. 23a.
  Page 86, abstract: “Of these, 480,700 (0.36%) had either Rh disease (373,300; uncertainty range: 271,800-477,500) or developed EHB from other causes (107,400; uncertainty range: 57,000-131,000), with a 24% risk for death (114,100; uncertainty range: 59,700-172,000), 13% for kernicterus (75,400), and 11% for stillbirths.” ↩
24.
Greenberg, David A. “The jaundice of the cell.” Proceedings of the National Academy of Sciences USA 99(25):15837–15839. 2002. Commentary on Baranano 2002; Rana's note 11. Mirror: PMC
1. 24a.
  Page 15837, first paragraph: “Another example is that of bilirubin, formerly dismissed as a waste product, whose image has been burnished by evolving evidence for a role in protecting cells from injury”. ↩
25.
Vitek, Libor et al. “Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels.” Atherosclerosis 160(2):449–456. 2002. Abstract only, read through the Europe PMC API. Fifty Gilbert subjects.
1. 25a.
  Page 449, abstract: “The prevalence of IHD in GS subjects (aged 49.7+/-9.0 years) was 2% (0.05-10.7%, 95% confidence interval), compared to 12.1% in a general population (P<0.05).” ↩
26.
Lin, Jing-Ping et al. “Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study.” Circulation 114(14):1476–1481. 2006. Abstract only, read through the Europe PMC API. 1,780 people followed for 24 years.
1. 26a.
  Page 1476, abstract: “Individuals with genotype 7/7 (population frequency of 11%) had approximately one third the risk for CVD and coronary heart disease as carriers of the 6 allele”. ↩
27.
McDonagh, Antony F. et al. “Reduction of biliverdin and placental transfer of bilirubin and biliverdin in the pregnant guinea pig.” Biochemical Journal 194(1):273–282. 1981. Abstract read through the Europe PMC API. Mirror: PMC
1. 27a.
  Page 273, abstract: “Injected bilirubin crossed the placenta from foetus to mother and vice versa, but injected biliverdin did not appear to cross without prior reduction to bilirubin.” ↩
28.
Chen-Xu, Michael et al. “Contemporary Prevalence of Gout and Hyperuricemia in the United States and Decadal Trends: The National Health and Nutrition Examination Survey, 2007–2016.” Arthritis & Rheumatology 71(6):991–999. 2019. Abstract read through the Europe PMC API. Mirror: PMC
1. 28a.
  Page 991, abstract: “In 2015-2016, the prevalence of gout was 3.9% among adults in the US (9.2 million people), with 5.2% [5.9 million] in men and 2.7% [3.3 million] in women.” ↩
29.
Wu, Xiangwei et al. “Urate oxidase: primary structure and evolutionary implications.” Proceedings of the National Academy of Sciences USA 86(23):9412–9416. 1989. Abstract read through the Europe PMC API. Mirror: PMC
1. 29a.
  Page 9412, abstract: “The mouse urate oxidase open reading frame encodes a 303-amino acid polypeptide, while the pig and baboon urate oxidase cDNAs encode a 304-amino acid polypeptide due to a single codon deletion/insertion event.” “Two nonsense mutations were found in the human urate oxidase gene, which confirms, at the molecular level, that the urate oxidase gene in humans is nonfunctional.” ↩
30.
Wu, Xiangwei et al. “Two independent mutational events in the loss of urate oxidase during hominoid evolution.” Journal of Molecular Evolution 34(1):78–84. 1992. Abstract only, read through the Europe PMC API.
1. 30a.
  Page 78, abstract: “Two nonsense mutations at codon positions 33 and 187 and an aberrant splice site were found in the human gene. These three deleterious mutations were also identified in the chimpanzee.” Oda and colleagues later found the codon-187 stop in the gorilla as well, on page 643 of their paper. ↩ ↩
2. 30b.
  Page 78, abstract: “Because the disruption of a functional gene by independent events in two different evolutionary lineages is unlikely to occur on a chance basis, our data favor the hypothesis that the loss of urate oxidase may have evolutionary advantages.” ↩
31.
Kratzer, James T. et al. “Evolutionary history and metabolic insights of ancient mammalian uricases.” Proceedings of the National Academy of Sciences USA 111(10):3763–3768. 2014. Read from the PMC PDF. Mirror: PMC
1. 31a.
