Findings: Rethinking synthetic cells

There is a basic tenet in cell biology and it goes something like this: All cells come from pre-existing cells.

This tenet is one of three put forward by scientists Theodor Schwann, Matthias Schleiden, and Rudolph Virchow in the 1830s; the other two are that all living things are composed of cells, and that cells are the basic unit of structure and function in living organisms. These tenets are so ingrained in our psyche that they can be recited, verbatim, by almost any molecular biologist.

Recently, scientists at the J. Craig Venter Institute in Rockville, Md., have been trying to bury the sacred mantra that cells come from pre-existing cells by creating cells from, well, nothing. The proposed cells, called synthetic cells, would be put together from scratch, using molecular machinery and genetic material from gutted cells.

Synthetic cells function as small, fragile cell analogs with a working genome and the bare protein essentials. But headlines like “Life from Scratch” on the online website ScienceNews Science News and “Scientists closer to creating artificial form of life” in India’s Economic Times give the misleading impression that scientists have recently borne witness to a resplendent like genesis inside the laboratory.

The strides in synthetic cell research are not tantamount to the synthesis of life — yet. Nevertheless, the research is interesting and worth examining.

Research in synthetic biology broadly veers down two paths. There are scientists, like John Glass at the Venter Institute, who hope to make a synthetic cell by taking a simple bacterium like Mycoplasma genitalium, extracting its genome, and cutting it down to the most bare-bones strings of functional DNA. This hand-assembled DNA can be transplanted into a cell, causing the cell to “boot up” and use the foreign DNA as if it were its own.

M. genitalium, a parasite that causes infections of the cervix, vagina, and urinary tract, is a standout organism in the field of synthetic biology because it has the smallest bacterial genome.

DNA is composed of a string of nucleotides, and each nucleotide can be thought of as a letter in a twisting, coiling sequence of code. Compared to human DNA, the genome of M. genitalium contains a scant 580,000 nucleotides. This makes it feasible to remove genes, one at a time, and see which are integral for survival and which are not.

Working alongside Glass at the Venter Institute is Hamilton Smith. Smith won the 1978 Nobel Prize in Physiology or Medicine and, in 1995, helped sequence the first bacterial genome. Smith and Glass have been knocking out genes in M. genitalium, in the hopes of creating an ultra-basic, working-class piece of genomic DNA, for nine years.

The team is trying to find genes critical for the survival of M. genitalium. The task is complicated because some genes have redundant functions. There are also several gene combinations, and testing every one of them could take years. Still, the team has found 100 genes that are loosely “dispensable” when removed individually.

The ultimate goal of Glass and Smith’s research is to create an organism called Mycoplasma laboratorium — a bacterium made of DNA synthesized entirely by hand. This theoretical cell has been affectionately dubbed “Synthia.” Still, Synthia, if created, would not be built from scratch. The genome would be assembled by hand, but the cell membrane and the proteins inside of it would be borrowed from a gutted cell. Essentially, this is cellular resuscitation.

Another issue raised by scientists, notably Vanderbilt University’s Tony Foster, is that the team at the Venter Institute is building an unknown organism — one that they do not have complete jurisdiction over because the functions of a fifth of M. genitalium’s genes are unknown.

Foster is one of a number scientists actively involved in a second approach to building synthetic cells. His method involves piecing cells together entirely from scratch. The method allows scientists to become intimately acquainted with every molecule comprising a living cell and is probably the closest approximation to synthesizing life from nothing.

One of the biggest hindrances to building synthetic cells (using either approach) is tackling the ribosome. Ribosomes are complicated cellular machines responsible for churning out proteins from strands of messenger RNA. They are big, unwieldy molecules that consist of more than 50 proteins and thousands of RNA nucleotides.

Piecing together DNA fragments that produce functional ribosomes — or building ribosomes from scratch — is a daunting task.

In 2004, Albert Libchaber of Rockefeller University took a gene for green fluorescent protein, collected some cellular machinery, and threw the whole bit inside a circle of lipid membrane proteins. The result was a blob that fluoresced green.

This leads to all sorts of interesting thought experiments, like taking the gene for hair color and the gene for Solanum lycopersicum and seeing if you can get a blond tomato. More importantly, research in synthetic biology poses the interesting idea that cells may be able to arise from nothing — an idea that
immediately draws parallels to early Earth.

If M. genitalium, one of the simplest bacteria on Earth, contains 580,000 genes, one may wonder whether it is possible for cells to contain 60 genes. Their origin and assembling also remains a mystery.

For now, the fledgling biologist can be safely chastised for getting the third and final tenet of cell biology wrong. Scientists have a long way to go before Synthia, or any other laboratory-engineered cell, will sputter and spark to life. Rudolf Virchow, who famously championed that “cells beget cells” over 150 years ago, may not have to worry about the rewriting of history just yet.