The Rule Behind All Life | The Central Dogma

Rosalind Franklin and Photo 51

0:00In 1962, three scientists walked onto a stage in Stockholm to accept the Nobel Prize for deciphering the secret of life: the structure of DNA. But what the committee left out of its speeches is that the key piece, the one that solved the whole puzzle, was obtained in secret.

0:25This is Rosalind Franklin, a brilliant crystallographer. In the early 1950s, she refined the X-ray diffraction technique until she achieved something no one else in the world had managed. After 100 hours of radiation exposure, she captured the famous Photo 51.

0:46To an untrained eye, it's just a blurry smudge. But to a crystallographer, that dark X is the unmistakable fingerprint of a double helix. The mathematics behind that image revealed the exact dimensions of the molecule. Franklin, with absolute scientific rigor, refused to publish until her calculations were finished.

1:11But behind her back, her colleague Maurice Wilkins took the photograph and showed it to James Watson. With that confidential data, he and Francis Crick built their three-dimensional model and published it immediately. While the two of them were starting to build their reputations, that same rigor was costing Rosalind her life.

1:33She died of cancer at just 37. That Nobel Prize was the crowning achievement of Watson, Crick and Wilkins, built on a foundation of data she never knew had been stolen from her. With the structure solved, Crick saw that a crucial piece was still missing: translation.

1:58He proposed that information begins in DNA, travels through RNA, and ends in proteins, always in one direction. Once it had become protein, there was no way to write it back into DNA. Crick named this idea the Central Dogma in 1958.

What is DNA?

2:21He wasn't trying to dictate an absolute truth, but to point out the general rule for how life works. But before we look at that rule, we need to understand what DNA is. DNA is deoxyribonucleic acid, a biomolecule that holds the information the organism needs to carry out certain metabolic processes.

2:48Deoxyribonucleic acid, or DNA, is a biomolecule made up of two strands with two fundamental properties. They are complementary, and they are antiparallel. Complementary means that the nucleotides on one strand always pair with those on the other in a specific way.

3:08Adenine pairs with thymine, and guanine with cytosine, through hydrogen bonds. And they're antiparallel because the two strands run in opposite directions. One is oriented 5′ to 3′, while the other runs 3′ to 5′. Each of these strands is built from small units called nucleotides.

3:31Every nucleotide has three main parts: a sugar called deoxyribose, a phosphate group, and a nitrogenous base. Together, these strands of nucleotides form the basic structure of DNA, which we'll look at more closely in the context of the Central Dogma. The Central Dogma rests on three fundamental cellular processes.

3:55The first is replication. Replication is the formation of a new strand from the original one. The second is transcription. That's where you get a single messenger RNA, a single strand. And the last one is to take the message we now have and translate it.

4:16And who carries that out? The ribosomes. Ribosomes are the workshops, the machinery that builds proteins, and proteins are involved in the many metabolic functions the cell performs. In short: DNA is copied in a process called replication.

4:37It's then transcribed into messenger RNA, which ribosomes read to build proteins. Before we go on, one thing needs to be clear. The animations we're about to see of replication, transcription and translation are specific to prokaryotes, and to Escherichia coli in particular.

DNA replication

4:57That doesn't mean eukaryotes lack these processes. Theirs are extremely similar. They just use some different proteins and involve a few extra steps. DNA replication begins with a tension that has to be relieved. DNA gyrase relieves it. It cuts the helix and reseals it.

5:21But what creates that tension? Helicase. It separates the strands by breaking the hydrogen bonds between the nitrogenous bases, and as it opens them it forms this structure: the replication fork. Single-stranded binding proteins, or SSBs, stabilize the separated strands to keep them from coming back together and to protect them from degradation by nucleases.

5:49At the replication fork, primase synthesizes a short stretch of RNA called a primer, which serves as the starting point for building the new strand. DNA polymerase III needs that primer before it can begin adding nucleotides complementary to the template strand, and it always works in the 5′ to 3′ direction.

