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One of the most important advances in the history of vaccinology was achieved only after the global pandemic: the widespread commercial deployment of nucleic acid-derived vaccines. At the time of writing, hundreds of millions of people have been vaccinated against SARS-CoV-2 (the virus that causes COVID-19). Most of these injections are Pfizer-BioNTech and Moderna products, both of which are a type called mRNA (messenger RNA) vaccine.

The mRNA vaccine, conceived decades ago but first released to the public during the pandemic, has so far fulfilled their promise. Both Pfizer and Moderna vaccines have proven to be about 95% effective against the new coronavirus. In addition, this vaccine can be adjusted relatively easily to target new variants of the virus, and its production does not rely on items that are difficult to produce in large quantities quickly. However, in the past six months, several shortcomings of mRNA vaccines have also attracted widespread attention: they rely on a deep-frozen supply chain and storage, and can produce serious side effects such as fever, chills, and muscle aches.

Therefore, people have high hopes for another nucleic acid vaccine that uses DNA instead of mRNA. DNA-based vaccines have most of the advantages of mRNA vaccines, but they do not produce significant side effects-and, crucially, they do not require refrigeration. These characteristics can make these vaccines a boon to rural and resource-poor areas. "If we really have to vaccinate 7 billion people, we may only need all possible technologies," said Margaret Liu, chairman of the International Vaccine Association's board of directors.

Inovio's device uses a technique called electroporation to sneak DNA vaccines into cells. Inovio's senior vice president of research and development Kate Broderick (Kate Broderick) has been working on this technology for many years, but the pandemic has provided motivation and funding to accelerate development. Spencer Lowell

However, DNA vaccines face major challenges. In many human studies, when ordinary hypodermic needles are used for administration, they can only produce weak immunity at best. However, if an ambitious small company in Pennsylvania, supported by the US Department of Defense, succeeds in its clinical trials, DNA vaccines supported by new delivery technologies will soon be added to fight COVID-19 and many other viral diseases In the struggle.

The company Inovio Pharmaceuticals is using a technology called electroporation, in which electrical pulses applied to the skin briefly open channels in the cells to allow vaccines to enter. After a standard vaccine injection, Inovio's electroporation device looks like an electric toothbrush, sticking to the skin. Press the button, and a weak electric field will enter the arm, opening the channel into the cell. This tool provides DNA vaccines with the power they need to function in the human body—at least the company says. This is an engineered solution to a biological problem.

Taking into account overseas combatants, the US Department of Defense (DOD) supported Inovio’s method with a $71 million contract to expand the manufacturing scale of its electroporation equipment, as well as an undisclosed amount to pay for the company’s COVID second And Phase 3 research -19 vaccine. The Bill and Melinda Gates Foundation provided the company with $5 million as part of its efforts to increase equitable access to the COVID-19 vaccine.

Inovio is currently completing the second phase of the study, which is testing the safety and effectiveness of the vaccine in relatively small groups in the United States and China, and these results are imminent. At the same time, the company has increased its productivity and plans to provide hundreds of millions of doses of the COVID-19 vaccine to the global population, provided that the vaccine proves to be successful.

But the problem is: the electroporation tool is critical to Inovio's vaccine, but it also adds a layer of complexity. It is both a driving factor and an obstacle. Inovio must not only produce vaccines, but also equipment and disposable tips. Any vaccination site that plans to receive Inovio vaccine needs not only the equipment, but also people who know how to use it. The public will have to build trust in the new institution. And all of this must happen during pandemics and crazy vaccine launches, characterized by a flood of misinformation, and in some ways people are reluctant to get vaccinated.

In this context, the idea of ​​using electronic devices to complicate mass vaccination has raised doubts. "This is not a standard method of delivering vaccines," said John Moore, an immunologist at Weill Cornell College of Medicine in New York City. The technology may be effective, but "its practicality is another issue entirely," he said.

Neither skeptics nor sharp questions raised by regulators stopped Inovio. In fact, although the company has conducted more than ten years of research and development in other disease fields, it has not yet marketed DNA vaccines. These are not normal times. Coronavirus has pushed many other new technologies, drugs and vaccines into the mainstream, and has created a large number of commercial success stories in the process. Inovio is betting that its technology will make it an elite group of winners in the pandemic era.

