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Copying enzyme design to make industrial catalysts

What does ‘directed evolution’ really mean?

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Published: 10 September 2020 (GMT+10)
wikipedia.orgGlucosidase-enzyme
The enzyme hexokinase. This enzyme changes shape by induced fit upon substrate binding to form enzyme-substrate complex. Hexokinase has a large induced fit motion that closes over the substrates adenosine triphosphate and xylose.Binding sites in blue, substrates in black and Mg²⁺ cofactor in yellow.

Enzymes are a vital class of proteins that are catalysts. That is, they speed up chemical reactions without being consumed in the process. Without enzymes, many reactions essential for life would be far too slow for life to exist.

For example, a reaction “absolutely essential” in creating the building blocks of DNA and RNA would take 78 million years in water. But an enzyme (orotidine 5'-monophosphate decarboxylase) makes this reaction go 1018 times faster,1 so it takes less than 3 milliseconds in the cell.2 Another enzyme (inositol phosphatase) speeds up a reaction vital in cell signalling and regulation by 1021 times. With the enzyme, the reaction takes 10 milliseconds; without the enzyme, it would take a trillion years. This is almost a hundred times the supposed evolutionary age of the universe (about 15 billion years)!3

There are also many essential enzymes for DNA repair, without which DNA would disintegrate rapidly. And the DNA would be useless unless its information could be decoded. This means that this very long and thin coiled molecule must be untangled constantly with topoisomerase enzymes. Then reading this information requires a double-sieve enzyme and many others vital for decoding and splicing the information in DNA.

This requires exquisite fine tuning of the amino acids so that the enzymes have the required shape. Indeed, the fine-tuning is at the atomic level, so the right atoms of the enzymes interact with the right atoms of the substrate. See for example the animation of the enzyme aconitase below.

Industrial catalysts

Catalysts are very important for industry as well. They are used for production of medicines and fuels, and to reduce pollution. Indeed, probably about 90% of all chemical products need catalysts at some point in their manufacture. However, industrial catalysts mainly use rare or precious metals. E.g. catalytic converters use platinum, rhodium, or palladium, which are similar in value to gold.

However, enzymes use common or earth-abundant metals (EAMs) such as magnesium, iron, and copper. If industry could make catalysts with EAMs, it would drastically lower cost and the environmental footprint. So scientists have now used enzymes from living creatures as the starting point to make industrial catalysts.4 This is one example of a rapidly expanding field called biomimetics: copying designs from nature.

Directed evolution?

wikipedia.orgFrances-Arnold
Frances Arnold, winner of the Nobel Prize in Chemistry (2018)

Sometimes these enzymes need to be tweaked, and the process is something they call by the oxymoronic term “directed evolution”. However, this is really directed selection. That is:

  1. Start with enzymes from living organisms—not from random proteins.
  2. Mutate the genes that code for these enzymes.
  3. Insert genes into bacteria
  4. Check the resulting enzyme for desired activity
  5. Select the best, discard the rest.
  6. Go to Step 2.

This is very important chemistry, for which Dr Frances Arnold of Caltech deservedly won a half-share of the 2018 Nobel Prize for Chemistry. But is it really a triumph for evolution over creation?

Not at all! Certainly, evolution and creation are diametrically opposed ideas—did life have a Maker or not? However, many observations actually fit well in both models, so can’t be used as evidence for one over the other. This is called the Fallacy of Overlapping Predictions. So we shouldn’t be surprised that we have interviewed two creationists who have worked in this field, for example Dr Dudley Eirich and Dr Matti Leisola. Even CMI marine biologist and geneticist Dr Robert Carter used directed selection to discover new and useful protein variants as part of his doctoral work.5

Directed selection provides no support for evolution

In particular, evolutionists often ignore the fact that natural and artificial selection are part of the creation model, as creationists both before and after Darwin understood. Indeed, natural selection existed before the Fall! This has nothing to do with evolution from prokaryotes to professors, for several reasons (compare Genetic algorithms—do they show that evolution works?):

  • Natural selection is not so much survival of the fittest but reproduction of the fittest. Many enzymes are needed for a reproducing cell to exist. Therefore natural selection cannot explain the origin of these enzymes. So we are left only with undirected chemistry, which goes in the wrong direction:

