Perspective On: A Drug Discovery Lab

Drug discovery research is a vast discipline in which different researchers and laboratories each concentrate on an area of the field. Some may focus on developing drugs for Alzheimer’s disease while others may be working on cultivating the newest allergy medicines.

Dr. Les Satin’s laboratory in the Department of Pharmacology at the University of Michigan Medical School has been involved in examining two very different areas: cellular diabetes research and studies of the neurobiology of traumatic brain injury.

“The common thread in both was originally my interest in ion channels and electrophysiology, which is historically a novel theme in each of these areas of study,” Satin says. “Having as a background synaptic physiology and membrane biophysics, both of these research areas were of interest to me.”

The undertakings of Satin and his team fall into different categories within drug discovery. As an example, the research team is interested in the mechanisms of drug action and thus has designed studies to figure out how drugs work. Another example is that it has also used drugs to probe different cellular mechanisms.

“We have [also] developed new probes with which to understand cells, such as fluorescence resonance energy transfer (FRET) probes that can read metabolic signals in living cells,” he says. “These probes, in turn, will allow investigators to test whether certain classes of drugs can be useful modifiers of these cellular processes, as gauged by how the probes in situ respond to the drugs.”

“For instance, a probe we recently developed can report the metabolic activity of a cancer cell that is known to drive cancer progression via cell proliferation,” Satin adds.

Measuring the activity of this probe and determining its sensitivity to compounds can facilitate the development of new anticancer agents.

Satin’s team is also involved in developing high-throughput platforms that can be used to screen compounds for their ability to mitigate brain cell death and damage following traumatic brain injuries.

“We did this with colleagues in the University of Michigan Engineering School; the instrument we designed could be important for developing new treatments, as there are currently no effective drug therapies for treating patients who have suffered a traumatic brain injury,” Satin explains.

Although Satin’s team has done work with the biotech industry and with the pharmaceutical sector, most of their research is supported by and related to the National Institutes of Health (NIH).

Laboratory structure

Satin runs an approximately 1,500-square-foot laboratory. The lab is set up with both benches and bays but also has many small procedural rooms.

“As electrophysiology is done on small (4-foot by 4-foot) air isolation tables by one person, and these workstations also often involve optical measurements of fluorescence, we need to be able to make the rooms dark too,” he says. “This is why we favor small rooms connected to a larger lab.”

The experiments are run by his staff, whose numbers from year to year vary somewhere between five and 10. And although Satin is the lab leader, he has, in the past, employed experienced faculty researchers to enrich the capabilities of the lab.

Satin’s lab team is made up of experts with diverse backgrounds: Some possess BS degrees in biology, chemistry, physiology, physics, or engineering, and others have graduate degrees in physiology, pharmacology, and biochemistry. Among his staff are also those seeking their MDs/PhDs. His own background is in neurobiology, with a strong emphasis on membrane biophysics. This diverse group allows Satin’s lab to tackle the many challenging experiments that could come through the door.

“It’s a fun mix,” Satin says of his team. “People with very strong lab experience and excellent hand-eye coordination usually do very well, and my management style is to be very supportive while letting people work and develop independently.”

“I hate to micromanage people, so that’s part of my motivation,” he adds. “I find that if you have very good people working with you, letting them ‘swim a bit on their own in the rapids’ makes them much better swimmers! It’s a risky method, but it works most of the time.”

Satin’s lab has a rather informal organizational structure, which is possible because of its small size.

“We have weekly lab meetings at a regular time and place, and we also have an annual meeting, which is often offsite with collaborators from the NIH and Florida State University, where we catch up with one another, plan our future research goals, and brainstorm,” he says.

As someone on an instructional track who is also a tenured faculty member, Satin reports to the chair of his home department—Pharmacology. It has more than 30 faculty members and was founded by John Jacob Abel as the first pharmacology department in the United States.

Kiran Vadrevu (foreground) and Matt Merrins.On the days he isn’t traveling, Satin’s schedule is packed. He checks in with each lab member in the morning, attends to any pressing tasks involving manuscript or grant writing, tends to his academic duties and committee work, has lunch with his group, corresponds with collaborators, and reviews journal manuscripts of other principal investigators and grants for the NIH and other funding organizations.

“I also try to spend some quality time thinking and planning,” Satin says. “I really like to ‘go to the blackboard’ with my people and discuss their most recent data and planned experiments. We [also] have weekly lab meetings for an hour or so on Monday mornings.”

Instrumentation, maintenance and inventory

Satin’s lab consists of several workstations to allow measurements of FRET and nicotinamide adenine dinucleotide phosphate-oxidase and electrophysiology/ patch clamping.