For decades, nucleic acid-based vaccines have attracted scientists because they can be designed quickly and are easy to manufacture. These vaccines are usually made of DNA (a double-stranded molecule that carries the genetic code of an organism) or messenger RNA (mRNA) (a single-stranded molecule that is complementary to DNA and carries instructions for DNA synthesis protein). DNA and mRNA vaccines can be thought of as a blueprint for instructing cells to produce specific proteins from viruses to trigger an immune response.

Inovio's vaccine contains a piece of DNA that encodes a protein used to produce coronavirus. If the body comes into contact with the real virus later, the immune system will recognize the protein and defend it. The DNA is first amplified in bacterial cells (top) and then purified (bottom). Spencer Lowell

When making nucleic acid vaccines, scientists first sequenced the genome of the virus. Next, they figured out which of these proteins is the most important and most easily recognized by the human immune system. Then they make DNA or mRNA to encode the production of the protein and make it into a vaccine. This genetic material is injected into the body, and nearby cells take it up and begin to follow their new instructions for making viral proteins. To the immune system, this looks like a viral infection and will produce a response. Now, if a real virus appears, the immune system is ready and ready to launch an attack.

Changing the design of a nucleic acid vaccine is as simple as inserting new code. This is very important when faced with frequently mutating viruses. In fact, several highly infectious variants of the virus that causes COVID-19, SARS-CoV-2, have emerged worldwide, and scientists have warned that currently available vaccines may be less effective against some of these viruses.

Despite the attractiveness of nucleic acid vaccines, before the pandemic, medical regulatory agencies had not approved nucleic acid vaccines for commercial use in humans. In fact, most nucleic acid-based vaccines have not yet passed mid-term clinical trials. The problem is: human cells cannot easily absorb foreign DNA or mRNA. After injection, most vaccines will remain inert in the body and eventually decompose without causing many immune responses.

Developers of mRNA vaccines have recently solved this problem by packaging the vaccine with chemicals. In one method, researchers encapsulate mRNA in fat droplets called lipid nanoparticles, which fuse with cell membranes and help vaccines enter the interior.

When the COVID-19 pandemic hits, companies such as BioNTech, Moderna, and CureVac are testing various mRNA vaccines against other viruses. Market pressure from the government and billions of dollars helped the company complete this work quickly. BioNTech's mRNA vaccines were first launched in the United States and Europe through cooperation with Pfizer, followed by vaccines from Moderna.

However, the delivery strategies used for mRNA vaccines have not yet been applied to DNA vaccines. This challenge led to a proliferation of creative development, and eventually electrical engineering methods.

Inovio's senior vice president of research and development Kate Broderick (Kate Broderick) said that the first human studies of DNA vaccines from the mid-1990s "completely failed." The vaccine did not trigger much immune response. "This is a huge surprise and disappointment," added Jeffrey Ulmer, who had been the head of preclinical R&D for the pharmaceutical giant GlaxoSmithKline until last year and is now an industry consultant. "Although very good data has been obtained in various animal models for various disease targets, it does not seem to be transformed into humans," he said.

The problem is to let DNA as a macromolecule not only penetrate the outer layer of the cell, but also penetrate the nuclear membrane of the cell into the nucleus. Unlike mRNA vaccines that can work in some cells outside the nucleus, DNA vaccines can only work in the nucleus. Some researchers infer that DNA vaccines work well in small animals, because the pressure generated by the injection needle will destroy many surrounding cells and allow DNA molecules to enter. But in larger humans, the pressure generated by the needle is relatively small, and there are fewer cells to absorb the vaccine.

Therefore, scientists began to experiment with more physical methods to provide vaccines and increase cellular uptake. Shan Lu, an immunologist at the University of Massachusetts School of Medicine, said: “This is common sense: It’s not like'please open the small window and let me in', but violently break the door.”

To this end, the researchers devised various creative methods to physically inject the vaccine into the body. They tried the sound hole technology and pressurized injection using sound waves to penetrate the outer layer of cells, and the sudden release of energy pushed the piston to deliver a narrow high-pressure liquid stream. They experimented with micro-shock waves, in which sparks generated by electrodes caused a micro-explosion, emitting energy waves, forcing the vaccine through the skin without a needle. They tried to use a gene gun to push DNA-coated gold particles into cells and microneedles, which are combined with vaccines and designed as skin patches.

