Solving the Hardest Problems in Structural Biology to Save Millions of Lives
At Macula X, we love working on the hardest problems, diving deep into the research, brainstorming solutions, and making our vision a reality. That’s what we’re doing in the field of protein structure determination.
There are over 20,000 proteins in the human proteome, proteins that carry out all of our cellular processes from metabolism to growth to the manipulation of genetic material. So understanding exactly what these proteins are and how they carry out these functions is crucial to understanding the human body and physiological processes.
Further, understanding what can go wrong and how we can fix it will enable us to develop cures to chronic diseases such as Alzheimer’s and cancer. And detailed structural information is often essential to drug development.
It’s crazy that despite the fact that proteins are what enable us to live, we only know the structure of 20% of the proteins in our bodies.
And this fact has largely been taken for granted. The status quo in biology has been that protein structures are expensive and difficult to uncover. We could accept that and continue moving along at this pace of incremental improvements in technology and year by year slowly discover a handful of proteins, but we’d be giving up so much:
- Curing chronic diseases — In order to even begin to propose drugs, we need to understand a mechanism by which the disease works. To date the protein data bank has 2227 proteins, while scientists predict that the human body has between 10,000 and 10 billion different species of proteins. How do we expect to efficaciously personalize medicine and cure a variety of diseases if we only know 22.7% of the entire human proteome at maximum? Aside from the entire proteome — diseases that have constantly garnered scientific attention such as Alzheimers involve complex protein cascades.
- Efficient and accurate drug development and protein therapeutics — Traditional drug discovery takes an extremely long time (anywhere from 1–2 decades). One of the main bottlenecks here is the high barrier to entry for accessing quality protein structures which provide key structural and chemical constraints on the properties of the molecules that we must design and synthesize as potential candidates.
- More successful clinical trials — Clinical trials are merely a reflection of scientists’ inability to understand the innate complexity of human biochemical transduction pathways and cascades. This causes medications to have unnecessary toxicity or side effects. Opening the door to accessing protein structures would act as a large step towards faster approval of medicines.
- Understanding how the human body really works
- All the while burning through trillions of dollars and decades of time
Despite all of the challenges due to proteins’ high molecular complexity, we kept coming back to this problem because we recognized the potential it held and realized how many lives could be saved.
With a Protein Structurome Project, we’d be able to address all of these issues and enable other researchers to do the same. With the help of advances in genomics, metabolomics, transcriptomics, and all of the other sub-omics fields, it holds the potential to revolutionize the entire field of medicine and save millions of lives.
By mapping out the pathways involved for particular disease modules, we can gain access to so many more therapeutic targets, predict side effects, and gain a new understanding of diseases.
Central to tackling protein structure determination though is understanding the limitations in current technologies.
Current methods are expensive, and time and space consuming
The main technologies being used to image proteins are X-ray diffraction, Nuclear Magnetic Resonance, and the newer Cryo-Electronmicroscopy. Each of these costs millions of dollars and can be unpredictable or inaccurate, often requiring months of trial and error. Protein imaging can often be a bottleneck in research, especially at academic labs with a lack of funding.
X-ray diffraction works by diffracting x-rays off of a crystalline array of proteins. Each protein needs to be crystallized and then placed in a 3d array where it will be placed in the path of an x-ray beam.
The x-ray beam hits the top layer and some bounces off while the rest passes through to the next layer. The same happens for each subsequent layer and the diffractions either compound or negate to give a final picture. Thus, the final image is essentially an average of all of the crystallized proteins in the lattice.
There are issues when the protein has “intrinsically disordered regions,” the flexible domains of the protein that can change shape. These domains appear differently in different crystals so when their electron density is mapped using XRD, those areas just come out to be a fuzzy blob. Often it is actually these areas that are responsible for a major part of the protein’s function.
Nuclear Magnetic Resonance
All nuclei are electrically charged so when they are exposed to an external magnetic field, they will jump to a higher energy level and change spin. (Remember electricity and magnetism are two parts of the same thing). Then, when the nuclei returns to its base level, it lets off energy of the same frequency as that which it increased. These radio frequencies can be mapped to specific elements.
The energy transition is also influenced by its surrounding environment so NMR can be used to get a full molecular image.
In addition to costing millions of dollars, it is difficult to prepare samples because it requires a large amount of highly concentrated solution and requires NMR active nuclei which makes it relatively insensitive.
One of the issues with XRD was the intrinsically disordered regions. To solve this problem, Cryo-EM freezes proteins to -180˚C to form vitreous (glassy) ice. Then an electron beam hits the molecule and due to electron scattering, the electron changes direction when it hit the molecule without losing energy (which would disrupt the structure).
With biologic molecules there can be low contrast and for obvious reasons, preparation is difficult. Freezing the molecule so that vitreous and not crystalline ice forms is hit or miss and maintaining its temperature throughout the entire process has a high overhead.
Further, Cryo-EM machines can cost up to $7M and up to $10,000 per day in maintenance. The large machinery requires a special room with vaulted ceilings and a reinforced floor.
So to recap, the issues to solve are: cost, size, time, and accuracy.
We’ve proposed a solution that uses nanopore technology to identify the sequence and structure of the amino acids in a protein. We project it would be 1000x cheaper, the size of an iPhone, take a matter of minutes, not weeks, and be accurate to the angstrom level. Read more about how it works here.
But right now this is just an idea — how can we make it a reality?
We’re working on the cutting edge of science and innovation and are aspiring to create the seemingly impossible.
What got us here is curiosity and passion, a willingness to explore complex science and try to make sense of it. We’ve asked so many what if questions and every time we encountered a roadblock, instead of running away or pretending it didn’t exist, we iterated, researched, and brainstormed solutions.
Even though the path ahead is unclear, we persevere and because we face new challenges each day, we grow. Through repetitive trial, failure, and feedback, we’ve improved and solidified our ideas. No one can know everything, so we’ve learned and grown alongside Macula X and this continual drive to solve the hardest problems because they’re hard is what will push us forwards.
The Human Genome Project took 13 years of scientists working globally to sequence a single genome and now we’re able to send a spit sample to 23andMe and in 2–3 weeks and for $100, you can see your own genome. With genomic data, we’re launching into an era of personalized medicine where we can predict disease before symptoms appear and treat genetic disorders.
If the genome is the script for the human body, imagine how understanding proteins, the actors, will revolutionize medicine.
We plan to launch a Human Proteome Project to structure >80% of the proteins in the human proteome. We’ll be able to cure chronic diseases, simulate clinical trials, and exponentially accelerate the speed of drug discovery and protein therapeutics.
Here’s our timeline for making that happen:
We need your help! If you care about our mission to solve the hardest problems in protein structure determination to save millions of lives and are able to provide insight or guidance, please reach out; we’d love to hear from you.
Macula Therapeutix is a company founded by Kiran Mak and Mukundh Murthy, two innovators passionate about changing the world by changing one of the most traditional and unquestioned methods that dictate how to acquire structural biology data.