What I Learned from Attending an International Drug Discovery Conference

To most people, medicine looks nothing more than a pill that you take once or twice a day. You ingest the pill, drink some water, and then go about your daily life. Most of the times, the pill works, but other times, it doesn’t.

Either way, there’s really nothing you can do about it. You just order your prescription from the local pharmacy and the pharmacy technician looks for the prescription in rows of neatly organized bottles, and then you follow the instructions on the labeled bottle.

In reality, drug discovery and development isn’t as efficient as this seemingly organized system. It takes 12–20 years and two to three billion dollars to develop a drug.

Therefore, it’s worth asking ourselves a couple of questions: How can we speed up the drug discovery process? And if we can’t speed it up, how can we make the general benefits of a particular drug compensate for the immense amounts of time spent in developing it and its cost for R&D?

Genomic medicine just might be the answer to the question. Instead of targeting proteins, we can target the genes involved in pathological processes and solve the problem at its root.

Imagine that all there is between our current and a longer healthspan is a locked door. Right now, we’re tirelessly trying to get through that locked door with a battering ram, but genomic medicine offers a simple solution to the problem: All we have to do… is open the door with a key.

Last Friday, I attended an International Drug Discovery Conference (with scientists from countries like Germany, Singapore, and China.

The way that we’re thinking about drug discovery is starting to fundamentally change.

Traditionally, we had small molecules that targeted a protein target, identified based on an SNP (single nucleotide polymorphism) in a coding gene. But now, things are starting to change.

Don’t get me wrong; small molecule drugs aren’t going away any time soon. However, we’re starting to identify new RNA targets and oligonucleotide therapies that can efficaciously fix a pathological problem at its genetic source.

We’re beginning to edit to DNA, craftily engineer tRNAs, and manipulate transcription and translation via engineered microRNAs. In doing so, we’re maximizing the efficacy and widespread scope of medicine to a height that we’ve never seen before.

Cystic Fibrosis is a genetic disease characterized by thick mucus that clogs the lungs and obstructs breathing. It causes mutations in the CFTR (Cystic fibrosis transmembrane conductance regulator) protein, an ion channel that conducts chloride ions.

There are currently six mutations that lead to this disease. Five of them are missense mutations, which means that an amino acid within the protein is substituted for an amino acid. Two drugs developed by Vertex Pharmaceuticals provide a treatment for patients with these five mutations.

The last mutation terminates the translation of the protein before the entire mRNA sequence is read. It’s called a “nonsense” mutation because the protein that it translates will not fold into a proper structure that retains its original function. This mutation can’t really be solved through a small molecule drug.

Professor John Lueck at the University of Rochester has been able to engineer Anticodon-engineered tRNAs that suppress the premature termination codon and instead add an amino acid. If you were to think of the amino acid sequence as a necklace, the CFTR mutation adds a knot where there shouldn’t be one, thereby shortening the length of the necklace. The engineered ACE tRNAs allow the necklace to grow to its original length by adding a necklace bead instead of tying a knot where the mutation is.

I had an amazing discussion with Dr. Søren Warming, who’s working with CRISPR cas systems in drug development. Through knock-in and knock-out experiments, scientists can identify how the activation or inhibition of a certain protein can cause certain phenotypic changes.

For example, if you were to create a small molecule drug A that inhibits a mutated enzyme B, you could try and simulate the inactivation of enzyme B by excising gene B from the relevant genome.

CRISPR Cas itself can also be used as a drug when it comes to gene editing. (If you haven’t read what I learned from the Gene Editing Conference at the Radcliffe Institute for Advanced Study, you can read that here). However, we can use cas9 to knock-out or knock-in specific genes, we must make sure that there are no obvious side effects. Dr. Warming works on testing for the side effects of CRISPR cas on the genome.

During one study, he found a bizarre result. He had excised a small portion of a gene from a specific locus only to find that the gene had inverted, grown in size, and then inserted itself upstream of the transcription start site! Its as if some mystical force made the gene reappear again! This shows that we need to carefully study the side effects of cas9 editing before we make it a reality.

Although we’ve been able to combat plagues and keep human mortality at a relatively low rate in the past century, antimicrobial resistance is predicted to cripple human populations in the near future due to an exponentially larger number of antibiotic-resistance bacteria produced via natural selection. Therefore, its super important to constantly be identifying viable antimicrobial targets in bacterial species.

Paul Dunman at the University of Rochester, has identified a new antimicrobial target protein called RNase RnpA, which is responsible for both mRNA degradation and tRNA maturation in Staphylococcus aureus bacteria.

His lab is currently screening for RnpA inhibitors, which will act as effective antimicrobials, due to the known function of the target RnpA!

Genomic medicine will likely disrupt the healthcare industry, if not in the next few years, within the next two decades!

Shoutout to Dr. Søren Warming and Dr. John Lueck for amazing discussions!

Thanks for reading! Feel free to check out my other articles on Medium and connect with me on LinkedIn!

If you’d like to discuss any of the topics above, I’d love to get in touch with you! (Send me an email at mukundh.murthy@icloud.com or message me on LinkedIn)

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