The latest Inovio device, the Cellectra 3PSP, is currently produced at Inovio's factory in San Diego. The handheld Cellectra can provide approximately one hundred doses per charge. Its electrodes send out a series of electrical pulses, causing nearby cells to open channels through which the vaccine can enter. Spencer Lowell

Among all these competitors, electroporation is particularly promising. Amy Jenkins, the biotechnology project manager of DARPA, a US military research organization, said: “It can be said that electroporation technology makes DNA vaccines truly a deployable technology again.” The agency invested in mRNA- and DNA. -Based on vaccines.

For decades, researchers have often used electroporation to transfer genetic material into cells in the laboratory. As part of the surgical technique, doctors also use a high-voltage version of electroporation to break down human cancer masses. Therefore, adapting it to a vaccine is not a fundamental step.

Inovio's latest electroporation device Cellectra 3PSP is handheld and battery-powered. Due to the limitation of the battery, it can provide about 100 doses per charge, and the service life is about 5,000 times. A disposable tip is required for each use. As with more traditional vaccines, the injection site is the upper arm. Vaccination starts with an intradermal injection of the vaccine dose-the injection is only deep in the skin. Then, press the tip of the Cellectra device against the skin, directly above the shooting location. An electrode approximately 3 mm long manages a series of four square wave electrical pulses with a current of 0.2 ampere, each pulse lasting 42 milliseconds.

According to a clinical study by Inovio, recipients will feel a short sting, similar to the level of pain people feel from a flu vaccine. On a pain scale of 0 to 10, the average score of the recipients is about 2.5 points-although it is said that the sensation is like a buzzing rather than stinging and pressure during injection.

The pulse causes nearby cells to temporarily open the channels through which the vaccine can enter. Once the electrical pulse is over, these channels are closed. "Now this DNA molecule is trapped inside the cell," said Broderick of Inovio. Then DNA "is like a code, so your cells become a factory for vaccine production," she explained. According to Lu from the University of Massachusetts, electroporation is usually 10 to 100 times more effective in stimulating immune responses than the same DNA vaccine provided by traditional needle injection alone.

In the past decade, Inovio’s DNA vaccines have been tested against HIV, Ebola, Middle East Respiratory Syndrome, Lassa fever, and human papillomavirus (HPV), and each vaccine is performed by some form of electroporation Tested. Broderick said that a total of more than 3,000 people received Inovio's electroporation drug, mainly through the first and second phases of the study.

In a phase one study involving 40 volunteers, Inovio's COVID-19 vaccine was administered in two doses, which proved to be safe and produced an immune response. The results do not tell us how many vaccines are effective against COVID-19 in real life. This will become clearer after the second phase of the ongoing study of 400 volunteers in the United States is completed. The company is also conducting a second phase of research on 640 volunteers in China, and is cooperating with the biotechnology company Advaccine Biopharmaceuticals Suzhou Co., Ltd. to commercialize the vaccine.

During the pandemic, some vaccine developers have been linking the different stages of their clinical trials to speed up the process. But Inovio cannot yet start the third phase of trials in the United States-it must first answer the US Food and Drug Administration's questions about the Cellectra 3PSP device. In September, the FDA notified Inovio of a partial “clinical suspension” of the trial, a strategy used by the agency when reviewers found unresolved safety or product quality issues by drug developers. Inovio's vaccine is equipped with a separate new device. Therefore, this requires additional independent oversight by the FDA's device examiner. Dennis Klinman said he is a former senior examiner of FDA vaccines and is now a consultant. Additional equipment supervision may be the reason for clinical shelving, he said.

Inovio said it plans to use the data from the second phase of the study to answer FDA's questions, but it will not disclose the specific details of the agency's enquiry. "This has nothing to do with the safety or use of the equipment in the clinic," Broderick said. "We need to clarify more logistical issues."