  Page 3764: “The activity of An30 demonstrates that uricase function was nearly enzymatically abolished before the pseudogenization events in ancestral apes.” Page 3763: “uric acid levels are 3 to 10 times higher in apes (including humans) as a result of parallel nonsense mutations that caused a pseudogenization of the uricase gene during the early Miocene era (∼17 Ma)”. ↩
2. 31b.
  Page 3763: “Uric acid is recognized as an antioxidant and it has been hypothesized to be an important antioxidant in the plasma (9), although its role in oxidative stress has been disputed (10).” ↩
3. 31c.
  Page 3765: “a recent hypothesis is that the loss of uricase may have aided the accumulation of fat stores in response to fructose, a major nutrient in fruits that were a primary staple of ancestral simians”. ↩
32.
Rana, Fazale. “Unitary Pseudogenes Have Function! Part 1.” Reasons to Believe. Jan 14, 2013. Saved to the source library. The page discusses the vitamin C (GLO) gene and does not mention urate oxidase.
1. 32a.
  Paragraph 1: “This advancement means the presence of shared unitary pseudogenes no longer demands an evolutionary interpretation. They can be understood as common design features in the genomes of humans and the great apes (and other organisms).” ↩
33.
Parkinson Study Group SURE-PD3 Investigators. “Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial.” JAMA 326(10):926–939. 2021. Writing group led by Michael A. Schwarzschild and Alberto Ascherio. Abstract read through the Europe PMC API. 298 patients; serum urate raised by 2.03 mg/dL. Mirror: PMC
1. 33a.
  Page 926, abstract: “Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18).” “Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years).” ↩
34.
Bergman, Jerry. “A book about human errors that don’t exist.” Journal of Creation 33(2):33–37. Aug 2019. Young-earth review of Nathan Lents, Human Errors (2018). Read from the creation.com web version, which has no page numbers.
1. 34a.
  Section Mutations are not evidence of poor design: “This condition, of course, is not a result of poor design, but due to one or more mutations, as are the other 6,000 or so mutation-caused diseases. And this would be expected from the Fall, something which Lents ignores—as do most ‘poor-design’ propagandists.” The condition is the broken vitamin C (GULO) gene. ↩
35.
Yewdell, Jonathan W. et al. “Defective ribosomal products (DRiPs): a major source of antigenic peptides for MHC class I molecules?” Journal of Immunology 157(5):1823–1826. 1996. Abstract only, read through the Europe PMC API.
1. 35a.
  Page 1823, abstract: “We propose that a significant source of self and viral peptides are defective ribosomal products (DRiPs), which consist of prematurely terminated polypeptides and misfolded polypeptides produced from translation of bona fide mRNAs in the proper reading frame. DRiPs are produced entropically, due to the inevitable imperfections inherent to protein synthesis or folding.” ↩
36.
Schubert, Ulrich et al. “Rapid degradation of a large fraction of newly synthesized proteins by proteasomes.” Nature 404(6779):770–774. 2000. Abstract only; the full text is paywalled at Nature.
1. 36a.
  Page 770, abstract: “Here we show, first, that DRiPs constitute upwards of 30% of newly synthesized proteins as determined in a variety of cell types”. ↩
37.
McShane, E. et al. “Kinetic Analysis of Protein Stability Reveals Age-Dependent Degradation.” Cell 167(3):803–815. 2016. Abstract only, read through the Europe PMC API. Counts kinds of protein, not the share of all chains made.
1. 37a.
  Page 803, abstract: “Many non-exponentially degraded (NED) proteins are subunits of complexes that are produced in super-stoichiometric amounts relative to their exponentially degraded (ED) counterparts.” ↩
38.
South, Paul F. et al. “Synthetic glycolate metabolism pathways stimulate crop growth and productivity in the field.” Science 363(6422):eaat9077. 2019. Abstract read through the Europe PMC API. Tobacco field trials. Mirror: PMC
1. 38a.
  Page eaat9077, abstract: “Depending on growing temperatures, photorespiration can reduce yields by 20 to 50% in C3 crops.” “Numerous homozygous transgenic lines increased biomass productivity by >40% in replicated field trials.” ↩