By Gordy Slack | Photos by Bart Nagel

CellScope (in foreground), in development by a team of students in bioengineer Dan Fletcher’s lab, would facilitate diagnosing disease through high-quality microscopic images.

Hybrid technologies—inventions born of parents from distant technological families—punctuate the history of innovation. Mount a water pump on a truck and you get a fire engine; breed a clock with a radio receiver and the clock radio is born; fuse a phone and a tape recorder and, suddenly, answering machines are everywhere. Engineers in Dan Fletcher’s bioengineering lab are working on their own contribution to that list with the development of the CellScope, a microscope clipped onto a standard-issue cell phone. It’s a small device that promises to put a significant dent in some of the world’s biggest medical problems.

Just two diseases—tuberculosis (TB) and malaria—are responsible for more than three million deaths and hundreds of millions of infections each year, according to the World Health Organization. The hardest-hit areas of infection are in poor and remote parts of the world, far from either doctors or medical equipment, so millions of sick patients never get diagnosed or treated. In the case of TB, most just go undiagnosed until they’re in very late, and very infectious, stages of the disease. Malaria is often easier to treat presumptively than to diagnose, so many uninfected patients do get treated, resulting in over-prescription of antibiotics to which the disease, in turn, is evolving a menacing resistance.

Malaria in a blood sample can be identified by the dark blue spots in the centers of some blood cells.

The CellScope, because of its portability and affordability, will make it possible for health care workers to get definitive diagnoses of TB or malaria from the field by imaging and analyzing blood samples in real time, says David Breslauer, a bioengineering grad student working with Fletcher’s lab.

The idea first arose two years ago in Bioengineering 164, Fletcher’s undergraduate class on optics and microscopy. Known both for his own enthusiasm and the excitement he inspires in his students, Fletcher challenged the class to design a microscope lens that could be affixed to an off-the-shelf cell phone for the purpose of remote diagnosis and screening.

“When the course was over, we had a good design and realized that, beyond just an exercise, this could be a very practical and powerful tool in the real world,” says Breslauer, who served as one of the student leaders of the project.

The current unit uses a modified cell phone belt attachment to hold a microscope lens onto the phone. The team is working with several prototype lenses of varying lengths, giving either low or high magnification, depending on the lens and the application. These are a vast improvement in size from the first version, which covered an entire tabletop. The team envisions that the final product, after the optics are optimized, will be only a few inches long and weigh less than a pound.

The group’s first objective was to achieve an optical resolution that would allow them to diagnose malaria, Fletcher explains, so most of the prototype’s specifications were worked out with that high-magnification standard in mind. Then, Wilbur Lam, a UCSF pediatric hematologist/oncologist and bioengineering grad student in Fletcher’s lab, suggested that, once they got the microscope to resolve malaria, they could work on a fluorescence-equipped version for diagnosing TB. Fluorescence on a cell phone had never been done before, but the optics specialists in the lab thought that making a lens for TB would actually be much easier.

 

Diagnosing either disease now requires specialized equipment far too costly and cumbersome for use in the field. For malaria, a 60x microscope with a controlled light source is necessary to get good images of a patient’s red blood cells. Even harder to come by is the medical expert who can analyze the images by interpreting the concentrations of malarial parasites darkening the centers of some cells.

The details of how the CellScope will be implemented in both the developed and the developing worlds have yet to be worked out. But, in theory, minimally trained medical technologists could take a blood sample, then magnify and snap a picture of it with the device. Initial diagnosis could be made from the image on the screen, and the medical technologist could then transmit it instantly to a medical center for confirmation. In just minutes, a clinician far from any medical facility could have a final diagnosis. Today, getting a positive diagnosis for malaria often requires sending a blood sample (or a patient) long distances to a lab for analysis, a costly process that can take days or weeks.

Diagnosing TB has been at least as slow and expensive as diagnosing malaria. Traditionally, fluorescent microscopes have been far too costly and unwieldy for Third World health care workers to bring into the field, let alone to have in local hospitals. Although TB can be visualized without fluorescence, this technique is less sensitive and more time-consuming to interpret. Culturing TB bacteria yields a definitive diagnosis but is impractical because a sample typically takes several weeks to grow.