In addition to Inovio, at least three other companies-Genexine, Takis, and OncoSec-are conducting human studies on electroporated DNA vaccines against COVID-19. Other companies, such as Ichor Medical Systems and IGEA Clinical Biophysics, have developed electroporation devices, which they license to pharmaceutical companies to provide DNA vaccines for other diseases. However, not everyone agrees that electroporation is a solution for DNA vaccines. Some groups continue to work on alternative delivery methods, hoping that the surge in interest from the pandemic will also push their strategies across the finish line.

In Inovio's two-step process, the DNA vaccine is first injected through a syringe. The Cellectra device is then pressed onto the skin to electroporate the cells. Spencer Lowell

The introduction of a new and unfamiliar device during the vaccination process, especially during a pandemic, will undoubtedly bring logistical challenges. These devices must be mass-produced and delivered, which will increase the cost of vaccines. Medical personnel must be trained to operate Cellectra. The extra step (electric shock after injection) increases the time of each vaccination. These inconveniences are not trivial considering that people have queued thousands of miles in car fleets to get the COVID-19 vaccine.

Moore, an immunologist at Weill Cornell University, said: "I don't know [Inovio's vaccine] will be used during this pandemic." Eventually people will vote with their feet or arms, which may be the case,” he said. Liu of the International Vaccine Association added: “We don’t even have enough people in the United States who have received enough training to give enough syringe injections. "Complicating things with new equipment and new management methods "will be very difficult to do," she said.

Then there is the question of consumers accepting unfamiliar skin-stimulating devices. "I think the device raises a bigger problem, not from a logistical point of view but from a marketing point of view," said Bruce Goodwin, who is currently in the Executive Office of the Joint Program of Chemistry, Biology, Radiology, and Radiology at the U.S. Department of Defense Leading biotechnology research. Nuclear defense (JPEO-CBRND). "A device that [seems] basically [like] a hybrid sonicator and stun gun is not necessarily the kind that a publicist wants to launch, unless there is no other choice."

On the other hand, the currently available COVID-19 vaccine cannot cover most parts of the world. Pfizer and Moderna's vaccines must initially be transported and stored in refrigerators at approximately –80 °C and –25 °C, respectively. (In February, Pfizer revised its storage guidelines to allow storage at –25 °C for up to two weeks.) None of the COVID-19 vaccines developed by Johnson & Johnson, AstraZeneca, and Novavax and the vaccines deployed in China and Russia are not needed Super cold refrigerators, but they all need to be refrigerated.

In many poor and remote areas of the world, this kind of complex refrigerator or freezer supply chain simply does not exist. Even in more developed and urbanized countries, stories of accidents abound. Poor temperature control damaged 12,000 doses on the way to Michigan. In a Massachusetts hospital, an unplugged refrigerator caused 2,000 deaths. A widespread power outage in Texas stopped deliveries, and officials scrambled to manage thousands of doses before they went bad.

Ulmer, a former GlaxoSmithKline researcher, said that a vaccine that can be stored at room temperature will avoid these pitfalls and "greatly facilitate the global distribution of the vaccine. This is a great advantage." According to the company. , Inovio's vaccine is stable for one year at room temperature of about 19°C to 25°C, and stable for at least one month in hot climates.

Pfizer and Moderna's mRNA vaccines also tend to cause flu-like side effects such as fever, chills, headache, muscle pain, nausea, and fatigue. Barbara Felber, a senior researcher at the National Cancer Institute's Vaccine Division, said some of these reactions were very strong. For example, within a few hours after receiving the mRNA COVID-19 vaccine, Ferber's 25-year-old son was shaking and trembling from head to toe while wearing all the blankets in his apartment. "His response was very bad, and we were on the phone with him all night," Ferber said. Of course, most people do not have this reaction, she added, and the side effects are temporary. "It is better to have [side effects] than to be infected by SARS-CoV-2," she emphasized.

The Centers for Disease Control and Prevention (CDC) tracks adverse events of the COVID-19 vaccine through a smartphone-based tool called V-safe, which recipients can use to self-report their symptoms. Approximately 25% of participants reported fever, and 42% reported headaches after taking the second dose of Pfizer vaccine. "I haven't heard of any of these types of side effects from anyone who uses electroporation for DNA injections," Ferber said.

