by Kate Adamala

In this age of endless personalization, you have your own identity: Your own case on your phone, your own photos on your desk, your own drink exactly how you want it from Starbucks. But what if you also had your own medicine, specifically designed to work best with your body? That’s the frontier of personalized medicine, and it’s happening now.

It’s a truism that people are different. Even identical twins are not truly identical. We understand that every person has a unique, individual combination of tastes, preferences, and traits. True, there are the so-called demographics. But this thing that we know without even thinking about it, goes out the window when it comes to medicine.

There, diseases are the common denominator, as if when a person becomes a patient their disease overrides their individuality.

Let’s look at an example. Almost every patient treated for Lou Gehrig’s disease (also known as ALS) receives a drug called riluzole, even though there are over 20 genetic mutations of ALS and an unknown number of causes. Why should we assume that one drug is the best treatment for all 20 variations? Another example: approximately 10% to 15% of the U.S. adults have gallstones[1], and anyone who doesn’t get surgery gets a drug called ursodiol. Here’s the secret: Ursodiol doesn’t work the same on everyone. In some people, it doesn’t work at all.

When a person becomes a patient, the diagnosis usually names a disease, like cancer or flu. It’s not “your cancer,” it’s “skin cancer,” or a little more specifically, something like “Merkel cell carcinoma.”

There are over 100 types of cancers[2], and in the U.S. alone over 14 million people have cancer[3]. That’s many more patients than types of cancer — what happened to “everybody is different”? Why are millions of unique cancer patients suddenly only allowed 100 or so different labels?

The short answer is: we don’t know all the types of cancer. We don’t have the resources to find the differences between those millions of different cancers, so we classify them as best we can, based on properties of the cancer cells. But while most neuroblastoma cells will show the same characteristic when stained with one particular iodine compound, they’re still individual cells from very different people, and they behave differently by themselves and in reaction to drugs.

Did you know that your genome evolves during your lifetime, and won’t look the same when you’re 80 as when you’re 18? That’s right: even in genetically identical twins, different patterns of changes will accumulate in theirs cells during their lifetime, and this epigenetic change adds diversifying factors on top of the differences in individual’s genomes, all of which affect how their bodies respond to outside influence both harmful and benign.

And there is yet more profound issue: we don’t even know how cells work. We know bits and pieces, but we do not have the inventory of all proteins in human cell, all pathways and all molecules. Without being able to understand how exactly cells work, we will not be able to understand the differences between individual people’s cells, or the differences between diseases in each individual.

Great advancements have been made in understanding biology, mapping out differences between cells, and in developing personalized medicine solutions. While we have some well-developed technologies, and even drugs going through the pipeline, all promising to deliver truly individual approaches to each patient’s disease, there is so much more work to be done before we can call this a solved problem.

The advents of genomics brought forth the idea that each disease can be uniquely genotyped, each mutation identified. We still cannot provide personal sequencing quickly and cheaply enough to get a complete genome of each patient, although the genome sequencing company Illumina recently announced a$100 genome[4] that, if real, might get personal genotyping within reach of most patients in the developed world.

Knowing the genome is only part of the solution, though. Even if we had a genome of every patient and a lot of the time we would not necessarily understand the results. A lot of work is being done on figuring out how each individual gene works, and what happens when things go wrong. We already know many specific mutations pointing to particular diseases. However, there are more diseases whose genetic background is unknown than ones tied to a particular gene. In fact, there are probably many diseases that will never be correlated with specific mutations in a particular gene. For all of those, each patient develops individual symptoms, and the disease resulting is a unique and seemingly irreproducible combination of patient’s own biochemistry. However, if we could build engineered cells, it would become possible to reproduce specific conditions of particular patient’s disease under very precisely controlled laboratory conditions. We could then build models of individual diseased cells.

For many years people speculated about the possibility of building cells from scratch. Amazing efforts from Craig Venter led to synthesizing a whole genome in the lab, producing a brand-new organism, called Mycoplasma laboratorium.[5] This is called top-down approach: we take a complex live organism and zoom in, simplifying it as much as possible to arrive at the simplest possible living cell. Most recent efforts from Venter and his colleagues gave us a brand-new organism with only 473 genes[6]. The caveat: we have no idea what 79 of those genes do. We know the bug needs them, but we don’t understand what for. This amazing success of top-down life building is a huge step to understanding life, and figuring out what processes are essential to life, but even an organism built entirely by humans is still 17% black box.

Enter: bottom-up strategies. Instead of taking existing living organism and stripping it down gene by gene, let’s start with non-living, but well known components, put them together into a cell-like entity. We call them synthetic minimal cells. Synthetic, because they’re completely made in the lab, and minimal because they’re so simple. This jerry-rigged cell will not be alive, but can perform some functions of life, like protein expression and communication with the environment. It’s much simpler than natural cells, and because we build those from scratch, we can understand exactly what’s going on inside.

Now we move from science into science fiction. Aspirational and fact-based fiction, but still not a tested and working reality.

Imagine if we could build a synthetic minimal cell, a completely artificial and well understood cell that replicates some important pathway from certain type of natural cells. For example, a certain complex pathway that, when malfunctions, can cause a bad disease. We could take the genes making up this particular pathway, put them together in synthetic minimal cell, and have the specific pathway, with as many (or as few) neighboring and interfering proteins interacting with our pathway. Then we can study the effect of many different drugs and drug candidates, looking at the best possible therapy that can fix whatever this pathway is lacking in function. The ideal synthetic minimal cell is dumb and simple, there are no background complex biology processes interfering with our experiment, nothing in the cell interfacing with our pathway signal — thus, less background noise and possibly easier, faster experiments.

Combine that dream with the recent, most real, advances of genotyping and the crazy progress in gene synthesis technologies we’ve been witnessing in the last decade. We will have this sci-fi medical scenario: we sequence patient’s sample, synthesize the exact variants of the genes that the particular patient has, with all the suite of personal mutations accumulated by this individual, and we stick it all in synthetic minimal cell.

If we could, right after the diagnosis, have a personal synthetic cell culture developed based on the very specific mutations of this particular patient’s cells, we could possibly screen through available drug cocktails, or test whole libraries of possible drugs much faster than it would ever be possible in live cell culture.

This certainly would not be an approach that we could use for every single disease. Not a magic bullet to cure them all, but possibly a good solution for some. More generally, synthetic cells could shorten the pathway from drug candidate to patient treatment, and lower the cost of biomedical research.

Science fiction mode off. We are not there yet. So far, we can make small, artificial genetic circuits work in synthetic minimal cells[7], we are not yet at the full natural pathway stage. But the pathway from research to application is shortening these days, and there is a lot of work being done on improving those synthetic minimal cell technologies.

There are many diseases that we already can treat pretty well with one-pill-fits-all approach. There are many others where specific combinations of drugs might be very well suited for a huge cohorts of patients. As we understand more biology, we’ll be able to make better drugs. If we build better tools to model specific biological systems, we might be able to test those new drugs in the synthetic cell model of that patient’s’ cell, making better use of existing drugs, combining them, adjusting doses, minimizing side effects and finally even testing new drug candidates for truly customized personal medicine approach.

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3034431/#s1title

[2] www.cancer.gov/types

[3] https://www.cancer.gov/about-cancer/understanding/statistics

[4] https://www.statnews.com/2017/01/09/illumina-ushering-in-the-100-genome/

[5] http://science.sciencemag.org/content/329/5987/52

[6] http://science.sciencemag.org/content/351/6280/aad6253

[7] http://www.nature.com/nchem/journal/vaop/ncurrent/full/nchem.2644.html