6:14On the leading strand, synthesis is continuous, because DNA polymerase only needs one primer. On the lagging strand it needs several, which produces short pieces called Okazaki fragments. These fragments begin with primer RNA, and because that RNA carries uracil instead of thymine, it has to be replaced with DNA to preserve genetic fidelity.

6:42DNA polymerase I handles this. It removes the RNA primers and puts DNA nucleotides in their place. Finally, ligase seals the fragments into one continuous strand. The process continues until all of the DNA has been copied, producing two identical molecules, each with one original strand and one new one. This is what's called a semiconservative mechanism.

7:20It's critical for life because the existing DNA serves as a template for new genetic material. Naturally, it's involved in processes related to reproduction. That's what ensures the continuity of the species. Imagine a newborn baby.

7:40To grow, a baby's cells have to divide millions and millions of times. And with every division, the DNA has to be replicated so that each new cell receives an exact copy of the genetic instructions. That same process is what lets a baby inherit traits from their parents, like mom's eyes or dad's hair, since DNA replication is key to passing genetic information from one generation to the next.

8:12When these mechanisms fail, a whole range of things can happen. They can lead to some kind of genetic disorder, and even to disease. Werner syndrome is a rare genetic disease that causes premature aging, due to mutations in the WRN gene, which codes for the Werner protein, a member of the helicase family.

8:39Without that protein working properly, cells build up DNA damage that speeds up aging and raises the risk of diseases like cancer and diabetes.

DNA transcription

9:00Transcription begins when the sigma factor of RNA polymerase binds to a promoter, which is marked by two consensus sequences: the −35 box and the −10 box, also known as the Pribnow box. This forms a closed complex, which the sigma factor converts into an open complex as the two DNA strands separate, creating a small transcription bubble of about 12 to 15 base pairs.

9:32With the +1 start site exposed, RNA polymerase begins linking together the first ribonucleotides, with no need for a primer. After roughly 10 nucleotides, the sigma factor is released, leaving the core enzyme to carry on with elongation. Along the way, the enzyme reads the template strand in the 3′ to 5′ direction and synthesizes RNA 5′ to 3′, adding adenine, uracil, cytosine and guanine.

10:09Ahead of the bubble, DNA gyrase removes the positive supercoils that build up, while the DNA that has already been transcribed rewinds behind the polymerase. Termination can happen in two main ways. In Rho-independent termination, the polymerase transcribes a region rich in guanine and cytosine, followed by a run of uracils.

10:34The newly made RNA folds back on itself into a hairpin, because guanines and cytosines within the same strand pair with each other. This destabilizes the RNA–DNA hybrid and releases the transcript. In Rho-dependent termination, RNA polymerase transcribes a rut site, where the Rho factor binds to the RNA.

11:03Using ATP, Rho moves along the transcript until it catches up with RNA polymerase, destabilizing it and releasing the transcript. The result is a single-stranded messenger RNA, complementary to the template strand and ready to be translated.

11:25Some external growth factors can influence whether genes are switched on or off, depending on the conditions. Under certain conditions, the cell will need particular proteins to carry out a specific function, proteins it might not need under others.

11:50This is critical for the cell to function under those conditions. Escherichia coli, the quintessential model organism, can adjust its genetic machinery depending on what nutrients are available in its environment. When lactose is the only carbon source, the bacterium lifts the repression of the lac operon, which lets it transcribe key genes and produce β-galactosidase, an enzyme that specializes in breaking lactose down into glucose and galactose.

12:24But if there's glucose in the medium, the picture changes completely: the lac operon stays switched off. That way, E. coli avoids wasting valuable resources on making an enzyme it doesn't need. Some genes are expressed regardless of environmental conditions.

12:46We call these constitutive genes. E. coli never stops making ribosomes, whether it's living on glucose or lactose, in the cold or in the heat. The gene for 16S ribosomal RNA is always switched on. Because without ribosomes there's no translation, and without translation there are no proteins.