Broderick, the company's head of research and development, said that for Inovio's DNA vaccine, the only side effect is an instant buzzing sound at the injection site.

The advantages of DNA vaccines, coupled with ease of manufacture and low cost per dose, are enough to persuade the Ministry of Defense to invest heavily in Inovio early in the pandemic. In June 2020, the agency allocated US$71 million to expand the production of the Cellectra device used for the COVID-19 vaccine. Nicole Dorsey, director of technology selection and evaluation at the US Department of Defense JPEO-CBRND, said that the Department of Defense will also pay for Phase 2 and Phase 3 studies of Inovio's clinical trial, which is responsible for overseeing funding. "The electroporation device may be a less attractive part of the DNA vaccine," but it is much easier to deploy it than to maintain overseas cold chain transportation, she said.

For the military, the logistics of the new equipment seems to be easy to manage. "Trying to launch these [Cellectra] 3PSP devices for 300 million people in every Walgreens in every corner-buddy, this is a logistical problem that may not be able to solve," said Chris Earnhart, the chief technology officer of the biotechnology-enabled project . JPEO-CBRND. "In the case of DOD, it is easy to solve because we have a very special population and the numbers are only lower."

Even if Inovio's technology and vaccines were not adopted in the civilian world during this pandemic, they may prove useful in the long run. Earnhart said: "The investment we are making now is related to the COVID response, but in many ways, we are also preparing for the next event. This may be a biological warfare event or another endemic epidemic." outbreak. "

Maybe it's time for a technical upgrade. Broderick of Inovio pointed out that people first started to give medicine via syringe around 1650, when goose feathers were used as needles. "This is actually a very outdated way," she said. "When we carry more computing power in our pockets than the moon landing, we should be open to newer vaccine delivery technologies."

This article appeared in the June 2021 print edition under the title "Vaccines Go Electric".

Emily Waltz is a freelance science journalist who specializes in the intersection of technology and the human body. In addition to IEEE Spectrum, she often writes for Nature Biotechnology magazine.

Implantable device can promote blood flow to help stroke recovery, but the test data is still questionable

BrainsGate hopes that its ischemic stroke system nerve stimulation device can help stroke patients recover better.

After a stroke, time is of the essence. Doctors need to restore the blood supply to the affected brain area as soon as possible-otherwise, due to lack of oxygen, millions of neurons and supporting cells will die quickly, leading to paralysis, loss of sensation or worse.

A new nerve stimulation device may help. The ischemic stroke system (ISS500 for short) stimulates a group of nerve cells behind the nose to promote the release of neurotransmitters and other signaling molecules, thereby enhancing blood circulation in the brain.

More blood flow means fewer cell deaths-which ultimately leads to improvements in muscle strength, walking ability and other motor functions.

However, experts are still divided on whether the Israeli company BrainsGate behind the equipment has made it clear that the ISS500 system is working as expected.

On December 10, an advisory panel from the U.S. Food and Drug Administration (FDA) unanimously voted that the device was safe. But the committee members are divided on whether the clinical trials have fully demonstrated the efficacy.

"It seems that there is indeed a safe level of biological effects here," said Michael Hill, a stroke expert at the University of Calgary in Canada, who advises BrainsGate. "This is a very interesting technology."

However, it is not clear whether the existing data volume is sufficient for BrainsGate to be approved. Hill said: "They may just need a little evidence to cross the finish line."

Out of concerns about the study design, 7 of the 13 members of the group insisted that another trial is needed to confirm the benefits of the device. But others pointed out that the regulatory threshold for device approval is usually lower than that of drugs, and they either wish ISS500 or give up making a final decision.

The FDA does not need to follow the recommendations of its panel, but it usually does. European regulators approved the device last year, but BrainsGate has been waiting for a US decision before starting any form of large-scale commercial promotion.

Jeffrey Saver, a vascular neurologist at the UCLA Stroke Center, co-led the clinical testing of the device and served as a scientific advisor to BrainsGate. He hopes the FDA will make a favorable ruling. "This is not my device," he said. "This is a new way of caring for patients."

For now, there are two main treatment options for patients with "ischemic" strokes (the most common type caused by blocked arteries to the brain). They can take drugs that destroy blood clots to clear the blockage, or insert tiny tubes in their blood vessels to physically remove harmful waste.

