What will geneticists and molecular cell biologists be doing in 2020? 10 years ago, genomic technologies like DNA microarrays were just beginning to change the way molecular biologists worked, and the draft sequence of the human genome was a year from publication. Over the next decade, genomics, in the form of high-throughput tools, and large sequence databases, completely transformed the day-to-day work of just about everyone in the basic biomedical sciences.

Today, new DNA sequencing technologies have rendered DNA microarrays obsolete for most of their original applications (although they are still useful for many applications). Biology is extremely technology-driven, and the technology changes unnervingly fast. So the state of molecular biology in 2020 is going to depend on the technologies that transform the field over the next 10 years. Those of you who plan to be in this business 10 years from now: it's time to start thinking now about how those technologies are going to change your research.

My picks for transformative technologies are fairly obvious, but how they'll change the day-to-day research questions geneticists and molecular biologists ask isn't so obvious.

The three up-and-coming, game-changing technologies are:

1. Even cheaper DNA sequencing

2. Induced pluripotent stem cells

3. Easy gene manipulation for vertebrates cells

Let's look briefly at these three:

DNA Sequencing
DNA sequencing technology has kept pace with Moore's law. A very crude comparison between Sanger sequencing (the older technology), and Illumina sequencing (one of the newer technologies): I can get ~700 bases of DNA sequence via Sanger sequencing for about $3-4, or about $0.006 per base. With Illumina sequencing, I can get a million bases of sequence for about $6 - $0.000006 per base.

This comparison is too crude for a variety of reasons (starting with the fact that I'm not considering the differences in error rates), but it illustrates the point: the cost of DNA sequencing is dropping rapidly, and getting your own genome completely sequenced for $1000 may very well be possible by 2020.

Stem Cells
Scientists now have the ability to create stem cells from 'normal' differentiated cells; such stem cells are called induced pluripotent stem cells, or iPS Cells. The fierce political debates over stem cell research (a big deal here in Missouri during the 2006 US Senate campaign) will seem as dated in 2020 as the battle between Netscape and Internet Explorer seems now.

In 2020, making iPS cells, and then differentiating them into just about any cell type we're interested in is going to be routine.

Easy molecular genetics
One of the main challenges to doing molecular genetics in mammalian cells is the difficulty of gene manipulation. One of primary ways biologists study genes is by making mutants: you alter or completely eliminate your gene of interest and look at the effects. Baker's yeast has been so tremendously successful as a research organism because our ability to manipulate genes in yeast has been unrivaled.

Doing experiments in cells other than yeast is going to get a lot easier in the next 10 years. In fact, manipulating genes in other organisms will be so easy that yeast is going to be almost completely obsolete as a research organism in 2020.

Technologies like custom zinc finger nucleases are going to make it possible to easily knockout or mutate genes in mammalian cells.

So how do these three technologies come together to transform day-to-day biology in 2020? First, model organism research in bacteria, yeast, flies, and worms is going to be much more limited because it will now be easy to do our studies directly on human genes in human cell lines. Studies that require more than cell lines (such as studies of embryonic development) will rely on vertebrate model organisms - zebra fish and mice.

Imagine how powerful the combination of easy gene manipulation and iPS cell technology will be: if you're interested in studying the role of a particular gene in nerve function, you can make mutants of your genes in a generic, easy-to-grow cell type like fibroblasts, transform those fibroblasts into stem cells, and then differentiate those stem cells into neurons.

My personal research interest is in the regulatory processes that control cell division, which I study in yeast. I ask questions about the effects of feedback loops, and of combinations of activating and repressing regulators that control key cell division genes.

Instead of working in yeast, in 2020 I'll be able to pick cancer mutants that potentially affect cell division (identified through extensive, cheap DNA sequencing of tumor samples), and manipulate them in any cell type I want. If I want to know the particular effect of a mutation on a feedback loop that controls the exit from mitosis (something that today is still studied most effectively in yeast), I can manipulate the relevant genes in different tissue types that give rise to different cancer types.

These powerful molecular genetics and stem cell tools can be further combined with the vast genetic experiment carried out by nature: human genetic diversity. In 2020, we'll study the molecular details of Parkinson's disease by collecting fibroblast samples from a genetically diverse set of human subjects, some with Parkinson's and some without. Using iPS technology, we'll observe the effects of this genetic diversity on the behavior of motor neurons, and follow up with directed genetic experiments.

The three transforming technologies - even cheaper sequencing, iPS cells, and easy gene manipulation - will enable researchers to harness human genetic diversity in their efforts to study the molecular biology of disease, which is going to result in extremely rapid progress in our ability to understand, diagnose, and treat those diseases.

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