The lab is also set up to accommodate two straight patch clamp rigs with Axon or HEKA Elektronik amplifiers mounted on Olympus inverted microscopes. “We use Sutter micromanipulators for moving electrodes. Electrodes are pulled on a Sutter P-97 pipette puller,” Satin says. “Then there are two Ca imaging systems based on Hamamatsu or Coolsnap cameras, with light coming from Sutter P-97 illuminator with a 10-position filter wheel or a Ludl filter wheel with a shutter and an Olympus light source.”

The FRET rig utilizes an Olympus IX71 inverted microscope with a TILL Photonics Polychome V light source and a Photometrics cooled image-intensified camera.

The optical systems mostly use Metamorph software for controlling experiments. The team also has an upright Olympus BX scope with a Gibraltar stage and Axopatch 200B used for patch clamping brain slices. The brain slices are made with a Leica VT1200S vibratome.

“General lab instruments include a plate reader from Biotek, a PCR box, a cooled centrifuge from Eppendorf, balances, pH meters, and the like,” Satin explains. “We also have equipment for gel electrophoresis and other standard protocols.”

Satin is largely in charge of maintaining the lab equipment, though he does get assistance from his department if the need for serious repairs arises. When a piece of equipment cannot be repaired or is no longer relevant, Satin tries his best to upgrade it.

Eric Glynn, working on intracellular calcium imaging system.“Since there are limited resources, this can be a challenge,” he says. “I just had to replace a tissue culture incubator and a computer that failed, and had to send an illuminator to Germany for repair. None of these were planned repairs or upgrades, and thus they drained my existing supply account. But they were unavoidable.”

Challenges

As in many academic research labs, Satin’s biggest challenge is acquiring and maintaining grant support.

“Without it, one cannot really do research,” he says. “Grant support pays all the salaries of the lab personnel; pays for all supplies and equipment (except for start-up funds provided by the university when faculty are recruited); and pays the running costs, such as purchasing animals.”

In addition to the economic aspects of running a lab, having the stamina to follow projects through to completion can be tough when the results don’t make sense based on what the researchers expect.

“Managing people is [also] hard work, something we as scientists are not exactly trained to do,” Satin says. “But one learns by experience. So I would say the hardest things—in no particular order—are securing research funding, managing people, dealing with the daily frustrations of research itself, and getting good data.”

And that’s not all.

“Publishing papers has become more difficult over the last few years too,” he adds.

But it is precisely the fruit of overcoming these challenges—the desire to see new data and experiment results—that gives Satin a renewed enthusiasm to get up each morning and repeat his efforts to run the lab.

“I usually can’t wait to get to work to see what progress we’ve made,” he says. “It’s just very exciting to see if your ideas [or] hypotheses were right or wrong. I tell students if that does not ‘float your boat,’ then you are in the wrong line of work!”

It also helps that Satin really likes working with people, especially young minds. Therefore, the teaching aspect of his job is yet another motivator for him.

Lastly, it’s the overarching scientific goals of the lab that keep motivation at optimal levels for this lab manager.

These goals include acquiring a new understanding of how type 2 diabetes develops and how it can be treated; developing a new understanding of how traumatic brain injury alters normal information processing at the level of single neurons; developing drug screening for traumatic brain injury; training tomorrow’s new scientists and researchers; and educating future physicians, pharmacists, and dentists.

“I think it is important to maintain one’s belief in science and in research, and for me, the data and how to interpret them are my key motivators,” Satin says. “I just love coming up with new ideas and experiments to test them.”

Incentives

Satin is well aware that his staff also have their own challenges and daily stressors. To alleviate some of their pressures, he constantly looks for ways to reward the lab team.

“We tend to eat a lot of cake and celebrate our victories,” Satin says. “We have lab parties at our house [and] we have lab lunches out at local restaurants, etc.”

In addition, Satin tries to compensate his staff fairly, despite tight budgets and salary freezes.

“I think managers have to be sensitive to the stress people experience in their workplace and in their careers these days, when life is pretty difficult and compensation (at least monetary compensation) is pretty much flat,” he says. “People also have to be encouraged and told they are doing a good job and an important job. I think we are all challenged these days in one way or another, so being sympathetic can help. Having good communication is also essential.”

Although, as Satin knows, he can do more to show his appreciation, he hopes that his team sees the incentive for the work as something larger.

“I hope that maintaining a stimulating yet supportive environment where science is the main motivation would be a strong incentive.”

Top instruments utilized

1. HEKA patch clamp

2. Ca imaging system

3. Fluorescence resonance energy transfer (FRET) system

4. Polymerase chain reaction (PCR) for genotyping

5. Cooled centrifuge

6. Polymerase chain reaction (PCR) machine

7. Plate readers

8. FLIPR Ca measurement assays