  • Directed selection has a goal, e.g. increased catalytic activity or stability. Natural selection is ‘blind’.
  • Directed selection is perfect. Only the best catalysts are taken to the next level, while others are discarded, i.e. extreme truncation selection. Real-world natural selection is nothing like that. Darwin himself talked about slight variations with only slight selective advantages. And this needs many generations to work, which is why long ages are necessary, although not sufficient, for evolution.
  • In these experiments, the artificial ‘reproductive’ rates are enormous. Nothing like this exists in real-world biology.
  • Mutation rates are also extremely high in these lab trials. They can afford to be, because they are dealing with only one gene out of thousands (E. coli has 4,401 genes). Also, the chemists ensure that something survives. But if the whole bacterial genome were subjected to such a high mutation rate, it would fall apart. Even much lower mutation rates of whole genomes can cause extinctions, such as a strain of the H1N1 influenza virus.

    Computer modelling shows that even truncation selection would not prevent overall degradation if the whole organism were subject to high mutation rates. See the paper Mutations: evolution’s engine becomes evolution’s end! under Truncation selection.

  • Related to this is the claim that random DNA sequences can produce novel functions. However, Dr Carter analyzed the claims very carefully and pointed out:

    By introducing random RNAs into the cell, Neme et al. inadvertently changed the genomic regulation patterns of already existing genes. No new functions were added. No evolution has taken place. While the experiment was ingenious, the conclusions they derived from it were unwarranted. Venema [Dr Denis Venema, of theistic evolutionary propaganda group BioLogos] was premature in his praise.
  • Finally, in real life, mutations are not random.

Work to be done

alamy.comTardi_hero
Water bear (tardigrade, lit. ‘slow-stepper’) crawling over a surface (magnified, because tardigrades are only 0.5 mm (0.02 in) long).

One problem with enzymes is that they are quite easily denatured. That is, their fine-tuned spatial arrangement can be disrupted, so they no longer function. This is a major reason why cooking kills bacteria—their enzymes are all denatured, so the cells can’t work.

However, many industrial chemical processes have conditions that are too harsh for most enzymes to survive. For example, high temperatures and pressures, highly acid or alkaline conditions, and the presence of organic solvents. Thus, with more directed selection, they hope to improve enzyme stability.

As a counter-suggestion, the living world has some creatures that can withstand extremes, so must have some way to protect their enzymes. Foremost are tardigrades. They can survive in boiling water, frigid liquid helium, six times the pressure of the deepest part of our oceans, and radiation doses 250 times the lethal dose for humans. And there are other extremophiles.

Another idea instead of modifying the enzymes to fit the process, do the reverse. That is, improve the process to make it more amenable to work with biology. For example, the production of the strongest man-made fibre, Kevlar®, requires harsh conditions, including boiling sulfuric acid. But spider silk is even stronger, and obviously made at ordinary temperatures, and uses only mildly acidic conditions that are not harmful to spiders. Clearly, tough materials can be made without harsh conditions. All we have to do is learn more from the Creator.

Conclusion

This work highlights the brilliant design of our enzymes. And it provides a huge head start to chemists trying to develop industrial catalysts. So far, it is beyond our capacity to design an enzyme from scratch. Just predicting the 3D structure of a folded protein from its amino acid sequence “is a longstanding challenge in computational biology.”6

Also, directed selection is good operational science. It provides not the slightest evidence that random chemicals could have formed the first enzymes without intelligence. But the term ‘directed evolution’ is hardly the first time where an alleged proof of ‘evolution’ is really a proof of natural selection.

References and notes

  1. Miller, B.G. and 4 others, Anatomy of a proficient enzyme: The structure of orotidine 5'-monophosphate decarboxylase in the presence and absence of a potential transition state analog, PNAS 97(5):2011–2016, 2000. Return to text.
  2. Lead researcher Dr Richard Wolfenden; cited in: Without enzyme catalyst, slowest known biological reaction takes 1 trillion years, sciencedaily.com, 6 May 2003. Return to text.
  3. Lad, C., Williams, N.H., and Wolfenden, R., The rate of hydrolysis of phosphomonoester dianions and the exceptional catalytic proficiencies of protein and inositol phosphatases, PNAS 100(10):5607–5610, 2003. Return to text.
  4. Bullock, R.M. and 17 others, Using nature’s blueprint to expand catalysis with earth-abundant metals, Science 369(6505):786, 14 Aug 2020. Return to text.
  5. Carter, R.W., Schmale, M.C., and Gibbs, P.D.L., Cloning of anthozoan fluorescent protein genes, Comp Biochem Physiol C Toxicol Pharmacol 138(3):259–70, 2004; doi:10.1016/j.cca.2004.07.002. Return to text.
  6. Yang, J and 5 others, Improved protein structure prediction using predicted interresidue orientations, PNAS 117(3) 1496–1503, 21 Jan 2020. Return to text.