However, approximately 10% to 15% of patients do not qualify for these interventions. Medication must be started shortly after the onset of stroke, and the increased possibility of cerebral hemorrhage will make some people too risky for thrombus destruction therapy. At the same time, some people’s blood vessel networks are twisted and tangled, and this maze-like structure makes it impossible to navigate them with any catheter guiding device.

ISS500, if approved, will provide a treatment option for stroke patients who currently have no other options.

The neurostimulator is built around a toothpick-sized device that consists of a bipolar electrode at one end, an electronic circuit board at the other end, and a curved connector in the middle. "The biggest engineering challenge is to minimize everything, to make the implant strong on the one hand and flexible on the other," said Eyal Shai, BrainGate's vice president of corporate stroke work.

The doctor uses an image-guided program-through CT scans, dental impressions, stereo cameras, and optical tracking software-to inject the device through the roof of the mouth into the correct location next to the neural target collection, the sphenopalatine ganglia (SPG). An ice hockey-shaped transmitter is placed on the cheek, and then wirelessly transmits energy to the implant through magnetic induction.

This rendering shows the disk-shaped transmitter powering the ISS500 after implantation. BrainsGate

More than 30 years ago, a pioneering research team led by Australian neurologist Peter Goadsby and Swedish neurophysiologist Lars Edvinsson first showed that electrical stimulation of SPG can promote blood flow in the brain of rats and cats.

But at the time, "the idea that nerves can change cerebral blood flow was destructive," said Goadsby, who now works at King's College London and UCLA. The metabolic activity of the brain—not the wires—is thought to drive blood circulation in the brain. Goadsby and Edvinsson, like most others in the field, continue to study more direct connections between SPG and nerve signals related to headaches.

For example, two years ago, a trial led by Goadsby showed that using a remotely controlled activation device implanted through the upper gums to stimulate the nerve bundles with high frequency and on-demand can help relieve the pain of patients with cluster headache attacks. But Autonomic Technologies, the company behind the device, went bankrupt in 2018-the new owner of the platform, a startup called Realeve, may still take a few years to bring this type of SPG neurostimulator to the market.

In principle, the ISS500 system can be used for headache treatment. BrainsGate co-founder and neurophysiologist David Yarnitsky of Rammbam Medical Center in northern Israel demonstrated in a proof-of-concept experiment in rats and dogs in the mid-2000s that it can also help drugs enter the brain.

However, BrainGate has long prioritized stroke rehabilitation. By gently stimulating the SPG in the right way—instead of over-exciting nerve bundles, as people might block headache pain pathways—the company has honed its technology to increase blood flow to the brain and restore nerve function.

Clinical testing of the ISS500 system began in 2006. A small feasibility test proved the device's potential in post-stroke care. Two subsequent randomized, sham-controlled trials jointly showed that SPG stimulation works best for stroke patients who affect the cerebral cortex (rather than other brain structures located deep in the head).

In these patients, the 4-hour daily ISS500 system treatment started within 24 hours after the ischemic attack and was performed within five consecutive days. Compared with sham treatment, it significantly reduced disability and improved quality of life indicators.

The response is especially obvious when doctors treat with low to medium intensity (stimulating the sweet spot). The strength of the hand has increased. Some people who have lost the ability to understand or express language begin to speak again soon after nerve stimulation.

However, BrainsGate initially did not position its device specifically for the treatment of cerebral cortical stroke. The importance of stroke positioning is only partially mentioned in the company's clinical development plan. In a key trial of 1,000 people—but before anyone knows the results of the trial—BrainsGate decided to modify its analysis plan and introduce a key test of the device's efficacy based solely on the results of cortical stroke participants.

Finally, the device showed little benefit in the entire research population. It only produced a meaningful improvement in disability measures in the subgroup of cerebral cortical stroke.

This analytical shift has angered some outside observers-as a result, many FDA consultants have decided not to recommend authorization for the time being. In their view, BrainsGate needs to conduct a better-designed confirmatory test.

It is now up to agency staff to decide whether such tests are required. A decision is expected to be made in February.