13:08And without proteins, there's simply no cell. Genes that never switch off like this are called constitutive genes. Believe it or not, this can play a part in whether certain diseases develop, as with the p53 protein, for example, which is involved in cancer.

13:34It's been observed to be highly expressed in these diseases, and it's linked to cell division. Another example is 4H syndrome. Here, the defect lies in subunits of RNA polymerase III, an enzyme needed to transcribe small RNAs that are essential for brain development.

14:02Without that machinery working properly, myelination fails from early in life, and the syndrome affects movement, coordination, teeth and puberty. Understanding how the pieces fit is one thing.

14:24Putting it into practice is something else entirely. Over at aequorea.net, a website I built for you, you'll find a Central Dogma minigame. If you think you've already mastered it, I challenge you to jump in, solve the sequences, and see where you rank on the global leaderboard. Let's see if you can beat me.

RNA translation

14:45The link's down below. But keep watching, because translation gets even more interesting. Translation begins when messenger RNA, or mRNA, binds to the small subunit of the ribosome, the 30S.

15:07This binding isn't random. The mRNA contains what's known as the Shine-Dalgarno sequence, which pairs with a complementary region of the 16S ribosomal RNA. This interaction positions the start codon correctly.

15:27Right at that spot, a special transfer RNA, or tRNA, settles in, carrying the amino acid formylmethionine. Once this tRNA is in place and everything is properly aligned, the large subunit of the ribosome, the 50S, joins in to form the complete 70S ribosome.

15:49Inside the ribosome are three key sites that tRNAs pass through, where the whole process takes place. The first to come into play is the A site, or aminoacyl site. This is where each new tRNA arrives, bringing an amino acid with it, and pairs with the matching codon on the mRNA through its anticodon.

16:17Once the tRNA is in place, peptidyl transferase, a ribozyme in the large subunit, forms a bond between the new amino acid and the growing chain, which at that moment is held by the tRNA in the P site, or peptidyl site.

16:37This site is the heart of the construction. It's where the tRNA carrying the amino acid chain being built sits. After the peptide bond forms, the ribosome shifts along the mRNA in a process called translocation. This movement pushes the tRNA that was in the P site over to the E site, or exit site.

17:06At this point, that tRNA has done its job and leaves the ribosome. The P site is now free for the tRNA that was in the A site, and the A site is open for a new tRNA to come in. And so, codon by codon, the ribosome moves forward, adding one amino acid after another, precisely and efficiently.

17:33Finally, everything stops when the ribosome reaches a special codon: a stop codon. No tRNA recognizes these codons. Instead, proteins that act as stop signals come in and cause the amino acid chain to be released.

17:54The ribosome comes apart and lets go of the mRNA, and the new protein is ready to work. DNA can only be written with four letters, one for each nucleotide, as we saw at the start.

18:19But how does that combination of letters get translated into a specific chain of amino acids? The answer is this table, sometimes also drawn as this wheel: the genetic code. Each codon, each group of three nucleotides, corresponds to an amino acid.

18:39Four letters in three positions give 64 combinations. Sixty-one of them code for amino acids, and the other three are stop codons. This specificity is thanks to a family of enzymes: the aminoacyl-tRNA synthetases.

18:59Each one has two recognition sites, one for an amino acid and the other for its matching tRNA. And it joins them together. There's one for each of the 20 amino acids, and they're the ones that make sure every amino acid arrives on the tRNA with the right anticodon.

19:23Deciphering this table took five years, from 1961 to 1966, and it began with Nirenberg and Matthaei, working with none other than E. coli, which we've been talking about this whole video. What they found next was the truly unexpected part: the same table works in archaea, fungi, plants and animals, and that, of course, includes us.

19:50That's why a bacterium can read a human gene and produce human insulin. That said, a handful of exceptions have been found. Human mitochondria, for example, read UGA as tryptophan instead of a stop codon, and some yeasts of the genus Candida read CUG as serine instead of leucine.