Helpful Resources

Readers’ comments

Nicholas S.
A man was observed walking backwards along a road. When asked why he was walking backwards, he replied, “I want it to appear that I am coming back from where I’m going.” The theory of evolution keeps going back in variable time (changes to the time abstract elements of the theory occurs every few years or so) to where it is sure (variable) as to when and how it all started and so on. At the same time the theory wants us to believe that everything fell into place and evolution is moving forward even though it is continually looking over its shoulder with ever changing hypotheses. String theory (abstract) becomes entangled with itself as there is no basis or evidence proof of its validity, There is no empirical measure of observed evidence to be able to have faith in string theory, whereas there is empirical evidence in enzymes being the catalyst for life to exist, Romans 1:20. Even though evolution is taught in schools, it is still abstract theory. Thank you Dr Jonathan Sarfati and also your CMI colleagues for your brilliant factual works, making them a pleasure to read.
Thomas R.
Nice article.

It highlights the fact that evolutionists really can’t demonstrate their beliefs.

If they mix a bunch of chemicals and produce a living cell, all they will have proven is that intelligent design works.

And if they do it quickly, all they will have shown is that millions of years are not necessary.
Dan M.
It continually amazes me how little still the scientific community understands about life, the inner workings of cells, and the creation in general. Yet secularists insist evolution is a fact and ridicule me for my belief in God which to me is a no-brainer given what little I do understand myself (Darwinistic evolution is NOT possible)? If they (secularists) know so much, they should be able to easily explain and then duplicate nature but are unable to do so because they don’t understand it.

For instance spider silk? It is a common very simple thing for God's nature to produce, but we can’t figure out how to do it ourselves, even with all our technology and brainpower. To make certain statements as facts about a system, you have to fully understand that system and they do not understand the simple things of the creation much less the complex. Therefore it is just their opinion or belief, not a scientific fact, that there is no God and nature evolved on its own.

In fact, naturalistic evolutionary beliefs are a fanatic religious manifestation as a result of rebellion, facilitated by the deceiver. He was a liar and a murderer from the beginning and seeks our ultimate destruction. Ignorance is one way in which civilization can be destroyed and the world is becoming more and more ignorant of its true creator (Hosea 4:6). One day everyone will understand and every knee will bow to one's destruction and another’s everlasting life (Philippians 2:10). Maranatha!
Nichola W.
I recently watched a conversation between a scientist, Lee Cronin, who is trying to create life in the lab and a messianic Jew, James Tour, who was trying to tell him that it’s not possible. This scientist is absolutely positive that he can do it, it’s just a matter of time. However he made statements that belie his confidence. Things like we don't know what life or biology is. He thought that James was being unreasonable and he said that he was more humble than James because he’s claiming not to know what life is.

But reading this article reinforces our belief in the Creator and that James is correct.
Jonathan Sarfati
Yes, Dr Tour is a Messianic Jew (like me). Note that we are both scientists as well. Dr Tour is one of the world's leading synthetic chemists. So when he argues against chemical evolution (‘abiogenesis’), he is making a proper argument from authority, and can back it up.

Conversely, Dr Cronin declared at the outset, “I’m an atheist.” An atheist must believe in chemical evolution (and many other anti-scientific things) by faith. So this debate was indeed about science vs. religion, but in the opposite way many people think. Dr Tour presented scientific evidence against chemical evolution, while Dr Cronin needed to believe chemical evolution by (blind) faith to hold on to his atheistic religion. But at least Dr Cronin was willing to go up against an informed critic, unlike other vocal chemical evolutionists.

Unfortunately Dr Tour is not a biblical (‘young earth’) creationist, and is not well informed on those issues.

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