If approved, the ISS500 system will become the second implantable device authorized to treat stroke in less than a year. As early as August, the FDA approved the MicroTransponder Vivistim system, which provides gentle electrical impulses to the vagus nerve in the neck, and has been shown to be combined with physical therapy to help with long-term stroke recovery.

Other supplementary equipment will follow up soon. Stroke clinics are experimenting with wearable hats that can provide magnetic or direct current stimulation to precise points in the brain. According to Realeve CEO Jon Snyder, his company is planning to test its research SPG neurostimulator as a stroke rehabilitation aid.

Saver, a neurologist at the University of California, Los Angeles, welcomed the arrival of these various nerve-stimulating treatment options. As he pointed out: "Stroke neurology first has a pharmacological age. Then it has an era of endovascular devices. And I think we have now begun the era of the third set of models-neuromodulation."

Venture capitalists are betting that tools to manage climate impact can bring huge benefits

Tekla S. Perry is a senior editor of IEEE Spectrum. For more than 40 years, she has been working in Palo Alto, California, reporting on the people, companies, and technologies that make Silicon Valley a special place. As a member of IEEE, she holds a bachelor's degree in journalism from Michigan State University.

Can software save the world from climate change and other environmental threats? We won't know the answer to this question for a long time, but a venture capital company is betting that a company that develops business management software to address climate change can make a profit when it tries.

Collin Gutman (Collin Gutman) is the managing partner of SaaS Ventures, a venture capital fund located in Miami and Washington, D.C., focusing on so-called early-stage investment in enterprise technology-which helps companies behind the scenes Tools, mainly software and services. It launched its first US$20 million fund in 2017 and its second US$50 million fund in 2020. It didn't turn to climate change investment until 2020, and since then, a quarter of new investment has targeted climate technology. Here's what Gutman said about the potential for climate investment, why they make sense now, and some of the for-profit climate start-ups that are developing.

IEEE Spectrum: Why is your company so unfamiliar with climate change investment?

Collin Gutman: We are not a double bottom line fund. We are purely profit-oriented. If it is done well, it is very good, but it is not something we invest in.

In 2020, we are looking for a company called Optera. They used to be a consulting company, but then turned to develop software that obtains information about the company's supply chain, supplier groups, and considers where the materials come from, who provides them, and how they travel to calculate indirect emissions from Final product.

When we investigated this company, we found that their buyers were not in the corporate social responsibility department, which was where the climate was concerned in the past, but in the office of the chief financial officer or vice president of supply chain management. In some cases , These offices have established an executive position responsible for sustainable development-Chief Sustainability Officer or Vice President of Sustainability.

This is an exciting trend.

The last two main high-level positions are the separation of a CISO [chief information security] officer from the CTO office, and the separation of a chief human resources officer from a chief diversity officer. The next iteration is to split the Chief Sustainability Officer of the CFO/Supply Chain Office.

Seeing this, we realized that these sustainability officials need technology to help them. This field has been called ESG technology for environmental sustainability governance. It can bring profits to startups.

So we did invest in Optera and started looking for other start-ups aimed at solving this new market.

Tell me about your other climate technology investments to date.

Cloverly also participates in carbon emission tracking, allowing companies and consumers to have more control over the purchase of carbon offsets, rather than letting companies purchase offsets as an all-or-nothing decision. Cloverly's tool predicts direct emissions from e-commerce orders, whether it is a manufacturer buying wool or a consumer buying a ticket, giving buyers the opportunity to purchase carbon offsets for the wool order or a seat on an airplane, and connect to sell appropriately compensated supplies The buyer of the supplier.

Our other investments are related to water.

We have a company called Klir, which is developing an operating system for water companies that integrates data currently processed separately—essentially a Salesforce for water tracking.

Another company, Neer, is developing an artificial intelligence platform integrated with sensors to manage water flow and water quality. They will be sold to utilities and breweries that have similar water management issues.

Finally, we invested in Fruitscout; they are managing crop yields, including water management, to predict how food will grow over time based on current conditions, forecast rainfall, and other factors. They are using AI to build model factories one by one. They started with apples and then made agave.

What are you looking for in a startup?

Mainly a great founding team and a market worth winning. Everything else is details. The recent changes are the second part-we now see the market related to the environment and sustainable development as a market worth winning.