20:21Well, first, there's a check that the codon pairs correctly with the anticodon, that they match properly. Second, the ribosome makes sure the correct codon is in place. Remember that to start making a protein, you need methionine, or in bacteria, formylmethionine.

20:46The next one has to do with the tRNA also being loaded with the right amino acid. When translation fails, the message may be written correctly, but the cell can no longer turn it into a working protein.

21:06If the ribosome is compromised, proteins can come out wrong, or not be made in large enough amounts to keep the cell running. Diamond-Blackfan anemia is a direct example. Here, the problem lies in genes that code for ribosomal proteins, which affects the ribosome's structure and its ability to make proteins from birth.

21:34As a result, the bone marrow can't produce red blood cells properly, leading to severe anemia, physical malformations and growth delays. And with translation, the cycle is complete.

Reverse transcription

21:56Information flowed from DNA to RNA and ended in proteins, just as Francis Crick proposed: always in one direction, always irreversible. Wait a second. What? That's not true. Excuse me?

22:16There are viruses that can turn RNA into DNA. Information can flow backwards. The Central Dogma has an exception, and it has a name: reverse transcription. In 1970, David Baltimore and Howard Temin independently discovered an enzyme no one thought could exist: reverse transcriptase.

22:47A discovery so groundbreaking it earned them the Nobel Prize five years later. This enzyme, found in retroviruses, takes viral RNA and converts it into DNA. That DNA travels to the nucleus of the infected cell and inserts itself directly into the cell's genome, where it can stay silent for years or start producing new copies of the virus.

23:14HIV is the best-known example, and understanding this mechanism is what made it possible to develop the antiretrovirals that save millions of lives today. But that information will have to flow into another video. The press at the time declared that the Central Dogma had been overturned.

23:34Crick responded that same year in Nature, and what he wrote was that he had never said RNA couldn't go back to DNA. What the Central Dogma ruled out was something else: information leaving a protein and going back into a nucleic acid. That still hasn't been observed. What was really corrected in 1970 wasn't the dogma itself, but a popularized version of it.

Conclusion

24:02For almost all of human history, we had no idea where to even begin with the question of how life works. Now we do. You know the information is written in four letters. You know it's copied before every cell division, that it's transcribed into a temporary message, and that there's a machine that reads that message three letters at a time to assemble proteins.

24:28You know which enzyme does each job, and in what order. You know what happens when one of those pieces fails. That's what a human being does, and a bacterium, and a fungus, and a tree, and everything that has been alive on this planet for the last three billion years.

24:53In the small portion of the universe we've managed to observe, no other process does this. Everything else is rock, gas and radiation. This happens in exactly one confirmed place. We reached that conclusion in less than a century. Franklin and Gosling took this photograph in 1952.

25:17Crick proposed the dogma in 1958, and the genetic code was deciphered in 1966. And remember: you are the cosmos deciphering itself.

Acknowledgments and resources

25:46Before I wrap up, special thanks to Dr. Erika Beatriz Ángeles, who was also my professor, for taking the time to do the interview you saw throughout this video. If you'd like to learn more about her work, I'll leave a link to one of her papers in the description. I hope you get a chance to read it.

26:06If you're left wanting to know more, on aequorea.net you'll find all the material that goes with the videos. There you can browse the papers, books and other sources I go through when researching each topic, in case you want to read further. I've also put together diagrams, summaries and other materials so you can go over the key points at your own pace.

26:30Every full video has its own transcript, split into chapters and searchable, so if you want to go back to an explanation, you can find it quickly. In the network, you can follow how concepts, people, discoveries and, of course, the videos connect, and see where in Aequorea each connection shows up.

26:53And if you like learning by playing, there are a few minigames to practice concepts from the videos. You can find all of this at aequorea.net. I hope it helps. Before I go, a special thank-you to everyone who chose to support Aequorea on Patreon from the very beginning. Thank you, truly, for helping me keep building this project.