3-D printer for small molecules opens access to customized chemistry

March 12, 2015
A machine that builds complex molecules from simple chemical building blocks was developed in the lab of University of Illinois chemistry professor Martin Burke. Credit: L. Brian Stauffer

Howard Hughes Medical Institute scientists have simplified the chemical synthesis of small molecules, eliminating a major bottleneck that limits the exploration of a class of compounds offering tremendous potential for medicine and technology.

Scientists led by Martin Burke, an HHMI early career scientist at the University of Illinois at Urbana-Champaign, used a single automated process to synthesize 14 distinct classes of small molecules from a common set of . Burke's team envisions expanding the approach to enable the production of thousands of potentially useful molecules with a single machine, which they describe as a "3D printer" for small molecules. Their work is described in the March 13, 2015, issue of the journal Science.

According to Burke, the highly customized approach that chemists have long relied on to synthesize small molecules is time consuming and inaccessible to most researchers. "A lot of great medicines have not been discovered yet because of this synthesis bottleneck," he says. With his new technology, Burke aims to change that. "The vision is that anybody could go to a website, pick the building blocks they want, instruct their assembly through the web, and the small molecules would get synthesized and shipped," Burke says. "We're not there yet, but we now have an actionable roadmap toward on-demand small-molecule synthesis for non-specialists."

Nature produces an abundance of small molecules, and scientists have already adapted many of them for practical applications. The vast majority of drugs are considered small molecules, as are many important biological research tools. A wide-range of technologies, including LEDs, diagnostic tools, and solar cells also rely on small molecules. "Small molecules have already had a big impact on the world," says Burke. "But we've barely touched the surface of what they're capable of achieving. In large part, that's because there's a major synthesis bottleneck that precludes accessing all of their functional potential."

Burke explains that chemists almost always develop a customized approach for manufacturing small molecules, designing a series of chemical reactions that, when applied to the right starting materials, yield the desired product. "Every time you make a molecule you have to develop a unique strategy. That customization is slow," he says. Furthermore, it requires expertise. "Currently you have to have a high degree of training in synthesis to make small molecules," Burke says.

The video will load shortly
University of Illinois chemistry professor Martin Burke explains a machine that can assemble complex small molecules from chemical building blocks. This could aid in rapid drug development. Credit: University of Illinois

In his research, Burke has been exploring the potential of small molecules to treat disease. Plants, animals, and microbes manufacture many small molecules with protein-like functions, and with some precise chemical modifications, Burke suspects it may be possible to optimize some of these to mimic the function of missing proteins enough to restore patients' health. To do that, he says, his team needs to synthesize and test not just the small molecule found in nature, but also new versions with targeted modifications.

Making those molecules is a major barrier to drug discovery, Burke says. "Doing real atomistic modifications to transform nature's starting points into actual medicines is really, really challenging. The slow step in most cases in the synthesis. As a result, many natural products don't get worked on in any practical way."

Burke's team took cues from nature to streamline the synthesis of the molecules they were studying, developing an approach that they have now expanded to make more general. "Nature makes most small molecules the same way," Burke says. "There are a small number of building blocks that are coupled together over and over again, using the same kind of chemistry in an iterative fashion." That means small molecules are inherently modular. So when Burke's team analyzed the chemical structures of thousands of different natural products, patterns emerged. "There are building blocks that appear over and over again, and we've been able to dissect out the building blocks that are most common," he says.

The small-molecule synthesizer that Burke's team built takes these building blocks - each with two chemical connectors that can be readily linked to the corresponding part on another building block—and snaps them together like pop beads using a standard chemical reaction. The team used the approach to synthesize 14 different small molecules, ranging from relatively straightforward linear structures to densely folded molecules featuring several chemical rings.

Burke's team has developed hundreds of these and made them commercially available. "But it's not really about the numbers," he says. "We are showing that with a very reasonable number of building blocks we can make many different types of natural products."

Burke says the technology is ready now to synthesize a range of very complex natural products, meaning the atom-by-atom modifications that researchers need to optimize these molecules into therapeutic compounds or technological tools are now accessible. He has founded a company, REVOLUTION Medicines, to use and continue to develop the technology for this purpose.

Ultimately, Burke says, he is excited about the opportunity to empower non-specialists - all kinds of scientists, engineers, medical doctors, and even the public - to produce . "When you put the power to manufacture into the hands of everyone, history speaks toward tremendous impact," he says. "A 3D printer for molecules could allow us to harness all the creativity, innovation, and outside-the-box thinking that comes when non-experts start to use technology that used to only be in the hands of a select few."

Explore further: A new set of building blocks for simple synthesis of complex molecules

More information: Synthesis of many different types of organic small molecules using one automated process, Science, www.sciencemag.org/lookup/doi/10.1126/science.aaa5414

Related Stories

Chemists create 'assembly-line' for organic molecules

September 11, 2014

(Phys.org) —Scientists at the University of Bristol have developed a process where reagents are added to a growing carbon chain with extraordinary high fidelity and precise orientation, thereby controlling the conformation ...

Recommended for you

LiH mediates low-temperature ammonia synthesis

August 24, 2016

Nearly half of the world's population is fed by industrial N2 fixation, i. e., the Harbor-Bosch process. Although exergonic in nature, NH3 synthesis from N2 and H2 catalyzed by the fused Fe has to be conducted at elevated ...

Selecting the right house plant could improve indoor air

August 24, 2016

Indoor air pollution is an important environmental threat to human health, leading to symptoms of "sick building syndrome." But researchers report that surrounding oneself with certain house plants could combat the potentially ...

3 comments

Adjust slider to filter visible comments by rank

Display comments: newest first

JohnHunt
not rated yet Mar 12, 2015
If this is able to build molecules which have no natural process of being made then scientists might be randomly or systematically poking around in novel chemical space and accidentally produce a chemical ecophage which, for example, would consume all atmospheric CO2 until completiion thereby potentially explaining Fermi's Paradox.
EyeNStein
5 / 5 (1) Mar 12, 2015
I hope they build in protections against folk who order a pint of SARIN when this goes full scale.
hillmeister
not rated yet Mar 13, 2015
This is awesome! This allows for exponential progress in chemistry, just like the progress of computer chips! :D

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.