At Fletcher’s lab in Stanley Hall, researcher Robi Maamari (B.S.’07 BioE) views a slide of TB-infected blood taken by the prototype CellScope. It looks more astronomical than hematological, with the TB showing up in green areas resembling star clusters against the blackness of the surrounding void. When stained, the creature that causes TB, Mycobacterium tuberculosis, glows bright green under light emitted at a wavelength of about 460 nanometers.

"The green clusters are either in the blood samples or they aren’t,” Maamari says, explaining that diagnosis is straightforward once the samples are magnified and lit with fluorescent light. “The challenge is getting a light with enough intensity in a compact package emitting just the right wavelength.”

While the CellScope’s use for TB diagnosis may have its greatest potential in Africa, Asia and parts of South America where the disease is most prevalent, it could also make a difference here at home. And, although the project was originally conceived as a way to bring medicine to the underserved, Fletcher’s team realized early on that, if the CellScope were likely to see the commercial light of day, it must first have a salable application in the developed world.

Even in major U.S. cities, the time it takes to get a TB screening is often compounded by hospital lab logjams and the time required to culture skin samples. An affordable and compact fluorescent microscope would change that by allowing health care workers to diagnose the disease on the spot.

Lam sees other possible applications for the CellScope. As a pediatric hematologist, he has many young patients undergoing chemotherapy for cancer. If the drugs used to attack their cancer cells kill too many white blood cells, these patients become vulnerable to infection. If too many red cells are lost, they become anemic. And if platelet levels dip too far below normal, they sometimes begin to bleed spontaneously.

Frequent trips to the hospital to monitor blood levels can add to the already huge burden of the disease, especially for families living far from their doctors or medical centers. And every visit to a hospital can expose immune-suppressed chemotherapy patients to dangerous pathogens, further risking their health.

Fitted with the same or similar lens used to diagnose malaria, the CellScope could allow patients to monitor their blood counts easily and inexpensively at home. Before long, Lam hopes, patients will be able simply to prick themselves for a blood sample, insert the sample into the device and push a button to send a microscopic image to the lab. After doing blood counts and other tests, the lab would then report relevant information back to patients and their doctors, letting them know how soon they need a blood or platelet transfusion and how careful they must be to avoid potential sources of infection.

Beyond these applications, the CellScope could also help implement and study broader efforts to combat infectious disease. Major anti-malaria projects backed by the Bill & Melinda Gates Foundation and other major non-governmental organizations must demonstrate the ability to perform good epidemiological studies. Good studies require solid data on the need for and effectiveness of different approaches. For example, to determine if one mosquito-net program is more effective than another in slowing the spread of malaria in an area, scientists must first establish the baseline of infection rates there, then periodically remeasure infection to track and compare progress of the different approaches. The CellScope could be a powerful and inexpensive data collection tool for such studies.

With minor modifications, in addition to blood samples, the device could also handle stool, urine and saliva specimens, making it possible to evaluate cholera, some urinary tract infections and sickle cell anemia. Beyond Berkeley, plant pathologists at the University of Florida hope to use the CellScope to capture images of crop plants in the field and send them out for instant expert analysis.

“I have no doubt there are many applications for a cheap portable microscope that can transmit annotated images that we haven’t even imagined yet,” Fletcher says. “Realistically, if manufacturers are going to invest in the device, there first has to be a market where people can afford to buy it.” 

CellScope team members (from left) Wilbur Lam, David Breslauer, Robi Maamari, Dan Fletcher and visiting researcher Andrew Fandrianto, a sophomore at Carnegie Mellon. Also on the team are Erik Douglas, Jesse Dill, Wendy Hansen, Tom Hunt, Chris Rivest and Neil Switz.

The group is still deciding how many functions to fuse into the same lens. Combining lenses, from an optics point of view, is tricky, Maamari says. But, alternatively, the researchers could design various sets of clip-on lenses and fluorescence filters, gearing the device toward a full spectrum of imaging applications. The team is also developing software to protect patient confidentiality but still allow users to annotate and transmit micrographs in a standard format that will mesh with existing medical record-keeping formats.

“The beauty of this project is that all the pieces were already there,” Lam says. “Cell phones, microscopes and cameras are ubiquitous in our society as ordinary technologies. But put them together, and you’ve got something completely new.”